-

The MD Anderson
Supportive and
Palliative Care
Handbook
Department of Palliative, Rehabilitation and Integrative
Medicine Division of Cancer Medicine
The University of Texas MD Anderson Cancer Center
Houston, Texas

SIXTH EDITON - 2018

Shalini Dalal, MD
Professor

Eduardo Bruera, MD
Professor and Chair

'
I~

THE UNIVERSITY OF TEXAS

1VIDAnderson
Gence:i:C£nter
Making Cancer History"
 7

Ack now ledg men ts

Mae C. Rodriguez in
The autho rs would like to acknowledge the work of Eden
handbook.
reviewing and editing all the medications throughout the

Disc laim er
tive Care
This book is adapted in part from The MD Anderson Pallia
a, and the Second
Handbook, First Edition, by Larry Driver and Eduardo Bruer
a which in turn
Edition by Ahmed Elsayem, Larry Driver, and Eduardo Bruer
d by Jose
was adapted from The Edmonton Aid To Palliative Care edite
gues who edited
Pereira and Eduardo Bruera. We appreciate in input of collea
or authored some of the chapter in this handbook.

Note to the Rea der

ation becomes
Medical knowledge is constantly changing. As new inform
and the use of
available, changes in treatment, procedures, equipment,
been reviewed
drugs beco me necessary. The information in this book has
treatment,
for corre ctnes s of facts, appropriateness of indications for
on side effects and
accu racy of medication dosages, and mention of comm
sher can acce pt
sequelae. Neith er the autho rs nor the edito rs nor the publi
have been made,
any legal responsibility for any errors or omis sions that
to the material
There is no warranty, expressed or impli ed, w ith respe ct
must review the
conte nt herein. Before presc ribing any drug, the reader
ts)for accepted
manufacturer's curre nt prod uct inform ation (pack age inser
ation pertinent to the
indications, dosa ge recom mend ation s, and other inform
especially impo rtant
safe and effective use of the prod uct desc ribed , This is
other forms of
when drug s afe given in comb inatio n or as an adjun ct to
th'? information, •
therapy. TH'e reader-is stron gly. advised. to confi rm that
nt legislation ·and
especially with regar d to drug usag e, comp li~s with curre
stand ards of pract ice.

f Texas Health Scienc e Center at Housto n, USA

Printing by UTHealth Printing Service s. The University o
© August 20 18
 Palliative Care
Palliative care is an appr oach that improves the

quality of life of pati ents and thei r families facing the

problems asso ciate d with life threatening illnesses,

through the prev enti on and relie f of suffering

by means of earl y identification and impeccable

assessment and trea tme nt of pain and othe r

problems, physical, psychological, and spiritual.

World Health Organization (WHO). National cancer control programmes:

policies
and managerial guidelines, 2nd ed. Geneva : World Health Organization,
2002 .
Table of Contents
Introduction ............................................. 1
Chapter 1 The Supportive and Palliative Care Program . . . . . . . . .. . 2

Chapter 2 Comprehensive Palliative Care Assessments . . . . . ... .. 6

Chapter3 Introduction to Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Chapter4 Pain Management .. . ... . ... . .. . ..... . .. . . ... . . . 17

Chapter 5 Chronic Nausea ... .. .. . . .. .. . .. . .. .. ... . . . . .. .. 41

Chapter 6 Chemotherapy-Induced Nausea and Vomiting (CINV) . .. 50

Chapter 7 Constipation ....... . .... . .... ... . . . . ..... . . .. . 55
Chapter 8 Anorexia and Cachexia . . . .... . . . ..... . .. . .. .. . . . 64
Chapter 9 Delirium and Palliative Sedation . . .. . . . . . . .. . .. . . ... 74
Chapter 10 Fatigue. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
Chapter 11 Dyspnea .... . . . .... .. .... . . . .... . ... . .. .. .... 86
Chapter 12 Hydration .. ..... . . .. ... ... ... .. . .. . . . . . . . .. . .. 92
Chapter 13 Hypercalcemia . . .... .. ........ . .... .. . .. . . . ... . 97
Chapter 14 Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Chapter 15 Anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
Chapter 16 Palliative Care in Pediatrics .. .. .. .. .... . . . ... .... 116
Chapter 17 Drug Interactions in Palliative Care .... . .. .. . . . .. .. . 122
Chapter 18 Palliative Radiation Therapy ... .. ............. . ... 131
Chapter 19 Oral Mucositis . .. . .. . ............... ... ....... 137
Chapter 20 Ethics ....... .. . . . . .. .. . . . . . . . . .. ... ... . . . . .. 140
Chapter 21 Giving Bad News .... . . . ... ... . .. . .. . . . . . . . . . . . 145
Chapter 22 Hospice Services .. . . ... ..... .. ... . ... • • • • • • • • • 152
Chapter 23 Bleedl·ng 0 I O I I O O O O O O O O O O O I
. .... .. .. . ...... . . . 159
Chapter 24 Sleep Disturbance . . . .. . . .. . . . ... • • • • • • • • • • • • • . 164
Chapter 25 Spiritual Care ....... ... . ... .. . • • • • • • • • • • • • • • • . 170
Chapter 26 Prognostication in Advanced Cancer. . . . . . . . . . . . . . . 177
Appendices 0 I O I I I IO o O I O O I O O I o I Of O t I I O o O I O I I I I O O I I I I I O I 183
Abbreviations
Routes of Administration Procedures

CT computerized tomography
iv intravenous
MRI magnetic resonance
po oral
imaging
sc subcutaneous

Frequency of Administration Miscellaneous

CNS central nervous system

ac before meals

around the clock/regularly CTZ chemoreceptor trigger zone

ate

bid 2 times a day DNA do not resuscitate

hs at bedtime GE gastroesophageal

pm pro re nata/as required GI gastrointestinal

q quantum/frequency ICP intracranial pressure

(e.g., q4h = every 4 hours)
IR immediate release
qid 4 times a day
SR slow release
tid 3times a day
WHO World Health Organization

Drug Types

NSAID nonsteroidal
anti-inflammatory drug

SSRI selective serotonin

reuptake inhibitor

TCA tricyclic antidepressant

 introduction
patients diagnosed with cancer develop a
number of devastating physical
and psychosocial symptoms due to the prim
ary tumor and/or metastatic
disease. In addition, there are a number of
acute and chronic side effects
because of the different treatments includin
g surgery, chemotherapy, and
radiation therapy. Most cancer patients hav
e a number of co-morbidities
capable of increasing the symptom burden
and decreasing the ability
to tolerate medications. Children require diffe
rent assessment and
communication strategies and strong part
icipation in their care by parents
and primary clinicians.

Supportive Care and Palliative Care develop

ed a body of knowledge on
the appropriate assessment and manage
ment of all these major problems.
However, healthcare professionals frequen
tly have limited access to up-to-
date information that can be easily applied
at the bedside.
Our handbook was conceived as a practica
l bedside tool to assist clinicians
in the daily care of their patients. We are deli
ghted to present the sixth edition
of our handbook. Our new edition reflects
recently acquired knowledge on
the assessment of the major physical and
psychosocial symptoms as well
as new pharmacological and non-pharma
cological interventions that our
department has adopted for the delivery
of supportive care and palliative
care at The University of Texas MD Anderso
n Cancer Center. In this edition
we have added a new chapter on prognos
tication.
Our handbook is not intended to provide
a scholarly review on each of the
different subjects and we have therefore
made an effort to keep all chapters
short, clinically oriented, and with a limited
number of references.
We hope that this information will help all
our colleagues in the daily care of
their patients and we welcome their commen
ts about ways to improve future
editions of our handbook.

We would like to express our gratitude to

our Managing Editor Deanna
Cuello for her invaluable help in making this
new edition possible.

Shalini Dalal, M.D .

Eduardo Bruera, M.D .
August2018
Introduction
1
Chapter 1 The Supportive and·
Palliative Care Program
at the University of Texas
MD Anderson Cancer
Center (UTMDACC)

Eduardo Bruera, M.D.

The Department of Palliative, Rehabilitation, and Integrative Medicine (PRIM)

was established in July 1999 at UTMDACC. The Section of Symptom Control
and Palliative Care started its clinical operations in early 2000. The program
initially consisted of an outpatient clinic center and a mobile inpatient
consultation service. In 2002 an Acute Palliative Care Unit (APCU) was
established. In 2008 after research conducted by our team demonstrating
that the name "Palliative Care" was a barrier for early patient referrals the
outpatient center and the consultation service names were changed to
Supportive Care. This name change resulted in a rapid increase of 41% in
the number of inpatient referrals and also approximately 1.7 months earlier
referral of outpatients to the Supportive Care Center.

During the last five consecutive years the Department and the clinical
programs have been the fastest growing clinical programs at UTMDACC.

The purpose of this chapter is to describe the current clinical programs.

SUPPORTIVE CARE CENTER

The supportive care center currently operates in two locations in the

hospital: the main location is on the 11th floor of the main building and
operates 5 days a week. The second center is located on the 8th floor of the
Mays Clinic location and operates three days a week.

2 Supportive and Palliative Care Prograrl1

gs

The services provided by the Supportive Care Center include:

• Assessment of physical and emotional symptoms

• Management of complex physical symptoms
• Management of emotional and psychosocial symptoms in patients
• Management of emotional and psychosocial problems in family
members
• Outpatient family conferences
• Help with transition to end of life care and hospice referrals in the
outpatient setting

Referrals to the clinic can by submitted on line. A same day consultation may
be requested for patients with significant physical or emotional distress and
is communicated physician-to-physician. All established patients receive a
24/7 contact information for the clinic and on-call pager, and are also able to
walk-in to clinic during working hours without an appointment if in significant
symptom distress or concerns.

MOBILE CONSUL T TEAM

Currently, there are six Mobile Consult Teams that operate daily, staffed by a
palliative medicine faculty physician and accompanied by a midlevel provider
and/or a palliative medicine fellow. The mobile teams provide consultation
service throughout MD Anderson including the pediatric outpatient and
inpatient care, the intensive care unit, the emergency center and all medical
and surgical wards.

Services provided include the following:

• Assessment of physical and psychosocial distress

• Acute symptom management including pain and other physical
symptoms
• Emotional support to patients and families
• Transfer to the Acute Palliative Care Unit when patients are in
significant symptom distress
• Family conferences and discharge planning
Consults can be made on line or by telephone to the consultation service at
71 3-404-1275. All consultations are seen the same day
as requested.

Supportive and Palliative Care Program

3
 THE ACUTE PALLIATIVE CARE UNIT (APCU)
The Inpatient APCU was established in 2002 f~llowin~ the model of existing
palliative care units in other areas of the world, 1nclud1ng the Edmonton
7
Palliative Care Unit.

Patients are admitte d to the APCU as transfers from the Mobile Teams
(approximately 75%) or as direct admiss ions from the outpatient Supportive
care Center (15%) and the Emergency Center (10%). In all cases patients are
suffering severe physical and/or emotional distress that cannot be managed
in their current setting of care. The main purpos e of the unit is to provide
stabilization of physical and emotional distress and to help patients transition
to commu nity-ba sed care either in a hospice setting or as outpatients.

Patients are seen every day by a board certifie d palliative medicine specialist
assisted by a full-time midlevel provide rs and/or a palliative medicine fellow.
In addition all patients have access to specially trained nurses, palliative
care pharmacists, a full-time chaplain, a full-time counselor, a full-time social
worker, and physical therapy and occupa tional therapy services. Patients arJ
offered regular access to music therapy, massage, acupun cture, pet visits,
and visits by specially trained artists.

In all cases the decision to transfer to the APCU is made by the palliative
medicin e specialist who has assessed the patient in the Mobile Team,
Emergency Center, or outpati ent Suppor tive Care Center. In all cases the
transfe r to the Acute Palliative Care Unit is decide d after reaching complete
consen sus with the primary oncolo gy team, the patient, and the family.

COMM UNITY -EXTE NSION SERV ICES

There is a robust Phone Care Program in which the Suppor tive Care Center
registered nurse respon ds to patient calls and online queries or concerns,
as well calls patients who were seen in clinic and are in need of more
frequen t monitor ing related to sympto ms. In all cases, the nurse conducts
a thoroug h assess ment and then consult s with the clinic physician to make
recomm endatio ns. The clinic pharma cist regularly makes calls to patients
who were seen in the clinic and underw ent methad one initiation or rotation.
The clinic counse lor conduc ts follow up counse ling via phone or video chat
on patient s that were seen in the clinic and require more frequen t counseling
but are unable to return to the clinic.

4 Supportive and Palliative Care pro9rs

The oepartment of Palli~tive, Reh~bilitation and Integrative Medicine
regularly collaborates_ with a considerable number of hospices in the
Houston area. There is a monthly Bus Rounds of a half day where patien
ts
are visited jointly by representatives of different hospices in town. This
is an
important educational activity that contributes to establish similar pathw
ays
to care and also some research between different organizations. MD
Anderson also organized an annual conference that is usually spons
ored
by not less than five hospices in the Houston area. The Bus Round
s also
frequently visits inpatient hospice facilities and nursing homes where
patients
are receiving hospice care.

Palliative Care Pearls:

• The supportive and palliative care services help patients at any point
of the cancer trajectory
• The main goal of the acute palliative care unit is to help with compl
ex
symptom control and to help transition patients to the community.
• The acute palliative care unit is not a hospice. However, it can help
with transition to hospice care.

Recommended Read ings

Fadul N, Elsayem A, Palmer JL, Del Fabbro E, Swint K, Li Z, Poulter
V,
Bruera E. Supportive versus palliative care: what's in a name?: a survey
of medical oncologists and midlevel providers at a comprehensive cance
r
center. Cancer. 2009 May 1; 115(9):2013-21.

Dalal S, Palla S, Hui D, Nguyen L, Chacko R, Li Z, Fadul N, Scott C,

Thornton V, Goldman B, Amin Y, Bruera E. Association between a name
change from palliative to supportive care and the timing of patient referra
ls at
a comprehensive cancer center. Oncologist. 2011; 16(1):105-11. Epub
2011
Jan 6.

Hui D, Kim SH, Kwon JH, Tanco KC, Zhang T, Kang JH, Rhondali W,
Chisholm G, Bruera E. Access to palliative care among patients treated
at a
comprehensive cancer center. Oncologist. 2012;17(12):1574-80.

Dalal S, Bruera s, Hui D, Yennu s, Dev R, Williams J, Masoni C, lhenac

ho
I, Obasi E, Bruera E. Use of Palliative care Services in a Tertiary Cance
r
Center. Oncologist. 2016 Jan;21(1):110-8

Supportive and Palliative Care Program

5
Ch ap ter 2 Comprehensive Palliative
Care Assessments

Davi d Hui, MD, MSc

such as
cance r patients frequently experience a multit ude of symptoms,
s of the
pain, fatigue, anorexia, cachexia and dyspnea, at different stage
lications,
disease trajectory as a result of progressive cance r and its comp
ors. Some
anti-neoplastic therapies, co-mo rbiditi es and psychosocial stress
impor tant principles include:
and
1) Many of these symptoms are under -repo rted, under-diagnosed
under-treated. Thus, it is impor tant to regularly screen for these
symptoms.
For
2) These symptoms are often inter-related and occur together.
high
example, a patient with uncon trolled pain may also present with
anxiety, depressed mood , insomnia, anorexia, and weight loss.
ce,
3) These symptoms are usually multifactorial in nature. For instan
increased pain expression can be related to tumo r progression,
psychosocial distress, chemical copin g behav ior or disinhibition
allow
related to delirium. Recognition of the key contributor(s) would
appropriate treatments to be delivered.
4) Routine symptom assessment may impro ve patien t outcomes.
A recent randomized contro lled trial repor ted that symp tom
screening with patient-reported outco mes in the oncol ogy setting
was associated with impro ved qualit y of life and overall survival
comp ared to no screening.
ive care
Based on the above understanding, the comp rehen sive palliat
diagnosis.
assessment has been devel oped to assist with scree ning and
not only
It consists of a struct ured panel of validated tools that examine
that modulate
physical and psych ologic al symp tom burde n but also factor s
most
symptom expression, such as delirium and subst ance use. The
frequently used tools are discu ssed here.

rnerits
Comprehensive PaiUative Care Ass esj
6
Edmonton Symptom Assessment System - Spiritual/Financial
(ESAS-SF, Appendix A)

ESAS measures the average intensity 10 symptoms (pain, fatigue, nause

a,
depression, anxiety, drowsiness, appetite, feeling of well being, shortn
ess
of breath and sleep) over the past 24 hours using an 11-point numeric
rating
scale from 0 (no symptom) to 10 (worst symptom). It has been validated
in cancer patients. Either the patient or the caregivers complete the
assessment. When ratings of all symptoms are presented graphically, rapid
analysis of the patient's overall symptom burden is possible. The most
recent
version of ESAS includes 2 additional items: spiritual pain and financial
distress, and is named ESAS-SF.

In general, an ESAS score of 1-3, 4-6 and 7-10 represent mild, moderate
and
severe symptoms, respectively. The cutoff for the screening of depression
and anxiety in palliative care is 2 or more on a 0-10 scale.

Mem orial Delirium Assessment Scale (MDAS, Appendix B)

MDAS is a 10-item questionnaire validated in cancer patients for delirium

assessment. Patients receive a score from 0 (none) to 3 (severe) for each
item, including reduced level of consciousness, disorientation, short term
memory impairment, impaired digit span, decreased attention, disorganized
thinking, perceptual disturbance, delusions, psychomotor abnormalities,
and sleep-wake cycle disturbance. A score of 7/30 or more is diagnostic
of delirium in patients with advanced cancer. The presence of delirium is
generally associated with higher levels of symptom expression.

CAGE-AID Questionnaire (Appendix C)

Alcoholism is highly prevalent (17%) and frequently under-diagnosed in

patients with advanced cancer. The CAGE questionnaire is a validated
alcoholism screening tool consisting of response to 4 items: Cut Down,
Annoyed, Guilty, and Eye opener, in relation to alcohol use at any time in
the past or present. The CAGE-Adapted to Include Drug Use (CAGE-AID)
questionnaire uses the same four questions, and added drug use in additio
n
to drinking.

Comprehensive Palliative Care Assessments

7
To improve the validity of the CAGE results, the ques
tionnaire should be
completed as part of the initial assessment and
especially prior to asking
the patient about drug or alcohol use as part of t~e
so~ial history. A positive
CAGE or CAGE-AID is defined by two or more affirm
ative responses to the
. ·t ms
four quest I0n I e • CAGE positivity is associated with younger age male
head and neck malignancies, earlier referral to pallia , ,
tive care, and higher
level of symptom expression, and more difficult to
control pain.

Performance Scale
A poor performance status is associated with ineli
gibility for many cancer
therapies, decreased function, reduced quality of
life, and a shorter survival.
The most commonly used tool to assess perform
ance status at MD
Anderson is the ECOG or Zubrod Performance Scal
e which is a numerical
rating scale that ranges from Oto 5, where 0=perfe
ct health, 1=limited
activity but otherwise ambulatory; 2=resting<50%
of the day; 3=resting
>50% of the day; 4=bed bound; and 5=dead .

Other common performance status scales include

the Karnofsky
Performance Scale (KPS) and the Palliative Perform
ance Scale (PPS). Both
scales are 11-point numeric rating scales from 0%
(death) to 100% (normal).
The PPS is specifically designed for palliative care
patients, and is based on
patient's ambulation, activity level, disease severity,
ability to care for self,
oral intake and level of consciousness.

Modified Edmonton Classification Sys tem

for Can cer Pain
(ECS-CP, Appendix D)

The ECS -CP was developed as a prognostic indic

ator for cancer pain , to
help health care providers in predicting those patie
nts with cancer with
complex pain syndromes. The ECS has five featu
res: mechanism of pain,
incidental pain, psychological distress, addictive
behavior and cognitive
function. In our modified version aimed at making
the completion of this
classification faster and easier, the clinician mus
t rate each of the five
features as a "Yes" or "No".

8 Comprehensive Palliative Care Assessl11en~

constipation Sco re
may augment
The constipation score derived from a flat abdominal X-ray
ng the large
clinical assessment of constipation. It is determined by dividi
, representing
intestine on a plain abdominal radiograph into four quadrants
and rectum.
the ascending colon, transverse colon, descending colon
, 1 (stool
For each quadrant, the clinician assigns a score of 0 (no stool)
lumen) or 3 (stool
occupying <50% of lumen), 2 (stool occupying >50% of the
een 0 and 12,
completely occupying the lumen). The total score varies betw
n. However, the
with a higher score indicating more significant constipatio
patient-rated
inter-rater reliability is only moderate and the correlation with
ul in assessing
constipation is low. Plain abdominal radiograph may be helpf
diarr hea-
patients with loose stool but suspected of having overflow
diagnosis and
presence of significant stool on X-ray could help confirm this
initiate aggressive laxative therapy.

Othe r Assessments
ed history and
Upon identification of a patient's symptom profile, a focus
es and to
physical should be performed to identify any reversible caus
function and
determine how these symptoms are affecting the patient's
w current drug
overall quality of life. A thorough medication history to revie
en while
use and adherence could help optimize the medication regim
side effects.
minimizing polypharmacy, drug interactions, and adverse
nts, support
Psychosocial history to examine the patient's living arrangeme
factors can have a
systems, and coping strategies is also essential, as these
Finally, it would be
major impact on symptom expression and care planning.
rstanding of
helpful to explore patients' decision making preferences, unde
illness and goals of care to facilitate advance care planning.

Palliative Care Pearls

for good
• Comprehensive palliative care assessment is essential
symptom management.
nts with
• Symptoms are common and often occur together in patie
needed.
advanced cancer. Multi-symptom assessment batteries are

Comprehensive Palliative Care Assessments 9

 logical distress have a major
• Delirium, substance use and psycho
sion.
role in modulating symptom expres
tor of patient survival, quality of
• Performance status is a key predic
treatments.
life, function and eligibility for cancer

Recommended Reading
Smith MJ, Cohen K, Passik S. The
Breitbart W, Rosenfeld B, Roth A, Mar;
le. J Pain Symptom Manage. 1997
Memorial Delirium Assessment Sca
13(3):128-37.
az
cEachern T, Marcelino S, Suarez-Alm
Bruera E, Schroeller T, Wenk R, Ma
enter assessment of the Edmonton
M, Hanson J. A prospective multi-c
Pain Symptom Management 1995
Staging System for cancer pain. J
10:348 -355
er P, Macmillan K. The Edmonton
Bruera, E. Kuehn N, Miller MJ, Selms
men
AS): A simple method for the assess
Symptom Assessment System (ES
Care 1991 7:6-9
of palliative care patients. J Palliative
o A, Bertolino M, MacDonald SM,
Bruera E, Suarez-Almazor M, Velasc
ts
stipation in terminal cancer patien
Hanson J. The assessment of con
m
retrospective review. J Pain Sympto
admitted to a palliative care unit: a
Manage. 1994 9(8):515-9
pain
i D, Bruera E. A personalized app roach to assessing and managing
Hu
2014 Jun 1;32(16):1640-6.
in patients with cancer. J Clin Oncol.
r JL,
Osta B, Chacko R, Poulter V, Palme
Parsons HA, Delgado-Guay MO, El
act o
patients with advanced cancer: imp
Bruera E. Alcoholism screening in
-8.
J Palliat Med. 2008 Sep; 11 (7):964
symptom burden and opioid use.
rs
ptom Assessment System 25 Yea
Hui D, Bruera E. The Edmonton Sym e.
er: Past, Present, and Future Developments. J Pain Symptom Manag
Lat
I
2017 Mar;53(3):630 -643.

m Monitoring With Patient-Reported

Basch E, Deal AM, Kris MG, Sympto
lled Tri~
Treatment: A Randomized Contro
Outcomes During Routine Cancer
65.
J Clin Oneal. 2016 Feb 20;34(6):557-

Assessll'le/1~
Comprehensive Palliative Care
10
 Chapter 3 Introduction to Pain

Yvonne Heung, M.D., M.S., Akhila Reddy, M.D.,

and Suresh K. Reddy, M.D., F.F.A.R.C.S.

Pain is one of the most commonly reported symptom in cancer patients,

experienced during active treatment as well as in the advanced and terminal
stages of cancer. The expression of pain be modified by cognitive and
psychological factors associated with serious illnesses and/or the process
of dying.

Definition of Pain
In 1979, the International Association for the Study of Pain define pain as
"an unpleasant sensory and emotional experience associated with actual or
potential tissue injury or damage. The intensity of pain varies with the degree
of injury, disease, or emotional impact." Pain is a self-reported subjective
experience which involves transmission of afferent noxious stimuli with an
expressive component manifesting as a reaction to painful stimuli.

Barriers to Pain Management

Despite knowledge that the majority of cancer pain can be well-controlled
with relatively simple medication regimens, at least 25% of patients with
cancer die with poorly-controlled pain. This discouraging fact is due to
multiple reasons:

• Inadequate assessment of pain

• Inadequate knowledge about treatment
• Fear of adverse effects of opioids
• Misinformation about opioid tolerance and dependence
• Poor access to interdisciplinary pain management
• Improper and misguided regulation by governing agencies

Introduction to Pain
11
 .
multiple fronts to opti· m1ze
Suc h defic ienc ies have been add ress ed on
man y medical school s have
pain man age men t for patients. For exam.ple, .
n abo ut pain assessment
revised their curricula to improve edu catio
gesics), and side effect'S.
trea tme nt opti ons (opioids and adjuvant anal
Various organizations such as the Ame rica n Can cer Society have worked to
.
. .
age men t. The Joint Corn rniss,
impr ove patient awareness abo ut pain. man . . 011
has impl eme nted strin gent
on Accreditation of Healthcare Organizations
acce ss to appropriate res ources
requirements requiring hospitals to .prov ide.
orm Controlled Substances Act I
Legislation such as the federal Revised Unif
to ease the regulatory burden of
and Texas Intractable Pain Act are in plac e
.
physicians' triplicate prescription requirements

Impact of Pain
cer carries negative
Untreated pain in patients with adva nced can
. The combination of pain with
physiological and psychological ramifications
exia, nausea, constipation,
other disease-related sym ptom s such as anor
/or inso mnia can significantly
delirium, dyspnea, depression, anxiety, and
misinterpreted as untreated
impair quality of life. Importantly, pain may be
suffering and /or a sign of impe ndin g deat h.

Causes of Pain
d into thre e different categories:
Pain in patie nts with canc er can be clas sifie

Tumor-related pain
nerves, bone, or vessels
• Imp inge men t on adja cent orga ns, tissues,
s
rs (e.g., interleukin ,
• Inflammation due to tum or-in duc ed med iato
kinins, etc.)

Man age me nt-r elat ed pain

• Diag nost ic proc edu res

• Che mot hera py-r elate d

• Radiation-related

• Procedural or surg ery- rela ted

to psi
Introduction
12
I - -
Non- canc er pain
• Unrelated etiology (e.g., myofascial, musculoskeletal, infection,
trauma, etc.)
• Chronic pre-existing condition (e.g. rheumatoid arthritis, diabetic
neuropathy, osteoarthritis, etc.)
r,
Most patients have at least one type of pain caused directly by their cance
pain. In
while most patients with advanced cancer have two or more types of
due
general, about 70-75% of patients with advanced cancer will have pain
and
to direct tumor involvement, 20-25% will have treatment-related pain,
5-10% will have pain unrelated to their cancer or treatment.

Types of Pain
Pain can be characterized by its temporal course (acute vs. chronic,
continuous vs. intermittent), severity (mild, moderate or severe) and
ts
pathophysiological mechanism (nociceptive, neuropathic or mixed). Patien
with
with advanced cancer generally experience chronic continuous pain
ssion
intermittent episodes of acute breakthrough pain secondary to progre
of disease, surgical intervention, or other treatments (see Table 1).
somatic
Recent multinational data revealed that 72% of cancer patients have
nociceptive pain, 35% have visceral nociceptive pain, and 40% have
to
neuropathic pain. Correctly classifying the type of pain allows clinicians
with
appropriately tailor treatment to the individual. This can be easily done
the Edmonton Classification System of Cancer Pain (see Appendix E).

Nociceptive pain
• Due to stimulation of nociceptors with afferent impulses propagated
along the spinothalamic nociceptive pathways
Somatic (skin, bone, muscle, vessels, mucosa)
• Constant, waxing and waning, or intermittent
• Gnawing, aching, occasionally cramping
• Localized

Introduction to Pain
13
 Visceral (organs)
• Constant, waxing and waning
(
• Aching, squeezing, cra mp ing
• Poorly localized, may be referred

Ne uro pat hic pain

• Due to compression, invasion, des truc
tion , or dysfunction
of the CNS or peripheral nervous sys
tem (but the various
pathophysiological me cha nism s are
not well understood)
Protopathic or dysesthetic pain (e.g
., deatterentation)
• Constant, waxing and wan ing

• Burning
• Localized but som etim es radiating
(e.g., postherpetic
neuralgia)
• Treated with tricyclic ant ide pre ssa nts
Epicritic or lancinating pain
• Paroxysmal
• Sharp, sho otin g (e.g., trig em ina l neu
ralgia)
• Treated with ant icon vuls ant s

ACUTE PAIN SY ND RO ME S
Diagnostic procedures
LJ.Jmbar puncture, Biopsies, thoracentesis
, paracentesis
Chemotherapy-related
Drug-specific infusions
Mucositis
Arthralgia and myalgia
Bony pain flare s (hormonal or growth facto
r stimulants)
Radiation-related
Dermatitis
Enteritis/proctitis*
Postoperative
Tumor embollzatlon
Catheter/tube plac eme nt*
Chest tube, percutaneous biliary stent,
percutaneous nephrostomy tube

14 · to
Introduction P'
UII

CHRONIC PAIN SYNDROMES

rumor-related
Nociceptive
Somatic
ssion)
Bony involvement (metastases, pathologic fracture, spinal cord compre
Soft tissue and muscle
Paraneoplastic (osteoarthropathy)
Visceral
Hepatic capsule distention
Bowel obstruction
Ureteric obstruction
Peritoneal carcinomatosis
Retroperitoneal syndrome
Adrenal pain syndrome
Neuropsthic
Cranial neuropathy
Cervical, brachia!, lumbosacral, sacral plexopathy
Cauda equine syndrome
Peripheral mononeuropathy
Leptomeningeal metastases
Chemotherapy-related
Peripheral neuropathy
Raynaud's syndrome
Steroid-induced (avascular necrosis, compression fractures)
Radiation-related
Brachia! plexopathy
Myelopathy
Burning perineum syndrome
Osteoradionecrosis
Surgery-related
Post-mastectomy
Lymphedema
Post-radical neck dissection
Post-thoracotomy
Post-surgical pelvic floor pain
Stump pain
Phantom limb pain

Table 1. Examples of Acute and Chronic pain syndromes

*can also be chronic

Palliative Care Pearls

afferent
• Pain is a subjective experience that involves transmission of
noxious stimuli with an expressive component manifesting as a
reaction to painful stimuli.
ely
• The majority of cancer pain can be well-controlled using relativ
simple medication regimens.
and/or
• Worsening pain may be misinterpreted as untreated suffering
a sign of impending death.
• Patients with advanced cancer generally experience chronic
pain.
constant pain with intermittent episodes of acute breakthrough

Introduction to Pain 15
 d t .
• Neuropathic pain is due to compression, invasion , es ruction
. m. ' or
dysfunction of the CNS or peripheral nerv ous syste

Rec om men ded Rea ding

aging pain • .
Dalal S Tanco K Bruera E. State of the art of man 1n Patients .
, , w,u
canc er. Cancer J . Oct 2013 ; 19(5): 379- 89.

ent Pain and Headache

Dalal s Bruera E· Assessing Can cer Pain. Curr
, 314 -324 .
Reports, August 2012, Volume 16, Issue 4, pp

Cancer Pain Asses

Koh M Protenoy R. Cancer Pain Syn drom es in
I
2010, refer 53_ 88.
and Management. Cambridge University Press

· to paI
lntroduct1on
16
chapter 4 Pain Management

Yvonne Heung, M.D., Akhila Reddy, M.D.,

and suresh K. Reddy, M.D., F.F.A.R.C.S.

Etteetive pain management involves understanding the complex interactions

between physiological, psychological, sociocultural, and cognitive
dimensions of pain expression and incorporating both pharmacological and
non-pharmacological modalities into the individualized treatment of patients.

Guidelines for Treatment of Cancer Pain

Various organizations have proposed guidelines for treating cancer
pain, including the commonly used three-step analgesic ladder from the
World Health Organization (WHO). The Agency for Health Care Policy
and Research (AHCPR) has also published Clinical Practice Guideline
No. 9: Management of Cancer Pain, offering a comprehensive review of
assessment and treatment principles. Others guidelines include those
from the American Pain Society, National Comprehensive Cancer Control
Program, and American Society of Anesthesiologists.

The basic principles of treatment are guided by pain severity, pain syndrome,
previous analgesic use, dosing, side effects, and pre-existing conditions.

Pain Severity
Pain severity guides the process of choosing a low-potency opioid versus a
high-potency opioid, in addition to adjuvant analgesics. Most low-potency
opioids are less suitable for severe pain due to dose limitations and presence
of a ceiling effect. Most cancer pain syndromes require treatment with high-
potency opioids. Interpretation of pain severity should be individualized for
each patient and interpreted in the context of other psychosocial symptoms.

Pa·
in Management
17
 Pain Syndromes

The type of pain - nociceptive, neuropathic or a combination of both _

guides the selection of the appropriate class of analgesics. It is important
to appreciate both the anatomical as well as pathophysiological componen
of pain. In the case that a pain syndrome is difficult to ascertain,
psychosocial and spiritual causes of pain should be excluded in order to
effectively treat pain.

Opioid History and Side Effects

Patient-to-patient variability in the responses to a specific opioid has been

widely documented. Some patients may respond surprisingly well to one
opioid after failing or developing side effects to others. This may be caused
by opioids acting on different receptor types and sub-types, as well as
genetic factors in opioid receptor constitution. This phenomenon will
influence drug selection within the same class.

Previous Opioid Dosing and Pharmacokinetics

Previous opioid dosing and pharmacokinetics reflect the degree of toleranc
to opioids. Patients who are opioid-naive typically require lower starting
doses. Opioid-tolerant patients with constant pain are likely to require
long-acting opioids, with shorter-acting opioids for breakthrough or inciden
pain syndromes. Frequent escalation of opioids may be required in certain
situations. However, rapid escalation of opioids, without reassessment for
recurrence of disease or psychological factors, should be avoided to preve1
opioid-induced toxicity.

Pharmacotherapy

Pharmacotherapy remains the mainstay of cancer pain treatment. Most

cancer pain syndromes present with moderate to severe pain that may be
associated with organ dysfunction and/or co-morbidities, necessitating
a multidisciplinary and cautious approach for optimal management.
Pharmacotherapies include opioids and non-opioids such as non-steroidal
anti-inflammatory drugs (NSAIOs) and N-methyl-0-aspartate (NMDA)-
Receptor Antagonists, and adjuvant therapies such as antidepressants,
anticonvulsants, corticosteroids, and bisphosphonates.

Pain Managel111
18
__J
Principles of Pharmacotherapy
, Choose drugs which match the pain syndrome
, Have a low threshold for prescribing opioids
, Add non-opioid adjuvant medications where appropriate
, The oral route should be the route of choice
, Be aware of psychosocial and spiritual factors in the high expression
of pain

Opioids
Opioids are the mainstay of cancer pain management, and are classified
as weak or strong opioids. Weak opioids include codeine, tramadol and
tapentadol, and commonly used for mild to moderate pain in opioid naive
patients. Ceiling effect may be seen and occasionally dose limited by the
acetaminophen content. Strong opioids include hydrocodone, morphine,
oxycodone, oxymorphone, hydromorphone, fentanyl, and methadone.

Pure opioid agonists in single-agent form are preferred for treating cancer
pain. These include morphine, hydromorphone, fentanyl, oxycodone,
oxymorphone, hydrocodone, and methadone. Dosages may be increased
in small increments until the desired analgesic effect is achieved or dose-
limiting side effects develop.

Partial opioid agonists and mixed agonist/antagonists are usually not

beneficial in the treatment of cancer pain due to psychomimetic side
effects. However, recent studies suggest buprenorphine may be useful
in certain clinical situations. Pharmacologically, buprenorphine is a
partial agonist to mu and ORL-1 receptors as well as antagonist to kappa
receptors. Buprenorphine is metabolized via CYP34A to its metabolite,
norbuprenorphine, and undergo rapid glucuronidation in the liver and
eliminated mainly via bile and stool. Buprenorphine can be an option for
patients With history of opioid addiction, bone pain, neuropathic pain, as
w~II as secondary hyperalgesia. It is also an option for patients on dialysis or
with unstable renal function as its pharmacokinetics are unchanged by renal
failure. Buprenorphine is available in intravenous, subcutaneous, transdermal
a~ Well as sublingual formulations. In elderly or opioid-na'ive patients wi th
mild to moderate pain, start a 5mcg/hour patch to be exchanged every
Week. At higher doses, withdrawal may be noted in patients on high doses of

PainM
anagement 19
opioid agonists. Of note, a minimum of 3 days is needed prior to uptitratio
Immediate-release opioids can be prescribed in the interim. n

General opioid guidelines (Table 1)

• The initial opioid choice may depend on patient and clinician
preference or familiarity, cost, prior experience and availability,
• use of Extended-release (ER)opioids or around the clock dosing
with immediate-release (IR) opioids are needed to maintain adequ
opioid levels
• All patients should have IR _opioids for breakthrough pain, usually
1
20% of the 24 hour dose.
• Maintain familiarity with equianalgesic dosing (Table 2) and
pharmacokinetics of opioids
• Differentiate between tolerance, physical dependence, and addicti

• Opioid side-effects should be expected and adequately managed.

Routes of Administration
The preferred route of opioid administration is oral; however other routes
may be used in situations where dysphagia, delirium, or bowel obstruction
present. In such cases, alternate routes include the following:

• Rectal: Safe, inexpensive, and effective but inappropriate for patie

with anorectal lesions or severe neutropenia/thrombocytopenia;
most opioids are available in or can be compounded into
suppository form; absorption may be variable
• Transdermal: Convenient; titration requires time; best used for stab,
pain syndromes
• Transmucosal: Ideal for treating breakthrough pain due to rapid
absorption through buccal mucosa
• Parenteral: Intra-venous (IV) or sub-cutaneous (SC); used for acute
titration or in situations where other routes are not feasible; regular
intermittent SC administration likely as effective as continuous
administration; equianalgesic dose conversion can be easily
calculated

81111
Pain pJlaria9
20
 • Neuraxial: Epidural or intrathecal opioids may be indicated in
situations where conventional management is ineffective; in some
situations they cause fewer side effects and may be more effective in
complex pain syndromes.
• Topical opioids such as morphine may be used for localized ulcers6

Initiating Opioid Therapy

• Begin with conservative around the clock (ATC) dosing schedules
and provide adequate rescue dosing (prn) for breakthrough pain. For
example, start with Morphine sulfate ER 15mg PO every 12 hours
ATC with Morphine sulfate IR 7.5mg PO every 4 hours prn.
• Titrate accordingly over the next 3 - 4 da,ys to achieve optimal pain
relief and then use as maintenance

Opioid Maintenance
• Frequent re-assessment is crucial to monitor for desired analgesic
effect, side effects or toxicity, and evidence ·of disease progression
• Upward titration of opioids may be necessary as tolerance develops
or disease advances, both of which may manifest as increased pain
expression
• Downward titration may be indicated if:
• Pain improves due to other palliative measures such as
radiation treatment, nerve blocks, or chemotherapy
• Satisfactory pain control is accompanied by excess sedation

• Toxicity appears

Adverse Effects of Opioids

• Patients who require opioids in high doses for prolonged periods
of time or who develop renal insufficiency may accumulate toxic
metabolites which can manifest as intractable nausea, somnolence,
or signs of neurotoxicity including hallucinations, confusion,
myoclonus, and hyperalgesia.
• Treatment includes hydration and opioid rotation. Symptomatic
treatment may include use of haloperidol for delirium (see Chapter 9,
Delirium).

Paint.1
anagement
21
J • In patients with renal insufficiency, opioid doses should Proba ,
4

reduced, even in the absence of overt signs of toxicity b bly be

. . . , ecause
the likely accumulation of metabolites. Methadone may be th Of
of choice in such cases. e drug

Adjuvant Analgesics

Even though opioids are the main analgesic regimen for the treatment of
moderate to severe cancer pain, adjuvant medications can also be used
as the first step or in conjunction with opioid analgesics. Antidepressants
1
I
anticonvulsants, local anesthetics, anti -inflammatories, corticosteroids
I

and bisphosphonates may serve as adjuvant analgesics for certain pain

syndromes including chemotherapy-induced polyneuropathy, post-herpetic
neuralgia, and various regional neural plexopathies. Adjuvants should be
initiated at a low dose and gradually uptitrated over weeks. In general, it may
1
take up to four to six weeks to observe an effect and responses can vary
substantially between individuals.

Commonly used adjuvants include the following :

• Amitriptyline/Nortriptyline 10 - 25 mg at night, titrated up to 150 mg

for neuropathic pain.
• Gabapentin 100 mg three times a day, titrated up to 300-600 mg
three times a day for neuropathic pain (up to 900 mg four times a
day maximum in severe cases). Other anti-epileptic agents include
oxcarbazepine, lamotrigine and topiramate.
• Dexamethasone for neuropathic, bone, and visceral pain
• Other adjuvants include lidocaine, ketamine, capsaicin, and
bisphosphonates

Bisphosphonates
• Following systemic absorption, they localize to bone and inhibit
osteoclastic activity
• Clodronate and pamidronate have been studied extensively in
multiple myeloma and breast cancer
• Zoledronic acid (Zometa) has been widely used in metastatic bone \
disease ~I
• Bisphosphonates may cause osteonecrosis of the mandible and/or \
maxilla, electrolyte abnormalities, renal impairment

Pain Managem e11t \

22
L
 • Dosing of common bisphosphonates

• Pamidronate: 90 mg intravenous every 4 weeks

• Zoledronic acid: 4-8 mg intravenous every 4 weeks

RANK-L inhibitor
Denosumab (Xgeva) is a monoclonal antibody with high specificity for
RANK-L, preventing osteoclast-mediated bone destruction and skeletal
related events (SRE) due to bone metastases in patients with advanced
cancer. SRE include pathological fractures, hypercalcemia, and metastases
requiring surgery/radiotherapy. Recommended dosing is 120mg
subcutaneously every 4 weeks.

NSAIDs for Bone and Inflammatory Pain

• Most NSAIDs such as ibuprofen, meloxicam and naprosyn are non-
selective, inhibiting the activity of cyclooxygenase enzymes (COX-1
and COX-2), while COX-2 inhibitors such as celecoxib predominantly
inhibit COX-2.

• COX-1, expressed in most tissues is involved in cellular processes

such as gastric cytoprotection, vascular homeostasis, platelet
aggregation, and kidney function, while COX-2 expression increases
during states of inflammation
• Unlike opioids, NSAIDS have a ceiling effect and do not exhibit
tolerance and physical dependence
• All NSAIDs have a Black Box Warning regarding an increased
risk of adverse cardiovascular thrombotic events and serious
gastrointestinal inflammation, ulceration, bleeding, and perforation.
• Compared to traditional NSAIDs, COX-2 inhibitors cause less GI
and platelet dysfunction, which may be useful in patients receiving
chemotherapy.

• Recently, the PRECISION trial demonstrated similar cardiovascular

risks for celecoxib at low doses (100mg BID) and NSAIDS at
moderate-high doses (e.g. ibuprofen 600mg TIO).

Practical r·1ps for Managing Cancer Pam

.
At MDA .
nderson, the management of cancer pain involves a comprehensive
evaluation th · 1· d P ·
at includes the type and intensity of pain, Persona Ize aIn

Paint-,
anagement
23
h
Goal (PPG), prior opioid use, risk factors for poor pain control (such as
impaired cognition, psychological distress) and risk for opioid misuse.
The PPG is the verbal or written goal stated by the patient describing the
desired level/intensity of pain that will allow the patient to achieve comfort
in physical, functional, and psychosocial domains. Most patients score their
PPG around 3.

Opioid-Na"ive Patients
Initial evaluation

• Is the pain related to the cancer? (Rule out non-malignant causes)

• What is the severity of the pain (on a 0-1 0 scale)?
• Where is the pain? (Consider the need for radiation or other therap~
• What is the baseline renal function? (Neurotoxic opioid metabolites
may accumulate in the dehydrated or renally-impaired patient)

Initiation and titration of analgesics

• Acetaminophen 325 mg and codeine 30 mg,

1 - 2 tablets q4h prn (Maximum 8-10 tablets/day)
• Acetaminophen 325 mg and Hydrocodone 5mg,
1 - 2 tablets q4h prn (Maximum 10 tablets/day)
• Remember to add an anti-emetics and laxatives to the regimen:
• Anti-emetic regimen: Metoclopramide (Reglan®) 10 mg
every 4 hours, can add 10 mg every 2 hours as needed for
breakthrough nausea for the first 48 hours.
• Laxative regimen: sennoside (Senokot®) 8.6 mg, 1 - 2
tablets twice a day, can titrate up to 4 tablets twice a day.
Add other laxatives such as polyethylene glycol (Miralax),
Lactulose, Bisacodyl suppository or enema as needed.

• Assess for effectiveness and side effects frequently

If a stronger opioid is indicated initially or early in the course of treatment:

• Start with morphine 10 mg orally (5 mg IV/SC) every 4 hours and 5

mg oral every 2 hours as needed for breakthrough pain
• Acetaminophen 325 mg and Hydrocodone 10 mg, 1 - 2 tablets q4h
prn (Maximum 10 tablets/day)

Pain Manage
me~
24
 • Hydromorphone 2 mg oral (1 mg IV/SC) every 4 hours and 1 mg oral
(0.5 mg IV/SC) every 2 hours as needed for breakthrough pain
• oxycodone 5 mg oral (IV/SC route not readily available) every 4
hours and 5 mg oral every 2 hours as needed for breakthrough pain
• In general, start with morphine and then select the next most potent
opioid
• continue anti-emetic and laxative regimen

• continue frequent assessment

Maintenance regimen
• continue current regimen as long as it is effective and indicated
• Add an adjuvant analgesic as indicated
• If stable, initiate a sustained-release regimen

I • Determine the total 24-hour opioid dose in mg (around the

clock + as needed doses)
• Using an opioid conversion table, convert to a daily
equivalent dose of morphine (MEDO)
• Prescribe the sustained-release opioid in divided doses
every 8 hours, 12 hours, 24 hours, or 72 hours depending
on the opioid selected
• Treat breakthrough pain with a short-acting opioid given every 1-2
hours by calculating 10-15% of the MEDO (e.g., for a patient on
sustained-release morphine 100 mg every 12 hours, give immediate-
release morphine at 20-30 mg every 2 hours as needed)
• We advise using the same opioid for both sustained-release as well
as breakthrough purposes, although using different opioids may be
necessary and advantageous in some situations
• Continue anti-emetic and laxative regimens, titrating to comfort as
necessary
• Continue adjuvants as indicated

• Continue frequent assessment

Opioid-Tolerant Patient
• Continue with ongoing evaluation of pain and other treatments
• Note history of response to previous opioids and side effects

Paint.1
anagement
25
 • Determine total daily opioid dosage (as described above), increase
by 30%, and give in divided doses every 4 hours (immediate releas~
or every 12 hours (extended release) with breakthrough dosing eve~
4 hours as needed
• Continue anti-emetic and laxative regimens, titrating to comfort as
necessary
• Continue adjuvants as indicated
• Continue frequent assessment
• Increase opioid dosing as needed as described above
• Convert to sustained-release regimen(as described above)
• If toxicity or side effects become problematic, consider opioid
adjustment or rotation

Intractable pain
If the pain appears to be refractory to rapid escalation of opioids, consider
concurrent factors:

) • Progression of tumor burden

• Psychological modifiers to pain expression such as adjustment
disorder, anxiety, depression
• Previous or ongoing chemical dependency
• Counsel the patient about the difference between
nociception and suffering
• Counsel the patient regarding the dangers of escalating
opioids
• Consider restricting treatment to long-acting opioids with
limited breakthrough doses
• Limit prescription of opioids to one physician only, if possible

• Assess the patient using the CAGE questionnaire

• Consider screening for risk of opioid misuse with SOAPP
(a tool for providers to determine the level of monitoring
necessary to safely provide long-term opioid therapy)

• Depression or anxiety
• Assess and treat the patient as outlined in Chapter 14,
Depression, and Chapter 15, Anxiety
• Consider psychiatric consultation

Pain ManagerTlei
26
 • sornatization and pain

• Discuss with the patient the difference between pain caused

by noxious stimuli versus pain related to chronic suffering
• Breakthrough pain
• Escalate the short-acting opioid and add methylphenidate
5 mg in the morning and 5 mg at noon if drowsiness or
sedation is present

• Consider radiation therapy or surgical consultation as

indicated
• Bone pain
• Consider NSAIDs
• Consider bisphosphonates
• Consider radiation therapy or orthopedic consultation as
indicated
• Neuropathic pain
• Tricyclic antidepressants: amitriptyline or nortriptyline 10 - 25
mg at night and titrated up to 150 mg as needed (choice of
drug depends on patient and side-effect profiles)
• Anticonvulsants: gabapentin 100 mg three times a day
. titrated over 3 - 5 days to 300 mg three times a day, can be
titrated up to 3.2 grams/day if necessary
• Others medications and interventions:
• Methadone
• Ketamine/dextromethorphan
• lnterventional: regional, sympathetic blocks
• Neuraxial medications: opioids, clonidine, local anesthetic, and
ziconotide

Opioid Rotation
• Usually required in cases of opioid-induced neurotoxicity
• May also be indicated
• when pain is uncontrolled despite high opioid doses
• when need for opioid escalation makes administration
difficult or impractical

PainM
anagement
27
D
 • when tolerance or dose-limiting side effects develop

• when a cheaper opioid alternative is appropriate

Rotation should be done as follows:

• Step 1: Calculate the total daily dose of the opioid

• Step 2: Calculate the dose of the new opioid using an equianalges~
dose conversion table
• Step 3: Reduce the new opioid dose by 30% -50% to account for
incomplete cross-tolerance between opioids
• Step 4: Prescribe the new opioid using either a scheduled short-
acting opioid at frequent intervals or a sustained-release
opioid
• Step 5: Order adequate breakthrough dosing (as described above)
• Step 6: Continue frequent assessment

Pain Management
28
 ,,
5" "'
a,
f
a:, ,..:, ,-;;-, ..,;.;'!
Available alone or in combination with
CII Short-acting: 30-60 mg every 6 Short-acting: 15, 30, 60mg tablets
3 Codeine PO 30-60 1-1.5 4-8 300mg acetaminophen. Ceiling effect
CII
hours Long-acting: NIA Long-acting: NIA
:::, around 400mg.
.. Short-acting: 25 mg PO every 6 Short-acting: IR from 50 mg tablets
Additional SNRI effect. Some
formulations contain acetaminophen
Tramadol IPO I 30-60 11.5 I 3-7 I hours Long-acting: ER from 100, 200, 300
Caution: risk of hypoglylcemia,
Long-acting: 100 mg ER daily mg tablets
seizure, serotonin syndrome.
A dual opioid agonist and
Tapentadol I Short-acting: PO every 4-6 hours norepinephrine re-uptake inhibitor.
IPO 1<60 11 .25-1.5 I 4-6 Short-acting: 50, 75, 100mg tablets
Long-acting: NIA
I Avoid MAOls, SSRls, and SNRls due
to potential for serotonin syndrome.
Short-acting: 5, 7.5, 10 mg tablets;
Short-acting: 5-10 mg PO every 4-6
2.5mg/5ml liquid, in combination / All short-acting analgesic formulations
Hydrocodone IPO 110-20 I 1-3 I 4-8 I hours
with acetaminophen Long-acting: contain either acetaminophen or
Long acting: Every 12 or 24 hours
10, 15, 20,30, 40,50,60, 80, 100, ibuprofen
preparations
120 mg.
Short-acting:
Short-acting: 15, 30 mg tablets; Avrulable tablet o, liquid p , _ o ,.
PO: 5-10 mg every 4 hours; IV: 2-4
PO 10 mg/5 ml, 20 mg/ml liquid Long- Short-acting preparations can
Morphine
I 1wsc
130
5-10 Io.5-1 13-6 mg every 4 hours. Long-acting: 15
1mg every 12 hours, or 20 or 30 mg acting: 15, 30, 60, 100 mg as every
I
be given via PEG tube. Rectal
12-hour preparations preparations (5, 10, 20 mg) available.
once daily.

Short-acting: 5 mg PO every 4 hours Short-aciiog; 5, 15, 30 mg tablets; 5 bl al . b' r .O

mg/5 ml, 20 mg/ml liquid va1 1a _e one or 1n co~ 1na 10n wit
Oxycodone IPO I 10-15 I o.5-1 I 3-6 I Long-acting: 10 mg PO every 12
hours
Long-acting: 1o, 20, 30, 40, 80 mg
r.
acetaminophen. Not av~1lable ~or
tablets as 12- hour preparations. parenteral or rectal adm1nistrat1on.
Short-acting: 5 mg PO every 4 Short-acting: 5,10 mg tablets
Oxymorphone IPOIV/ Poor bioavailability, must be taken on
15-10 I0.5-1 3-6 hours Long-acting: 5 mg PO every Long-acting: 5, 10, 20, 40 mg as I
SC I 112 hours empty stomach.
12-hour preparation

PO 15-30 3-5 Short-acting: PO 2 mg every 4 hours Short-acting: 2, 4, 8 mg tablets; Available as tablet or liquid
I
I\) Hydromorphone 0.5-1 1mg/ml liquid Long acting: 8, 12, 16, p_reparation. Short-acting can be given
IV/SC 15-20 4-5 IV/SC: 0.5-1 mg every
co 32, mg as 24 via PEG tube. Rectal preparations (3
 "',
Equianalgesic conversion tables
Table 2 - Opioid Conversion

Opioid From Parenteral From Same From Oral From Oral

Opioid Parenteral Opioid to Oral Morphine to
To Parenteral Opioid to Oral Morphine Oral Opioid
Opioid Opioid

Morp hIne 3 1 1
Codeine NIA NIA 0.15 7 -
Hydrocodone NIA NIA 1· 1· -
Hydromorphone 5 2.5 -
5 0.2
Oxycodone NIA NIA 1.5 0.7
-
Oxymorphone 0.1 10 3 0.3
Meperidine 0.13 4 0.1 10
Tram adol NIA NIA 0.1 10
1. Take the total amount of opioid that effectively controls pain in 24 hours.
2. Multiply by conversion factor in table. Give 30% less of the new opioid to avoid partial cross
tolerance.
3. Divide by the number of doses/day.
• For doses of Hydrocodone < 40mg/day, conversion factor of 1.5 to morphine is recom mended

METHADONE is 10-15 times more potent than morphine (see section on Methadone)

erl
Pain Managertl
30
Table 3 - Fentanyl patch to morphine conversion (per manufacturer
package insert)

PO MORPHINE DURAGESIC DOSE

Mg/day Meg/hour
45 -59 12
Dose Adjustment
60-134 25
Initiation Dose
135-179 25+12
180-224 50
225-269 50+12
270-314 75

315-359 75+12

360-404 100

404-494 125

495 -584 150

585-674 175

675-764 200

765-854 225

855-944 250

945-1034 275

1035-1124 300

Note: This table accounts for a 50% dose reduction for incomplete cross-tolerance (see section on
Transdermal Fentanyl) .

Sustained-Release (SR) Opioids

• Because the active drug is gradually released from SR opioids,
they can be taken at convenient, extended intervals: every 12 or
24 hours for morphine-SR, hydromorphone-SR, and oxycodone-
SR. Infrequently, every 8-hour dosing may be necessary in some
patients.

• Transdermal fentanyl can be used every 72 hours, but occasionally

can be prescribed for every 48 hours.
• In opioid-na'fve patients, initial dosing with short-acting opioids
allows for rapid, safe, upward titration. Initiating a SR opioid can be
accomplished when relative pain control and dosing stability are
achieved.

• Patients with renal insufficiency are at greater risk for metabolite

accumulation when taking SR opioids.

Paint.1
anagernent
31
 • Changing from an short-acting opioid regimen to SR opioids sh
be done as follows:

•
0uld

Step 1: Calculate the total daily dose of the short-act'

. . b 1ng
'
op101d used y the patient

• Step 2: Divide the dosage into the desired dosing int

erva1s
of 12 hours or 24 hour? based on the formulation
and the drug

• Step 3: Prescribe adequate breakthrough dosing with sh

acting opioid on.

• Escalation of the SR opioid may be necessary due to the

development of opioid tolerance or progressive disease. The amou~
of increase is usually based on the total breakthrough dose used in
24 hours.

• SR opioids may be discontinued in certain circumstances: unstable

pain, opioid toxicity, and renal insufficiency.

• Changing from a SR opioid regimen to short-acting opioids should

be done as follows:

• Step 1: Calculate the total daily dose of the SR opioid

• Step 2: Schedule the short-acting opioid every 4 hours
along with breakthrough dosing every 2 hours as
needed. Start the short-acting opioid 12 hours after
the last SR opioid dose.

T
Transdermal Fentanyl
C
For a patient who is unable to take oral medications and does not have
u
access to the enteral route, transdermal fentanyl provides a convenient,
p
generally well-tolerated alternative. It is a slow-onset, long-lasting opioid
h
delivery system which offers convenience and satisfactory pain control.
However, caution should be taken with titration, as rapid escalation may
result in side effects.

Changing from other opioids to transdermal fentanyl should be done as

follows:

• Step 1: The conversion table for MEDO to FentanyI patch provided)

3
by current pharmaceutical packaging instructions (Table
may be too conservative and may rarely even precipitate ver
symptoms of withdrawal and/or uncontroII ed pai·n · Moreo
these ratios are not meant to be used bidrectionally to
~I I
erT1 8
Pain Mana9
32
 convert from Fentanyl patch to MEDO. Based on two of our
recent studies, we recommend a simple and convenient
conversion ratio of 2.5 which can be used bidirectionally
from Fentanyl in mcg/hr to MEDO and back (e.g. MEDO
60mg + 2.5 = Fentanyl patch 25mcg/hour and Fentanyl
25mcg/hour x 2.5 = MEDO 60mg).

• Step 2: Continue the previous opioid for 6-8 hours after applying the
patch due to slow onset.

• Step 3: Prescribe adequate breakthrough dosing based on the

calculated daily total.

• Step 4: Change the patch every 72 hours (infrequently, patients will

require every 48 - 60 hour dosing).

Discontinuing transdermal fentanyl should be done as follows:

• Step 1: Calculate the equivalent dose of the new opioid.

• Step 2: Calculate the scheduled interval and breakthrough dose of
the new opioid.
• Step 3: Remove the patch and start the new opioid 12-18 hours later
(the half-life of transdermal fentanyl is more than 12 hours
after discontinuation).
• Step 4: Prescribe adequate breakthrough dosing for the window
period.

Transmucosal Fentanyl

Oral transmucosal fentanyl provides rapid systemic dosing via absorption

through oral mucosa in cancer patients. It may be useful for some
patients with breakthrough pain of quicker onset and duration. A 20mcg
transmucosal fentanyl is equivalent to approximately 8-10 mg of oral
morphine. Of note, fentanyl sublingual spray is absorbed 70% and may be
more Potent.

REMS

T~e Food and Drug Administration (FDA) Amendments Act of 2oo 7 requires
Risk Evaluation and Mitigation Strategy (REMS) from manufacturers to
demonstrate that the benefits of a particular drug outweighs its risks. The
Transmucosal Immediate Release Fentanyl {TIRF) REMS Access program,
the fir t d t
s approved REMS in the opioid class, was develope to preven
Paint.,
anagernent
33
D
 misuse, abuse, addiction, overdose and serious complications related to
TIRF use. At the time of publication of this book, successful completion
01
the TIRF REMS Access program (https://www.tirfremsaccess.com/TirfUI/
rems/home.action) is required for prescribers of transmucosal Fentanyl
and
similar education programs (http://www.er-la-opioidrems.com/lwgUl/rerns;
home.action) are strongly recommended for prescribers of extended-releaS!
and long-acting (ER/LA) opioids.

Methadone

Methadone is a synthetic opioid and NMDA antagonist, serving as a

potent weapon in treating cancer pain of multiple etiologies. It is a valuable
and important opioid at step 3 of the WHO analgesic ladder and can be

-
considered a useful first-line strong opioid2. Available in both oral and
parenteral forms, Methadone should be used under the guidance of a pain
or palliative medicine specialist.

Characteristics of Methadone include excellent absorption, high lipid

solubility, high potency, long but unpredictable half-life, lack of known
metabolites, decreased opioid cross-tolerance, and low cost. Its unique
pharmacodynamic and pharmacokinetic properties contribute to its unique
ability to relieve pain that is unresponsive to other potent opioids. One caveal
is that methadone's potency and long half-life can also make it somewhat
challenging to manage, especially when converting from another opioid.
Recent studies indicate that methadone is 10-15 times more potent than
morphine; most drug interactions with methadone involve inducers or
inhibitors of the cytochrome P450 system. In addition, methadone modestly
increases QTc interval at higher doses. Our study in a palliative care setting,
using a lower median dose of methadone as compared to other studies,
failed to show any prolongation of QTc interval3. Recently, methadone
received a Black Box warning for this side effect and guidelines have been
issued in regards to EKG monitoring and methadone use. Despite this,
methadone has emerged as a very useful drug in intractable pain, especially
when the pain is both somatic and neuropathic.

Familiarity with equianalgesic dosing and caution is needed in prescribing

methadone:

• Gradual titration with frequent assessments is mandatory.

eot
Pain ManagerTI
34
.J
 • Rotating from methado~e.to other opioids is challenging and
should be done by phys1c1ans with expertise and training in using
methadone.

• Drugs sharing the s~me cytochrome system may interact with

methadone, e.g. anti-fungals, some antibiotics, antivirals.

• Be cognizant of use in conjunction with other medications with the

potential to prolong QT interval.

Opioid Tolerance and Dependence Issues

Cancer pain is often under treated for various reasons, including myths and
misinformed attitudes about tolerance and dependence. Patients may have
fears about addiction and physicians may be reluctant to prescribe opioids
for that reason. Health care providers managing cancer pain should be
aware of the differences between opioid tolerance, physical dependence,
and psychological dependence ("addiction").

Opioid Tolerance

Increasing opioid requirements to control pain may indicate the development

of tolerance. The mechanism of this normal physiological phenomenon may
be alterations at the opioid receptor level or changes in opioid metabolism.
The development of tolerance varies greatly among patients. In situations
where tolerance is suspected, all efforts should be made to rule out disease
progression. Due to cross-tolerance phenomenon seen with opioids,
opioid rotation can be done if tolerance becomes problematic or if patients
experience dose-limiting side effects. The fear of tolerance should not
prevent clinicians from prescribing opioids earlier in the disease trajectory.

Physical Dependence
Ph ·
Ys1ca1 depe d · · 'd
n ence is a normal physiological effect of chrome op101 use.
Upon abrupt d . h . 'd
re uct1on or discontinuation of the opioid, or w en an op101
antagonist · . .
a ·t . is used, patients may display signs of withdrawal, including
91 at1on tr .
rnusc ' ernulousness, fever, diaphoresis, mydriasis, tachycardia, and
le or abdo · · f · 'd ·
ind· minal cramping. If reduction or cessation o op101 s 1s
icated th ..
day, ' e opioid dose should be gradually tapered by 10 %- 20% each

Paint,1
anagernent

35
 Psychological Dependence ("Addiction")
Psychological dependence ("addiction") is the psychopathological
compulsion to use a substance despite physical, psychological, or social
harm. Substantial evidence confirms that cancer patients taking opioids
appropriately for cancer pain are at minimal risk for developing psychologi~
dependence.

Chemical Coping
Chemical coping is an aberrant behavior commonly observed in cancer paiQ
This phenomenon occurs when patients use pain medication to cope with
emotional distress or suffering. Chemical coping through self-medication can
become more obvious with stressful situations such as receiving bad news,
displays of high emotional expression, and aggressive demands for pain

)
medications. Risk factors for chemical coping may include history of alcoh~
or substance abuse, co-existing psychiatric disorder, younger age, and
limited coping mechanisms. However, such factors do not necessarily signify
that a patient is chemically coping. Management of chemical coping involves
an individualized, multidimensional physical and psychosocial approach
including behavioral counseling by an interdisciplinary team.

Pseudo-addiction
While drug-seeking in chemical.coping is motivated by the desire to relieve
psychosocial distress, in pseudo-addiction it is motivated by uncontrolled
nociceptive input. The two syndromes can be difficult to distinguish as
they initially present with similar behaviors; however, the distinction typically
becomes clear over time. Improved assessment and management of pain
should resolve the phenomenon of pseudo-addiction.

Aberrant Opioid Use

When aberrant opioid use is suspected, a personalized interdisciplinary
approach is strongly recommended. Providers may choose to implement
frequent monitoring through state-specific Prescription Drug Monitoring
databases, scheduling follow-up visits with shorter intervals, and urine drUQ
screens. If available and indicated, other specialties such as Psychiatry,

,ti \
Pain Manage/11
36
a

psychOOI gy' Social Work, Pharmacist, Addiction Medicine may need to be

considered.

at risk of respiratory depression due to opioid misuse

For thOSe . '
harmacy, or polysubstance use, providers should consider prescribing
polyp . t. f h
Naloxon e in the outpatient. se ting or t e.purposes of rapidly reversing
. 'd overdose and respiratory depression.
op1O1 . Caregivers will need to be
educated on naloxone use and the importance of contacting emergency
personnel (911).

Non-pharmacological Treatments of Pain

, Stimulation or ablation
, Nerve blocks
, Physical therapy
• Psychological therapy

• Integrative therapies (e.g. acupuncture and massage)

Principles of anesthetic procedures in cancer pain

• Usually reserved for patients unresponsive to conventional
treatments

• Appropriate for patients who demonstrate persistent dose-limiting

side effects to a number of opioids
• Useful in regional pain syndromes
• Neurolytic or destructive procedures are usually reserved for
patients with advanced disease due to adverse effects

Useful Anesthetic Procedures

• Celiac plexus/splanchnic block for abdominal visceral pain, e.g.,
Pancreatic cancer pain
• Subarachnoid neurolytic block for extremity pain and thoracic wall
Pain in terminally-ill patients
• Epidural/intrathecal opioids ± local anesthetic for neuropathic or
Plexopathy pain

• Cordotomy for lower extremity intractable pain

Paint.,
anagen,ent

37
 • Vertebroplasty (injection of cement into a vertebral body)
Kyphoplasty (insertion of an inflatable balloon to create a ~~it
I
the cement) may be useful for the reduction of pain and P Yfor
reventi 0
of further loss of vertebral height associated with spinal c n
fractures ornpressil\i

• Radiofrequency ablation (high frequency alternating current th .

passed from a needle electrode into surrounding tissue resui/118
1
in frictional heating and necrosis) or cryotherapy can be usefu ~~r
1
painful osteolytic metastases

Physical Therapy and Integrative Medicine

Physical therapy and integrative medicine modalities, such as massage,
ultrasound, hydrotherapy, acupuncture, and trigger-point injection, may be
indicated for musculoskeletal pain and may enhance exercise tolerance in
patients undergoing rehabilitation. Skillful soft-tissue manipulation is proba~
underutilized.

Psychological Therapy
Cancer patients may benefit significantly from psychological therapies such
as guided imagery, meditation, relaxation, biofeedback, and other cognitive-
behavioral counseling.

Note to the Reader

For the purposes of this chapter, we assume that the reader understands
the basic pharmacological principles and caveats associated with the drugs
mentioned. Although we have alluded to a number of side effects associated
with some of these medications, the reader should refer to a pharmacology
textbook or the Physicians' Desk Reference for detailed information.

Concise pain management algorithms can be found in the M. D. Anderson

Cancer Center Intranet system, under the Clinic Portal tab, click on "Practice
Algorithms by Disease", then "Clinical Management", then "Cancer Pain."

For those problematic situations where pain and other symptoms are
refractory to initial management, the Symptom Control and Palliative Care
service is available to assist via one-time consultation or multiple follow-

,) I
Pain Manage"1
38
 . ·ts as indicated. To access this service, call the Palliative Care and
upVISI
·i·tation Medicine Center triage pager at (713) 404 _ 1275
Reha b11 •

Palliative care Pearls

, Pain is a multidimensional experience that requires multidimensional
assessment
, Because pain and other symptoms change rapidly in the advanced
cancer patient, regular and frequent assessments are necessary
, Reassure the patient and family that pain can be relieved for the
most part
, Reassure the patient and family about concerns and fears regarding
opioids
, Explain to the patient the differences between physical dependence,
addiction, and tolerance
, Almost all patients with advanced cancer require treatment with
opioids. Therefore, prescribers should be aware of, but not limited
by, concerns about dependence and addiction
• Encourage physical activity
• Effective pain management requires tailoring the regimen to the type
and intensity of pain
• Schedule around the clock opioid administration with adequate
breakthrough dosing
• Diagnose and treat opioid-related side effects aggressively
• Add adjuvants if indicated
• Prescribe anti-emetics and laxatives proactively
• Consider non-pharmacologic options including anesthetic and
neurosurgical approaches, if appropriate
• Beware of opioid use in patients who are experiencing delirium or
somatization
• Benzodiazepines and phenothiazines may cause unwanted over-
sedation and aggravate confusion
• Beware of the pitfalls of polypharmacy
• Treating patients with pain should include assessment of total pain
(nociception, psychological distress, and spiritual distress) and
addressing the patient as a whole in body, mind, and spirit.

Paint.1
anagement
39
Recommended Reading
Textbook of Palliative Medicine, Part 8 Pain, edited by Bruera, Higginso
n,
Ripamonti & von Gunten

Dalal s, Tanco K, Bruera E. State of the art of managing pain in patients 'Ni~
cancer. Cancer J. Oct 2013; 19(5): 379-89.

Bruera E, Palmer JL, Bosnjak S, et al. Methadone versus morphine as a fir~.

line strong opioid for cancer pain: a randomized, double-blind study. J Clin
Oncol. Jan 1 2004;22(1):185-192.

Reddy S, Hui D, El Osta B, et al. The effect of oral methadone on the OTc
interval in advanced cancer patients: a prospective pilot study. J Palliat Med.
Jan 2010;13(1):33-38.

Davis, M. Twelve reasons for considering buprenorphine as a frontline

analgesic in the management of pain. J Support Oncology. Nov 2012; 10(6):
209-19

Pain r,1ana9
e11i
40
_......t
chapter 5 Chronic Nausea

- h Arthur, M.D.
JoseP

Introduction
•is described as an unpleasant subjective feeling of an urge to vomit
Nausea ,
and manifested by autonomic symptoms like tachycardia, pallor, salivation,
and flushing. It may or may not be associated with vomiting. Vomiting is
the act of forcefully expelling stomach contents through the mouth with the
combined actions of the abdominal muscles, diaphragm, and the opening of
the gastric cardia.

Chronic nausea is often defined as nausea occurring for > 4 weeks in the
general population. However in the palliative care population, nausea is
considered chronic if it lasts more than a week. It is a common symptom
with a frequency of 32-98% in patients with advanced cancer and occurs
almost universally in the last few days of life. Nausea appears to be more
prevalent in younger patients, women, and patients with gastric, breast, or
gynecological malignancies

Etiology
The etiology of nausea in cancer patients is often multifactorial. The interplay
of these causative factors is illustrated in Figure 1

Chronic N
ausea
41
r Figure 1: Multifactorial causes of nausea in patients with ca
ncer
Opioids (and its
1'intracranial metabolities)
pressure Other drugs

Metabolic
abnormalities ---..
\ t I Autonomic
dysfunction
Nausea
Bowel
Ch~motherapy

I \
obstruction induced

Peptic ulcer
disease
t
Constipation
Radiation
therapy

Pathophysiology

Figure 2 illustrates the possible pathophysiological mechanism of nausea.

Generally, vomiting occurs when a group of neurons in the medulla
oblongata called the vomiting center is activated by neuronal impulses from
four main areas: the chemoreceptor trigger zone (CTZ), the gastrointestinal
(GI) tract, the higher cortical areas, and the vestibular apparatus. The CTZ,
located in the floor of the fourth ventricle is outside the blood-brain barrier,
and therefore accessible to emetogenic substances in the bloodstream. The
GI tract may activate the vomiting center directly and/or indirectly via visceral
vagal afferent signals to the CTZ.

Various neurotransmitters are involved in the transmission of emetogenic

impulses to the CTZ and the vomiting center. The major ones are: serotonin
which acts on the serotonin-3 (5-HT3) receptors, dopamine which acts on
dopamine-2 (D2) receptors, and substance P which acts on natural killer-
1(NK-1) receptors. Others include histamine and acetylcholine which act on_
the histaminic and muscarinic receptors respectively. These are prominent ir
motion sickness related vomiting.

5ei
Chronic Nall
42
Figure 2. Pathophysiology of Nausea and Vomiting

Opioids, metabolites

- ).
cytoto><i c drugs, toxins

Gastrointestinal Tract

Contraction and
distention, chemic1
t lntrscranial pressure toxins, radiation,

"_____ ,,z, •
scrv & psychogenic
5 cytoto><ic drugs
lt~;uli, i.e., p_ain, sight, smell
end anticipation
VOMITING CENTER : Vague nerve :

Neurotransmitter receotors·
• 5-HT, = Serotonin type 3
4 D3=Dopamine type 3
M=Muscarinic
• NK-1= Neurokinin type t
NAUSEA AND
VOMITING * Ht- Histamine

Assessment of Chronic Nausea

Nausea is a subjective symptom and its definition and severity may vary from
person to person. It is often helpful to follow these steps when assessing a
patient with nausea

Step 1: Determine the intensity (using a O - 10 rating or visual analog

scale), onset, duration, frequency, temporal factors of nausea
episodes and of coexisting emesis. Determine quantity and
quality of emesis. Assess bowel movement regularity.
Step 2: Review patient history regarding site of tumor involvement,
previous therapies including chemotherapy and radiation, and
medication regimen to determine potential causes of nausea.
Step 3: Examine the patient to assess hydration status, exclude bowel
obstruction, CNS involvement, autonomic failure and other
mechanisms.
8tep 4: Conduct diagnostic studies if pertinent such as laboratory
evaluation of electrolytes, serum calcium, liver and renal
function. Abdominal x-rays may reveal bowel obstruction or
constipation.

Chronic Na
usea
43
77
 Management of Chronic Nausea

A). General Measures:

1. Environmental modifications:
Advise patient and family to avoid stimuli that are known to exacerbate
nausea such as smells of perfumes, detergents, and food being
prepared.

2. Correction of Underlying Causes

Treatment of underlying cause(s) of nausea and vomiting is important.
Examples include:
• Treatment of constipation with an improved bowel regimen.
• Opioid rotation may abate nausea and enhance pain control.
• Corticosteroids and/or radiation therapy may alleviate raised
intracranial pressure.
• Counseling, explanation, and reassurance may benefit patients
suffering from high anxiety or anticipatory nausea.
• Electrolyte imbalances should be corrected, and volume-depleted
patients should be hydrated.
• H2 antagonists or proton pump inhibitors may relieve gastric or
duodenal mucosal irritation.
• Antibiotics may abate underlying infection.
• Hypercalcemia may respond to hydration and bisphosphonates.
• Mechanical bowel obstruction may require decompression using
a nasogastric tube and corticosteroids, anticholinergics, and
somatostatin analogs. In refractory cases, a venting percutaneous
gastrostomy tube might be required
• A nasogastric tube may be necessary for management of copious
vomiting, bowel obstruction or abdominal distention.

B). Pharmacologic Measures

Pharmacological disruption of the receptors involved in the transmission

of the emetogenic impulse is the major target of antiemetic medications.
A list of commonly used antiemetics and their recommended doses is
shown in Table 1.

Chronic Nausel
44
 I e-2 (D2) receptor antagonists. They work centrally to block
oopsmn
. e receptors in the CTZ and the vomiting center. There are
doparnIn .
I sses of medications: a) butyrophenones (e.g., haloperidol), b)
three ca
othiazines (e.g., prochlorperazine), and c) substituted benzamides (e.g.
' phen I pramide). Known side effects include extrapyramidal symptoms,
rnetoco .
ess and CNS depression.
restlessn

Metoclopramide is the drug of choice for chronic nausea in advanced

cancer Patients. It is unique because it blocks dopamine receptors both
centrally in the CTZ and peripherally in the gastrointestinal tract and also acts
as a prokinetic agent thereby increasing gut motility. At high doses (~120 mg/
day) it is also capable of blocking serotonin receptors (5-HT3). Drowsiness
and diarrhea are common side effects. This medication is contraindicated in
complete bowel obstruction.

Concerns of extrapyramidal symptoms (EPS) with metoclopramide use:

Generally, EPS develop as a result of the loss of dopaminergic neurons,
deficiency of dopamine, or blockade of dopamine from acting on the
central dopamine receptors, coupled with an increase in acetylcholine
activity in the brain. Metoclopramide, just like with many other dopamine
receptor antagonists, is known to cross the blood-brain barrier to inhibit
central dopamine receptors in the brain. It may also increase the release of
acetylcholine in the central nervous system, and hence can cause EPS. EPS
symptoms such as acute dystonia and akathisia can occur after short term
use whereas tardive dyskinesia (TD) and parkinsonism may occur after long-
I term use.

TD is the most concerning metoclopramide related EPS complication.

Some national guidelines estimated its prevalence to be 1-15% after usage
of metoclopramide for at least 3 months. As a result, the Food and Drug
Administration in 2009 issued a black-box warning regarding long-term or
high-dose use of metoclopramide because of the risk of developing TD.
It recommends use to be restricted to not more than 12 weeks except in
rare cases Where the benefits are believed to outweigh the risks. However,
8 10
~~ reView found that the risk of TD from metoclopramide is likely to be
<110 Which i
s much lower than initially perceived.
The incide
Well t . nee of EPS specifically in advanced cancer patients has not been
s Ud1ed In
· our anecdotal experience EPS are rarely observed in this
j Chron1c N
auaea
45
 1
I
patient population. Therefore we continue to recommend metocloprarnide f

the first line drug for the management of chronic nausea and gastroparesis~
in patients with advanced cancer since the antiemetic benefits of this dru .
911
these patients outweigh the risks.

5-hydroxytryptamine-3 (5-HT3) receptor antagonists. These act

both centrally and peripherally by binding to 5-HT3 receptors in the CTZ
and the gastrointestinal tract. Examples include dolasetron, granisetron, 1

ondansetron, which are first generation 5 HT3 receptor antagonists, and

palonosetron, a second generation 5 HT3 receptor antagonist. The major
side effects are constipation and headache. 5-HT3 antagonists are most
effective in chemotherapy-induced nausea but have minimal effects on
opioid-induced or chronic nausea. Moreover, they can decrease motility,
thereby worsening gastroparesis and constipation, and are expensive.

Neurokinin-1 (NK-1) receptor antagonists. These work by blocking the

NK-1 receptors in the CNS. They are a relatively new class of antiemetic
medications and are used more in chemotherapy induced nausea and
vomiting. Examples include aprepitant and fosaprepitant. Dizziness,
anorexia, diarrhea, nausea are the most common side effects.

Corticosteroids. The mechanisms of action are unknown but it is believed

that they work through multiple actions. They are believed to decrease
nausea and vomiting by interfering with prostaglandin synthesis. They are
also thought to decrease serotonin production in the central nervous system
(CNS). A third possible action is that they reduce the permeability of the
blood-brain barrier and may therefore limit the penetration of emetogenic
agents to the brain or reduce chemotherapy or radiation-induced brain
edema. Common side effects include fluid retention, anxiety, insomnia,
gastrointestinal upset, and immunosuppression. As soon as a good
response is observed, it should be tapered to the minimal effective dose.

Benzodiazepines. Their mechanism of action in managing nausea and

vomiting is unclear but their sedative, anxiolytic and amnesic properties ha
been implicated. They are particularly useful in treating anticipatory nausea,
Examples include lorazepam and diazepam. Common side effects include
dizziness, sedation, confusion, and fatigue. Because of their side effects,
they are rarely used in our patient population.

use'

_......-
Chronic NII
46
 . . tamines: Antihistamines like phenothiazine meclizine and cyclizine
Ant1h1s . . '
b locking H1 receptors in the vestibular apparatus vomiting center
I

cTZ although they belong to the phenothiazine family They work at

and the . . . ·
'bular sites when vertigo or motion sickness is a problematic concurrent
vest1 .
m They also possess ant1muscarinic properties. They are not first-
symPtO •
.ices in treating opioid-related nausea.
linecho
Anticholinergics: These work by inhibiting muscarinic receptors in
the gastrointestinal system (to decrease G.I. secretions) as well as the
vestibular and medullary centers. Their CNS and anticholinergic side effects
can worsen delirium. Examples are hyoscine butylbromide, hyoscine
hydrobromide (scopolamine), and glycopyrrolate. Hyoscine butylbromide
and glycopyrrolate have less penetration to the blood- brain barrier and thus
have much fewer CNS side effects than hyoscine hydrobromide.

Others:
• Octreotide, is a somatostatin analog that reduces GI
secretions and motility and is very effective in cases of bowel
obstruction.
• Dronabinol (Marino!), a cannabinoid, may be helpful
in treating resistant chemotherapy-induced nausea, but
may promote somnolence, clouding of the sensorium, and
hallucinations.
• Olanzapine is an atypical antipsychotic agent that blocks
multiple neurotransmitter receptors including the dopamine
and serotonin receptors which are involved in nausea. It has
been reported to be effective in various clinical situations
such as the treatment of nausea and vomiting refractory to
standard antiemetics, the management of chronic nausea
in palliative care patients, and the treatment of intractable
nausea due to opioids, neoplasm, and/or medications.
Common side effects include sedation, weight ·gain, and an
association with the onset of diabetes mellitus.

Chronic N
ausea
47
D
TABLE 1. Common medications used in the manag
ernent
chronic nausea Of

• With prokinetic effects

Metoclopramide 5-10 mg PO/IV every 4-6h Prokinetic effects via acet •

1
release; blocks both O an~ ~holine
receptors (high doses) HT3
Domperidone 10mg orally every 6h Available via lnvestigational N
D . h ew
rug 1n t e US for severe GI
disorders refractory to standard
therapy. Refer to GI medicine if
needed

• Without prokinetic effects

Haloperidol 0.5-2 mg PO/IV every 4-6h Also useful for anxiety, restlessness

Prochlorperazine 5-10 mg PO/IV every 6-Bh or 25 Also blocks H1 receptors;

mg PR every 12h prochlorperazine is less sedating
than promethazine

Promethazine 12.5-25 mg PO/IV/PR every Also blocks H1 receptors; less

4-6h D-blocking properties than
prochlorperazine

Olanzapine 2.5-5mg PO twice per day Binds to multiple receptors includi~

D, 5HT3, H1 and acetylcholine
receptors

Serotonin antagonists:

Ondansetron 4-8 mg PO/IV every 6-Bh more expensive than other classesd
anti emetics

Granisetron 1 mg PO/IV twice/day 1st generation agent similar to

ondansetron but longer acting

Acetylcholine antagonists:

Scopolamine 1.5mg TD every 72h Can cross the blood-brain barrier

and cause CNS side effects

H1 receptor antagonists:

Diphenhydram ine 25-50 mg PO/IV every 4-6h Very sedating

Meclizine 12.5-25 mg PO every 6-Bh More effective if nausea is related

to motion

Other useful agents:

·odoftii118
Dexamethasone 1-4mg PO/IV every 6h Usually used for short pen on9
due to the side effects wi th prol
use

Dronabinol Concern for CNS side-effects (e).g.

2.5-5mg PO every 12-24h ranoia
dizziness, drowsiness, pa
3
Abbreviations: PO, oral; IV intravenous; TD, transdermal; PR, per rectum; D, dopamine; sHT ,
serotonin, H1, histamine

48
 . t'"e care Pearls
pa111a 1 •
Chronic nausea is a common and distressing symptom in the
• palliative care population

• Underlying factors should be identified and corrected when possible

• Always rule out constipation in a patient presenting with chronic

nausea and/or vomiting.

• Metoclopramide is the drug of choice for chronic nausea, opioid

induced nausea and gastroparesis

• SHT-3 receptor antagonists have relatively less efficacy in chronic

and opioid induced nausea as compared with other agents.

• oexamethasone can be used as an adjuvant for refractory nausea.

Remember to taper down to the minimal effective dose as soon as
response is achieved.

Recommended Reading
Pereira J, Bruera E. Chronic nausea. In: Bruera E, Higginson I (eds).
cachexia - anorexia in Cancer Patients, 2:23 - 37. New York: Oxford
University Press, 1996.

Rao AS, Camilleri M. Review article: metoclopramide and tardive dyskinesia.

Aliment Pharmacol Ther. 2010 Jan;31(1):11-9.

Smith HS, Cox LR, Smith BR: Dopamine re'ceptor antagonists. Ann Palliat
Med 1:137-42, 2012

Dalal S, Del Fabbro E, Bruera E. Symptom Control in Palliative Care-Part

I: Oncology as a Paradigmatic Example. Journal of Palliative Medicine. 9(2):
391-408. 2006

Chronic N
ausea
49
 Chapter 6 Chemotherapy-Induced
Nausea and Vomiting
(CINV)

David Hui, MD, MSc, MSc

Chemotherapy induced nausea and vomiting (CINV) is one of the most

common side effects experienced by cancer patients, and is frequently
ranked as the top symptom affecting their quality of life during treatment.
Significant advances in the management of CINV including corticosteroids,
serotonin receptor (5HT3) antagonists, and most recently, neurokinin 1
receptor antagonists. Nevertheless, a small proportion of patients continue
to experience severe CINV despite treatment.

Types of CINV
• Acute emesis happens within 24 hours after chemotherapy
administration. Usually begins in 1 to 2 hours and peaks at 4 to 6
hours.
• Delayed emesis happens after 24 hours of chemotherapy
administration, and can last for 4 days or more. It is most common~
associated with cisplatin, but may also occur with carboplatin,
cyclophosphamide and anthracyclines.
• Anticipatory emesis is a conditioned response in patients who
experienced severe nausea with previous cycles of chemotherapy.
This typically begins -3 to -4 hour.

Risk Factors for CINV

• Treatment-related factors include the emetic risk of
chemotherapy (most important) and concomitant radiation.
• Patient-related factors include female, <50 years, and previousr
treatment-related nausea and vomiting. Alcohol use predicts iowe
likelihood of CINV.

ndvo01iti/19
Chemotherapy-Induced Nausea a
50
 enic Levels of Intravenously Administered
er,1etOQ
. oplastic Agents
Ant1ne . .
, High risk, >90% nsk of_ CINV In the absence of antiemetic
prophylaxis-~nthr~cycl1ne/cycl_ophosphamide combination,
carmustine, c1splatIn, carboplat1n (AUC ~4) cyclophosphamide
(>1500 mg/m2), dacarbazine, mechlorethamine, streptozocin
, Moderate risk, 31-90% risk-alemtuzumab, azacitidine,
benamustine, busulfan, carboplatin, clofarabine, cyclophosphamide
(~1500 mg/m2), cytarabine (>1000 mg/m2), daunorubicin,
doxorubicin, epirubicin, idarubicin, ifosfamide, irinotecan, irinotecan
liposomal injection, oxaliplatin, romidepsin, temozolomide, thiotepa,
trabectedin
, Low risk, 10-30% risk-aflibercept, atezolizumab, belinostat,
blinatumomab, bortezomib, brentuximab, cabazitaxel, carfilzomib,
catumaxumab, cetuximab, cytarabine (!51000 mg/m2), docetaxel,
elotuzumab, eribulin, etoposide, 5-fluorouracil, gemcitabine,
ipilimumab, ixabepilone, methotrexate, mitomycin, mitoxantrone,
nab-paclitaxel, necitumumab, paclitaxel, panitumumab, pemetrexed,
peylated liposomal doxorubicin, pertuzumab, temsirolimus,
topotecan, trastuzumab-emtansine, vinflunine
• Minimal risk, <10% risk-bevacizumab, bleomycin,
2-chlorodeoxyadenosine, cladribine, daratumumab, fludarabine,
nivolumab, obintuzumab, ofatumumab, pembrolizumab, pixantrone,
pralatrexate, ramucirumab, rituximab, trastuzumab, vinblastine,
vincristine, vinorelbine

Emetogenic Levels of Orally Administered Antineoplastic

Agents
• High risk, >90% risk of CINV in the absence of antiemetic
prophylaxis-hexamethylmelamine, procarbazine
• Moderate risk, 31-90% risk-bosutinib, cabozantinib, ceritinib,
crizotinib, cyclophosphamide, imatinib, lenvatinib, TAS-102,
temozolamide, vinorelbine
• Low risk, 10-30% risk-afatinib, alectinib, axatinib, capecitabine,
cobimetinib, dabrafenib, dasatinib, etoposide, everolimus,
fludaraine, ibrutinib, idelalisib, ixazomib, lapatinib, lenalidomide,
olaparib, osimertinib, nilotinib, palbociclib, pazopanib, ponatinib,
Panobinostat, regorafenib, sonidegib, sunitinib, tegafur uracil,
th alidomide, trametinib, vandetanib, venotoclax, vorinostat

Chernotherap Ind
Y· uced Nausea and Vomiting 51
 • Minimal risk, <10% risk-busulfan, chlorambucil, eroltinib ..
st1
hydroxyurea, melphalan, methotrexate, pomalidomide r ' ~. t1 ni1
. . . . , uxol1t1nib '
sorafenib, 6-th1oguanine, vermurafenib, vismodegib '

National Cancer Institute Common Terminology Criteria for

Adverse Events v4.03 (NCI-CTCAE): Nausea and Vomiting
• Grade 1-nausea: loss of appetite without alteration in eatin
9
habits; vomiting: 1-2 episodes (separated by 5 minutes) in 24 h
ours
• Grade 2-na~sea: oral int~~e decre~~ed without significant Weig~
loss, dehydration or malnutrition; vomItIng: 3-5 episodes (separate(!
by 5 minutes in 24 hours
• Grade 3-nausea: inadequate oral caloric or fluid intake, tube
feeding, TPN for hospitalization indicated; vomiting: .::6 episodes
(separated by 5 minutes) in 24 hours, tube feeding, TPN or

)
hospitalization indicated
• Grade 4-vomiting: life-threatening consequences, urgent
intervention indicated

• Grade 5-vomiting: death

Prevention and Treatment of Anticipatory Emesis

• Antiemetics should be initiated prior to chemotherapy administratior
• Reassurance and effective use of antiemetic agents to prevent aC1t.,
and delayed effects of CINV can be helpful to minimize anticipatory
emesis.
• Benzodiazepines (lorazepam 1-2mg PO daily or twice daily)
and non-pharmacologic interventions (relaxation techniques,
desensitization, hypnosis) may be useful.

Prevention and Treatment of Acute and Delayed CINV: A

Practical Approach
Selection of anti-emetic agents for prophylaxis should be based on
the highest emetogenic level among the intravenously administered
antineoplastic agents (see above). Note that doses shown below are shown
for general reference only. Individual practice may vary.

d vor111tini c
Chemotherapy-Induced Nausea an
52
 I Regimens for CINV prophylaxis according to ASCO 2017
Tabe,
Guidelines

togenic Neurokinin 1 5HT3 Dexamethasone Olanzapineh Others'

Eme ory antagonist antagonist
risk ca Ieg
• D1 or D1 ·3b • D1° • D1-4dd
High risk: non· • D1-4 0
ACchemo

High risk: AC • D1 or D1·3b • D1° • D1• • D1-4 0

chemo

High risk: • D1 or D1·3b • D1° • D1• 0 0

carboplatin
AUC-1:4

Moderate risk: • • D1 or D1-3' 0 0

Others

Low risk • D1 (either class)g 0 0

0
Minimal risk 0 0 0

Abbreviations: AC, Adriamycin and cyclophosphamide; AUG, area under the curve, 5HT3, serotonin

, solid dots (•) indicate mandatory medication for prophylaxis while open dots (o) indicate optional
medication (e.g. for rescue)

• Approved neurokinin 1 antagonists include aprepitant 125 mg PO day 1 and 80 mg PO day 2 and
3; fosaprepitant 150 mg IV day 1; netupitant-palonosetron 300 mg/0.5 mg PO day 1; and rolapitant
180 mg PO day 1.

c Approved 5HT3 antagonists include granisetron 0.01 mg/kg IV, 2 mg PO, transdermal patch or
10 mg SC day 1; ondansetron 8 mg BID, 3x 8 mg soluble films or 8 mg IV day 1; palonosetron 0.5
mg PO or 0.25 mg IV day 1; dolasetron 100 mg PO day 1; tropisetron 5 mg PO or 5 mg IV day 1;
ramosetron 0.3 mg IV day 1.

dfor high risk non-AC chemotherapy, dexamethasone dose is 12 mg PO or IV day 1, then 8 mg PO

or IV daily days 2-4. However, if rolapitant is used, dexamethasone is given as 20 mg PO or IV day 1
and 8 mg BID days 2-4. If neuokinin 1 antagonist not given, dexamethasone dose is 20 mg PO or IV
day 1, then 8 mg PO BID days 2-4

• for high risk AC chemotherapy or moderate risk carboplatin AUG :!:4, dexamethasone dose is 12 mg
PO or IV day 1. However, if rolapitant is used, dexamethasone is given as 20 mg PO or IV day 1

'for moderate risk (non-carboplatin) chemotherapy, dexamethasone dose is 8 mg PO or IV day 1.

Add 8 mg PO or IV day 2-3 if known risk of delayed CINV (e.g. cyclophosphamide, doxorubicin,
oxaliplatin)

g for low risk chemotherapy, either 5-HT3 antagonists (as dose as footnote C) or dexamethasone 8
mg PO or IV may be given on day 1 as prophylaxis

• for high risk chemotherapy, olanzapine 1o mg PO day 1-4

0th
' er common regimens for breakthrough CINV may include metoclopramide 10 mg PO/IV q 4-6h,
prochlorperazine 5-10 mg PO/IV q4-6h, promethazine 12.5-25 mg PO/IV q4h, dronabinol 5 mg/m2
PO Q2·4h, nabilone 1-2 mg PO BID, and lorazepam 0 .5-2 mg PO/IV q4h

Chernoth
erapy-lnduced Nausea and Vomiting
53
 Palliative Care Pearls
• Prevention is key in the management of CINV. This requires
appropriate identification of emetogenic risk and use of a t·
n i-erner1
prophylaxis. c
• Clinicians tend to underestimate patients' experience of CINV
particularly for the delayed phase. '

• Patients on chemotherapy may have nausea and vomiting from

causes other than CINV. Some important etiologies include bowel
obstruction, hypercalcemia, brain metastasis and opioids.

• In addition to prevention and treatment of CINV, it is important

to assess hydration status, food intake and other common
chemotherapy associated complication s (e.g. mucositis, diarrhea),
and to initiate proper therapies when appropriate.
\
Recommended Reading
Hesketh PJ . Chemotherapy-induced nausea and vomiting . N Engl J Med.
358(23):2482-94, 2008

NCCN Clinical Practice Guidelines in Oncology: Antiemesis. (http://www.

nccn.org/professionals/physician_gls/PDF/antiemesis.pdf)

Roila, F., Herrstedt, J., Aapro, M., Gralla, RJ, Einhorn LH, Ballaton, E. et al.
Guideline update for MASCC and ESMO in the prevention of chem 0th erapY·
and radiotherapy-induced nausea and vomiting: results of the Perugia
243
consensus conference. Annals of Oncology 21 (Supplement 5): v23 2-V '
2010

Hesketh PJ, Kris MG, Basch E, Bohlke K, Barbour SY, Clark-Snow RA, K
PC Jordan '
Danso MA, Dennis K, Dupuis LL, Dusetzina SB, Eng C, Feyer ' . an
· tics· Amenc
Noonan K, Sparacio D, Somerfield MR, Lyman GH. Antieme · . oncol.
Society of Clinical Oncology Clinical Practice Guideline Update.J Clln
2017 Oct 1;35(28):3240-3261

vo"'jlifll
Chemotherapy-induced
Nausea and Ji.
54
 chapter 7 Constipation

Ahsan Azhar MD., FACP.

I constipation may affect 50% of patients w ith advanced cancer and up

to go% of pati~~ts taking opioid~ (opioids induced constipation; OIC).
Unfortunately 1t 1s often underestimated and goes undiagnosed, until it

1 becomes burdensome and causes significant distress. Because of the

variability of normal elimin~tion patterns: co~stipation in an individual patient
should be defined according to that patient s experience. Appropriate

1 management includes evaluation and treatment of potential contributors if

possible, use of laxatives and dietary approaches

Table 1: Rome Ill Diagnostic criteria for Functional

I Constipation*
1 Must include two or more of the following:

a. Straining during at least 25% of defecations

b. Lumpy or hard stools in at least 25% of defecations

ra c. Sensation of incomplete evacuation for at least 25% of

defecations
d. Sensation of anorectal obstruction/ blockage for at least 25%
of defecations
e. Manual maneuvers to facilitate at least 25% of defecations (e.g.,
digital evacuation, support of the pelvic floor)
f. Fewer than three defecations per week
2

i
Loose stools are rarely present without the use of laxatives
3 Insufficient criteria for irritable bowel syndrome
• C~iteria fulfilled for the last 3 months with symptom onset at least 6 months
prior to diagnosis

Constipation
J 55
 Common Causes of Constipation

Appropriate management includes evaluation of the etiology (Figure _)

51
Figure 5-1: Common Causes of Constipation

Opioids Tumor compression/

Neural plexus invasion

I
Other drugs:
Anticholiner-
gics, TCA,
calcium,
aluminum,
anatcids, iron +- Dehydration or
poor oral intake

Autonomic
I t \
failure Metabolic disorders - Immobility
1' Ca, -J, K
or hypothyroidism

Common Complications of Constipation

• Worsening abdominal pain and distention especially in patients wi~

existing pain or retroperitoneal malignancy

• Nausea and/or vomiting

• Anorexia and early satiety

• Overflow (pseudo) diarrhea

• GI obstruction (fecal impaction)

• Hemorrhoids or anal fissures

• Urinary retention

• Confusion/delirium - especially in elderly patients.

• Dyspnea - Abdominal distention limiting diaphragmatic excursio

.n

Diagnosing and Evaluating the Severity of Constipation

. . can bec0~
If not sought after proactively, management of const1pat1on
quite complex and challenging. At worst it can very well be the re
.
Primary .
source of suffering for the patient as distress from seve
constipation may be perceived as greater than pain in cancer
patients

56
Its
 • Obtaining a careful bowel history, including regularity of the bowel
movements, pattern of abdominal discomfort or complaints such as
bloating, nausea or vomiting, tenesmus, or painful bowel movements
is valuable.
• Abdominal examination should include assessment of bowel
sounds, distention, firmness, tenderness, or palpable masses,
which could be tumor or stool. Digital rectal examination may
reveal information about rectal tone, hemorrhoids, painful fissures
or fistulae, scarring or stenosis, an empty rectal vault (which may
indicate proximal impaction), or hard impacted feces.
• Abdominal radiograph can provide an objective assessment of fecal
load by obtaining a constipation score that quantifies the amount
of stool in each quadrant (ascending, transverse, descending colon
and rectum). Each quadrant is assigned a score from 0-3 where
0=no stool, 1= stool occupies less that 50%, 2=stool occupies
>50% but <100% and 3=stool occupies 100% of the lumen. A
score greater than or equal to 7/12 is considered to reflect severe
constipation (see Figure 2).

Constipation
57
 Prevention of Constipation
• Explain to the patient and family the various reaso
ns for co
and discuss general measures used to alleviate it 1n • nstiPaur.
· Part1cui •11
educate the patient about the myth that constipatio . ar,
n is a res I
poor oral intake or anorexia; rather it may be the cau ut of
se of it.
• Encourage adequate fluid intake.

• Avoid excess dietary fiber, which can actually make con t· .

s ipat1on
worse when hydration status is suboptimal, although nat
ural fruit
fiber may be beneficial.

• Be alert to the patient's medication regimen and eliminate

constipating drugs when feasible.

• Prescribe laxatives concomitantly with opioids and titrate the bOWel

regimen to effect.

• A change in the type of opioid may relieve severe constipation.

) Methadone and fentanyl are less constipating than morphine.

Treatment of Established/Ongoing Constipation

There is little evidence to establish guidelines and great variability exists in
choosing the right agent or combination of agents.

• Treating secondary causes like titrating offending agents other

than opioids, correcting electrolyte imbalance and better control of
endocrine issues.
• In patients with opioids use, start a bowel regimen with stimulant
laxatives such as Sennoside 1-2 tablets (up to 4 tablets if not
effective) twice daily as an initial approach.
st
• There is no evidence to support combination of docusate, a ool
softener with sennosides. In fact a study from Canada concluded
that combination was less effective in inducing laxation than
sennoside alone.
• If constipation persists osmotic agents like lactulose, sorbitol
'
or polyethylene glycol (PEG) may be necessary. Compared wi
lactulose, studies have shown polyethylene glycol to be more
effective and better tolerated, however it may be expensive.
. t enerfl8•
• Intractable cases may require a bisacodyl suppos1tor~, ~le~ed tor
1
or milk-and-molasses enema but use of such agents 1s 1tm
,., t.
lpsll•
cons t
58
 acute short term management. Each rescue enema should be
followed by an increase in the oral laxatives.
• Manual digital dis-impaction or endoscopic interventions may
sometimes be necessary. Proximal impaction may require
magnesium citrate.
• Peripherally active mu-opioid receptor antagonists (PAMORAs) such
as methylnaltrexone, naloxegol and naldemedine are approved for
OIC, while use of alvimopan is restricted for postoperative ileus and
only available through a restricted program for short-term in-hospital
use. Great care should be to taken to rule out bowel obstruction
prior to giving these agents, as use may result in perforation of
bowel. The most common side effect is abdominal pain, diarrhea
and nausea. Consideration should be given to cost when prescribing
these agents.
• Agents like Lubiprostone (selective Chloride Channel activator,
increasing intestinal secretions and motility) and Linaclotide
(a synthetic peptide) are also used for treatment of chronic
constipation. However, the usefulness and safety of these in cancer
patients is not clear.
• Acute intestinal pseudo-obstruction (Ogilvie' syndrome) may respond
to a trial of neostigmine. But adverse effects like bradycardia and
increased respiratory secretions are concerning.
• In cases of partial small bowel obstruction, a trial of steroids
should be considered. Laxatives and Metoclopramide may worsen
the condition. If there is no response or the patient develops
complete obstruction, then octreotide or glycopyrrolate and gastric
decompression should be tried.
• Integrative Medicine approaches include use of probiotics,
acupuncture and trans-electrical stimulation (TES). There is
insufficient data to recommend use of these modalities for
management of OIC in cancer patients.

Constipation
59
D
Table 2. Classification, dosages and pharmacological
properties of laxatives
Laxative Onset of Mechanism Usual adult Comments
action (h) dose

Bulk forming agents: 12-24 Hold water in stool 3-4 g/d Patients should
• Natural (psyllium) and cause distension 4-6 g/d be able to
• Synthetic(methylcellulose) increase fluid
intake, other~se
impaction might
occur.

Contact cathartics: 6-10 Stimulates peristalsis variable Additive risk of

• Anthraquinones 2-6 by direct action 65-130 mg hepatotoxicity
• Diphenylmethane on the myenteric 15-60ml when docusate
• Castor oil plexus. Reduces net is used in
absorption of water combination with
and electrolytes other contact
cathartics.

Emollient (lubricant): 6-8 Lubricant and stool 15-45 mUd Might lead to
• Mineral oil softener serious lipoid
pneumonia if
aspiration occura.

Variable, Increase stool 8-25 g/d Might cause

Osmotic agents:
• Polyethylene glycol generally osmolarity leading to 15-30 ml flatulence and
• Lactulose 24-48 accumulation of fluid 15-30ml distension.
• Sorbitol in the colon
30ml Avoid in patien~
• Magnesium hydroxide 0.5-3 Draw fluid into the
200ml with renal or heart
• Magnesium citrate intestine
failure.

24mcg Mainly for chrolt

• Lubiprostone Type-2 chloride
twice daily idiopathic and
channel activator that
IBS-constipation
induces secretion of
OICinnon-
fluid in the intestine cancer patients

Only for chroniC

• Unaclotide Increases chloride 72-290
mcg once idiopathic and
and bicarbonate 1BS-constipati(I(\
secretion into the daily
May cause sevei9
intestinal lumen. diarrhea and
Intestinal fluid dehydration,
increases and GI
transit is accelerated

60
 2-24 Methylated form
hersllY acting One dose Contraindicated
perlP receptor of the mu-opioid (0.15mg/ in Bowel
11-opl~~lsts (PAMORAs): antagonist naltrexone kg) SUBQ Obstruction.
anta~hylnaltrexone that does not cross
• Me every other Cases of Bowel
the blood brain day as perforation
barrier thus blocks needed; do have been
peripheral effects of not exceed reported when
opioids in the GI tract MAX of used in patients
without affecting one dose with pelvic
centrally mediated in a 24-hr masses, bowel
analgesia. period obstruction and
concomitant use
Oral dose- of Bevacizumab
450mg
once daily

Pegylated 12.5- Avoid with

• Naloxegol
(polyethylene glycol- 25mg once grapefruit (or
modified) derivative daily juice). Start with
of naloxone lower dose if GFR
< 60mg/dl

• Naldemedine 0.2mg once Avoid use in

daily severe liver failure

• Alvimopan 12 mg, 30 For short-term

minutes hospital stay
to 5 hours to reduce the
prior to incidence of post-
surgery, operative ileus
followed
by 12 mg Not approved for
twice daily OIC as increased
beginning risk of myocardial
the day infarction in
after patients on
surgery opioids when
until used long term
discharge
for a Extremely
maximum expensive
of 7 days
(maximum
total
treatment:
15 doses
(180mg
total))

Proklnetlc agents: Variable Decrease transit 40-120 For refractory

• Metoclopramide time through upper mg/d constipation.
• Domperidone intestine 30-80 mg/d Might be useful
in colonic inertia
secondary to
spinal cord injury.

Constipation
61
 Stimulant Laxatives: Variable Unclear mechanism, 1-2tab
• Senna 24-48 increase intestinal twice daily Prodrugs th
• Bisacodyl peristalsis and (upto4 get acuvatei\
secretions tabs BID) COion by b n
action B' acteri~
. · 1sac0d)j
might cause
cramping·
. insorn
Patients as 1't e
activated , 9811
. In Sn, U
intestine. a
Surfactant:
• Docusate
24-72 Acts as a detergent 1OO-BOOmg :----..
Not shown to be
to soften the fat
of added benefit
and increase water
penetration hence

--
softening the stools

Palliative Care Pearls

• Constipation can cause significant distress in patients with advance
malignancies and unnecessary suffering along with a heavy cost of
burden on the health care system.

• The multifactorial etiology of constipation leads to underestimation of

the magnitude of suffering and impact on the quality of life for these
patients with advance cancers.
• Constipation may present with atypical symptoms such as
worsening appetite, nausea, abdominal distention, overflow diarrhea
or acute intestinal pseudo-obstruction (Ogilvie's syndrome).
• Opioid induced bowel dysfunction can be prevented by
administration of effective bowel regimen, but this simple therapeutic
intervention is often overlooked.
• Opioids inhibit peristalsis and reduce the GI secretions with
very limited tolerance to this effect, hence causing constipation.
Preventive laxative therapy must be commenced with any opioid
treatment, and failure to do so might result in higher expression
1
5
°
distress secondary to constipation comparative to pain symptorT1 ·
• Psyllium (dietary bulk fiber) should be avoided in patients wi th
suboptimal oral hydration as in those cases it can worsen th8
constipation.
t shown
• Docusate as stool softener is not recommended as has no
added benefits and adds to cost, pill burden and side effects.
. proved bY
• The peripheral opioid antagonist Methylnaltrexone ,s a~ with
. . . . t' in patients
FDA for treatment of op101d induced const1pa ,on . with
advanced illnesses. This drug is contraindicated in patien~s nts at ri#
bowel obstruction and should be used with caution in patie

62
 of GI perforation because of concomitant illnesses or drugs that can
induce perforation.

ended Reading
Reco rnrn
suarez-Almazor M, Velasco A, MacDonald s Hanson J The
sruera E, . . . . , .
ent of const1pat1on 1n terminal cancer patients admitted to a
assessm
palliative care unit: A retrospective review. J Pain Symptom Manage 9(a): 515
_519, 1994.

Mancini I, sruera E. Constipation in advanced cancer patients. Support care

Cancer 6(4):356 - 364, 1998.

Jay R. Thomas. Constipation and Diarrhea. In: Bruera E, Higginson I, Gunten

c, Morita T (Eds). Textbook of Palliative Medicine and Supportive Care. 557-
563, CRC Press, Ed 2, 2015.

Luthra P, Burr NE, Brenner DM, Ford AC. Efficacy of pharmacological

therapies for the treatment of opioid-induced constipation: systematic review
and network meta-analysis. Gut. 2018.

Nee J, Zakari M, Sugarman MA, Whelan J, Hirsch W, Sultan S, et al. Efficacy

of Treatments for Opioid-induced Constipation: A Systematic Review and
Meta-Analysis. Clin Gastroenterol Hepatol. 2018.

Constlpat·
•on
63
h
 Chapter 8 Anorexia and Cachexia /J

~i
Rony Dev, DO and Shalini Dalal,MD

Cachexia is among the most debilitating and potentially life-threatening I:

complication of advanced cancer and in the past was seen as an inevitable
and intractable. Cachexia is characterized by involuntary weight loss, musde
wasting with or without the loss of fat, and is associated with symptoms
of fatigue, immune dysfunction, and a variety of metabolic and hormonal
alterations. Anorexia, defined as the loss of appetite or desire to eat,
frequently accompanies cachexia, and together may be referred to as the
anorexia-cachexia syndrome (ACS).

Anorexia-cachexia syndrome has a high prevalence and consistent

association witjl negative clinical outcomes. Anorexia, cachexia, or both
occur in roughl; 80% - 90% of patients with advanced cancer. Cachectic
cancer patients have a decreased response, experience more side-effects,
and are less likely to tolerate chemotherapy. Patients with cachexia are
also at higher risk of infections, and have decreased survival and quality
of life. The frequency of cachexia is higher in some cancers, such as
.
gastrointestinal . can cer) and 1ung
(pancreatic cancer, esophageal and gastnc
cancers.
·,I
. d rnultifacton,
The etiology of the anorexia cachexia syndrome rs complex an
(see Figure 6-1). Chronic inflammation, marked by an elevated serum h xia.
. protein
C-reactrve . . of pafre nts with cac ed
. levels, are found .rn the maJonty

The complex interactions between the tumor and host resu It ·n I increase e
production of pro-inflammatory cytokines and tumor pro ducts that haVts
d fat) effeC ·
central (poor appetite) and peripheral(wasting of muse 1e an tive
. 1· ·stance, re Ia
Hormonal changes such as low testosterone, rnsu rn resr . d wit~
. I o associate
growth hormone deficiency and ghrelin resistance are as
cancer cachexia and elevated pro-inflammatory cytokines.
severe pain,
Secondary Nutrition Impact Symptoms (dental problems, iting,
. t
altered taste, mouth sores, dry mouth, early satre Y, nausea ' vorn
loriC
constipation, dysphagia and depressed moo d) can decrease ca csct#'
d
Anorex
64
intake and d
a d a 'sta r ,
associated . rva ,on component to the .
. With cachexia. Decreased to d . catabohc process typically
of gast rointesr1. 0 intake
na1 obstruction that m may also be the result
treatment. ay respond to endosc . .
op,c or surgical

Clinical Assessment and 0 . .

iagnos1s
The clinical assessment includes
. a careful history th .
(quantity and composition) Nutr,·t,·on at rs focused on nutrition
' a11mpact s
and body composition, a physical ex ymptoms (NIS), weight
am and any reve 'bl
abnormalities. . rs, e metabolic

Weight loss of ;:: 5% within a 6 month period

appears to be the most
consistent factor used to define cancer cache · Th .
. xra. e rate of weight loss
and an underweight BMI <20 are alternate proposed measures for defining
..
cachexia.

Advanced cancer patients with cachexia may have multiple concurrent

symptoms (NIS) that compromise oral intake, and contribute to nutritional
decline. A multidimensional tool such as the Edmonton symptom
assessment scale (ESAS) can be used to assess for the presence and
severity of common symptoms such as anorexia, nausea, depression and
fatigue. Additional symptoms that affect nutritional intake include early
satiety, constipation, oral disease or mucositis, odynophagia, dry mouth,
dysphagia, and dysgeusia should be also assessed. Many of these NIS can
be managed effectively with inexpensive interventions e.g.Metoclopramide
for early satiety or nausea and laxatives for constipation. The psychological
component of cachexia is also important to consider during the initial
evaluation, since eating meals together is important for social integration,
as well as the goals of individual patients may vary, since for some patients
an improved appetite may be a higher priority than the recovery of muscle
and Physical function. Other patients may have distress revolving arou nd
changes in body image due to weight loss.

Body Composition
Although b0th . · ·h hexia
th muscle and fat are usually depleted in patients wit cac '
elosses Of • that the
bod adipose and muscle tissue may be independent so
Ycomposition in patients with the same BMI could vary considerably.
~ore)ti
a and Cachexia 65
 Most patients reporting weight loss have normal or elevated BMI'
. . sanda
significant proportion of obese cancer patients (20%) are sarcope .
nic With
loss of lean body mass without decrease in fat. Therefore, muscle Wasr 1~
may be under recognized and masked by adipose tissue. Patients Withing
the combination of sarcopenia and obesity have a worse prognosis
, and a
higher risk of chemotherapy related adverse effects.

The least invasive method to assess body composition is with

anthropometry involving measurements of the triceps skin-fold thickness
using calipers (in millimeters), the midarm circumference (in centimeters) and
entering them into the following equation:

Mid-arm Muscle Area = (mid-arm circumference in centimeters) minus pix

tricipital skin fold thickness in millimeters) 2/ (4 x pi) minus a correction fact01
of 10 for men and 6.5 for women.

Bioimpedance analysis (BIA) relies on the different electrical properties of

\ fat and muscle(increased water content).The bioimpedance devices are
relatively easy to use and not burdensome to patients, but may provide
falsely elevated results of muscle mass when patients have edema.
Additional information such as the ratio of resistance and reactance (phase
angle) provided by BIA may also be useful for prognostication.

osition
DEXA scans are based on the three component model of body comp
DEXA uses two X-ray energies to measure body fat, muscle, and bone_ .
. • e pos1t1on
mineral. DEXA is more burdensome to patients (must be 1n supin
while image is taken) than BIA and more expensive. The results m~Y b~ as
viewed as whole body estimates of body fat, muscle, and bone minera
well as regional body estimates.
witn
I. t'
CT scan is expensive and not practical for many pal ia ive care patient 5
d tor
. t' ely evaluate
cachexia. However for those patients who are being rou in . between
· usefuI to distinguish. sue 111·q)'
the purpose of re -staging and follow-up, CT 1s
.
muscle and adipose tissue. Especially . obese pat1en
1n . t s, adipose tis

mask profound underlying muscle loss (sarcopenia).

Management h ,i:icl
0
nt of anorexia cac
There is no standard treatment for the manageme e are
syndrome. As mentioned previously, the causes O
f this
-
syndrom
~c,c" 'I
Anorexia ao
66
 rnultifactorial, and therefore a multidimensional approach is often needed
address multiple areas including the managem t f
to . . . en o symptoms that
1 ntribute to cachex1a, appetite stimulation nut ·t· • •
co . , n 1ona1 counseling, exercise
an d counseling. Treatment should be individualized t k' .
.. , a Ing into account
patients overall cond1t1on and goals of care.

1 Symptom management: Treatment of ACS should b . . h

. ~rn~
identification a~d ~anagement of Nutritional Impact Symptoms (NIS) that
could be contributing to decreased nutritional intake For . t
,1 • ins ance, early
satiety is the most common gastrointestinal symptom in cachectic patients
and can be treated effectively with metoclopramide (10mg every hours
4
orally). Metoclopramide enables the stomach to accommodate and improves
gastric motility. Constipation may also contribute to early satiety, and can
easily be treated with titration of laxatives such as senna or polyethylene
glycol. Depressed mood can also lead to decreased oral intake, and should
be managed with counseling, and antidepressants if indicated. Mirtazapine
and olanzapine may be useful agents for both depression and nausea. Like
metoclopramide, mirtazapine has 5HT4 agonist activity which promotes
gastric emptying and intestinal secretions. For patients complaining of taste
alterations, zinc supplementation has objectively improved dysgeusia in a
study of patients with advanced cancer and is warranted in patients with
dysgeusia, since this supplement has few side-effects.

2. Appetite Stimulation: Progestational agents (such as megesterol

acetate) or corticosteroids may be helpful in improving appetite in some
patients. Unfortunately the weight gain due to progestational agents
appears to be predominantly fat or fluid, rather than lean body mass. The
major drawback of these agents is their side-effects. Megestrol acetate has
been shown to improve appetite, fatigue and general well being in 60% of
patients. The usual starting dose is 160mg/day, titrating slowly upwards,
to a maximum of 800mg/day. Common side-effects include hypertension,
hyperglycemia, fluid retention, thrombosis, and low testosterone in male
patients. The risk for thromboembolism appears to be dose dependent and
is diminished at doses <48omg /day. If patients are started on megesterol
and there is no benefit, the dose should be gradually decreased, as th ere
is a risk of precipitating adrenal insufficiency. Megesterol should absolutely
be avoided in patients with a history of deep venous thrombosis, pulmonary
embolism, or severe cardiac disease.

Anore Xia
· and Cachexia

L
Corticosteroids may stimulate appetite and decrease nausea as Well.
effects of corticosteroids on appetite and food intake are usually lirn•t The
. I 0dto
couple of weeks and the side effects of these drugs increase drarn t· a
, . a 1ca1,
over time. Therefore, corticosteroids should generally be reserved for Y

patients with limited life-expectancy (less than 6 weeks). There is no

established dose for corticosteroids. In studies, doses of prednisone .
. rang1n
9
from 20mg-40mg, or dexamethasone at an equivalent dosage have been
used.

cannabinoids: Dronabinol, a synthetic cannabinoid, is approved for use in

anorexia related to AIDS and chemotherapy-induced nausea and emesis. In
cancer patients with anorexia, a large multi-center trial showed no benefit of
dronabinol or cannabis extract over placebo. Further, the use of dronabinol
is also limited by undesirable central nervous side-effects at higher doses I

such as sedation, confusion and perceptual disturbances. These side-

effects are especially of concern in advanced cancer patients, as they are
also at risk for delirium. As regards combination therapy, a large trial showed
no clinical benefit when dronabinol was added to megestrol acetate.

Anamorelin (a synthetic analogue of Ghrelin, agnostic hormone) has been

found to improve lean body mass but, unfortunately, no functional outcomes
as compared to placebo in 2 randomized, controlled studies against
placebo. One concern about this drug is that it stimulates the release of IGF·
1 and this product has been associated with tumor growth in some studies
and more research is needed.

Enobosarm is a selective muscle androgen receptor modulator. In recent

th
studies it has been found to improve lean body mass and muscle streng
in advanced cancer patients. Other selective androgen modulators are
undergoing clinical trials.

3. Immune modulation Preliminary studies using NSAID's such as

ibuprofen and celecoxib have shown lowered C-RP levels and increase nd
I'd0 rnide a
lean body mass. Non-specific immune modulators such as tha 1 c&
d ca0
melatonin may improve multiple symptoms associated with advance bodY
·
· and poor appetite. Thalidomide has 1ncre
·incIud'1ng ·insomnia ased. leanhigh cos1
mass in one placebo controlled trial but its history of teratogencitY, ·on•
, . fgat1
1
and potential for side-effects at high doses, may limit further inves

68
 20mg of melato . d'd
a ran domized, placebo-control led trial ' nin , not show
1
n rnent in weight in cancer patients.
improve

Multimodal interventions Although single-agent therapies under

~vestigation sue~ as myostatin inhibitors, and specific proinflammatory
cytokine antibodies, ma~ yet p~ove ~o. be effective, ultimately, a multimodality
approach is always required, since rt is unlikely that any single intervention
will consistently improve outcomes.

A comprehensive multimodality intervention that includes a combination

of pharmacological agents, exercise, nutrition and symptom management,
is likely to be the most effective therapeutic approach to cachexia. A
number of active trials are evaluating pharmacologica l agents such as
thalidomide, L-carnitine, non-steroidal anti-inflammator ies and beta blockers
in combination with nutritional counseling and caloric supplementation.
In addition the correction Qf hormone and vitamin deficiencies (e.g.
testosterone and vitamin D) will enhance the likelihood of muscle gain and
functional improvement.

5. Nutrition and Counseling: Families of patients who are able to eat

00
should be advised that frequent small meals may be more tolerable than
three large meals daily. A nutritionist can help assess the patient's nutritional
d status and advise regarding dietary options to maximize caloric intake.
Studies of nutritional counseling in patients with cancer do show potential
improvement in caloric intake but failed to show improvements in clinical
outcomes

Patients with a predominant starvation component due to obstructive

gastrointestinal tumors or painful mucositis as a result of head and neck
cancer treatment may benefit from artificial nutritional support.

The use of Artificial Nutritional Support

:f As a general principle patients should feed via the simplest method. While
th0
r} gastrointestinal tract is working, oral intake is preferable, a nd th e goal
should be Weight maintenance or reduction of weight loss. Multiple trials
f
, o oral f1Utritional supplementation in cancer have revealed no benefit in
l~I terrns of weight
· · S
gain, body composition or functional outcomes. peer re
'f
oral nutritional supplements may be useful, although their benefit needs to

Anorexia and Cachexia

I 69
be confirmed in large randomized trials. Small preliminary trials u .
. . . . sing elth
specific amino acid comb1nat1ons (HMS, arginine, glutamine) or L- .. er
carn1t1ne
have shown gains in lean body mass.

Enteral feeds may be considered if intake is either inadequate or not

. . Possibl
orally. Tubes can be passed via the nose into the stomach or proximal e

small intestine, or inserted through the abdominal wall into the stomach or
intestine. Nasogastric tubes are often irritating to patients and are usually
used only in the short term, while gastrostomy tubes may result in leaka
99 0!
gastric contents and perforation. In addition, both NG and gastrostomy tube
feeds can increase the risk for aspiration, interfere with social functioning
and although blenderised home-prepared food can be given, the risks of
tube blockage and contamination are increased. Patients with head and
neck, esophageal cancer, or severe mucositis may benefit from enteral tube
feeds. Ultimately, the projected life expectancy (usually >6 weeks) and qua!~
of life should justify the risks and complications of tube insertion.

D
Although both enteral and parenteral feeding may have a role in patients
with cancer, very careful patient selection is required and more importantly,
good communication with patient and their carers is mandatory, so that they
understand the benefits vs. burdens.

Intravenous feeding (parenteral nutrition) should only be considered when

the gastrointestinal tract is either inaccessible or not functioning, or feeding
requirements cannot be met with eating and/or enteral tube feeding. It
should be noted that systematic reviews suggest parenteral nutrition
is harmful when provided to cancer patients undergoing radiation or
chemotherapy so when considering PN in patients with advanced disease
the following citeria should be considered.
· of
1. There should be a clear nutritional risk along with the diagnosis
cancer (e.g. intestinal obstruction or fistula)
. I st 6-12
2. Patients should have an estimated life expectancy of at ea
weeks
3. They should have a reasonable quality of life with a KarnofskY
performance score of >50 (100 normal - 10 moribund)
4. They should be medlcally stable
. ·tabilitY
5. Psychosocial factors should be considered to assess sui N
• · ter P
6. Patients and carers should be able to learn how to adrnini5

70 Anore"ia a11 ::J I

d c11cll'
 >
I
.
fons are potentially lit-threatening and include catheter related
cornPlica i • • • •
. d thromboembohsm, deficiencies or excesses of electrolyte, trace
1 sepsis an
1ernen,t
.
vitamin or minerals and
.
hepatic
. .
comphcat1ons such as cholestasis,
I\ e , and rarely, cirrhosis.
i steatos1s
' arY artificial nutritional support via the enteral (PEG tube or
\ In sumrn , . .
tric tube) or parenteral (PN) routes is inappropriate for most patients
nasogas .
. advanced cancer and in the case of PN may hinder the transition to
with .. I
. Artificial nutntiona support (AN S) does not enhance response
hospice. , ..
. neoplastic therapy or s1grnf1cantly abate its toxicity and clinical
to ant1- • • •
outcomes such as survival or quality of hfe. ANS is also expensive, may be
associated with serious side effects (e.g., septicemia, electrolyte and glucose
imbalances), and is uncomfortable for patients and families to maintain at
home. compassionate communication is required to address the benefits
and burdens of nutrition and to reframe the condition from that of "starving
to death" to the more complex condition of irreversible cancer induced
Jlli metabolic abnormalities which impair the normal utilization of nutrition even
J when adequate calories are provided.

Palliative Care Pearls

• Clarify for patients and family that anorexia is a result of the cachexia
syndrome rather than the root cause of weight loss. Understanding
this concept will decrease patient-family conflict and diminish
1.l resentment towards health care-providers who may be perceived
to be neglecting the problem. Families will be less likely to pressure
patients into eating (resulting in nausea and psychological distress).
• Explain that aggressive enteral or parenteral nutrition will not have a
significant impact on well-being or survival.
• Encourage the eating of favorite foods for the comfort and
enjoyment, as their nutritional value may be of limited importance
towards the end of life.
• Explain potential complications of PN and their lack of benefit for the
vast majority of patients. This will help the patient and family make
an informed decision about their use.
• A comprehensive multimodality approach to cachexia is essential,
and should include general measures such as nutritional counseling,
exercise, and symptom control plus multiple specific pharmacologic
agents directed at the mechanisms of cachexia.
iii~·
1r

AnoreXi
a and Cachexia
I 71
Recommended Reading:
. T Artificial nutritional support. In: Egidio Del Fabbro E
sowIIng • , duard0
Wendy oemark-Wahnefried, Tim Bowling, Jane B· Hopk'Inson
Bruera, ..
. k'e E. Baracos. Eds. NutntIon and the Cancer Patient. Oxto d · and
Vic I r . Oxford
University Press, 2010.

Bruera E. Pharmacological treatment of cachexia: Any progress? 8

' UPPort
Care Cancer 6(2):109 - 113, 1998.

Del Fabbro E, Dalal S, Bruera E.Symptom control in palliative care--Partll:

cachexia/anorexia and fatigue.J Palliat Med. 9(2):409-421, 2006 .

MacDonald N, Alexander R, Bruera E. Cachexia-anorexia-asthenia. J Pain

Symptom Manage 10(2):151 - 155, 1995.

Del Fabbro. Multimodality therapy for cachexia In: Egidio Del Fabbro,
Eduardo Bruera, Wendy Demark-Wahnefried, Tim Bowling, Jane B.
Hopkinson, and Vickie E. Baracos. Eds. Nutrition and the Cancer Patient.
Oxford. Oxford University Press, 2010.

Dev R, Wong A, Hui D, Burera E. The Evolving Approach to Managementol

Cancer Cachexia. Oncology 2017;31(1):23-32.

;ii
c ac11e
. 8 r,d
72 A,1ore}(J8
 products
rumor
(Eg:
tNL••F
IYI I
PIF)

+
INR.At.NATION
tProlnflammatory Cytokines NEUROENDOCRINE
+ ALTeRATION8
(t IL-1~, IL-6, TNF-a) ~--•
and I ( such as changes in
testosterone, cortisol, growth
other Inflammatory mediators
hormone, ghrelln levels)

+
COMMON MANIFESTATIONS OF CACHEXIA SYNDROME
FltLOII Muscle Loaa Llvar Slcknea1 Behaviors
tUpolysis jProteolysis j Acute phase !Appetite ,
!Protein synthesis protein response Fatigue, Depression
t CRP

Figure 1. Hypothetical model for th• pathogeneala of cancer cachexlL

Al>breviationa : CRP C-rnctio protein; IL interleukin; LMF lipid mobilizing factor ; PIF prot1olysi1 inducing
factor ; TNF
tumor n,croaia factor

Anore..ia
and Cachexia
73
Chapter 9 Delirium and Palliative
Sedation

Maxine de la Cruz, M.D.

Delirium is the most common neuropsychiatric condition that occu .

rs 1n
about 26-44% of advanced cancer patients admitted to an acute care
hospital and over 80% of patients with advanced cancer at the end of life
Delirium is often missed and underdiagnosed resulting in misinterpretatio~ 1

of symptoms, inappropriate medical interventions, distress and conflict

among patient and care providers. Universal screening for at risk patients
is recommended. Delirium is reversible in about 30-50% of cases, and has
been shown to be associated with increasing morbidity and mortality in
patients with advanced cancer. Education of medical staff and families is
important in the care of patients with delirium along with treating possible
medical causes and controlling distressing psychomotor symptoms.

Clinical Presentation
The diagnosis of delirium is based on the DSM-V-TR criteria:

• Disturbance of consciousness (i.e. reduced clarity of awareness

of the environment) with reduced ability to focus, sustain, or shift
attention.
r,
• A change in cognition (such as disorientation and language .
disturbance) or the development of a perceptual disturbance th81 '.'.
not better accounted for by a preexisting dementia.
• The disturbance develops over a short period of time (usually hours
to days) and tends to fluctuate during the course of the day.
• It results from an underlying medical conditi~n, sub st~nce frorn the
intoxication or withdrawal, or multiple etiologies as evident
medical history.

datiol l;
1rati\18
1 se
74 Delirium and pa
 ....---
t~ 1
''
l'nical subtypes of dehnum have been described:
Three c 1
• Hyperactive: confusion + ~gitation ± hallucinations ± delusions
± rnyoclonus ± hyperalgesia (may be mistaken for psychosis or
extrapyramidal side effects of medications)
• Hypoactive: confusion + somnolence ± withdrawal (may simulate
depression)
• Mixed: alternating symptoms of both hyperactive and hypoactive
delirium. This is the most common subtype in advance cancer
~, patients.

!~ Screening for high risk patients is recommended. Different assessment tools

have been developed for use in different clinical settings. Examples include
Memorial Delirium Assessment Scale (MDAS), Confusion Assessment
Method (CAM), and Delirium Rating Scale (DRS). Studies have shown
that most of the major assessment tools are equally effective in diagnosis
,ai delirium so the key is in its appropriate use.
~r.
111
The use of screening tools also assists clinicians in differentiating delirium
'- from other conditions that may present similarly such as depression, anxiety,
insomnia, dementia, or increased expression of certain symptoms such
as pain.

Causes of Delirium
(Figure 9-1) shows the most frequent causes of delirium in cancer patients.
Medication side effects (particularly opioids) are the most common cause
in the presence of dehydration and
1 of delirium in cancer patients especially
renal failure. Infection is another common cause of delirium particularly in
neut~openic patients. The etiology of delirium is often multifactorial and a
!
J specific cause often remains unidentified. However, this should not deter the
clinicians from looking for underlying causes as many cases of delirium are
.~ reversible if identified and treated.

Delirium
J and Palliative Sedation
75
 Fig ur e 9.1
causes of Delirium in Canc
er Patients
Medications
e.g . op ioid s
ant ich olin erg ics
cor tico ste roi ds Inf ect ion
ant ide pre ssa nts e.g . pn eu mo nia ElectrolYte
uri na ry tra ct '
Other Medical Conditions
e.g.w1
'thd wa l
ra
syndromes (alcohol,
ben zod iaz e~i nes
neu role pt1 cs
\
;nferon imb
h alance e.g
ypercalcernia·
hyp ona tre rnia '
medication, nicotine), --
nutritional deficiencies,
coagulopathy, anemia
-- --
I . - Dehydration
Side effects of __ ., De lir iu m
______
Ch em ot he r% ay o
or Radiation ... __ rgan failure
/ \
therapy e.g. hepatic,
\ renal
Hy po xem ia lnt rac ran ial
Endocrine Paran;oplastic
disease syn romes
e.g.hypogly~~mia,
hypothyro1d1sm e.g . pri ma ry and
me tas tat ic brain
tum or, lep tom e-
nin gea l disease,
or stroke

Ma na ge me nt of Delirium
St ep 1: Assessment.

• Maintain a high index of su

sp ici on . As k family me mb
about new symptoms espe ers or nurses
cially at nig ht tim es
• Use screening tools su ch as
-M DA S (See Ap pe nd ix B), nd
DRS. These screening too ls CAM, a
sh ou ld be us ed even in pa th
overt signs of delirium to ma tients wi no
ke an ea rly dia gn os is.
• Ask the patient specifically
ab ou t ha llu cin ati on s (they
tactile than visual) an d delus are more otten
ional tho ug hts . Patients fre
do not volunteer information quent!~ f
ab ou t the se sy mp tom s. Dia 0
delirium can still ma de even gnosis
if the se sy mp tom s ar e no
t present.
• Look for clinical signs of se
psis, op ioi d toxicity, dehy
metabolic abnormalities, or drat'.~n,
oth er po ten tia l ca us es of
dehnurn.
• Order appropriate lab ora tor d coun,t
y tests, su ch as a co mp let
electrolytes, calcium (with e ~l~~irT1agin9
albumin) renal an d liver fun
teSt s such as ch es t x-ray or
0ther tests as ind
bra in CT cti o ' . 11 or
or MRI, an d 02 saturatio
icated.

76 c111t!O"j
Delirium and pa l nati"e se
 • Non-pharmacological Treatment
steP 2.
• Ensure physically safe environment and minimize noise and
excessive light.
• Ensure presence of familiar objects, and a visible clock and calendar.
Enlist family to assist with patient re-orientation.

Step 3: Pharmacologic treatment of symptoms.

• Agitation/hallucinations: Antipsychotics are the recommended

medications for the treatment of delirium symptoms. Haloperidol
remains the gold standard and is shown to be effective in majority of
patients with delirium. Starting dose for haloperidol is 1-2 mg poise/
iv q6h and 1-2 mg q2h poise/iv prn. For severe agitation, haloperidol
may need to be given more frequently initially (e.g. 1-2 mg q30 min
sc/iv prn during the first hour and q1h prn thereafter). Note: the oral
bioavailability of haloperidol is approximately 60-70% and this should
be taken into account when converting from the oral to parenteral
route and vice versa. It is important to bring agitated delirium under
control as rapidly as possible to prevent patient, family, and staff
distress or injuries. Once symptoms are under control, start reducing
the dose to the minimal effective dose.
• Other antipsychotics such as chlorpromazine may be used
if adequate doses of haloperidol is ineffective or there are
contraindications for its use. It is generally more sedating and may
be given as a·scheduled and as needed regimen. Starting dose is
usually 12mg IV Q6H and 25mg IV O2H as needed for agitation.
Atypical antipsychotics, such as olanzapine, risperidone and
quetiapine, can also be used in the treatment of delirium.
• Benzodiazepines are not recommended except in cases where
delirium is secondary to alcohol withdrawal, or if contraindication to
antipsychotic use is present such as seizures, extrapyramidal side
effects, or severe arrhythmia. In such cases consultation to palliative
care, psychiatry or neurology specialists is recommended.
Slep 4: Treatment of underlying medical condition.

• Opioid toxicity: rotate opioids (see Chapters on Pain Management).

• Sepsis: start appropriate antibiotics after discussing treatment
options with the patient and the patient's family.
• 0ther Drugs: discontinue all possible implicated medications,
especially benzodiazepines, anticholinergics, corticosteroids,

I Delirium nd
Ir a Palliative Sedation 77
 antidepressants, certain antiemetics and antivirals, antibiotics
(quinolones), cimetidine and ranitidine.
• Dehydration: start intravenous or subcutaneous hydration as soo
as possible. In the home or hospice settings, hypodermoclysis Wi~
normal saline at 60 - 100 ml/hour, or alternatively give boluses of
500
cc administered over 1 hour, three or four times daily.
• Hypercalcemia: treat with hydration with saline and
bisphosphonates.
• Hypoxia: treat the underlying cause and administer oxygen.
• Brain tumor or metastasis: consider high-dose corticosteroids.

Step 5: Education of family and medical staff.

• Confusion and agitation are expressions of brain malfunction and not

necessarily of discomfort or suffering. Disinhibition is one of the main
components of delirium and may result in two possibly distressing
phenomena:
• Dramatic expression of previously well-controlled physical
symptoms by grimacing or moaning: Family or staff may interpret
this as aggravation of symptoms rather than merely increased
expression. In addition to observer distress, this can lead to the
patient's excessive use of opioids and/or adjuvant drugs and the
accompanying potential for exacerbation of delirium.
• Unreasonable requests of family or staff (e.g., "I want to go home
now."): If these requests are not immediately addressed, the patient
may become hostile. Unless appropriately explained to the patient's
family, this disinhibited behavior may be quite distressing to them.
• Our own research showed that up to 75% of patients have recall
of their own symptoms after delirium resolution and significant
associated distress. Hypoactive delirium is as distressing for patients
as hyperactive delirium.

A simple clinical algorithm for assessing and treating delirium is shown in

Figure 9-2.

edlltiO~
Delirium and Palliative 5
78
_..a1
figure 9-2
.. Assessment and Treatment Algorithm
oe11nurn
Sere~~ (using MD~S _or other instrument), if
pos1t1ve, apply criteria to diagnose delirium

Hyperactive Hypoac tive No further action

or Mixed - consid er but continue
treatm ent with observation
low dose
Manage hyperactive haloperido/
symptoms
(with haloperidol or Reassess
alternative neuroleptic).

Assess patient for and treat any reversible causes:

• Perform approp riate laborat ory tests
• Review drug regime n and change opioid
or other medica tion if indicate d
• Evaluate for cerebral causes
• Determine hydrati on status
• Review environ ment

Counsel and educate:

• Patient
• Family
• Staff

Reassess

Refrac tory delirium

- consider the addition of
midazolam and palliative
sedation

Palliative Sedat·10n .in

Refractory De 1·mum
.
• Palliative sedation (PS) is defined as "the monitored use of sedative
medication to reduce patients' awareness of intracta~le 8nd .
refractory symptoms near the end of life when other interventions
have failed to control them". .

Deliriun, a
nd Palliative Sedation
79
h
 symptom specific measures
• Clinicians should attempt all available
re labeling a symptom as
including consultation of specialists befo
refractory.
mon Indication for PS.
• Refractory delirium is the most com
ing symptoms and not to hasten
• The goal of PS is to control distress
ned if possible. PS should
death. Consciousness should be maintai
Death or Euthanasia.
be differentiated from Physician Assisted
discussed with the patient (if
• Reasons and goals of PS should be
nted in the medical records.
possible) and/ or the family, and docume
Use the lowest dose possible
• Midazolam is the drug of first choice.
tinuous sc or IV infusion of
to provide comfort, e.g. commence a con
ng to clinical response.
midazolam at 1mg/hour and titrate accordi
n or sedation such as the
Use tools to monitor the degree of agitatio
- (Appendix F) to guide
Richmond Agitation Sedation Scale (RASS)
therapy.
e PS and consider reducing it
• Regularly reassess the need to continu
roved.
or discontinuing if indication for PS has imp

Updates in Delirium
ition of lorazepam to
• In a recent study by Hui et. al, the add
reduction in agitation at 8
haloperidol resulted in significantly greater
hours, than haloperidol alone
in RASS score in agitated
• Minimal clinically important difference
delirium patients is > 4
re is increased symptom
• Screening for delirium is important: The
e percent of patients
expression in patients with delirium. Sixty-on
care specialist were
with a diagnosis of delirium by a palliative
missed by the primary referring team.

Palliative Care Pearls

• Because delirium is common in pall
iative care patients, routine
screening is recommended.
family and bedside nurses to
• Take a good peripheral history from
sorium.
check for fluctuating cognition and sen
be incorrectly diagnosed
• When delirium is missed, patients may
insomnia resulting in
to have depression, dementia, anxiety, and
symptoms.
appropriate management and worsening

e<f11do'1
Delirium and Paliiali~
80
r , High symptom e~pr~s~ion may ~e misinterpreted for worsening
symptoms resulting. in inappropriate medical interventions and
onflict among family and staff. Drugs that could be causing or
:ggravating delirium should be discontinued.
, Intractable delirium may herald impending death.

' mended Rea d"mg

Reco m
sruera E Bush SH, Willey J, Paraskevopoulos T, Li Z Palmer JL Cohen MZ
I
I I I
. ·nd O Elsayem A. Impact of delirium and recall on the level of distres
s,ves1 , s
in patients with advanced cancer and their family caregivers. Cancer 2009
May 1; 115(9):2004-12.

Pereira J, Hanson J, Bruera E. The frequency and clinical course of cognit

ive
impairment in patients with terminal cancer. Cancer 79(4):835 - 842, 1997.

Centeno c, Sanz A, Bruera E. Delirium in advanced cancer patients. Palliat

Med 18(3):184 - 94, 2004.

Lawlor PG, Gagnon B, Mancini IL, Pereira JL, Hanson J, Suarez-Almazor

ME, et al. Occurrence, causes, and outcome of delirium in patients with
G advanced cancer: a prospective study. Arch Intern Med 160(6):786 - 94,
2000.

• Hui D, Bush SH, Gallo LE, Palmer JL, Yennurajalingam S, Bruera E.

Neuroleptic dose in the management of delirium in patients with advanced
cancer. J Pain Symptom Manage. 201 OFeb:39(2):186-96.

Elsayem A, Curry Iii E, Boohene J, Munsell MF, Calderon B, Hung F, et al.

Use of palliative sedation for intractable symptoms in the palliative care unit
of a comprehensive cancer center. Support Care Cancer May 7, 2008.

Delirium and
Palliative Sedation
81
Chapter 10 Fatigue

Sriram Yennu, M.D. M.S.

Fatigue, or the physical or mental or psychological exhaustion resulting

from exertion, is transient in most of us. For patients with advanced cancer
I

however, fatigue may be a severe, chronic, subjective symptom that

decreases their capacity for physical and mental work and persists despite
rest.

In the context of the other symptoms that impact the advanced cancer
patient, the burden of fatigue results in lack of energy, malaise, lethargy, and
diminished mental, physical and psychosocial functioning that profoundly

) impairs the patient's quality of life. Patients may experience fatigue early
in the course of their disease and may even have treatment-related
exacerbations of the problem. Virtually all patients with advanced cancer will
experience fatigue, especially more severe and debilitating as the disease
progresses towards end stage. The presence of fatigue may also magnify
other symptoms affecting the patient. Despite its frequency, severity and its
effect on quality of life fatigue is underdiagnosed and undertreated.

As with other symptoms in patients with advanced cancer, the causes of

.
fatigue are multifactorial. These include problems related to t he can
. . . . I d' ders such
and/or its treatment, underlying systemic pathophys1olog1ca isor
as inflammation, and other causes (Figure 8-1).

82
 •1• underlying causes of Fatigue in patients with advanced cancer
Figure 8

Cachexia Mood
Deconditioning
Disorders

Renal/Hepatic/
\ I Inflammation/
Cytokines
Heart Disease
Fatigue
Bioimmunotherapy/
Cancer related
Chemotherapy/ ___,,...-- ;f
symptoms

t
Radiotherapy /

Dehydration Anemia
Infection Tumor
Byproducts

1 Assessment of Fatigue
t The severity of fatigue can be measured on a scale of O - 1O (where o equals
U no fatigue and 10 equals the worst fatigue imaginable) (e.g. as measured by
Edmonton symptom assessment scale) or by other numeric or verbal rating
scales. The best assessment of fatigue is multidimensional and considers

j ::::~;:~::i~:s 8
~~e ::~:~:~~~~~::·: ; : r~~:::f:~~:~~~: :~eir0

j impact upon the patient. Certainly, underlying cancer factors and treatments
must be considered, as must other systemic pathophysiological problems
and psychological distress. Laboratory investigations and imaging studies
should be based on indications derived from the patient history and physical
findings.

Management of Fatigue
As with other problematic symptoms in advanced cancer patients,
management of fatigue should address possible underlying etiologies as
well as the patient's expression of symptoms. Always, attempt should be
made to treat the underlying cause. However if the underlying cause cannot
be corrected or identified symptomatic treatment should be considered as
outlined below:

Fatigue
83
b
 Step 1: Treat underlying problems.

• Pain: (See Chapter 3, Pain Management.)

• • d' turbances: (See Chapter 12
• Depression, anxiety, stress, or seep
1 1s ,
Depression and Chapter 13, Anxiety).
• Dehydration: (See Chapter 10, Hydration).
• Anorexia/cachexia: (See Chapter 6, Anorexia and Cachexia).
• Polypharmacy: Simplify medication regimens.
• Infection: Give appropriate antibiotics.
. f ked red blood cells or administer epoetin
• Anemia: Trans use pac .' .
alpha 10,000 U sc three times weekly as indicated.
• Immobility: Prescribe activity as tolerated.
• Endocrine: Treat Hypogonadism in males, Vitamin D deficiency,
Thyroid disorders if possible.
Step 2: Always consider non-Pharmacological measures such as physical
activity/exercise (endurance or aerobic or brisk walking), exposure to
sunlight in mornings (approximately for 30 min), Yoga and cognitive
behavioral therapy.

Step 3: Administer pharmacological agents.

• Corticosteroids: There is reliable evidence that corticosteroids such

as dexamethasone (4 - 8 mg bid) given for short duration (1-3 weeks)
may mitigate fatigue in advanced cancer patients. Evidence points
towards its benefit in patients with predominant physical fatigue.
• Psychostimulants: Psychostimulants (e.g., methylphenidate 5 - 10
mg in the morning and 5 - 10 mg at noon) may be beneficial in
the treatment of fatigue related to concurrent problems such as
depression, anxiety or drowsiness due to opioids.
• Antidepressants: SSRls may improve energy levels in some fatigued
patients, though their benefit is unproven.

Multimodal Therapy for treatment of fatigue:

In many instances due to the multidimensional nature of fatigue it may not
be possible to relieve fatigue by a single medication or non-pharmacological
intervention. In those instances an attempt to combine one or more
treatments with no adverse interactions may be considered. For example:
Exercise when combined with methylphenidate may potentially Increase
f•t1gll'
84
 >
t of both these interventions in improving fatigue, fitness levels and
theeffec .
overall function.
therebY
\'
palliative care Pearls
• Fatigue is the most common and chronic symptom in patients who
have advanced cancer.
• Treatment of fatigue in advanced cancer patients will likely be more
difficult than in patients with earlier stage disease.
• Patients and their families should be educated about the burden of
fatigue that accompanies advancing cancer, advised to make efforts
to modify activities and rest, and advised to optimize nutrition and
hydration as early as possible.
• Aggressive treatment of concurrent symptoms and interdisciplinary
approach in management of fatigue by medications such as short
course of corticosteroids, methylphenidate in fatigue patients with
drowsiness or depression, exercise and cognitive behavioral therapy
may be effective in the mitigation of fatigue.
• Physical activity or exercise as tolerated is the best evidenced based
treatment to date.

Recommended Reading
Sriram Yennurajalingam, MD; Eduardo Bruera, MD Palliative Management of
Fatigue at the Close of Life: "It Feels Like My Body Is Just Worn Out" JAMA
I 2007; 297:295-304.

Yennurajalingam S, Frisbee-Hume S, Palmer JL, Delgado-Guay MO, Bull J,

Phan AT, Tannir NM, Litton JK, Reddy A, Hui D, Dalal S, Massie L, Reddy
SK, Bruera E. Reduction of Cancer-related Fatigue with Dexamethasone:
I A Double-blind, Randomized, Placebo-controlled Trial in Patients with
Advanced Cancer. J Clin Oncol 31(25):3076-3082, 9/2013.

Yennurajalingam S, Bruera E. Review of Clinical Trials of Pharmacologic

Interventions for Cancer-Related Fatigue: Focus on Psychostimulants and
Steroids. Cancer J 20(5):319-24, Sep-Oct, 9/2014.

Fatigue
85
Chapter 11 Dyspnea

David Hui, MD, MSc, MSc

Introduction
Dyspnea is defined by the American Thoracic Society as "a subjective
experience of breathing discomfort that consists of qualitatively distinct
sensations that vary in intensity." Many terms have been used by patients to
describe dyspnea, such as chest tightness, heavy breathing, hunger for air
smothering or suffocating feeling. '

Dyspnea is a one of the most distressing symptoms, and is particularly

common in in patients with advanced diseases. Its prevalence ranges from

D
10% to 79% in patients with advanced cancer, 90-95% in patients with
chronic obstructive pulmonary disease, and 60 to 88% in patients with heart
failure.

Dyspnea is associated with fatigue, depressed mood, reduced functional

status, decreased quality of life and increased mortality. Similar to pain,
dyspnea can be classified as persistent dyspnea or breakthrough dyspnea.
According to a recent Delphi study, breakthrough (or episodic) dyspnea
is "characterized by a severe worsening of breathlessness intensity or
unpleasantness beyond usual fluctuations in the patient's perception.
Episodes are time-limited (seconds to hours) and occur intermittently, wilhOf
without underlying continuous breathless." These episodes may be triggered
by exertion, emotions, comorbidities and/or external environment. Among
patients with advanced cancer, approximately 20% have persistent dyspnea
only, 60% have breakthrough dyspnea, and 20% have both.

_A
Mech anism
b classifitj\l
Dyspnea is often multifactorial in nature. Comm on causes can e
as follows:
ncer (e.9·
1. Direct involvement of the respira tory system by the ca ttusion),
airway obstruction, lymphangitic carcinomatosis, pleural e "
D)'SP~

86
 Acute respiratory ~omplications (e.g. pos
tobstructive pneumonia,
2. pulmonary embolism)

complications of cancer treatments (e.g.

bleomycin induced .
3. pulmonary fibrosis, radiation induced
pneumonitis, pneumonectomy)
4_ comorbid conditions (e.g. chronic obstructive pulmonary disease,
heart failure, cachexia, anemia)

Th0 above pathologic pro~es~es can resu

lt in various abnormalities, such
as hypoxemia, hypercaprna, airway pressu
re alterations, and increase
in chest wall muscle effort. These are detecte
d by chemoreceptors,
rnechanorceptors, J receptors, irritant rece
ptors, baroreceptors and
chest wall receptors throughout the body,
resulting in activation of
afferent pathways, ultimately resulting in the
perception of dyspnea in
the somatosensory cortex. Importantly, the
sensation of dyspnea may
be modulated by many factors such as emo
tional distress, activation of
trigeminal nerve and opioids.

Assessment of Dyspnea
By definition, the gold standard for diagnos
ing dyspnea is the patient's
self-report. Multiple studies have demonstrat
ed that objective measures of
physiologic changes such as tachypnea, tach
ycardia, decreased oxygen
saturation, pulmonary function test abnorm
alities only have low correlations
with the intensity of dyspnea.

Assessment of persistent and breakthrough

dyspnea should include the
following :

1. Intensity and unpleasantness of dyspne

a, using validated patient
reported outcomes
2. Duration and progression
3. Functional impact
4. Treatment history
5· Associated sym
ptoms, such as fatigue, cough, weight loss
6· Modulat
ing factors, such as emotional distress
7· Pote
ntial etiologic factors
There
are numerous patient reported outcomes ·
to assess the intens1·ty of
dyspnea in different patient populations and
with different time frames. For
r
Dy8Pnea

L 87
 <
instance, the Edmonton Symptom Assessment Scale examines the average ,
intensity of dyspnea over the past 24 hours with an 11-point numeric rating
scale, where 0=no dyspnea and 10=worst possible. The Cancer Dyspnea
Scale is a validated questionnaire that examines a patient's dyspnea over
the past few days. It consists of 12 items with choices that range from 1
I
(not all all) to 5 (very much). It has 3 subscales (sense of effort, sense of
anxiety and sense of discomfort) and a total scale. A higher score denotes /
greater dyspnea.

i
'>
Management of Dyspnea
,i
Management of dyspnea includes the following: (1) treat any underlying v·

cause(s), (2) palliative measures to reduce the sensation of dyspnea, and (3) (
manage any modulating factors. i:

)
~1
Effective treatment of reversible conditions, such as pneumonia, pulmonary
embolism, COPD exacerbation, heart failure exacerbation, airway
1:
obstruction amenable to stenting, could potentially reduce dyspnea.
Importantly, it often takes time for the conditions to improve, and thus 11'.

palliative measures are often necessary even if only on a temporary basis. lJ1
iY

!·
Palliative measures include pharmacology and non-
pharmacologic measures.
• Multiple randomized controlled trials have demonstrated that
systemic opioids help relieve dyspnea as compared to control,
without inducing respiratory depression when dosed properly. t,,
'·
Opioids may reduce dyspnea by decreasing the neuromechanical
dissociation in the respiratory center, modulating the sensitivity of
chemoreceptors, increasing peripheral vasodilation, and reducing ;,
1
anxiety, Although morphine has been studied mostly, all opioids
are believed to be similarly effective at equianalgesic doses. The \
starting doses of long and short acting opioids can be similar to pain t
management (e.g. morphine sulfate 15 mg PO q12h, and morphine
sulfate 7.5 mg PO q2h PRN dyspnea). For patients already using :
1
opioids for pain control and still experiencing significant dyspnea, d '
they should be instructed to use.the opioids for dyspnea as well, an 'i'
to increase the long acting opioids (e.g. by 30%). ,i,
• Corticosteroids have been used to reduce inflammation, and case
reports have demonstrated its benefit in patients with central airwaY

88
 obstruction and lymphangitic carcinomatosis. A common dose is
dexarnethasone 4-8 mg PO BID x?-14 days.

• sronchodilator~ ~ay be helpfu~ in patients with evidence of

bronchoconstnct1on or underlying obstructive airway disease.
• The effect of benzodiazepin~s on dyspnea has been mixed and
.1nconclusive. Because
d of. their
. . potential for excessive sedation ,
·ncreased falls an prec1p1tat1ng delirium, they should be avoided in
~eneral except in rare cases In which dyspnea remains refractory
despite maximal conventional measures.

• Indwelling pleural catheter and pleurodesis are equally effective in

reducing dyspnea in patients with large volume malignant pleural
effusion.
, Low flow supplemental oxygen (up to 5 L/min) have been found to
reduce the intensity of dyspnea in patients with hypoxemia but not
those who were not hypoxemic.
• Non-invasive ventilation such as bi-level airway pressure (BiPAP)
has been demonstrated to relieve dyspnea in cancer patients,
particularly among those with hypercapnia.
• High flow oxygen delivery device can provide up to 60 L/min of
humidified oxygen via nasal cannula, and may reduce shortness of
breath in addition to oxygenation.
• Heliox, a mixture of oxygen and helium, has been shown to
decrease dyspnea in cancer and COPD patients.
• A portable fan directed to face could potentially reduce dyspnea by
stimulating the trigeminal nerves.
• Specialized multidisciplinary dyspnea clinics address breathlessness
in a multidimensional fashion.
• For patients with good performance status and COPD, pulmonary
rehabilitation has been found to improve dyspnea .. It typically
consists of patient education, physical recondition, upper extremities
exercises and lower extremities exercises.
• Other non-pharmacologic measures include acupuncture, chest wall
.vibration, and self-management interventions.
• Psychological interventions are needed for patients with significant
anxiety and/or depression.
• In hospitalized patients with severe refractory dyspnea despite
maximal supportive measures above, palliative sedation may be

Dyapnea

89
 considered in selected individuals after careful discussion with
patients, caregivers and healthcare team to relieve suffering.

Palliative Care Pearls

• Dyspnea is a subjective experience of breathing discomfort that
consists of qualitatively distinct sensations that vary in intensity.
Objectives findings such as tachypnea, decreased saturation,
decreased FEV1 only have weak association with dyspnea intensity.
i". I
,\\
• A careful history on dyspnea should inquire about the type
(persistent and/or episodic), triggers/modulators, timing/duration anc
\
I
I
I.
I,
,I treatments and troubles/impact.
JI
111 • Management of dyspnea includes (1) treat any underlying cause(s},
11 \ij (2) palliative measures to reduce the sensation of dyspnea, and (3)
I
reduce any exacerbating factors.
if I
I
I I;

:1, • Palliative measures should be personalized when possible:

I . supplemental oxygen for patients with hypoxemia, bronchodilators
1,j for patients with bronchoconstriction, corticosteroids for patients
with inflammation, thoracentesis for patients with moderate/large
effusions, non-invasive ventilation for patients with hypercapneic
respiratory failure or respiratory muscle fatigue.
• Non-pharmacologic therapies include fan to face, acupuncture,
chest wall vibration, and self-management interventions may also be
considered.
• Dyspnea is often associated with anxiety/depression, which
may in turn increase the expression of dyspnea. Thus, attention
to the psychological aspect of care is essential part of dyspnea
management.

Recommended Reading
Barnes H, McDonald J, Smallwood N, Manser R. Opioids for the palliation
I

H
of refractory breathlessness in adults with advanced disease and terminal
.I
illness. Cochrane Database Syst Rev 2016;3:Cd011008.

Bausewein C, Booth S, Gysels M, Higginson IJ. Non-pharmacological

interventions for breathlessness in advanced stages of malignant and non-
23
malignant diseases. Cochrane Database Syst Rev. 2008 ;( 2):CD0056 ·
DOI: 10.1002/14651858.CD005623.pub2.

90
L
\ K Frisbee-Hume S, Park M, Tsao A, Delgado Guay M et
\ f(lgore
1 , . '
Ht.Ji D, sone for Dyspnea in Cancer Patients: A Pilot Double-Blind
rnetha . . ,
al. oe)(a. controlled Tnal. J Pain Symptom Manage 2016;52(1):8-16.
dorn1zed,
Ran .
I ado M, Chisholm G, Withers L, Nguyen Q, Finch c, et al. High-
. D Morg .. .
Ht.JI , en and bilevel pos1t1ve airway pressure for persistent dyspnea in
floW o)(YQ . h dvanced cancer: a phase II randomized trial. J Pain Symptom
. ts wit a
pat1en 2013;46(4):463-73.
Manage
MJ Hui o, currow DC. Opioids, Exertion, and Dyspnea: A Review
Johnson_d 'ce Arn J Hosp Palliat Care 2016;33(2):194-200.
of the EvI en .

all MB, Schwartzstein RM, Adams L, Banzett RB, Manning HL,

parsh tt· . I A . Th . S .
sourbeau J, et al. An o Ic1a mencan oracIc oc1ety statement: update
on themechanisms, assessment, and management of dyspnea. Am J
. Grit care Med 2012;185(4):435-52.
RespIr

Simon ST, Higginson IJ, Booth S, Harding R, Weingartner V, Bausewein

C. Benzodiazepines for the relief of breathlessness in advanced malignant
and non-malignant diseases in adults. Cochrane Database Syst Rev
2016;1 O:Cd007354.

Dyspnea
91
,
Chapter 12 Hydration

Paul Walker, M.D.

Whether to use parenteral hydration as a standard practice in the hospice/

palliative care setting remains uncertain. Usual hospital care mandates that
all patients be routinely hydrated. Conversely, traditional hospice models
have promoted the concept of not administering parenteral fluid during the
terminal phase of incurable illness. Arguments have been put forward to
support both approaches in the management of the terminally ill.

A Cochrane Review (2014) found an insufficient number of good quality

studies on this question and that a significant benefit was not able to be
shown for hydration. Included in this review was a well conducted but under-
powered study that was not able to show hydration of 1 liter (L) per day to
improved symptoms, quality of life or survival (Bruera, 2013).

In individual patients it is important to remember that dehydration may cause

problems that exacerbate patient suffering, such as confusion and renal
failure, resulting in accumulation of active drug metabolites. Accumulation of
opioid metabolites in particular can cause sedation, confusion, restlessness,
myoclonus, seizures, and even hyperalgesia. Hydration is a recognized
treatment for patients exhibiting opioid toxicity and can also reduce the risk
of patients developing toxicity especially if they are on high opioid doses.
One study found less overall symptoms, less sedation and l~ss myoclonus in
hydrated patients (Bruera, 2005). Patients with malignant bowel obstruction
I or other conditions that may limit oral fluid intake can prematurely deteriorate
from dehydration leading to delirium. Hydration in these patients can restore
cognition and quality of life.
111
1

1:lii Contrary to these considerations, one study found that fluid retention
,,I symptoms related to pleural effusion, ascites and peripheral edema may be
higher in hydrated patients (Morita, 2005). It appears prudent to consider
the patient's on-going problems, weighing the risks and benefits when
considering whether to hydrate.

Hydration
92
 . . it can be important to consider the symbolic and cultural
In add1t1on, tion as it may be seen as representing care, hope and trust.
value of hydraf the roll of hydration with patients and families can ascertain
551·ons o
oisCLl lues and wishes about hydration.
·r beliefs, va
th01

nt of Dehydration
Assess me .
• symptoms of dehydration include the following:
, Fatigue
, constipation
• Dry mouth/thirst (this is more frequently due to opioids,
other drugs, and oral complications of cancer rather than
dehydration).
, Physical examination may reveal the following signs of dehydration:
• Confusion
• Postural hypotension
• Poor skin turgor
• Decreased jugular venous pressure
• Dry mucous membranes.
• Laboratory evaluation may reveal the following:
• Decreased urine sodium
• Elevated hematocrit reflecting hemoconcentration
• Hypernatremia
• Elevated BUN and normal creatinine in early dehydration
• Elevated BUN and elevated creatinine indicating
deterioration in renal function in late dehydration.
• Evaluation of fluid intake and output will reveal the diminished output
typical of hypovolemia.

Decision-Making Regarding Hydration

• Consider the symptoms of dehydration in your patient. In some
cases, the relationship between a given symptom (i.e., fatigue or
confusion) and dehydration can only be established through a short
th erapeutic trial of hydration.

Hydration

93
 <
• Consider the disadvantages of hydration· issues of c
. , · are at horn
or 1n rural areas, cost, worsening of pre-existing congestive e
failure, etc. heart

• Choose the most effective and simplest hydration system, and

measure the expected outcome.
• If no improvement is observed, or if the patient or family feel
that the toxicity or discomfort is worse than the potential be~efit,
discontinue the treatment.

Methods of Hydration

When the decision is made to hydrate the patient, various options are
available. Patients able to take fluids orally should do so, as this is the
preferred route. However, patients who are unable to maintain oral fluid
intake should receive parenteral hydration. Patients with patent IV lines can
be hydrated by that route unless it becomes problematic. Then, the preferred
route becomes subcutaneous administration of fluids, i.e., hypodermoclysis
or "clysis."

Fluids may be administered via clysis either as a bolus or continuous

infusion. Advantages of clysis include the following:
I I

• Easy site access

• Suitability for administration at home by the patient or family because
of its ease of use and safety
• Ability to use these sites for up to 7 days
• Easy stoppage of clysis infusion and disconnection to facilitate
patient mobility
• Freedom of limbs and freedom from IV poles or pumps when clysis
is administered via daily boluses.
Hypodermoclysis can be initiated to fit varying clinical situations, including
the following:

• Rehydration
Fluid type: normal saline
Rate: 70-100 ml/hour via continuous infusion

94
 . aintenance or augmentation
f/utd m .d d t .
• . type: two th1r s ex rose and one third normal saline or 5%
Fluid e and ½ normal saline
dextros . ,
. 40 _80 mUhour (continuous infusion),
Rate. Lb . .
1000 m gra~ity overnight (overnight clysis), or 500
ml bolus bid, with each bolus infused over 1 hour (bolus
clysis).

idase may facilitate fluid absorption, but it is not necessary in most

HyaIuron d . . t fl 'd b
. to effectively a minis er u1 su cutaneously. If significant amounts
Patients .f . ·t .
. k from the sc 1n us1on s1 e consider starting a new site at a different
of fluid lea
· 10cation.

ongo,•ng Reassessment of Treatment

The patient's clinical status should be routinely monitored and infusion
volumes adjusted as needed to prevent overhydration. Fluid volumes of 1-1.5
Uday are usually sufficient to maintain adequate urine output and normal
laboratory values in these patients. The assessment measures mentioned
above should be used.

If at end stage it becomes appropriate to discontinue hydration, medication

regimens, especially opioids, may need to be adjusted to preclude
accumulation of metabolites.

Palliative Care Pearls

• The decision to hydrate a patient should be individualized based on
that patient's specific problems and assessment of the risks and
benefits.
• If hydrating a patient, the volume of hydration should be titrated
frequently while attending to the clinical response rather than using a
cookbook approach.
• Terminally ill patients generally require less fluid than less gravely ill
patients do.
• Edema is not a good indicator of hydration status in patients with
advanced cancer. Edema more often is a result of tumor blockage
of lymph nodes accompanied by impaired venous or lymphatic
drainage or of cachexia-related hypoalbuminemia.

Hydration
95
 • Thirst or dry mouth is not a reliable indicator of dehydration. It c
be controlled with frequent sips of water, ice chips, and good 0 :~
hygiene.

Recommended Reading
Cochrane Database Syst Rev. 2014 Apr 23; 4 Medically assisted hydration
for adult palliative care patients. Good P, Richard R, Syrmis W, Jenkins-
Marsh S, Stephens J.

Bruera E, Hui D, Dalal S, Torres-Vigil I, Trumble J, Roosth J, et al. Parenteral

Hydration in Patients with Advanced Cancer: A multicenter, double-blind,
placebo-controlled randomized trial. J Clin Oncol 2013; 21(1):111·8.

Bruera E, Sala R, Rico MA, Moyano J, Centeno C, Willey J, Palmer JL.

Effects of Parenteral Hydration in Terminally Ill Cancer Patients: A Preliminary
Study. J Clin Oncol 2005; 23:2366·71.

Morita T, Hyodo I , Yoshimi T, lkenaga M, Tamura Y, Yoshizawa A, et al.

Association between hydration volume and symptoms in terminally ill cancer
patients with abdominal malignancies. Annals of Oncology 2005; 16:640-7.

Hui D, Dev R, Bruera E. The last days of life: symptom burden and impact
on nutrition and hydration in cancer patients. Curr Opin Support Palliat Care.
2015;9:346·54.

96
 t r 13 Hypercalcemia
·1

~·
~1chaP e
,,, Iker, M,D.
paul ,,a

~
\
ia of malignancy and hyperparathyroidism account for more
ercalce rn . .
HYP a1. f cases of hypercalcem1a. Although the list of other possible
t han 90?o o . .
,~ t of hypercalcem1a 1s long they are much rarer (e.g. excessive
causes . . . b'I' . 1· .
. nd vitamin D 1ngest1on, 1mmo 11zat1on, 1th1um, thiazide diuretics,
I calc1urn a
· . t·de paget's disease, MEN 1, 2A, sarcoid and other granulomatous
tenpara 1 , • • •

11, . s' Hypercalcem1a 1s a common metabolic emergency in advanced

disease .,.
r Specifically, it occurs in 20-30% -% of cancers although most
, cance.
ly in cancers of the breast, lung and kidney as well as multiple
frequent
myelorna (Table 11-1). Although hypercalcemia in a small number of cases
ijl may be due to direct bone destruction in metastatic disease mediated

1 by cytokines (most usually in breast cancer), in most cases, it is due to

11
1~ production of PTHrP, a parathyroid hormone peptide analog, produced
by the tumor. This is a paraneoplastic process that causes increased
1
~ osteoclast activity, resulting in bone resorption liberating calcium into the
circulation, as well as increased renal calcium resorption .. The onset of
symptoms associated with hypercalcemia may be insidious, but as the
tumor progresses, the symptoms may become more severe and difficult to
manage. Hypercalcemia is reliably associated with low survival and it has
been proposed as a marker for palliative care referral.

Table 11-1
Malignancies associated with hypercalcemia
Tumor Incidence(%)
Lung 25-35
Breast 20-25

Hematologic 14
·Myeloma 10
·Lymphoma · ' ;:
3
·, ,.,

Head and neck 6-8

97
 Renal/bladder (Renal) 8

Esophagus 6

Cervix/uterine 5

Unknown Primary 5-7

Prostate 3

Colon 2

Hepatobiliary 2

Skin 1

Other 6-7

Clinical Presentation
The clinical features of hypercalcemia (Table 11-2) are nonspecific, and
require the clinician to keep a high index of suspicion to perform the
appropriate tests and make the diagnosis. The severity of the symptoms
is related to the rate of increase in serum calcium as well as the serum
calcium level. Due to the relatively rapid elevation in serum calcium seen in
malignancy, the symptoms of cramping, abdominal pains, acute pancreatitis,
and peptic ulceration that occur with the more chronically elevated calcium
levels of primary hyperparathyroidism are rarely seen.

Table 11-2
Clinical Findings in Hypercalcemia of Malignancy

• Anorexia
• Nausea and vomiting
• Constipation or ileus
• Polyuria
• Dehydration
• Fatigue and weakness
• Confusion
• Coma

·a
98 Hypercaicel!l'
 nosis
oiag . . highly protein-bound. The unbound (ionized) serum .
a1c1urn is . . .
serum c will fluctuate with changes 1n the serum protein concentration.
calc·urn level t · · ' d ca Ic1um,
. wh'1ch makes up
1

• ally active componen 1s ionize

iolog1c
The phys 1 45%of the total plasma calcium. The total serum calcium level
Proximate Y 1· . I
ap f
alone is there o .re of limited use for c 1nica purposes.

. calculation of the corrected serum calcium level is performed

c1ass1cally
. aformula such as the following: Ca (corrected)= Ca (measured)+
u~n~ (4-serum albumin)] Conventional units [e.g., mg/di]. Alternatively, direct
m
[O.Seasure ment of ionized calcium, can be performed in many institutions and
now is the preferred test.

Table 11-3
Hypercalcemia: Treatment Modalities

, Parenteral fluid rehydration (iv or sc)

With normal1saline 1-3 L/day or more
• Bisphosphonates
Pamidronate 90 mg iv over 2 hour.
lbandronate 4 mg iv over 2 hour.
Zoledronate 4-8 mg IV over 5-30 minutes. (Drug of choice)
• Corticosteroids
Dexamethasone 6-16 mg/day
Prednisone 40-1 oo mg/day
' Calcitonin 4-8 IU/kg sc q 6-12 h

For Patients Refractory to Bisphosphonates consider:

• Denosumab 120
thereafter mg sc on days 1, 8, 15, and 29 and every 4 weeks

Treatment

Although the median . .

treatment ca survival is approximately 1 month in these Patients
n~~mefued ,
st
eva ating symptom complex caused by

99
,..,,
hypercalcemia. This improves comfort and quality of life and provides the
patient time to complete unfinished business.

Management of hypercalcemia is based on treating the severe fluid Volume

depletion by administering parenteral fluid. Normal saline is the preferred
fluid. One to three liters a day may be administered depending on the
patient's cardiac status and ability to tolerate a rapid volume increase.
Hydration alone may correct mild hypercalcemia.

Treatment with a bisphosphonate reduces osteoclast mediated bone

resorption and is usually required if the patient is symptomatic or the
corrected serum calcium level is> 12 mg/dl Zoledronate is the drug of
choice .. Four milligrams of zoledronate may be used initially, with 8 mg
administered in relapsed and refractory cases. Alternative bisphosphonates
are pamidronate and ibandronate. Premedication with acetaminophen 500·
650 mg po prevents the fever, myalgia, and leukopenia that occur following
initial administration of these aminobisphosphonates. Careful prehydration
and slow administration should be considered if renal impairment is present

In urgent, life threatening situations, it is advisable to coadminister calcitonin

I/1I ·'II
I with a bisphosphonate to achieve a more rapid effect. Calcitonin is the
II,\
1
most rapid agent in lowering the serum calcium levels, although it is
less efficacious than bisphosphonates and is subject to tachyphylaxis
within 2-3 days. Is is usually administered administered intramuscularly or
subcutaneously every 12 hours. Nasal administration of calcitonin is not
efficacious for treatment of hypercalcemia.

In steroid-responsive malignancies such as myeloma lymphoma that may

rod
P uce 1, 25 dihydroxyvitamin D,corticosteroids such as dexamethasone or
prednisone are indicated.

Administration of medications that can contribute to hypercalcemia, such as

vitamin D and thiazide diuretics, should be stopped. Use of teriparatide is
contraindicated in hypercalcemia.

Monitoring the serum calcium level every 1-2 days initially, together wi! h
creatinine, BUN, electrolytes, and magnesium is appropriate.

lireatment of hypercalcemia does not provide a cure but rather ternporarilYe

. ted bon
reduces the calcium level through the inhibition of osteoclast-me dia

e,,,la
100 Hypercalc
I . periodic monitoring is appropriate, and repeat treatments may be
resorption,. approximately 10% - 20% of patients, hypercalcemia is resistant
.ed. n ·t t'
reau1r ent. In these s1 ua ions, an alternate bisphosphonate may b
~ern e
!\ tO (118 n
tried,
b, which is marketed to prevent skeletal related events from bone
05urna
oentastases like bisphosphonates, .
has also been found to be effective .
in
rTle rnia of malignancy. It 1s a human antibody against RANKL d
ercalce . .. . an
hYP hrough inhib1t1on of osteoclast maturation, activation and function.
works t ff t' . .
nshown to be an e ec 1ve option 1n patients that are refractory
II h8S bee
. h sphonates. In one study, 64% of bisphosphonate refractory
to b1SP 0
. who denosumab lowered serum calcium within 1odays with
patients,
responses . Concern has been raised that the study dosage of
, durable
· mg sc on days 1, 8, 15 and 29 and every 4 weeks thereafter may have
120
an increased risk (5-13%) of severe hypocalcemia especially in patients
with renal dysfunction or vitamin D deficiency Some patients have needed
correction of resulting severe hypocalcemia with administration of calcium
supplementation. Despite this concern denosumab has been recommended
if bisphosphonates are contraindicated due to severe renal impairment.

Palliative Care Pearls

• Therapy decisions should be based on the corrected serum calcium,
or preferably the ionized calcium concentration, as well as the
presence of symptoms.
• Because the clinical features of hypercalcemia are often difficult to
distinguish from those of the underlying malignancy, a high index of
suspicion is necessary.
• Parenteral hydration and bisphosphonate administration are the
mainstays of therapy Denosumab can be effective in refractory
cases.
• Hypercalcemia is associated with short expected survival in most
patients and therefore palliative care referral should be considered.

Recommended Reading
~ajor P, Lortholary A, Hon J, Abdi E, Mills G, Menssen HD, Yunus_ F, Bell
' Body J, Ouebe-Fehling E, Seaman JJ. Zoledronic acid is superior to
Parnidronate in the treatment of hypercalcemia of malignancy: a pooled

liYpercaicemia
101
r
i I analysis of two randomized, controlled clinical trials. J Clin Oncol 19:558-
567, 2002.

Hu Ml, Glezerman IG, Leboulleux S, lnsoga K, Gucalp R, Misiorowski W,

I
I Yu B, Zorsky P, Tosi D, Bessudo A, Jaccard A, Tonini G, Ying W, Braun A,
Jain RK. Denosumab for Treatment of Hypercalcemia of Malignancy. J Ciin
I Endocrinol Metab 99: 3144-3152, 2014

Tsuda M lshiguro H Yano I Toi M . RE: Denosumab for Patients With

Persistent or Relapsed Hypercalcemia of Malignancy Despite Recent
Bisphosphonate Treatment . J Natl Cancer Inst . 2014 ; 106 (7):dju137

Adhikaree J, Newby Y, Sundar S. Denosumab should be the treatment of

choice for bisphosphonate refractory hypercalcaemia of malignancy. BMJ
Case Rep. 2014 Jan 30;2014.

Wagner J, Arora S. Oncologic Metabolic Emergencies. Hematol Oncol Clin

North Am. 2017 Dec;31(6):941-957.

102
 chapter 14 Depression

armack, Ph.D., Sujin Ann-Yi Ph D

CindY L C ' · ·,
duardo Bruera, M.D.
and E

I The diagnosis of cancer can have a profound effect on an individual's

sychological wellbeing. Depressed mood, sadness, grief, and anticipatory
p t ' '
i feelings of loss are no uncommon in patients diagnosed with cancer. The
majority of patients adapt well to their illness using previously established
coping strategies including support from their family and friends, as well
as their spiritual or religious faith. Healthcare providers can decrease the
t psychological burden of cancer with empathetic care and an emphasis
on preventing unnecessary suffering. Patients who are at the end-of-
life often need additional support to manage uncontrolled physical and
psychological symptoms. Psychological distress, including depression, may
require a collaborative approach to care including palITative care physicians,
psychiatrists, psychologists and other mental health professionals.

Almost twenty-five percent of palliative care patients experience some

degree of depression, with roughly 14.3% experiencing a Diagnostic and
Statistical Manual (DSM)-defined major depression. Identifying clinical
depression in cancer patients can be challenging for healthcare providers.
The DSM-5 diagnostic criteria for major depressive disorder incorporates
the presence of somatic symptoms, including fatigue, poor appetite and a
change in the quality and quantity of sleep. However, somatic symptoms
may be present in patients secondary to the burden of cancer, so it is
important to carefully assess their cause. For example, cancer patients may
take frequent rest breaks and nap one to two times per day due to high
Physical symptom burden including pain and fatigue. Those with clinical
depression, however, may use sleep as an "escape" and may spend very
little time awake or out of bed during the day.

~s such, it is imperative to assess cognitive dimensions of depression,

1nclud· . · demora1·izat'ion,·
ing persistent sad or depressed mood; anhedonia;

Depress·ion
103
[
 feelings of hopelessness, helplessness or guilt; social withdrawal; and
suicidal ideation.
.
• Cancer patients may experience fluctuations in mood where they l
are able to note some happiness during the day. Clinical depression.;'
on the other hand, is characterized by a depressed mood where the'
person notes persistent feelings of sadness that tends to last all day 11
and occurs on a daily basis. f
• Anhedonia needs to be carefully assessed because many cancer f
patients have significant functional decline that restricts their ability t,;
to participate in previously enjoyable activities. However, anhedonia ,
characterized by the loss of interest and pleasure in previously joyful ,..
activities and relationships with family and friends may be a useful
marker for clinical depression. Additionally, patients may note a lack
of willingness to do activities that are within their physical ability or ,.
no desire to attempt to creatively modify activities to fit their physical "
capabilities.
• Cancer patients may endorse demoralization, a sense of having
lost meaning and purpose in their lives, particularly if they have
experienced changes in functional status that result in limited ability ~;
to engage in important roles or responsibilities. Demoralization can
lead to clinical depression if cancer patients are unable to adjust and ::
establish new sources of meaning. ::;,
• Cancer patients without clinical depression may lose hope for a t1
111
cure but are able to transfer hope for symptom management and a
·1//II
1// /il/l.i good quality-of-life. Patients with clinical depression lose hope for ~.
11ri11,. I any facet of their life to improve and may feel helpless in their ability \
),;/I 11
to control any aspect of their lives. They may express guilt over their I~
11,ji',I;/
disease cause or the effect it has on their loved ones.
,1!.l:1·1:
,,I .
•1J1,
1 • Cancer patients may have occasions where they feel like being
, I alone, particularly when they are experiencing high symptom
burden. Those with clinical depression however, isolate themselves
and may keep their concerns and feelings to themselves.
• Cancer patients may have frequent thoughts of death given the
th81
1; I gravity of their illness. Those with clinical depression may feel
I
I
I
I they would be better off dead and may express suicidal ideation.
,I ,I
I,

Approach to Depression in Patients with Cancer

A thorough diagnostic interview is critical for assessing whether patients d
are clinically depressed, are having an adjustment disorder with d~press;d.
mood, or are adjusting appropriately with some minor fluctuations in mo
oepresslo'1
104
t1
\ . tervieW, attention to feelings of persistent feelings of sadness
the1n ,
ouring . hopelessnes s, helplessness, worthlessness, guilt, and suicidal
donia, .
! anhe_ (even mild or passive) are needed to identify patients with major
ideation . The threshold for depression and anxiety using the Edmonton
I ress1on. .
\ deP torn Assessment Scale is very low. Patients with a score of ;?: 2/10 on
'· syrnP I should be screened further.
either scae
, . nt Questions in Diagnostic Interview for Assessing Depression
1_pert1ne
' • current psychologic~~ symptoms, n~ting the frequency, intensity and
\ duration of the cognitive and somatic symptoms of depression.
• Also assess for anxiety symptoms. Research indicates higher
symptom expression and poorer quality of life in those with
, comorbid depression and anxiety.
11
• Previous history of clinical depression.
1. "Have you ever taken an antidepressant or any other
medications for anxiety or your nerves?" (noting not all
patients know what an anti-depressant is and have different
ways of describing mental health issues).
2. "Have you ever seen a psychiatrist, psychologist or a
counselor?"
• Past history of alcohol or drug use/abuse

• Assess family history of psychiatric illnesses

2. Assessment of Patient Safety is Pertinent in Every Palliative Care

Consultation

• Directly ask the patient if he or she has contemplated suicide

a. "Have you had thoughts about suicide or taking your own
life?" Do not assume all patients know the meaning of the
word "suicide." It is important that the definition be included
in an assessment.
b. If yes, when is the last time he/she had such thoughts? Has
the patient ever acted on these thoughts in the past?
c. If recent suicidal ideation, is there a current plan to act on
these thoughts?
d. Is the patient able to verbalize reasons for living or not
harming him/herself?

Depression
105
3. Minimize Medications Contributing to Depressed Mood

• Steroids
• Anticonvulsants
• Alpha interferon, interleukin-2

• Sedatives/tranquilizers

• Beta-blockers
4. Rule Out Medical Co-morbidities Resulting in Depression

• Thyroid dysfunction
• Poorly controlled pain
• Hypogonadism
• Hypoactive Delirium, Hypercalcemia

5. Psychotherapy

• Allow the patient time to express fears and end-of-life concerns. If

family members interfere with emotional expression, consider a split
counseling session.
• Listen to how patients speak, paying close attention to the presence
of ruminative thoughts indicating inadequate cognitive and emotional
processing.
• Referral to Supportive Care Psychology may be needed for
additional assessment and/or more intensive counseling. Patients
may require specialized empirically based techniques, such as
cognitive-behavioral therapy, which are provided by psychologists.
• Support groups may be helpful. Make specific referrals and give
contact information. Social workers may be able to assist with
setting up these services.

6. Pharmacological Interventions

In conjunction with supportive psychotherapy, antidepressant medications

are critical component in the treatment of clinical depression in cancer
patients. Antidepressants usually are selected depending on the patient's
presenting symptoms.

• Tricyclic antidepressants are sedating and may be beneficial tor

selected patients with agitation and insomnia. Their effectiveness_g
can be determined with plasma levels. Side effects may be troublirl '

·o~
oepressi
106
 sionally serious including hypotension arrhythmias and
dOCC a . '
an . ation. Tricychcs are also lethal in overdose.
const1p
'Ve serotonin reuptake inhibitors (SSRls) are the newest
seleCtI f 'd
• d't·on to the range o anti epressants and have fewer troubling
11
ad
side effects as compare d to th . e tnc~chc
· · antidepressants.
· Side
rnaY include nausea, insomnia, headaches and sexual
effects
dysfunction.
d generation antidepressants have qualities in addition to their
, seco n . . .
antidepressant effect that may be benef1c1al to patients. Venlafaxine
. mall doses (25-37.5mg/day) has been used successfully to
insntrol hot flashes. M'1rtazap1ne
. (7.5-15mg/day) has been shown
co stimulate appetite · an dbecause of its· sedating quality has been
to 'd f . .
useful as a sleep a1 or insomnia.
, Psychostimulants, such as methylphenidate have also been effective
in treating depression. One of the benefits of using methylphenidate
is that there is not waiting period to become effective.
, compared to healthy individuals cancer patients usually respond to
lower doses of antidepressant therapy.
, Starting doses for some commonly used antidepressants:
• Amitriptyline 25 mg/day (hs)
• Sertraline 25 mg/day
• Fluoxetine 1Omg/day
• Mirtazapine 15 mg/day (hs)
• Methylphenidate 5 mg in the morning and 5 mg at noon

Bereavement
Bereavement is the normal emotional response to the loss of a loved
one and its expression varies markedly across different cultural groups.
Bereavement is a personal experience and often proportional to the strength
and quality of the attachment with the deceased. Healthcare providers
should be able to recognize individuals at risk for complicated bereavement
and offer preventive interventions and referral.

Risk Factor for Complicated Bereavement

• Sudden or unexpected death

• Trauma associated with the disease (severe cachexia, painful death)
• stigmatized issues (AIDS, suicide)
Depression
107
b
 • History of maladaptive coping (alcohol or drug abuse)

• History of psychiatric disorder

• Dysfunctional families (unhealthy attachment styles)

• Poor social or financial support

Palliative Care Pearls

I I,
Most patients are resilient and cope with the psychological burden of having
I cancer.
' I 'I I

I '.ii 1
Sadness, depressed mood and demoralization are common in cancer
patients and responds to supportive psychotherapy.

Clinical depression occurs in roughly 14% of palliative care patients and

may be characterized by persistent sadness, suicidal ideation/thoughts,
pervasive hopelessness, worthlessness, guilt, and anhedonia.

Pharmacotherapy in combination with psychosocial interventions may be the

most effective approach to treating clinical depression in cancer patients.
These patients require specialists in psychosocial care.

Patients who appear sad and withdrawn may have hypoactive delirium.

Psychostimulants have the advantage of a rapid onset of effect in treating

clinical depression near the end-of-life.
I 'I
/! /
I
1',
Recommended Reading
.j' ,j
American Psychiatric Association. Diagnostic and Statistical Manual of
I' 1
I

'/1•1 ,1 Mental Disorders, fifth edition (DSM-5) Washington, DC. 2013

Carmack CL, Parker PA, Shinn EH. The clinical assessment of distress.
In Duffy JD, Valentine AD (eds). MD Anderson Manual of Psychosocial
I
I
' Oncology. New York: McGraw Hill' Medical, 2011 .

r Li M, Fitzgerald P, Rodin G. Evidence-based treatment of depression in

196
patients with cancer. Journal of Clinical Oncology. 2012; 30(11):1187-1 ·
8nd
Mitchell AJ, Chan M, Bhatti H, et al. Prevalence of depression, anxiety,
adjustment disorder in oncological, haematological, and palliative-care

108
 lysis of 94 interview-based studies. Lancet On
. . ameta-ana
settings. co 1ogy.
·160-174.
2011: 12·
. NH Montagnini, M. Recognizing depression in palliative care
Noorani, ' of Palliative Medicine. 2007; 10(2):458-464.
palients. Journa1

Ternple. Seo tt . Brief Cognitive

. behavior. therapy for cancer patients: Re-
. the CBT paradigm. New York. Routledge, Taylor & Francis Group •
.oning
1ris1
2017

VignaroI.1, E, Pace EA ' Willey J, et. Al. The Edmonton Symptom Assessment
SvStemas a screen tool for depression and anxiety. J Palliat Med 2006;
9(2):296-303.

WilsonKG, Lander, M, Chochinov HM, Diagnosis and management of

depression in palliative care. In: Chochinov HM, Breitbart W (eds). Handbook
cfPsychiatry in Palliative Medicine, pp 39-68. Oxford: Oxford University
P1ess, 2009.

109
 ter 18 Palliative Radiation
cha P Therapy

Mangona, M.O., Mary Frances McAleer, M.D., Ph.D.

victor S·
I
\'
i
. . therapy (RD plays an important role in the multidisciplinary
Radiation .
ement of patients with cancer. Forty percent of all patients referred
rnanag . h 11· t'
RT receive treatment wit pa 1a 1ve as opposed to curative intent. Local
tor · 1· . t It' f I ·
ITT~ beeffective 1n re 1ev1ng symp oms resu 1ng rom ocal disease. Bone
metastases, brain metastases, spinal cord compression, superior vena cava
syndrome, and bleeding are situations in which RT can have an effective
symptomatic role.

CT planning ('simulation') is usually used to define the radiation field and

for dose calculation. The radiation treatment is then delivered by a linear
accelerator in a heavily shielded room. For the radiation planning and
treatment delivery, it is important to remember that patients must be able to
lie still, unattended, for 10-20 minutes at a time. Such immobilization may not
be possible for patients who are in uncontrolled pain, delirious or orthopneic.

Typically, one RT treatment (fraction) is given per day, 5 days per week
(Monday through Friday). The goal of palliative RT is to use a short treatment
schedule to provide effective symptom relief with minimal treatment-related
side effects without a protracted treatment course. Commonly used palliative
RT regimens include:

• 8 Gy in a single fraction (one treatment)

• 20 Gy in 5 fractions (4 Gy per fraction, 1 week)
' 30 Gy in 10 fractions (3 Gy per fraction, 2 weeks)*
• 35 Gy in 14 fractions (2.5 Gy per fraction, ~3 weeks)
• 40 Gy in 15 fractions (2.66 Gy per fraction, 3 weeks)
' 40GY·in 20 fractions (2 Gy per fraction, 4 weeks)
' 45 GYin
· 15 fractions (3 Gy per fraction, 3 weeks)
•most com
mon regimen
Palliative Ra . .
d1at1on Therapy
131
llllliiiii.....
 C
;
rJ The choice of palliative RT regimen depends on tumor factors (e . ; lo
f, l . ' 9 ·,
Cation 1;
histology, disease extent, previous RT), patient factors (e.g., performance '{
status' and patient preference. Side effects depend on the RT dose as
1, . . , Well f.'
as body site and volume treated. Acute side effects are self-limiting, tend to
increase with increasing total RT dose and treatment volume, and tend to /
resolve within 2 weeks of treatment. Late side effects (> 90 days after RT)
can be permanent, but tend to be less significant in the palliative setting /
given the low RT dose used and the limited life expectancy of patients f
receiving palliative treatment. f,,_

.~-
' l
Bone metastases
Pain is experienced by 70% of patients with bone metastases and is
r,1
the most common pain syndrome in cancer patients. Investigation of a r
patient with painful osseous metastases includes a history and physical
examination, and imaging (X-ray, bone scan, CT, PET and/or MRI when
e'(1
1,.
indicated).
1:it
A multidisciplinary approach to management can help reduce pain and £1'1
morbidity and increase mobility and quality of life. Important disciplines
,tt
include radiation oncology, orthopedic surgery, palliative care, medical
••,l
l•~•

oncology for consideration of systemic therapy (bisphosphonates, .g.., .

chemotherapy), interventional radiology, and rehabilitation and occupational I(,
~ti
therapy.
·11
• RT: Provides effective and cost efficient management of painful bone ~-
1
metastases. Local RT is the modality most commonly used. A meta- h-
analysis revealed no significant difference in pain relief between
single (8 Gy, x 1) and multi-fraction RT (overall response rate 58%;
1
complete response rate 23%) but did result in higher retreatment ~:
rate (20% vs 8%). One 8-Gy fraction is therefore the treatment of \~
choice to palliate painful uncomplicated bone metastases (i.e., \
r,·
in the absence of neuropathic pain, spinal cord compression or l~
1
impending pathological fracture). Our experience with stereotactic 1;
spine radiosurgery (SSAS) using high (ablative) RT doses in 1 or 3 t1i
·i fractions has provided durable palliation and high local control for /t1
the treatment of new or recurrent spine lesions, including tumors of '\
radioresistant histology (e.g., renal cell, melanoma, and sarcoma). ~'.:
Systemic radionuclides can be considered for multiple painful bone r
metastases with bone-targeting agents such as Radium-223, which \
\,\!

Palliative Radiation TheraPY

132
....
 n found to improve overall survival in patients with androgen-
has bee tastatic prostate cancer.
·stant rne
res' : Lytic lesions ~thigh risk of fractur~ in_weight bearing
, surgery hould be considered for prophylactic fixation, followed by
bones s
postoperative RT.

d compression
S 111al cor . .
P, I cord compression (SCC) involves compression of the dural sac and
tents by an extradural tumor mass.
spina sec usually occurs in patients with
con . tory of bone metastases, but may be the first presentation
known his . . .
af cancer. Urgent diagnosis and treatment 1s required as neurological
0
symptoms progress rapidly over 24-48 hours, and neurological outcome
On pretreatment neurological status. Trials have found that after RT
depends . . ..
tor Sec, g4% of patients who were ambulatory pnor to RT retained ability to
ambulate, compared ~ith 63% of p:tients requirin.g am~ulation assistance,
I
: 38%of paraparetic patients, and 131/o of paraplegic patients.

, Symptoms: Central or radicular back pain, rapid onset motor and

sensory loss, bowel and bladder dysfunction.
, Work-up: Neurological examination and gadolidium-enhanced MRI.
The entire spine should be imaged, as multiple sites of epidural
disease may be present.

• Management: Immediate administration of dexamethasone (empiric

dosing, 10 mg IV then 4 mg every 6 hours is commonly used with
gastrointestinal prophylaxis) followed by urgent consultation with a
radiation oncologist and a spine neurosurgeon. Treatment should
be individualized taking into consideration patient's performance
status, medical comorbidities, neurological function, and preference.
If technically feasible and medically acceptable, patients with
vertebral instability or bone compression should be treated with
Primary surgery followed by postoperative RT. This approach
has shown higher preservation of ambulation in patients with
new onset paralysis. Primary RT is used for patients who are not
surgical candidates, or when there is no spinal instability or bone
~ompression. There is no evidence that neurological oytcomes are
improved With higher RT dose. Chemotherapy may be considered
as initial therapy in cases with highly chemosensitive tumor hi5tology
(e.g., srnan cell lung cancer or lymphoma).

Palliati'ie ... d' .

ria •at1on Therapy
133
r- ...
Brain metastases
Brain metastases are seen in 20-40% of all cancer patients. Prognosis is
generally poor, with a median survival of 2-4 months. The best outcomes are ,
seen in patients with good performance status (KPS> 70), younger age (<SO ,
years), solitary metastasis, and no extracranial disease, improving median
survival to 7.7 months.

• Symptoms: 2/3 of patients have neurological symptoms such as

!
I ii headache, seizure, cognitive dysfunction and motor or sensory
deficits.
I, ::1
>r.;i,
l 11::; • Workup: Gadolidium-enhanced brain MRI is superior to CT
I )
,,i1,:1 for detection and differentiation between single and multiple
metastases.
• Management: Corticosteroids reduce peritumoral edema and
usually provide rapid relief of neurological symptoms. Whole brain
radiotherapy (WBRT) is recommended for multiple brain metastases
1
(30 Gy in 10 fractions). For patients with a resectable, solitary brain
metastasis, minimal extracranial disease and good performance
status, surgical excision followed by WBRT has shown significant
reduction of death by neurologic causes. When the solitary lesion is
unresectable, stereotactic radiosurgery (SRS) after WBRT provides
a survival benefit, and a local control benefit has been reported
for patients with 2-4 metastases. SRS alone for small metastases
shows similar local control to resection. Addition of WBRT to
SRS for up to 3-4 metastases, however, worsens neurocognitive
function without definite improvement in survival, and therefore,
WBRT is routinely delayed until further progression. Addition of
memantine helps prevent neurocognitive decline after WBRT. Use
of SRS alone for patients with 5-10 brain lesions has been shown
to be non-inferior to SRS alone for 2-4 lesions, with similar overall
survival observed in both treatment groups. For patients with po~r
performance status and life expectancy < 2 months, corticosteroids
and best supportive care may be appropriate.

Superior Vena Cava Syndrome

. • n of ttie
Supenor vena cava (SVC) syndrome results from external compressio
ill . .. xtrernitie5·
Svc, 1mpa1nng venous return from the head and neck and upper e
:11! The most common neoplastic etiologies of SVC syndrome include prirnarY
nd
or nodal metastases from non-small cell and small cell lung cancer a
lymphoma.

Palliative Radiation ftl,,.¢

134
L 111111
pill
arns· oyspnea, orthopnea, headache.
• symPt ·
. . Neck and chest venous distention, facial and upper extremity
sign•
5
• edema, plethora, especially when recumbent.
nagernent: Supportive (oxygen, head elevation), RT and/or
' Mhemotherapy,depen
a d'1ng on h'1stoIogy. Stenting provides the most
mediate relief and should be considered when cardiovascular
1:mprornise is evident. The role of corticosteroids and diuretics is
~ontroversial. Corticosteroids should be withheld if SVC syndrome is
initial presentation of malignancy and there is concern for lymphoma.
Treatment often should be initiated urgently due to respiratory

distress.

Advanced Lung Cancer

over 2/3 of patients with lung cancer have advanced disease at presentation
and a median survival of 4-7 months. Local radiotherapy can effectively
palliate hemoptysis and chest wall pain due to rib or vertebral body erosion,
with response rates of >70%, and cough has been shown to improve
1 following RT in 50% of cases. A recent meta-analysis concluded no
r difference in symptom control endpoints with high- vs. low-dose thoracic RT.
Asurvival benefit was seen with high-dose RT (3 Gy x 10), but with increased
toxicity and longer treatment time. For patients requesting shorter treatment
, or with poorer performance status, hypofractionated regimens offer effective
palliation (e.g., 4 Gy x 5 once-daily fractions, 8.5 x 2 once-weekly fractions,
or 10 Gy x 1 fraction).

Other symptoms
• Bleeding can occur from a primary or metastatic tumor in
pulmonary, gynecological, gastrointestinal, genitourinary, head and
neck, or other site. Local palliative RT can provide very effective
palliation with response rates of >80%, although durability of
hemostasis has been shown to vary. A single fraction of 6-10 Gy,
Which can be repeated, or a multi-fraction regimen (e.g. 3 Gy x 10)
can be used.
• p .
. ain can result from tumor mass effect (e.g., large cervical cancer
'.nvading pelvic structures). Palliative RT can provide palliation of pain
in this setting.
• Ulcerative skin lesion with bleeding, odor, discharge, and pain can
occur from primary skin cancer, breast or other superficial cancer
Palliati
"e Radiation Therapy
r 11111111

eroding skin, and from nodal or cutaneous metastases. Symptom

8
from tumor ulceration can be palliated with local RT.

Palliative Care Pearls

• RT plays an important role in palliating symptoms due to local
malignant disease
1 • Optimize symptom management prior to sending patients for RT
• Single-fraction RT provides very effective palliation of painful bone
.·r
:11,!
~·G'-1·
II
metastases
!lr•ij1
1!''·1
If! • Metastatic disease to the brain conveys a poor prognosis but may
\~ be treated with corticosteroids, whole brain RT, surgery, and/or
radiosurgery in selected patients
·4__
i
,\1·

.1:·;i:1 • Spinal cord compression must be ruled out when rapid onset
J~n / 1~1! 11 neurological changes involving bowel, bladder and ambulatory
,: 1-:
function occur and, when identified, requires prompt neurosurgical
or RT intervention
• Symptoms from locally advanced lung disease such as hemoptysis,
chest wall pain, and cough can be palliated with local RT

Recommended Reading:

Chow E, Harris K, Fan G, et al. Palliative radiotherapy trials for bone

[~
metastases: a systematic review. J Clin Oncol 2007; 25(11):1423-36.
11

Loblaw DA, Perry J, Chambers A, et al. Systematic review of the diagnosis !1

and management of malignant extradural spinal cord compression: the \
Cancer Care Ontario Practice Guidelines Initiative's Neuro-Oncology Disease
Site Group. J Clin Oneal 2005; 23(9):2028-37.
\
Sperduto PW, Berkey B, Gaspar LE, et al. A new prognostic index and
1,,
comparison to three other indices for patients with brain metastases: an
analysis of 1,960 patients in the RTOG database. Int J Radiat Oncol Biol \
Phys 2008;70(2):510-4.

Rodrigues G, Videtic GMM, Sur R, et al. Palliative thoracic radiotherapy in

lung cancer: An American Society for Radiation Oncology evidence-based
l
clinical practice guideline. Pract Radiat Oncol 2011; 1(2):60-71.

Palliative Radiation ThersPY

136
~\
 c;hapter 19 Oral Mucositis

pa\'id Hui, MD, MSc, MSc

. . defined as the inflammation and ulceration of membranous

Mucos1t1s, . .
an occur throughout the gastro1ntest1nal tract. The incidence is
rnucosa, c .
st 100%in patients undergoing chemoradiation for head/neck cancer,
alrno " h' h d h h
ao%a mo ng patients rece1v1ng 19 ose c emot erapy/hematopoietic
ll transplant (HSCT), and 20-40% among patients on conventional
stem Ce
chemotherapy. Grade 3 or 4 mucositis may be associated with severe
pain, dehydration, bleeding, and superinfections (bacteremia) requiring
hospitalization.

Clinical course
usually begins a few days after treatment with erythema and the
development of easily detachable white plaques. Mucositis peaks at around
one week, with the formation of a pseudomembrane and ulceration. Pain
is usually present at this phase, because of the exposition of the richly
enervated underlying tissue. Fungal, bacterial, or viral infection may occur,
especially in immunosuppressed (neutropenic) patients, lengthening the
' clinical course.

Diagnosis and Staging

Diagnosis is clinical, and the use of validated scalesfgrading systems is

I recommended.

Oral soreness and erythema I Asymptomatic or mild symptoms, intervention

not indicated

Ul_cerations, but able to eat solids I Moderate pain, not Interfering with oral intake;
modified diet indicated
Oral ulcers and able to take liquidl? only I Severe pain, interfering with oral intake

Ora1 t.1uco8itia

137
r"' 11111
1'

~- /
-l
4 Oral alimentation impossible Life-threatening consequences;
urgent Intervention indicated

5 - Death

l
Prevention of Oral Mucositis
I
• Practice of good oral hygiene and use of baking soda mouth rinses
f
'
every 4 hours .

Recommended Interventions for Prevention of Oral Mucositis f

(MASCC Guideline 2014) .
.I
I
I~
ifo1
Oral care protocols All age group and all cancer treatment modalities / 1%
i' Oral cryotherapy (30 minutes of ic ing) Patients receiving bolus 5-fluorouracil
,,_'
u .I
i'
chemotherapy or high dose melphalan with or
~1
without total body irradiation, as conditioning fl
for HSCT
t,If
Recombinant keratinocyte growth factor-1 (e.g. Patients with hematologic malignancies on high-
Palifermin)' dose chemotherapy and total body irradiation, !ire'
followed by autologous HSCT m
Low level laser therapy Patients receiving HSCT conditioned with high- ~JC
dose chemotherapy
Patients with head and neck cancer receiving I·,~
radiotherapy, without concomitant chemotherapy
~-iSi
Benzydamine mouthwash Patients with head and neck cancer receiving
moderate dose radiation therapy (up to 50 Gy), t\~
without concomitant chemotherapy

Zinc supplementation Patients with oral cancer receiving radiation or

chemoradiation

'\,
;~
1ij 'Not indicated in patients with solid tumors because there is a theoretical risk of promoting cancer
growth
~1,
;l__}
·~
I
l·_Jl
\~1,
1~: Treatment of Established Oral Mucositis
i~ • Maintenance of good oral hygiene and adequate hydration is ~'~!
V'I
·!i 1

t'j
1
essential
\
\\
• Topical analgesia may be useful for short term pain relief of
mucositis.
\\i
..

1!1 5
• Morphine sulfate mouthwash 2%, swish and spit, q4h to q h
l.·11
J •
•
Doxepin 0.5% mouthwash may be considered
Magic (or Miracle) mouthwashes (preparations vary, but
generally consist of lidocaine for pain control. Use 10ml
'
1' \11,(

squish and spit q4h to q6h

\.(,,\
'~
Oral ft'lucosili'
138
,.\
 • Lidocaine viscous 10-15ml PO swish and spit QID
• Xyloxylin 10ml PO swish and spit q4h PRN
,,,.,ic opioids remain the mainstay in management of pain.
t
• sys 0111
rrent guidelines recommended against the use of chlorhexidine
• ~~uthwash for the treatment of mucositis in patients undergoing
radiation for head and neck cancer.
trnent of infections as appropriate for candidiasis and HSV
• 1ire a
\I infection

palliative care Pearls

• The presence of oral mucositis usually indicates that other parts of
\1 the alimentary tract are involved. Thus, one should always assess
the presence of diarrhea, abdominal pain, nausea and vomiting.
• Patients should be encouraged to ensure good oral intake and oral
hygiene.
• Prevention is key in the management of mucositis. Cryotherapy, low
level laser therapy, benzydamine mouthwash, zinc supplementation
and recombinant keratinocyte growth factor-1 may be considered in
selected patients.
• A multidisciplinary team consisting of oncologists, supportive care
specialists, dentists, dietician, and others may be helpful in both
prevention and treatment of mucositis, particularly for high risk
patients.

Recommended Reading
Lalla RV, Bowen, J, Barasch A. et al. MASCC/ISOO Clinical Practice
Guidelines for the Management of Mucositis Secondary to Cancer Therapy.
Cancer 120(10):1453-61. 2014

Bensinger W, Schubert M, Ang K, Brizel D, Brown E, Eilers JG, Elting L,

Mittal BB, Schattner MA, Spielberger R, Treister NS, Trotti A. NCCN Task
Force report: prevention and management of mucositis in cancer care. J Natl
II C
ornp Cancer Network. 6 Suppl 1:S1 -S21. 2008
,1 Worthi ngton HV, Clarkson JE, Bryan G, Interventions for preventing oral
rnucositis
S fo r patients
• with cancer receiving treatment. Cochrane Database
t
YS Rev. 2011 Apr 13; 4:CD000978.

cti• Oralt.,
139
r. 11111111

Chapter 20 Ethics

Larry Driver, MD

The relief of suffering is a cornerstone tenet of health care, particularly so in

:j the palliative care patient. Clinicians are morally obligated to assess and treat
:1~ pain and other symptoms that impose a heavy burden on the quality of life
':! !1
for a patient whose lifespan is acutely limited by advanced cancer. However
'
I'
the efforts to therapeutically intervene to relieve these symptoms are often
:1·
·II'
accompanied by considerations of real and theoretical ethical issues
H'.
I interlinked with the clinical situation.
I
,ir,1
'I
Clinicians who care for advanced cancer patients have an obligation to
understand basic ethical concepts and issues just as they have an obligation
to be competent in treating pain and other problematic symptoms in these
patients. Understanding these fundamental principles will facilitate not only
the clinical treatment offered but also the clinician's ability to communicate
clearly with the patient and family during difficult times. Rational and
competent care delivered compassionately along with honest and empathic
communication about the clinical situation is the basic expectation of moSl
patients and the moral obligation of healthcare professionals.

nd
Ethical decision making in the palliative care setting is multidimensional a
nd
includes issues pertinent to the patient, family, and health care providers a
society at large. A brief sampling of these issues includes the following:

'ii'
11:i • Patient's rights and autonomy
[I I
i Ii • Patient's and caregivers' therapeutic goals and expectations
Id
:ii
• Interrelationships among patient, family, caregivers, and clinicians
• Therapeutic processes and outcomes
• Communication
• Disclosure and confidentiality
• Informed decision making and consent
• Psychosocial and spiritual care
• Obligation versus option to treat
EtlljCS

140
11111111
r • senefit
versus burden of treatment
·ive versus palliative therapy
, curat
, Withholding versus withdrawing treatment

• Quality of life
, DNA orders
, Futile care
, Allocation of resources
, concept of double effect.
, Opioid analgesic management in the context of contemporary
society

This list should serve to provoke thinking about the myriad issues that come
into play when caring for the patient with advanced cancer who has not
responded to curative efforts and whose hope lies in aggressive palliative
care to mitigate symptoms, optimize the quality of life, and ease the burden
of dying. The context of care may influence thinking and decisions and may
include issues such as patient age, lifestyle choices, and etiology of the
terminal condition among others.

Ethical Concepts

For our purposes, clinical ethics can be thought of in two ways. The tenet of
consequential ethics provides that a good or right action is determined by
the consequences of that action. In essence, if the outcome is good, then
the action taken was right, but if the outcome is bad, then the action was
wrong. The outcome retrospectively supports or calls into question the act.

On the other hand, the foundation of principle ethics implies that guiding
laws or Principles determine the rightness of an action. These principles are
derived from the historic moral, ethical, and medical traditions espoused by
st0
Ari tle, Hippocrates, Galen, Maimonides, Paracelsus, and others in ancient
times and by the likes of Kant, Mill, Osler, Saunders and others in more
recent Philosophical and medical history. These guiding principles include
the following:

• Nonmaleficence: The physician should cause no harm to the patient.

("Primum non nocere" or, "First do no harm.).
• Beneficence: The physician should help the patient.
I Ethics

-...........__ 141
 ..
• Autonomy: A competent patient has the right to accept or reject
,
medical treatment, and a surrogate decision maker can act on the l
patient's behalf if the patient is unable. f
• Justice: Clinicians should act with fairness toward the individual t
patient, recognizing that society often has broad concerns that may f'
overshadow the needs of the individual. f'
• Benefit / Burden: Medical treatment should provide more benefit
;'I
than risk or burden to the patient. In addition, principled decision
,,1/
making should consider the benefit/burden ratio of a treatment,
an approach that may be thought of as relative-burden decision
1'
making.
it
• Sanctity of life: Human life is deemed worthy of respect and
preservation. Most ethicists, as well as national and international
:\ palliative care organizations, adhere to this fundamental Hippocratic 0i
principle as a cornerstone of principled decision making. However,
proponents of euthanasia and physician-assisted suicide would
argue that when considering the relative importance of beneficence, 1,
one might acceptably ignore the principle of sanctity of life.

Various factors can have impact on these principles and may even modify
their application. These factors include familial relationships, religious and ,i
cultural issues, medical economics and justice issues, allocation of limited
resources, and evolving aspects of the patient-clinician relationship. 1~.

\•
Advance Directives
A cornerstone of advance care planning, the advance directive is simply ,~I
a legal document that communicates what types of medical treatment an ,~
individual desires or whom they would like to make medical decisions for :~
them. This information may be particularly useful in the case of the advanced
'th II
cancer patient who is receiving palliative care and should be discussed wi 1.:i

the patient. •1

I
\
I
1
The Texas Advance Directives Act, which became effective September ·
1999, consolidated the Natural Death Act, Durable Power of Attorney for
th
Health Care Act, and Out-of-Hospital DNR Act into a single statute. Wi in \
this act are updated provisions for Medical Power of Attorney, Living Will
"\
(Directive to Physicians and Family or Surrogates), and Out-of-Hospital I
\'
DNA Orders. There are specific definitions of advance directive, artificial
nutrition and hydration, health care or treatment decision, irreversible

ftt,IC9

142
!·\ cond~·t·on' and
i
. ustaining treatment, medical power of attorney, terminal
!lfe-s .
witness. The Act unequivocally asserts that health care
\! condition, st follow the mandates of a patient's directives and provides
·ders
1 rnu · d' t· ·
proV al protection for obeying 1rec 1ves and sanctions for failing to follow
i,.i1both le9 Advance
directives may be changed or revoked by the patient at any
thern- on Directives that were executed prior to September 1
anY reas · . '
l: tirne for . I'd
rna1n va I but are governed by laws 1n effect at the time
i' 1999, red Texas processes and procedures for DNR orders were revised by
they were

execute · hange effective April 1, 2018, and should be reviewed and

the r statute c
l l fur · · s.
d by clinician
understoo
\ MD Anderson's policies and processes for advance care
Upda~es ~f eluding advance directives and advance directive forms, may
planni~g, in b calling the telephone numbers or visiting the Section of
1. be reviewed Y
d Ethics website listed below.
h Integrate
',

11 Medically Inappropriate Interventions and Just Allocation of Clinical

1

bResources
I
Apatient or family may occasionally request treatment that the physician
deems medically inappropriate or futile. In this situation, MD Anderson policy
provides a step-by-step mechanism to:

• review the dilemma;

• determine the medical appropriateness of a treatment intervention;
• make a decision that respects the patient's autonomy, physician's
judgment, and institution's integrity, and facilitates the just allocation
of medical resources.

ji) This P~licy is outlined in publications entitled Ethical Principles for

Allocating Clinical Resources and Policy on the Determination of Medically
Inappropriate Interventions, both of which may be obtained from the Section
of Integrated Ethics.

~1 Acomplete d r1 . .
A e neat1on of clinical issues and full exploration of ethical
It concepts Perti . .
, the re d ,
J be nent to the palliative care of advanced cancer patients is
ope of this chapter. Instead, we hope that this chapter piques
.
I a er s ethi ·
, exp1 cal consciousness and provokes the reader to seriously
0
i: re the eth'
,

1
ics of Palliative care by:

....__
Ethics
143
l?
• Accessing the materials on the Recommended Read' I'
. . . ing ist below
• Visiting the Section of Integrated Ethics 1ntranet website th
. a ttp·;;
inside.mdanderson.org/,d epartments/1ntegrated-ethics/i ndex.htrn1·

• Calling the Section of Integrated Ethics at (713)792-87?5

• Calling the Department of Social Work at (713)792-6195
• Calling the Department of Chaplaincy and Pastoral Education at .
(713)792-7184.

The Section of Integrated Ethics in Cancer Care provides education I

consultation, research, and policy development in clinical ethics. The Ethics

Consultation Service assists patients, families, and health professionals in
decision-making and responds to formal requests for consultation as well
as informal "curbside consults ," and regularly makes proactive ethics rounds
I •

in several MD Anderson care locations. This service can be contacted by

calling pager (713) 404-2863.

Recom mended Readin g

Beauchamp TL, Childress JF. Principles of Biomedical Ethics, 7th Ed.
Oxford: Oxford University Press, 2012.

Bruera E. Parenteral Opioid Shortage - Treating Pain During the Opioid-

Overdose Epidemic, July 18, 2018, DOI: 10.1056/NEJMp1807117

Quill TE, Miller FG. Palliative Care and Ethics. Oxford: Oxford University
Press, 2014.

Randall F, Downie RS. Palliative Care Ethics, 2nd Ed. Oxford: Oxford
University Press, 1999.
nd
Randall FM. Ethical issues in palliative care. Acta Anaesthesiol Sca
43:954-956, 1999.

144
 Giving Bad News
;

. E, fpner, M.D.
0811
,el

ead News? . .. .
, What Is ts one's
. any information that s1grnf1cantly and' adversely affec
dneWSIS '
sa h tuture (1). Bad news may pertain to disea se recurrence, failure of
. . . . .
vieW of t e of-hfe issues,
. t to affect a desired result, treajment tox1c1ty, and end-
' treatrnen issues, and
j lack of further curative treatment options, resuscitation
. such as ss the
, to a hospice. Because technology has allowed us to asse
t referra1 laboratory tests
course of the disease and response to treatment through
news many times
and other exams, patients with cancer may receive bad
often need to
during the course of their illness. Palliative care providers
y members·who are
deliver bad news. For instance, some patients and famil
ventions, such as
, entering hospice find it difficult to forego aggressive inter
the end of life,
hemodialysis or total parenteral nutrition, as they approach
outweigh potential
even though the potential risks of those interventions far
covered by
benefits. Furthermore, these interventions are typically not
financial burden.
hospice benefit, so pursuing them can create significant
an anxiety-
Whatever the circumstances, bad news is almost always
producIng event that can threaten ones sense of hope.
1 .
·

Why Is Giving Bad News Difficult?

se or condition at
Medical training overemphasizes curing the patient's disea
th eexpense of t · · · Desp1t·e
raining 1n psychosocial or relational aspects of care.
· d quar1ty of
rt1 ition that paII'1at·1ve medicine focuses on symptom relief an · · b'I'
recogn
• still
e, Palliative'Phys·Ic1ans . experience burnout as a result of their 1na 11ty
1o"fix" many .. ..
symp toms and fully satisfy patients and their families. In g1v1ng
bd
a news,. mo·8t Phys1cI . . they are not
abJ 1 ans seem particularly distressed when . ..
eto give tbe r . . (2). This beco mes muc h more s1gn if1cant when
the h . ./ Patie nt hope
P YsIc1an p . of a cure,
has .' reviously was overly optimistic about the prospect .
not d1scu ved the
Patient . ssed the prognosis with the patient, or has not invol " . "
in decisi on maki.ng about treatment, thus themselves taking on

Gi11inga

~New
8
145
 #
the responsi·b·,i·,ty for the outcome . In these. circumstances when f
. ·ng bad news the physician may feel guilty and acect W't ,•· ,
gM withhold inforrnar 'h
the patient or use tactics to make the bad new 1onkom
.
s less serious than 't
is. Delivering bad news 1s also a complex task . • i actuan
, consisting of preparin Y .a
. d .. .f .
the discussion, gathenng an g1v1ng 1n ormat1o n, addressing the t· g for r-
. .
emotions and negot1at1ng a treatment plan . Pa 1ent's
s1c1ans ha f.
, Moreover many phy . .
had little or no training in giving bad news (3) , J
ve fr
f
Wh at Hap pen s Wh en Giving Bad New
s Goes Badly?
Because bad news often has negative implicat
ions for one's future, the
anticipation of bad news is a threat that can
create a crisis situation for the 1~
patient. This means that both the communicati
on of the clinician takes on ~i
disproportionate significance when compare
d with what might be otherwis
If giving bad news is not handled with tact, emp e. t9
athy, and honesty, it can
permanently damage the relationship with the
patient.

Ho w Do Pat ien ts Wa nt To Be Told Bad

News?
Studies have unequivocally shown that almost
all cancer patients want much
information about their illness, although ther
e may be significant variability in
the amount of information they desire. Patients
want information given with
sensitivity and tailored to their particular nee
ds, and they value physicians
who are more likely to listen to them and are
empathic when they get upset.
Patients also want to be partners in decision
making when there are options ,
available. A disconnect exists between patie
nts and their physicians with
regard to hope. While most doctors frame hop
e in terms of the ability to
offer a cure, patients equally value being offe
red up-to-date treatment. being
completely informed about the circumstances
of their care and having a
good relationship with their doctor

How Can a Me tho d of Giving Bad New

s be Helpful?
As with any complex procedure, having a tried
and true method that one
can master over time builds confidence . How
ever, the method muSt have
a rationale and goals, be flexible enough to ada
pt to the different bad d

L=porates
news situations, and have steps that can be
• •• d
· d When a meth0
practice ·
it
patient preferences for g1v1ng ba news, can result ,n
.

t,jeY1 5
Giving sad

d
 . f ction for the patien t, assure inform ed consen t, and improv e
d 50t1s a .
, crease . 1adaptation of the patient.
1fl hOIOQICa
the psYc

ES protocol for Givin g Bad News (1, 4)

fh8 5pll< ..
rotocol for g1v1ng bad news breaks the bad news discus sion
sr1KES P
rne . nt into six steps that reflect the basic. tasks of giving bad news:
. the pat1e . . . .
with . facilitation, 1nformat1on gather ing, and information disclosure,
parat1on,
pre tin the patient, and negoti ating a treatm ent plan. It can be adapte
d
suppor 9 · · ons, · I d' · ·
rnber of bad news s1tuat1 inc u 1ng g1v1ng a cance r diagnosis,
to a nu . the trans1t1
· · on from curat·1ve to pa11·1at·
discuss1n9 1ve care, d'1sclos1· ng medica
· l
liciting the patien t's prefer ences for end-of -life care (e.g., DNR) and
errors, e
. •ng ·informed consent. The steps of SPIKES are as follows:
obta1rn

Step 1: SETTING UP the intervi ew

Goals

• To prepare yourself for the intervi ew

• To establish rappor t with the patien t and put the patien t at ease

• To facilitate inform ation exchan ge.

Process

• Reflect on the task at hand. Have a plan in mind before you see the
patient
• Arrange for uninte rrupted time
• Decide who should be presen t. Ask the patien t which caregiver (s)
he or she would like to be in the room
• Determine wheth er the patien t is ready. "I'd like to discus s your
results. Would this be ok?"
• Sit down when you speak to the patient. Try and be calm and speak
slowly.

• Have facial tissues handy

• Maintain eye contac t.

Giving Bad N
ewa
147
 RCEPTION of the illness.
Step 2 _. Find out the PATIENT'S PE

Goals
erstands
• To determine what the patient und
mily
• To assess denial in the patient/fa
ning
• To promote rapport through liste
ations and concerns.
• To understand the patient's expect

Process:
"Tell me what you've been tol ,,
• Ask open-ended questions i.e.,
tand the reason for the tests·~ · or
"I'd like to make sure you unders
erstanding
• Correct misinformation and misund
is hard to hear this"
• Address denial." I can see that it
with wish statements. " 1 wish it
• Address unrealistic expectations
were as easy as that"

• Define your role.

e information
Step 3: Get an INVITATION to giv

Goals
or she is
determ ine how mu ch informa tion the patient wants and when he
To
ready to hear it.
r
information needs may change ove
• To acknowledge that patient
later on in the illness may not find
time. For example most patients
al.
that seeing their CT is information
regarding information disclosure.
• To resolve conflicts with families

Process
who wants information in detail
• Ask "Are you the type of person
or.... "
cern. "Can you tell me why you are
• Explore sources of family con
information with your dad?
concerned about discussing this

dNe't'fS
Giving ea
 . . the patient KNOWLEDGE and information.
4'G1v1nQ
5teP ·

00als
are the patient for the bad news
• To preP
e patient understanding.
, To ensUr

process
• "Forecast" the arrival of bad news i.e., "I'm afraid I have some bad
news ...
, Give the information in small parcels
, Check periodically for understanding
, Avoid using medical jargon. Even words like "biopsy" may be a
mystery to some patients

, Address all questions.

Steps: Responding to patient EMOTIONS. There are times when physicians

need to be healers. This is especially important when patients are
upset.

Goals

• To address emotional responses

• To facilitate emotional recovery ( you can't listen to information when
your mind has been numbed by bad news"

• To acknowledge our own emotions (doctors have feelings too!)

Process

• Anticipate emotional reactions. They occur frequently and we should

not run from them.
' Have facial tissues handy
' Don't speak from your own limbic lobe. When you are feeling
helpless, resist the temptation to try and make the bad news better
than it really is.
• "F' ' II
ix it responses such as "it is not as bad as you think may
• II

backfire on you.
• Support the patient (see table below) by using empathic responses
to expressions of emotion such as crying. These will actually lower
the ernot·ion ·1n the
room.
Q''
•Ying Bad N
ewa
149
11111111.
 • Clarify emotions you are not sure about u II

. . . se tell rne rnor0 "

• Validate the patient's feelings.

Responding to Patient Emotions

"I can see how upsetting this Patient feels you

is to you." are tuned in

Validating statement "It's very common for patients p

to feel this way." atlent feels "normal."

Exploratory question "Can you tell me what you are p

thinking right now?" atient feels you are Interested.

Listening + Empathizing + Validating + Exploring = Psycho!og1cal

• Support

Step 6: Communicating a STRATEGY and SUMMARY.

Goal

• To ensure that there is a clear, negotiated plan for the future

Process

• Make treatment recommendations. Patient uncertainty is reduced by

their having a road map" for the future
II

Ensure patient understanding Ask tell me what you understood

II
•
about the plan"
• Provide options for treatment. Patients need to know when the
options for treatment can produce different outcomes. This may
be especially true in advanced disease when quality of life is a
consideration.
• Understand barriers and concerns the patient may have
• Communicate your role. Patients will be comforted by knowing you
will follow them

Palliative Care Pearls

. nt that
• Delivery of bad news is always an anxiety-producing eve
significantly affects the patient-physician relationship.
. h ews with
• Prepare for the discussion beforehand and give t e n
honesty, tact, and empathy.

150
 s sit down and maintain eye contact Give th .
AlwaY . · e patient enough
• tirne to ask questions and express emotions .
he patient about his/her understanding of th
, ASk t d' .
e con 1t1on and
determine how much he/she wants to know.
. e the information directly and clearly and avo'id .
, G1v . . .
jargon and prov1d1ng false hope. using medical

• ,...Avoid terms that may refle

,, ct abandonment, such as "We have
nothing to otter to you.
, Validate the patient'~ feelings and emotions and provi
de support to
the patient and family.
, In situations where the potential outcome of treatmen
t is unfavorabl
you can help the patient "prepare for the worst but hope
for the e,
best".

Recommended Reading
Buckman R, Kason Y: How to break bad news a guide
for health care
professionals. Baltimore, Johns Hopkins University Pres
s, 1992
Whippen DA, Canellas GP: Burnout syndrome in the prac
tice of oncology:
results of a random survey of 1,000 oncologists. J Clin
Oncol 9:1916-1920,
1991

Ptacek JT, Eberhardt TL: Breaking bad news. A review

of the literature.
JAMA 276:496-502, 1996

Baile WF, Buckman R, Lenzi R, et al.: SPIKES-A six-step

protocol for
delivering bad news: application to the patient with canc
er. Oncologist
5:302-311, 2000

Gi'ling Bad ._,

,,ews
151
b
 h a p te r 2 2 Hospice Services
C

D
Angelique Wong, M

m
us e of wh o you are. You matter to the last mo ent of Your
"You matter beca lly b t ,
. .
do all we can, no t on ly to help you die peacefu , u also to ,
llte, and we wr ll
live until you die".
--Dame Cicely Saunders

W ha t is Hospice?
to denote
Ci ce ly Sa un de rs firs t used the word hospice Ji
In 1967, Dame has its roots in
care tor the dy ing pa tient. The word hospice
specialized a
sh elt er or re st to the weary or sick travelers on
the tradition of offering re, geared
sp ice is a ph ilo so ph y, not a specific place of ca
long journey. Ho le at the latter
ng hu m an e an d co m passionate care for peop
towards providi le pa tients to live fully and
~I

ar e to en ab
ess. The goals
phases of a terminal illn d by their
tai n the be st qu ali ty of lite possible surrounde
comfortably and to ob an affirmation of
to the las t da ys of lite . Hospice is, therefore,
loved ones up :-
a no rm al pr oc es s.
lite and regards death as t
tr
le in the Un ite d State s (US) since the
en availab
Hospice services have be n exponentially.
de ca de s sin ce , ho sp ice services have grow
mid1970s. In the nal illness were
14 , ap pr ox im ate ly 1.6 million people with termi
In the year 20 lliative t
re po rte d by the in the National Hospice and Pa '
served by hospice, as increas e in a sp an of 10
2%
CO), representing a 16
Care Organization (NHP t 48 % of all Me dicare dea
th5
nt NHPCO report, ab ou
years. Per the most rece r, th e
un de r the ca re of a ho spice program. Howeve
in the US in 2016 were 2016, implying
s rema ine d low , be ing a median of 24 days in
th
leng of stay ha the
ice services very late in
th at patients are still being referred to hosp
disease trajectory.

·ces
Hospice serv•
152
 Offered by Hospice
(\'ices
se rvices are provided for by profession als and specialists in end-of-
ice se . . I d h . .
t-JoSp ese specialists inc u e a P ys1c1an and/or an advanced practice
care. Th · I k h
life . a hospice nurse, soc1a wor ers, ome health aides, chaplains
· t s o f any age are e1·1g1'bl e to receive hospice
prov1der, nagers. Pat1en
d case ma . . . .
an . atter certification by a physician as having a terminal illness with a
services t ncY of six months or less if the disease were allowed to take its
rte expec a . . .
1
course. If the patient lives beyond six months, services could still be
1
. d as long as a p hys1c1an
natura . . cert'f'11es e 1·1g1'b'I'
11ty.
continue
l hospice enables the patient and family to experience the final
In genera ,
le and meaningfu l manner. Part of
Of life together in a comfortab
its goal is to prepare the patient and family for a death experience that
is satisfactory to them. There is particular attention given to the control
of symptoms such as pain, dyspnea, constipati on, fatigue, nausea, and
anorexia. Spiritual and psychoso cial issues are likewise addressed by
members of the hospice team. Other specific services covered by the
hospice program are enumerat ed in Table 1

Table 1. Services offered by hospice

Physician services for medical direction of patient's care
Regular home visits by registered nurses

Home health aides for services such as dressing and bathing

Social work and counseling

Spiritual care

Medical equipment and supplies appropriate for patient care and comfort

Medications for symptom control and relief of pain

Volunteer support to assist patient and loved ones

Family bereavement services for 13 months after death

Hospice offers four different levels of care depending on the need of the
Patient or the family.

1
· Routine Hospice Care is the most common level of hospice care.
With this type of care, an individual receives hospice care at their
residence or in a facility such as nursing home where patient resides.
Family members are responsib le for 24-hour custodial care und er
th e direction of the hospice team. If very distressing symptoms arise
th at cannot be controlled by simple changes in medication, or th e

Hospice Sel'Vi·
ces 153
 family becomes quite overwhelmed w ith the situation th 1
, e eve1 of
•
.
care can be changed to continuous home or general inp ti
. . a ent care.
2. Continuous Home Care 1s caret pr~v'.dedf for between 8 and
24
hours a day to manage an acu e cns1s o pain or other syrn t
hospice nursing staff, allowing patients to stay at home. This
care can be extended as deemed necessary.
~;s
by
Pe of

3. General Inpatient Care is provided when symptoms cannot b

managed at home and patients are admitted to an inpatient fa~ili
such as hospice inpatient facility or a hospice-contrac ted facilit ty
under the direct care of the hospice team. Y

4. Inpatient Respite Care is available where patients are admitted to

contracted facilities such as nursing homes, so the family can rest
and recuperate. There is a limit of 5 days per billing period.
f.

When Hospice Referral is Appropriate

When discussion regarding hospice is started, most patients and families
enter the uncomfortable phase of transitioning from active treatment to II

supportive care. There is the fear that making that transition to hospice it

conveys a message of "losing hope" or "giving up on the patient." In fact,

the opposite is true, in that hospice brings hope of quality of life-of good
days during the last days of life. Otten, families are unprepared for such a
l·
change that they may fail to appreciate hospice and what it can provide.
Timing of hospice referral is also a challenging task for health care providers.
Sometimes, it can become difficult for health care providers to recognize
that the patient would benefit more if the goals of care were geared towards
comfort and maintenance of a good quality of life as opposed to active
curative treatment.

Several guidelines can be used by health care providers and families in

order to maximize benefit from hospice and spare the patient and family
unnecessary procedures and expectations. Ideally, patients should be
referred as early as possibl0 wh0n the determination of the appropriate tif116
·
. ma d e. Patients · r II
is usually have peaks and valleys in their disease time ine.
·
' w I, en the Intervals between the peaks becom e shorter that signal I tif'TlO
118
is
to step back and grasp the bigger picture. Often, poople do not see wtiat is
· · t'S
obvious until they are able to reflect upon the situation. When the patren
. gains
· over a short period, when there are more losses tt,an
d ecrine ·1s rapid

in the patient's health situation, progressive decline in the patient's tunction

·ceJ
Hoepice~ ,
154
 or new probl ems arise, hospi ce referral shoul d then
t reverse' . .
na.t will no . ts are eligible for hosp ice with many diagn oses includ
t" pat1en ing
.
be made. disease, and stroke , but hospi ce care may also be appro priate
r heart
ca.nee , 'th frequent hosp1·ta1·1zat·ions, progr essiv
. e weigh
. t loss, menta
. ntsWI l
for pa.tie . r overall functi onal declin e. .
deterioration, o

. nd the Care give r

Hospice a
. r the caregiver for the patien t plays a major role in the care
The family o
. They are the prima ry advoc ates and suppo rt for the patien
of the dying. . t.
the people who prima rily carry out the task of daily medic ation
These are
. s·,ng 24 hour custo dial care, and psych osoci al and spiritual suppo
d1spen ' rt
for the patients. They perfo rm these duties in additi on to having
to prepare
themselves for the loss of a loved one. Careg ivers never stop perfor
ming
their previous roles; they still contin ue to be mothe rs, fathers, and
caregivers
to other people and memb ers of the work force. There is treme
ndous
pressure and stress on careg ivers to functi on in all capacities. This
is where
the special relationship of hospi ce staff and the family/caregiver
is realized.

Hospice offers suppo rt to the family. For families' emoti onal and
spiritual
needs, the hospice social worke r and chapl ain are able to help
family
members through difficu lt times . Stres s brings out the best and
worst in
people, so these professionals are traine d to addre ss strong emoti
ons,
disruptive behaviors, and difficu lt grieving. Therefore, hospi ce could
be
avery good resource for the family. Home health aides provide
some
respite from the caregiver role of bathin g and groom ing. Hospi ce
nurses
provide a sense of secur ity that medic al proble ms will be addressed
in a
timely manner. Each memb er of the team likewise becom es an
outlet for
, socialization , as f ·1 · the pat1en
amt y memb ers often stay home while · t ·ts 1
·11 .

1 A large number of families repor t regret for not having had hospi
ce services
much earlier Th' · .
· is 1s partly becau se of the suppo rt they receiv •
e. Having to
accept loss and h ·
t k aving to let go of a loved one is a frightful an d d'ff'
1 1cuIt
~.~c t~ .
ch e is never prepa red to tread this road. During these exceptional .
aIlenging ti .
mes, hospi ce plays an impor tant part.

~OSpices .
ervices

155
,--
I
How to Enroll in Hospice
Certification of terminal illness for hospice benefits is clinically d
- . Id'1rector or an .In d'IvI'duaI's physician. Certif' eterrnined
the hospice med1ca . bY
.. . 1cat1on can
only be done by a phys1c1an. One can continue to receive hosp·
ice care as
long as the hospice medical director or the individual's physician .
. . , continue
to certify a prognosis of 6 months or less. Hospice care is provided .
In two
90-day periods of care, followed by unlimited 60-day periods. Face-to-fa
encounters with either.the hospice physician or hospice nurse practitione~e
prior to the beginning of the third and subsequent benefit periods are
required.

The patient or representative may revoke participation from hospice at any

time in writing. A verbal revocation of benefits is not acceptable. Discharge
from hospice can also occur in the following circumstances:

(1) The beneficiary moves away from the geographic area that the
hospice defines in its policies as its service area;
(2) The beneficiary transfers to another hospice;
(3) The beneficiary's condition improves and he/she is no longer
considered terminally ill. In this situation, the hospice will be unable
to recertify the patient; or

(4) Death of beneficiary.

Who Pays for Hospice Care

Hospice care is less costly than care provided for in hospitals, nursing
homes, or other specialized institutions. As the family is the primary resource
and much of the care is done at home, less high-cost technology is used
in the care of the patient. In the US, hospice services are generally covered
by Medicare, Medicaid, the Department of Veterans Affairs, most private
.insurance, HMOs, and many managed care organizations.
. . If .ins urance is not
available or is not enough to cover the costs of services, the patient andlor
. can pay-out-of-pocket. Some hospices provide care fort hose who are
family
not able to afford services through charity donations.

.
All services . for the treatment of the patient's
required . . I ·11ness
termina 1
will•
be covered by hospice. For the federal fiscal year 2018, Me d.Icare hospice
payment rates are $192 for routine home care, $172 for inpatient respite
care, and $743 for general inpatient care.
·ces
Hospice serv'
156
 also has an annual cap for total r~imburs~ment per patient, which
1 .1edicare IY $28 689 for 2018. All hospice services required by Medicare
iv'
0
imate '
15 8ppr ~ d to patients are paid for by this reimbursement (see Table 1).
,n8t provide orne hospices with little room to pay for extra or high-cost
-rnis 1eaves s trnents, such as radiation, blood transfusions, or palliative
·altY trea
5peCI
..,, theraPY·
cne,,·0
. s that hospice cannot provide include costly treatments such
er service
oth nteral nutrition (TPN) and regular laboratory work and diagnostic
total pare
as . Hospices with large numbers of enrolled patients are more able to
·rriaging.d't' nal services, sue h as ·1npat·1ent units
1
· and therapies on a limited or
0
tter ad I 10 . . .
. basis. Under the Medicare Hospice Benefit, Medicare will not pay
tirrie-tna1
ent of the terminal illness that is not for symptom control or pain,
fortreatm . . . . .
another provider that duplicates care for which hospice 1s required
care fro m
'de or care by another provider not arranged by hospice.
to prov1 ,

Selecting a Hospice Program

Choosing the right hospice is an important part of end-of-life decision
making and should be done carefully. The best time to make these difficult
decisions is before a crisis occurs when choices can be made without
added stress or time constraints.

Hospice services can vary by providers, so it is important to select a hospice

program that will meet the individual needs of the patient and family. There
may be several hospice programs available in a certain region or area,
allowing the opportunity and ability to select the most appropriate one.
Family and patients should be encouraged to ask questions and review
all information that may be provided by friends and family who have had
previous experience with a particular hospice, health care providers, the
state health department, insurance company, NHPCO, and the Internet.

~fter making a list of one or more hospices in the community, the next step
is to interview each program being considered to ensure that all desired
~ervices can be provided to the patient. Some questions to ask should
include:

• Is th e hospice accredited? If so, by whom?

• What services exactly will the hospice provide for the patient?

Hospices .
erv1ces
157
 • How often will visits be made from the nurse and 0 th
er staff?
• Are the nurses and physicians certified? ·
• Is the hospice for-profit or nonprofit?
• How are services provided after hours?
• Where is the hospice's inpatient facility (or contracted in Pat'Ient
facility)

Palliative Care Pearls

• Hospice care is appropriate for patients entering the last weeks t0
months of life who decide to forgo disease-modifying or curative
treatments and want to instead focus on maximizing quality of life.
• Palliative care focuses on preventing and relieving suffering for
patients and families facing advanced illness.
• Palliative care arose from the hospice movement but is not limited to
end of life/hospice care.
• Patients do not have to have a DNR nor do they have to be actively
dying in order to receive hospice care.
• Hospice care provides care to patients and their families but is often
underutilized or initiated too late in the disease trajectory.

Recommended Reading
National Hospice and Palliative Care Organization: History of Hospice Care
http://www.nhpco.org/history-hospice-care

NHPCO Facts and Figures: Hospice Care in America 2014 Edition http://
www.nhpco.org (Accessed on February 02, 2015).

NHPCO Facts and Figures: Hospice Care in America 2018 Edition http://
www.nhpco.org(Accessed on August 08, 2018).

Dying in America Improving Quality and Honoring Individual Preferences

Near the End of Life, Institute of Medicine, 2014. http://www.iom.edu/
. ·dual·
Reports/2014/Dying-ln-America-lmproving-Quality-and-Honoring-ln d,vi
Preferences-Near-the-End-of-Life.aspx

·ces
158 Hospice Ser,''
,,.....-- N

G118Pter 23 Bleeding

. M lik, MD and Marieberta Vidal, MD

Jirl'II S a

. . reported to occur in approximately 6-14% of patients with

Bleeding i5
advanced cancer. When it does
.. occur, hemorrhagic episodes can be very
. g for patients,
frightenin . families, and
. health. care. professionals. Management
of bleeding in palliative care r~qu1res cons1derat1on of the underlying etiology,
possible interventions to allev1at~ or reverse underl~ing cause, risk to benefit
ratio of interventions, and most importantly, the patient 1s overall disease
burden, life expectancy, and goals of care.

Mechanism
Bleeding may occur in advanced cancer patients by local damage caused
by tumor growth and also by systemic abnormalities caused by the cancer
itself, by its treatments, therapeutic/prophylactic anticoagulation, or the result
of comorbidities.

Fungating head and neck or lung tumors close to blood vessels are the two
most common sources of bleeding caused by local tumor damage.

Around 50% of advanced cancer patients present with clotting

abnormalities; therefore, mixed local/systemic causes for hemorrhage are
common. Systemic coagulation abnormalities might arise from liver failure,
cancer treatments, sepsis, anticoagulant medication use, bone marrow
suppression, and primary coagulopathies involving clotting factor or platelet
abnormality.

Classification
Acute epis0 d · t· t
. es are generally catastrophic and caused by cav1ta 1ng umors
in the lung . · · 1 d
s or other organs, especially when 1nvas1on of maJor b oo
vessels is · · I
. Present. Bleeding may present internally, such as 1ntracrania
or intrabd . · .
ominal, or externally, such as hemoptysis, hematemesis,

Bleeding

159
11111
 hematochezia, melena, hematuria, vaginal bleeding , with severe epis
potentially leading to shock. Odes

Chronic bleeding
. episodes are. less
. threatening and may pre sent as minor
.
hemoptys,s from endobronch,al disease, bleeding from ostom·1es due to
stoma vascularity, or bleeding from cutaneous fungating tumors.

Workup
Focus on detecting the underlying cause.

Perform a comprehensive history with identification of patients at risk for

bleeding (by detecting etiologic factors cited above).

Identify goals of care to outline management. In patients with greater life

expectancy and good overall quality of life, volume resuscitation with IV fluids
and/or blood transfusions should also be considered. If goals of care are
mostly palliative in nature, measures to stop bleeding without resuscitative
measures are reasonable.

Laboratory Studies should be individualized depending on goals of care, and

may include, but are not limited to: complete blood count, platelet count,
activated partial thromboplastin time, international normalized ratio (INR),
cultures, more specific coagulation system workup, and imaging.

Management
General measures

1. Identify patients at risk for massive external bleeding

• Minor recurrent episodes of epistaxis, hemoptysis, hematemesiS,

hematuria, and hematochezia
• Large head and neck tumors close to blood vessels
• Liver failure
• Thrombocytopenia
• Large centrally located lung tumors
• Refractory leukemia and myelodysplasia

L 160 s1eedi119
 'II

• . nt and family education and awareness

50 pat1e
z. 1ncrea d families with the above risk factors should be made aware of
·ent an ·t·
pat1 . threat in a sens1 1ve manner, so as not to evoke fear Ed t
otent1a1 . . . uca e
the~ to place a patient with severe hematemesis or hemoptysis in a left
11185
tarn cubitus position to prevent aspiration. Next, apply pressure at
la teral de ·nts in access1'bl e areas. It ·1s aIso ·important to commu . t
eedinQ poi . . nica e
bl . f massive bleeding with other health care providers involved .
the risk o 1n
·ent's case.
thepat1
. . evidence of bleeding
3 Min1rn1ze . . . .
·The sight of the bleed1n_g 1s very frightening for most people, especially for
the patient and the family. Use dark red towels, bed sheets, pillow covers,
bassinets and utensils to camouflage blood and make the bleeding event
appear less pronounced.

4. Reduce anxiety
Fast-acting sedatives such as lorazepam (IV) and midazolam (IV or SC)
should be readily available and given to the patient during active massive
bleeding. Ongoing psychological support should be provided to the
patient and family.

Specific Treatments
Local

• Packing is indicated when bleeding originates from organs such as

the nose, vagina, and rectum, or from stomas. It may be done with
or without pressure in order to achieve hemostasis. Surgical swabs
might be impregnated with hemostatic agents such as acetone,
epinephrine, formalin, and sucralfate. Concomitant application of ice
or silver nitrate cauterization might be considered. Thromboplastin,
which comes in powder form, may be applied under dressings.
• Hemostatic dressings with agents such as gelatin, microfibrillar
collagen, fibrin, and alginates may be used to absorb the oozing
from smaller hemorrhagic wounds. Minimally adherent dressings
such as soft silicones, hydrogels, petroleum jelly gauze, and foam
dressings used as initial dressing layer help to prevent pain and local
trauma with dressing changes when used together with absorptive
dressings.

131Ao, .. ,
""'-'Ing

161
I. Radiotherapy is effective to decrease bleeding from lu ng, rectum
bl dd
vagina, head and nee_k, an d a. er can~ers. Single radiation
---

fractions are as effective as multiple fractions to control bl eed1ng.

,
,

, Endoscopic interventions with the injection of sclerosin

'
ligation, or laser coagulation are useful to control bleeding nOt ·
from the upper gastrointestinal tract, but also for bleeding fromonly
the
lungs and bladder.
, lnterventional radi~logy pr~ce?ures,. such as transcatheter and
transcutaneous arterial embohz~t1on, might be indicated in selected
head and neck, lung, gynecologic, and gastrointestinal cancer
patients.
• Surgery also might be indicated for selected patients who are
considered appropriate for the procedure. It consists of ligation
of larger vessels, removal of bleeding tissue, or mass reduction of
tumors encroaching upon vessels.

Systemic
• Vitamin K is an option for patients with liver disease or impaired oral
intake. It can be delivered orally, intravenously, or subcutaneously,
and the indicated doses are 2.5-10mg.
• Octreotide 50-100µg subcutaneously or intravenously twice daily
might be used to control gastrointestinal bleeding. The dose can be
titrated up to a total of 600µg daily.
• Antifibrinolytic agents examples are tranexamic acid (10mg/kg IV
q6h infused in 1h) and aminocaproic acid (4-5mg in 250ml over 1h IV
then infusion of 1g/h until bleeding stops , or a maximum of 8h). Oral
versions of these medications are also available, and the dosing is
variable.
• Blood products must carefully be considered as a palliative
option by weighing the harms vs. benefits. They are indicated if the
transfusion has potential to alleviate symptoms and improve quality
of life.
• Packed red blood cells play a role in symptomatic anemia,
and benefits post-transfusion may last for up to three weeks,
• Platelet transfusions are a consideration for symptom control
in the presence of gum bleeding, epistaxis, large painfu~
t1
hematomas, and continuous bleeding from gastrointeS nal
or genitourinary malignancies. Platelet transfusions are not
recommended for prophylaxis.

s1eedi119
162
L
 • Fresh frozen plasma might be indicated in selected patients
with specific coagulation factor deficiencies or those in
whom fast reversion of anticoagulation is needed .

. f"e care Pearls

pa111a 1 . .
'f patients at high risk of severe and catastrophic bleeding. Document
1dent1 y . th . k f .
nd communicate e ns o massive bleeding with other health
in notes a . . '
'ders involved 1n the patients case.
care prov1

e the patient and family members in a compassionate manner about

, educa t . .
. k of bleeding and its consequences. Setting expectations earlier can
thens . .
help decrease patient and family stress 1n the event of a major bleed.

prepare for bleeds with dark red colored towels, sheets, and bassinets
should be readily available for patients at risk for catastrophic bleeding.
Midazolam or Lorazepam must be readily available in cases of catastrophic
bleeding to reduce the distress inherent of seeing oneself massively
bleeding.

Treat with the following options:

• localized hemostatic measures, more invasive endoscopic and

embolization techniques
• systemic measures such as transfusions and pharmacologic
therapies

Recommended reading
Gagnon B, Mancini I, Pereira Jet al. Palliative management of bleeding
, events in advanced cancer patients. J Palliat Care 14:50-4, 1998.

, Hague J, Tippett R Endovascular techniques in palliative care. Clinical

Oncology. 2010;22(9):771-780.
Pe ·
reira J, Phan T. Management of bleeding in patients with advanced
cancer, The Oncologist, 9:531-70, 2004.
Harris DG N · r t
. ' Obie SIR. Management of terminal hemorrhage 1n pa ien s
1th
r' : advanced cancer: a systematic literature review. J Pain Symptom
1r, anagernent, 38(6):913-27, 2010.

81 eeding

163
I Chapter 24 Sleep Disturbance

Sriram Yennu, MD

Self-reported
. .. sleep disturbance
. (SD) in patients with advanced cancer .1s a
s1grnf1cant source of distress and impacts negatively on QOL· Th e frequency
of SD in patients with cancer ranges from 24% to 95% · Cancer pat·1entshave
higher probability of being hospitalized or institutionalized , further worsernng
•

the sleep disturbance.

Type of sleep disturbance

SD is classified into two categories:
• Dyssomnias: the patient suffers from changes in the
amount, restfulness, and timing of sleep (insomnia,
hypersomnia, sleep apnea and circadian rhythm sleep
disorder).
• Parasomnias: typically characterized by abnormal behavior
during the sleep (nightmare disorders, sleep terror disorders,
sleepwalking disorders).
• The most commonly reported SD in cancer is frequent waking.
Behaviors of cancer patients that disrupt the sleep cycle include
spending more time in bed, reduced daytime activity, or mental

stimulation.
• Others important causes SD:
• Restless legs syndrome (RLS) is a common disorder in
cancer patients. RLS consists of involuntary limb movements
with a striking periodicity resulting in insomnia.
• Obstructive sleep apnea is a SD in which breathingt
repeatedly discontinued during sleep. This is the moS 1
common type of sleep apnea. It occurs when oropharyngea
muscles intermittently relax and block airway during sleeP•
The most noticeable sign of obstructive sleep apnea is
snoring and it is more common for overweight patient.

Sleep Disturb811 c;e

164
 tors and common causes of sleep disturbances
~isl< fac
to be more common among female and older patients. One
Dappears . . .
S . r factors that affect sleep quality 1n patients living with cancer is
0
f the rnaio 1!
ce of poorly controlled symptoms, especially pain and dyspnea . .. Jf
he presen . .
t hosocial distress (anxiety and depression). Patients with pain can
nd psyc
a . e difficulty with sleep onset and sleep maintenance.
expenenc
. nd sedative/hypnotic medication use have also been reported as a
fatigue a .
. k factor to develop SD. More than half of patients (52%) attributed their SD
;: "intrusive thoughts" and 45% attributed their SD to physical discomfort.

Diagnosing and evaluating sleep disturbances

Sleep quality is assessed by two different ways:

• objective, such as sleep duration, sleep latency, number of arousals

• subjective, such as depth or restfulness of sleep

Mainly, in our clinical practice, it is feasible to assess self-reported sleep

disturbances using the ESAS Sleep Item. The best cut off score is 3/10.

Management of SD
. The first treatment of SD should be preventive.

• Prevention of sleep disturbances

Here are some simple sleep hygiene tips for patients:
• Go to bed at the same time each night, and rise at the same
time each morning.
• Sleep in a quiet, dark, and relaxing environment, which is
neither too hot nor too cold.
• Make your bed comfortable and use it only for sleeping
and not for other activities, such as reading, watching TV,
or listening to music; remove all TVs, computers from the
bedroom.
• Avoid physical activity at least 6 hours before bedtime;
physical exercise during the day, light exercise in the
afternoon, at regular time contributes to better sleep.
• Natural light during the daytime hours especially in the
afternoon promotes a good sleep.
Sleep 01
llturbance
165
 C
• Avoid large meals before bedtime.
• Excessive
. or regular use of caffe1ne
. (tea or coff )
cause insomnia and restless sleep· 1• • • ee may
I th ' imit caffeine ·
ess an two servings per day and intake to
noon. , suspend all use after

• Avoid even power naps after noon.

• Treatment of Sleep disturbances

The management
. of sleep
. disturbances as in the case of fat'igue requires
.
a mult1modal approach, including non-pharmacologic and h
(Table 1) interventions. P armacologic

Non-Pharmacological Management
Lifestyle interventions such as exercise, sleep hygiene (cf above), cognitive
behavioral therapies (CST)- insomnia, and muscle relaxation have been
demonstrated to be effective in the treatment of primary insomnia.
Preliminary evidence indicates that yoga-a mind-body practice and form
of exercise-may improve sleep among cancer survivors. In a randomized,
controlled clinical trial yoga intervention (Yoga for Cancer Survivors [YOGAS]
program compared with standard care for improving global sleep quality
(primary outcome) among post-treatment cancer survivors suffering from
moderate or greater chronic sleep disturbance demonstrated greater
improvements in sleep quality and reduced need for sleep medications.

CST is a multimodal intervention with behavioral, cognitive, and educational

components. The behavioral intervention included recommendations to
restrict time in bed to the time slept. CST aimed to revise false beliefs and

misconceptions about sleep.

Another promising method used in the treatment of sleep disturbances in
advanced cancer patients is bright light therapy. Light therapy is usedndto
expose your eyes to intense but safe amounts of light for a specific a
regular length of time (-30 minutes).

Physical exercise of sufficient frequency, intensity and duration improves

cancer-related fatigue but also sleep disorders.

s1eeP Disturbance
166
d
 logic Management
p~artTlaco . .
. ines are used because of their sedative properties to reduce
zod1azep . . .
sen leeP onset and to improve sleep efficiency. Despite their effect
tirne to s . .
the tterns and architecture, agents acting at on the gamma-amino-
51eeP pa . .
on . 'dfbenzod1azep1ne receptor, such as zaleplon and zolpidem do
tYncac1 . . . '
blJ clear clinical role for cancer patients with sleep disturbances
othavea . . . .
n nts are associated with a high frequency of falls among cancer
These age
patients.
. essants are the first choice if the patient presents with major
Ant1depr . . . . .
·
ion complicated by insomnia. Selective serotonin reuptake inhibitors
depres S . . .
ve a role 1n the treatment of insomnia other than depression-related
do not ha
. mnia because of its very low sedating effects.
1nso ,

Mirtazapine acts on different receptors, including serotonin and histamine

receptors. It's sedating, can stimulate appetite, and is less toxic when
compared with other antidepressants.

Multimodal Interventions
As there are limited studies in palliative care patients regards to the most
effective therapy, it may be reasonable to provide a trial of combination of
interventions which target various dimension of SD so o provide a clinical
effective response in a short period of time. For example a trial of melatonin,
counseling and methylphenidate may be beneficial in patients with SD and
fatigue. However close monitoring of efficacy and side effects is a must.

Sleep o·
isturbance
167
 C

~ b l e 1: Pharmacological Management of SI eep Dlsturbanc

' ' , I e
drowsiness . sh
memory lo;s ootterrn
zaleplon 5-10 mg coordination i r ack Of

Short-onset, brief Rapid sleep inductlon-

1-d_ur_a_t_lo_n_ _ _ _- i -- - - -- - - - l limited effect on sleep'
maintenance
Triazolam 0.125 mg
sedation, delirium nd
fatigue, 'a
0.5-1 mg
i- - - - - - t - - - - - + -No-clear
Alprazolam
- advantage
---1
exacerbation
Short-onset,
over benzodiazepines; of respiratory
Intermediate
costly; minimal suppression when
duration of action
1 - - - - - - - - + - - - - - - - - - - I anxiolytic effect combined with opioids,
Zolpidem 5-10 mg even at a low dose

Zopiclone 5-7.5 mg tolerance occurs

i -Eszopiclone
--------t- - - - - - - - - t - - - - - - - - - 1 rapidly
3 mg • and prolonged
use can increase sleep
Adequate effect in disturbances
Intermediate onset,
sleep induction and
1----------+--------~
duration maintenance; risk of
1--Lo_r_az_e_p_a_m_ _ _-i_o_._5-_4_m_g_ _ _ _---1 daytime drowsiness

Tamazepam 7.5-15mg
To use as first choice increased risk of . ·
Longer latency to treatment when daytime sedation,
onset, prolonged associated with confusion,
activity (off label depression constipation,
treatment for cardiac conduction
Insomnia) abnormalities,
orthostasis and
Amitryptilene 25-100 mg anticholinergic activity

lmipramine 25-100mg

Doxepin 25-100 mg

Trazodone 25-100mg
Start with 15 mg at
Mirtazapine 15-30 mg bedtime.
extrapyramidal effects,
Used mainly in sleep
dizziness, tiredness,
Variable activity (off disturbance related to
label treatment for akathisia
delirium/psychosis.
insomnia)

Haloperidol 0.5-5 mg

Risperidone 0.5-1 mg

Olanzapine 5-10mg

Quetiapine 25mg

rt,ance
s1eeP DislU
168
d
 . care pearls:
pa
,nat•"e disturbance is underreported and undertreated. Sleep
• sieeP
. t rbance affects th e qual'tI Y of l'fI e of patients
· with advanced
dis U . . /f .1
illnesses and their caregivers am1 y members.
mprehensive evaluation of all symptoms related to sleep
• AGO I .
disturbances is extreme y important.
the setting of sleep disturbances in advanced illnesses, always
• Ievaluate
n for the presence of d e1·1num.
.

• When treating patients with sleep disturbances, it is very important

to use a multimodal approach that includes both pharmacologic and
non-pharmacologic interventions.

, Recommended Reading:
Yennurajalingam S, Chisholm GB, Palla SL, Holmes H, Reuben JM, Bruera
E. Self-reported Sleep Disturbance in Patients with Advanced Cancer:
Frequency, Intensity, and Factors Associated with Response to Outpatient
' Supportive Care Consultation: A Preliminary Report. Palliat Support
Care(4):1-9. e-Pub 11 /2013.

Yennurajalingam S, Balachandran D, Pedraza Cardozo SL, et al. Patient-

1 reported sleep disturbance in advanced cancer: frequency, predictors and
screening performance of the Edmonton Symptom Assessment System
sleep item. BMJ supportive & palliative care. 2017;7(3):274-280.
I I

Davis MP, Khoshknabi D, Walsh D, Lagman R, Platt A. Insomnia in Patients

With Advanced Cancer. American Journal of Hospice and Palliative
Medicine®. 2014;31 (4):365-373.
(
Davis MP, Goforth HW. Long-term and Short-term Effects of Insomnia in
1
Cancer and Effective Interventions. The Cancer Journal. 2014;20(5):330-344.
I

Morin CM, Colecchi C, Stone J, Sood R, Brink D. Behavioral and

Pharmacological therapies for late-life insomnia: a randomized controlled
t.I
na · JAMA 1999;281 :991-999.
I

169
 chapter 25 Spiritual Care

Marvin omar Delgado-Guay, MD

. Spiritual Care In Patients w~

Spirituality and Religiosity and
Advanced Illness and Caregivers
Patients with life-threatening illnesses might suffer with existential and
spiri!Ual concerns, along with the burden caused by physical, emotional
and financial distress, and the suffering of the caregivers. Every single d~y
of our journey, walking as members of the palliative care team, we enter into
the life of those patients with whose soul is broken. We are very privileged to
be able to touch sacred ground and to know and be able to explore wishes
also at the end of life. Using the Go Wish Game cards our team reported that
the ten most common •very important" wishes identified by patients with
advanced cancer at the end of lite were "to be at peace with God'; ·to pray";
"to have my family with me"; "to be free from pain"; "not being a burden
to my tamily"; ·to trust my doctor"; "to keep my sense of humor"; "to say
goodbye to important people in my life"; "to have my family prepared for my

death"; and "to be able to help others".

The characteristics of spirituality and religiosity overlap considerably. Main
common themes include a relationship with a God, spiritual being, Higher
Power, or reality greater than the self (i.e., not of the selij; transcendence
or connectedness unrelated to a belief in a higher being; existentialism j .e.,
not of the material world); meaning and purpose in life; and life torce of the
person, which integrates aspects of the person and multiple themes-

Spirituality has been defined as "the aspect of humanity that refers to tne
way individuals seek and express meaning and purpose and the waY theY
experience their connectedness to the moment, to self, to others, to nature,
and to • significant or sacred". Its meaning is not limited to participation in
th
organized religion; rather, it encompasses a belief in God, family, naturalisrn,
rationalism · humanism,
· an d even the arts. It is also connected to f'in din9
direction, self-worth, belonging to a community, to love, to be 1oved, and

car•
5pfrltl.l8 I

170
 ------..ii

.. d through see k'1ng reconc1·1··

1at1on when relationships are
facilitate
is o~en
broKen- . .
. ·tuality is a d1mens1on of personhood, religion is a construct
as spin
Where k'ng that enables the conceptualization and expression of
an rna I •
of hUrll . Religion includes a structured belief system that addresses
· ·tuahW•
1 f h' I
spir • s often with a code o et 1ca behavior and philosophy.
. ·tual issue '
spin ·t als enact and manifest the meaning of the sacred· they
rgious
1 nu '
Re . hared meaning, foster belonging and bridge the boundary
establish s .
between
the personal and the social. I!

. . i·ty is a lifelong developmental task, lasting until death. It serves

sp1ntua 1 . . .. .
j
5evera I Purposes in different stages of life. Sp1ntuahty and religion continue ,
to play an important role across cultures globally. Spirituality is experienced
broadly as an important dimension of how patients live with advanced and
terminal illness. Factors that help and give strength during the illness process
include strong spiritual components of family relationships, the meaning of
God/a higher being, and spiritual practices.

Many individuals recognize their life-threatening illness as an opportunity for

spiritual growth, therefore these individuals who have access to spirituality
through meaning, purpose, connections with others, or connections with a
higher power will have the spiritual resources necessary to adjust to adverse
circumstances. Spirituality provides a system of meaning that emphasizes
hope, adaptation, insight, and the belief that circumstances are not
senseless or meaningless. Having a sense of spirituality has been identified
as an important coping resource.

' It is extremely important to recognize, independently of the stage of the

illness, that patients may benefit from having their spiritual needs addressed
as experiencing some form of religious/spiritual struggle may serve as a
barrier to illness adjustment. Even among patients who do not consider
~hernselves religious or spiritual, spiritual needs are frequent. It is extremely
irn~~rtant that the interdisciplinary team explore, .assess, and support th e
spiritual needs and concerns of patients and their caregivers and to work as
a team to d · · f 1·f
ecrease their suffering and improve their quality o I e.
Facing a l'f1 . . I ..
e-threatening illness and the end of life can be a spintua crisis.
lhe ass 'f ·
essment of spiritual/religious needs can identify the speci ic services

I Sp1m. .
I '"" 8 1Care
171
b
 C

and assistance the patient most desires and 1s

• a· first
. st •
needs-tailored interventions. ep in designing

Healthcare providers and medical institutions often do not do

of attending to this dimension of the patient's ca re. Attent1on
. toa rgood
I' . Job
spiritual issues might provide a significant influence on several ime igious/
indicators of quality care and reduces the use of agg ress1ve
. care portant
at th 8
~Ii~. ~d

.44% of. advanced

" patients
. · 8p1ntual
.reported experiencing spiritual pa1n. . . pain
1s defined as a pain deep 1n your soul (being) that is not phys1
·ca I"• pat1ents
.
with spiritual pain might have significantly lower self-perceived religiosity
and spiritual quality of life. Assessment of spiritual distress, identifying
spiritual needs, and facilitating appropriate spiritual care at several time
points throughout the continuum of care is essential. The use of Edmonton
Symptom Assessment Scale - financial and spiritual (ESAS-fs) might allow
us as clinicians to start exploring the presence of spiritual pain. This tool
might help us to open the channel of communication with our patients and
to find distressing spiritual issues or spiritual needs. Further validation of this

tool is needed.
The most common spiritual issues in patients with advanced cancer
include: 'seeking a closer connection with God or one's faith,' 54%; 'seeking
forgiveness (of oneself or others),' 47%; and 'feeling abandoned by God,'

28%.
Patients with l~e-threatening illness struggle with spiritual/existential
. · I h 11 es of their illness. As
concerns alongside the physical and emot1ona c a eng th
the patient's condition deteriorates, the emphasis shifts from 'fighting' e
illness to making the most of the time left, These spiritual concerns could
. ers and staff
t
be addressed by: having someone to talk to, supper 1ve car ,
showing sensitivity/ taking care to foster hope.
. d /concerns
Caregivers of patients with advanced illnesses have spiritual
. k'nee11 activ1t1es
s ..
and suffering also. They might be engaging in "meaning-ma ,ng
by
. expressing important values such as hope, dignity, togetherness, .
th n farnilY
involvement, continuity, and demonstrating their desire to streng e
ties and deepen personal growth. Caregivers, who are more religious feel
more positively about their role as caregivers, get along better with those for
whom they provide care and express less caregiver distress.
5plrit1JSI care
172
 . of life of caregivers might decrease proportionally to the
fhe quah_tYe decline of the general health, functioning, and worsening of
prog
ressiv
f the patients.
Th . t' f t· .
e1r sa 1s ac 1On 1n the spiritual and meaning
ptorns O . .
sY111 . i ht decrease dunng the dying process, possible due to lack of
domain rn g ort to their spiritual needs at that stage of life. Caregivers with
' ·tual SUPP ' '
spin . had higher levels of anxiety, depression, denial, behavioral
•ritual pain
sP' ent dysfunctional coping strategies, and worse quality of life
d '
15 engagern I

who did not have spiritual pain.

than those
. . rtant to pay attention to the patients' and caregivers' cultural and
It 1s ,rnpo
. • identity and spiritual needs and their spiritual distress/struggles
sp1ntua 1
along the continuum of care.

The spiritual assessment should be patient-centered and guided to the

extent to which the patient chooses to disclose his or her spiritual needs. It
is recommended that it be incorporated into the social history section of the
patient's overall history and physical examination. Care providers conducting
the assessment should not impose their beliefs or answer relevant questions
or concerns the patient may have; such questions and concerns should be
referred to a professional chaplain . In addition, this process does not oblige
care providers to discuss their beliefs and practices. The main goal of the
spiritual assessment is to understand the role of spiritual and religious beliefs
and practices in a patient's life and the role they play in the patient's ability to
cope with advanced illness.

A clinical validated tool developed at the George Washington Institute

for Spirituality and Health is the FICA (faith, importance, community, and
address) Spiritual History tool. FICA provides a way for the clinician to
efficiently integrate the open-ended questions into a standard medical
st0
hi ry and can be used by health care professionals (Table 1).

Spiri~ual Care integrated into the Supportive/Palliative Care

setting
Spiritual c
h are must be part of the biopsychosocial-spiritual approach to
ealth care d
I ett . ' an Palliative care programs are developing strategies to
ect 1nstitut' •
W'th
1 . ional change and resources to assist health care providers
care irnproving th eir
· d ellvery
· · 1·,nary pa 11·1at·1ve
of spiritual care. The interdisc1p
I rnoctel of s . . .. . .
pintual care proposes inclusion of the spiritual domain 1n
Spiritual C
I are
173
the overall screening and history-taking process as well as a full sp·1ntua1
.
assessment by the professional chaplain as needed.

Spiritual interventions can be understood as therapeutic strategies that

incorporate a spiritual or religious dimension as a central component oft
intervention. Religious or spiritual activities can be practiced through the he
continuum of care to help support persons with a life-threatening illness,

Religious interventions are more structured, cognitive, denominational I

external, ritualistic and public, whereas; spiritual interventions are more

cross-cultural, affective, transcendent and experiential. Interventions should
be agreed with the patient, and tailored to their worldly perspectives to help
them during an illness or crisis.

Prayer is a powerful form of coping that helps people physically and

mentally. Prayer is a communication or conversation with divine powers or a
"higher self". Prayer is practiced by all Western theistic religions and several
of the Eastern traditions (e.g., Hinduism, Sikhism, Buddhism and Taoism).
Group prayer is associated with a greater wellbeing and happiness while
solitary prayer is associated with depression and loneliness. In medical
settings, forgiveness and repentance are within the purview of a pastoral
counselor and clergyperson. Both prayer and bibliotherapy with sacred
writings must be consistent with patients' needs and requests.

Meditation produces the sense of calm, limited thought, and attention.

Meditation is widely used as an alternative therapy for physical ailments.

Cognitive-behavioral therapy (CBT) represents a unique category of

psychological interventions based on scientific models of human behavior,
cognition, and emotion CBT intends to reduce distress directly, target
symptoms, re-evaluate thinking and promote helpful behavioral responses.
Provision of spiritually oriented or spiritually attuned approaches to
psychodynamic psychotherapy pays especial attention to the role religious
nd
beliefs, God-representations, and spirituality play in the psychic world a
health of the patient.

Chaplains can help patients and families find meaning In their hospitalization
and illness experiences. At the same time, they can provide traditional rituals
including prayers, blessings, baptisms, funerals, and periodic memorial
services at the hospital for families of patients who have died. When
Spiritual care
174
 ropriate, another service provided by the chaplain is to serve as a liaison
aPP atient and family's faith community.
to the P

need to be aware of the very strong spiritual and religious needs of the
we ' ·11
patients with a life-thre~t~rnng ness and their caregivers. We can help to
I

·dentify spiritual and religious needs and struggles. We can facilitate the
1
ection with the chaplain and further spiritual care needed
conn ·

An Interdisciplinary team approach with multiple interventions to provide

a touch of hope and a touch of love to decrease suffering and to improve
the quality of life of patients with advanced and terminal illnesses and their
caregivers.

Palliative Care Pearls

• Spiritual care is part of all members of the Supportive and Palliative
Care team. It is an essential domain of quality Supportive and
Palliative Care.
• Spirituality and religiosity play important roles in patient's abilities
to cope with disease-related symptoms, improve quality of life, and
affect medical decision-making near death.
• Patients with advanced illnesses report spiritual concerns and needs
arising from illness.
• Many patients with advanced illnesses desire spiritual care from
medical providers, but its provision remains infrequent.
• Family/caregivers of patients with advanced illnesses may
experience typical patterns of spiritual well-being and distress in
parallel with patients. Always look for that spiritual distress on them:
• An Interdisciplinary team approach with multiple interventions to
provide a touch of hope and a touch of love to decrease suffering
and to improve the quality of life of patients with advanced and
terminal illnesses and their caregivers.

Recommended Reading
Delgado-Guay MO. Developing a Healing Environment for Broken Souls
of Patients with Life-Threatening Illnesses and Their Caregivers. J Pain
Symptom Manage. 2018 Apr;55(4):1231-1236.

Spiritual Care
175
 Delgado-Guay MO, Rodriguez-Nunez A, De la Cruz v Fri'sb H
' ee- urne S
Williams J, Wu '

J, Liu D, Fisch MJ, Bruera E. Advanced cancer patients' reported .

wishes
at the end of life: a randomized controlled trial. Support Care Can
cer.
2016;24(10):4273-4281.

Delgado-Guay MO. Spirituality and religiosity in supportive and palliative

care. Curr Opin Support Palliat Care. 2014 Sep;8(3):308-13

Delgado-Guay MO, Hui D, Parsons HA, Govan K, De la Cruz M, Thorney

S, Bruera E. Spirituality, Religiosity, and Spiritual Pain in Advanced Cancer
Patients. J Pain Symptom Manage. 2011 ;41 (6):986-94.

Borneman T, Ferrell B, Puchalski C. Evaluation of the FICA tool for spiritual

assessment. J Pain Symptom Manag 2010;20(2):163-73.

Peteet JR, Balboni MJ. Spiritualty and religion in oncology. CA Cancer J Clin
2013;63:280-289.

Table 1.
FICA Tool

F - Faith, Belief, Meaning Questions

Do you consider yourself spiritual or religious? .
1
Do you have spiritual beliefs that help you cope with stress?
What gives your life meaning

I - Importance and Influence What importance does your faith or belief have in your life:
How would you rate the importance of faith/belief in your hie?
(Not at all to Very Important) s? I
Have your beliefs influenced you in how you handie st r~s .

-
What role do your beliefs plan in your health care dec1s1on-
making?

C - Community
A - Address in Care
-
Are you a part of a spiritual or religious community?
Is this of support to you and how? h re important
Is there a group of people you really love or w o a
to you?
Ider to use this
How would you like your health care prov f r you?
information about your spirituality as they care o

L
care
SplritU 8 I
11s
jiiiP

chapter 26 Prognostication in
Advanced Cancer

David Hui, MD, MSc

In the last months of life, patients with advanced cancer, their family
caregivers and clinicians are faced with many complex decisions related to
cancer treatments and care planning, such as whether they should proceed
to the next line of palliative systemic therapy, whether a palliative procedure
is warranted, and when a referral to hospice care is appropriate. A patient's
expected survival can fundamentally shift the risk-to-benefit ratio for many
of these palliative interventions, and represents one of the most important
considerations in healthcare decision making.

Over 80% of patients with advanced cancer desire to know about their
prognosis. Indeed, patients who expressed an understanding that they have
a poor prognosis are less likely to consider chemotherapy at the end-of-life.
There are several principles related to the science of prognostication.

1) Prognostication is a longitudinal process. Survival estimates may

change over time. Multiple dialogues are necessary to ensure
patients have a good understanding of their illness trajectory.
2) Prognostic factors vary by the stage of disease. The prognosis for
early stage cancer is driven mostly by cancer-related factors, while
the prognosis for advanced stage disease is driven more by patient-
related factors.
3) Accuracy is dependent on patient population (disease type, where
along the disease trajectory), clinician characteristics (professional,
experience), the nature of prognostic question/tool, and the metric of
determining accuracy.
4) There is always uncertainty in prognostication. Clinicians can
acknowledge the uncertainty while facilitating decision making
(Hoping for the best and preparing for the worst).

Prognostication in Advanced Cancer

177
 This chapter focuses on patients with far advanced cancer, defined a th
. . s ose
with a survival of 3 months or less. We will provide an overview to the two
main approaches to formulate prognosis: (1) clinician prediction of survival
(i.e. clinical gestate) and (2) actuarial prediction of survival (i.e. calculation of
probability of survival based on prognostic factors/models).

Clinician Prediction of Survival

Table 1 shows the 3 major approaches to predicting clinician prediction of
survival. The probabilistic question and surprise question generally have
higher accuracies (C-index: 65-90%) compared to the temporal approach
(C-index: 50-60%).

Table 1. Three Approaches to Clinician Prediction of Survival

Temporal question Surprise question Probabilistic question

Question How long will this Would you be surprise What is the probability
patient live? if this patient died in that this patient would
(specific time frame)? die in (specific time
frame)?

Answer Any time frame from Yes or no Probability from Oto

days to decades 100%

Limitations Relatively low accuracy Threshold for Requires

with this approach "surprise" varies understanding of
Clinicians frequently among clinicians probability
overestimate survival Highly dependent Highly dependent
on time frame of on time frame of
prognostication prognostication

50-60% (C-index) 60-90% (C-index) 50-90% (threshold)

Accuracy -

Prognostic Factors
In the setting of far advanced cancer, all patients have serious life-threatening
illness. Thus, disease characteristics become less important. A patient's
survival is driven more by various clinical and laboratory markers.

csocer

.
Prognostication in Advanced
178
Table 2. Clinical and Laboratory Prognostic Factors in the Far
Advanced Cancer Setting
I
Prognostic domains ,:'.{<~ ~:lt,t Clinical prognostic factors ,,~1{1r,1i\ aboratoryprognostic fac tors
Functional failure Decreased performance status Decreased hand grip strength

Respiratory failure Dyspnea

Nutritional failure Dysphagia-anorexia-cachexia Hypoalbuminemia

syndrome Hypogonadism
Weight loss
Sarcopenia
Decreased phase angle

Cognitive failure Delirium

Inflammation Anorexia-cachexia Leukocytosis

Sarcopenia Lymphocytopenia
Elevated C-reactive protein E
Elevated erythrocyte
sedimentation rate
Others Edema Hypercalcemia
Elevated LDH

Prognostic Models
Although the above prognostic factors are well established, it is often difficult
to apply them in practice to formulate a specific prognosis, partly because
prognosis is often driven by more than one single factor. To address this
issue, multiple prognostic models have been developed, with the Palliative
Prognostic Score and the Palliative Prognostic Index being the most
validated. A high score generally indicates a poorer prognosis. These two
scores have prognostic accuracies (C-index) ranging between 65% and
85%,

Prognostic Calculators
While PaP score and PPI have both been well validated in the far advanced
cancer setting, several barriers prevent the application of these prognostic
scores in everyday practice, including cumbersome calculations, difficulty
in interpretation, and suboptimal accuracy (65% to 85%). To overcome
these challenges, prognostic calculators have been developed that facilitate
calculation and interpretation. For example, www.predictsurvival.com
provides survival estimates based on 7 different prognostic models
(Figure 1).

Prognostication in Advanced Cancer

179
 11111111

Table 3. Palliative Prognostic Score and Palliative p

Index rognostic

Scoring
Karnofsky Performance Status Palliative Performance Scale
10-40 2.5 10-20
2:50 0 30-50 4
2:60 2.5
0
Dyspnea (at rest) Dyspnea at rest
Present 1.0 Present
Absent 0 Absent 3.5
0
Anorexia Oral intake
Present 1.5 Severely reduced
Absent 0 2.5
Moderately reduced
1.0
Normal
0
Total WBC count Delirium (not solely caused by a single
>11000 cells/mm3 1.5 medication)
8501-11000 cells/mm3 0.5 Present 4.0
s8500 cells/mm3 0 Absent 0
Lymphocyte percentage Edema
0-11.9% 2.5 Present 1.0
12-19.9% 1 Absent 0
2:20% 0

Clinician prediction of survival

1-2 weeks 8.5
3-4 weeks 6
5-6 weeks 4.5
7-10 weeks 2.5
11-12weeks 2
>12 weeks 0

Figure 1. Prognostic Website to Estimate Survival

[ PredictSurvival.com ]
Estitruiting Sun,iv.at l n P'atients wi th Advallced Cancer u si ng Multipi. Prognostic Models ·
!icScotl(PaP~
Thil calcul.alot pro'-A<hs survival Htirnat.H for patients with advanced canc•r bued on mulUple prognostic lndicH, incll.lding the
Pall~we P~tic Score with e>.lirlum (0-PaP), Pdiatlvt Progn0$tlc lndell: (PPI), Perfom,ance Stlitus-Sutd Palllatlve Progni»tle lndU '
P•rtormance 5tat~llkit (KPS, PPS, and ECOG)

Intended o nty for patients with .i surviv.il or s i• month1 or Ins. Di,t.a is most valid in lhe one to thru month nnge.
Erur •• many 'ilf1ab6n • po1slbM and 1hil progno11ic c.atelJLllol 'Nil provide 1UMV1I data buad on publlll'ltd studies.

Required for:
How Long 00 You Thn. the Patient WIii Live7
Palutln Perfotmance Sule (PPS) ti1JR1
:----rSi
Enitr H
l,.,
Much H You Can:
PaP,o.PaP
PPS, PPI

~-....
fu , - ~ •I

......
l<AmolM)' PartOf'ff'lal'U Staws (KPS) l::1&IRl ---, 1 KPS, PtP, l).PtP
[ii.....--. - ECOO, p5.pp1
ECOG P a ~ a S&Mus l::il1Q2

--
ppt_, p5.ppl
Orallnt»a fu.-...i~ pPt. p5.pPI
Dyt()Ma at l\tst
l l~ N
PPI, f'l•PP(, PfP, D-P.I:
0.liriutn ' PPI, PS-PPI, O-P•
Anorull2
tu,--... •! PIP,O-PIP
Tou,I WBC {n Wcc )
/u,-~ •I PtP, 0-PIP
u. ..,, -..tM! , )
L~ P•~~ PtP, tJ-P-'
'"""-

ed cancer
180 . t·10n In Advanc
Prognostica
physical Signs of Impending Death
In the last days of life, there are several tell-tale bedside physical signs to
inform the diagnosis of impending death. In the Investigating the Process of
Dying Study, presence of any of these signs in patients admitted to an acute
palliative care unit strongly suggests that the patient is likely to die within the
next 3 days.

• Inability to close eyelids

• Non-reactive pupils
• Drooping of nasolabial fold
• Hyperextension of neck
• Death rattle
• Grunting of vocal cords
• Decreased response to verbal/visual stimuli
• Respiration with mandibular movement
• Cheyne Stokes breathing
• Pulselessness of radial artery
• Peripheral cyanosis
• Decreased urine output

• Upper gastrointestinal bleed

Palliative Care Pearls

• Many cancer patients desire to know about their prognosis, which
has important implications for cancer treatments and care planning.
• By limiting the time frame of prognostication, the surprise question
and probabilistic question appear to be more accurate than the
temporal question.
• In the advanced cancer setting, the 4 clinical prognostic factors
are decreased performance status, dyspnea, dysphagia-anorexia-
cachexia syndrome and delirium.
• Various prognostic models have been developed, including the
Palliative Prognostic Index and Palliative Prognostic Score.
• Use of web-based calculators may facilitate formulation of prognosis
(www.predictsurvival.com).

Prognostication in Advanced Cancer

181
r Recommended Reading
Baba M, Maeda I, Morita T et al. Survival predictlo f
. . n or advanced
patients 1n the real world: A comparison of the palli t· cancer
.. . . a ive prognostic
score, dehnum-pall1at1ve prognostic score palliative P .
' rognost,c index
nd
modified prognosis in palliative care study predictor model. Eur J a
2015;51:1618-29. Cancer

Hui D, Dos Santos R, Chisholm G et al. Clinical signs of impend'ing death in

cancer patients. Oncologist 2014;19:681-7.

Hui D. Prognostication of survival in patients with advanced cancer:

Predicting the unpredictable? Cancer Control 2015;22:489-97.

Hui D, Dos Santos R, Chisholm G, Bansal S, Crovador CS, Bruera E.

Bedside clinical signs associated with impending death in patients with
advanced cancer: Preliminary findings. Cancer 2015;121:960-7.

Hui D, Park M, Liu D, Paiva CE, Suh SY, Morita T, Bruera E. Clinician
prediction of survival versus the palliative prognostic score: Which approach
is more accurate? Eur J Cancer 2016;64:89-95.

ed caoce'
Prognostication in Advanc
182
Appendices

Appendix A. The Edmonton Symptom Assessment Scale-SF

Date: Time:

Please circle the number that best describes your symptoms:

No Pain
Worst Pain
0 2 3 4 5 6 7 8 9 10
No Fatigue
Worst Fatigue
0 2 3 4 5 6 7 8 9 10
No Nausea
Worst Nausea
0 2 3 4 5 6 7 8 9 10
No Depressed
Worst Depression
0 2 3 4 5 6 7 8 9 10
No Drowsiness Worst Drowsiness
0 2 3 4 5 6 7 8 9 10
No Shortness Worst Shortness
of Breath 0 2 8
3 4 5 6 7 9 10 of Breath
Best Appetite Worst Possible
0 2 3 4 5 6 7 8 9 10
Best Feeling or Worst Feeling of
Well Being 0 2 3 4 5 6 7 8 9 10 Well Being
Best Sleep Worst Sleep
0 2 3 4 5 6 7 8 9 10
No Financial Distress Worst Financial Distress
01~34.56
(Distress/suffering experienced secon ary to financial issues)
7 8 9 10

No Spiritual Pain Worst Spiritual Pain

0 1. 3. 4 5 6 7 8 9 10
(Pain deep in your sou;/being that 1s no physical}

Completed by: Patient Family

Appendices
183
Appendix B: The Memorial Delirium Assessment Scale
INSTRUCTIONS: Rate the severity of the following symptoms of delirium
based on current interaction with subject or assessment of his/her behavior
or experience over past several hours (as indicated in each item.)

ITEM 1-REDUCED LEVEL OF CONSCIOUSNESS (AWARENESS): Rate

the patient's current awareness of and interaction with the environment
(interviewer, other people/objects in the room; for example, ask patients to
describe their surroundings).
0: none (patient spontaneously fully aware of environment and interacts
appropriately)
1: mild (patient is unaware of some elements in the environment, or not
spontaneously interacting appropriately with the interviewer; becomes
fully aware and appropriately interactive when prodded strongly; interview
is prolonged but not seriously disrupted)
2: moderate (patient is unaware of some or all elements in the
environment, or not spontaneously interacting with the interviewer;
becomes incompletely aware and inappropriately interactive when
prodded strongly; interview is prolonged but not seriously disrupted)
3: severe (patient is unaware of all elements in the environment with no
spontaneous interaction or awareness of the interviewer, so that the
interview is difficult-to-impossible, even with maximal prodding)

ITEM 2-DISORIENTATION: Rate current state by asking the following 10

orientation items: date, month, day, year, season, floor, name of hospital,
city, state, and country.
0: none (patient knows 9-10 items)
1: mild (patient knows 7-8 items)
2: moderate (patient knows 5-6 items)
D 3: severe (patient knows no more than 4 items)

ITEM 3-SHORT-TERM MEMORY IMPAIRMENT: Rate current state bY

using repetition and delayed recall of 3 words [patient must immediately
repeat and recall words 5 min later after an intervening task. Use alternate

. es
Appen dic
184
sets of 3 words for successive evaluations (for example, apple, table,
tomorrow, sky, cigar, justice)].
0: none (all 3 words repeated and recalled)
1: mild (all 3 repeated, patient fails to recall 1)
2: moderate (all 3 repeated, patient fails to recall 2-3)

3: severe (patient fails to repeat 1 or more words)

ITEM 4-IMPAIRED DIGIT SPAN: Rate current performance by asking

subjects to repeat first 3, 4, then 5 digits forward and then 3, then 4
backwards; continue to the next step only if patient succeeds at the previous
I
one. 1~
0: none (patient can do at least 5 numbers forward and 4 backward)
1: mild (patient can do at least 5 numbers forward, 3 backward)
2: moderate (patient can do 4-5 numbers forward, cannot do 3
backward)

3: severe (patient can do no more than 3 numbers forward)

ITEM 5-REDUCED ABILITY TO MAINTAIN AND SHIFT ATTENTION:

As indicated during the interview by questions needing to be rephrased and/
or repeated because patient's attention wanders, patient loses track, patient
is distracted by outside stimuli or over-absorbed in a task.
0: none (none of the above; patient maintains and shifts attention
normally)
1: mild (above attentional problems occur once or twice without
prolonging the interview)
2: moderate (above attentional problems occur often, prolonging the
interview without seriously disrupting it)
3: severe (above attentional problems occur constantly, disrupting and
making the interview difficult-to-impossible)

Appendices
185
I ITEM 6-DISORGANIZED THINKING: As indicated during th e ,in tervIew
. b
rambling, irrelevant, or incoherent speech, or by tangential • circu mstantial Y
or faulty reasoning . Ask patient a somewhat complex question (to r example
'
"Describe your current medical condition."). '
0: none (patient's speech is coherent and goal-directed)
1: mild (patient's speech is slightly difficult to follow; responses to
questions are slightly off target but not so much as to prolong the
interview)
2: moderate (disorganized thoughts or speech are clearly present, such
that interview is prolonged but not disrupted)
3: severe (examination is very difficult or impossible due to disorganized
thinking or speech)

ITEM 7-PERCEPTUAL DISTURBANCE: Misperceptions, illusions,

hallucinations inferred from inappropriate behavior during the interview
or admitted by subject, as well as those elicited from nurse/family/chart
accounts of the past several hours or of the time since last examination.

0: none (no misperceptions, illusions, or hallucinations)

1: mild (misperceptions or illusions related to sleep, fleeting hallucinations
on 1-2 occasions without inappropriate behavior)
2: moderate (hallucinations or frequent illusions on several occasions with
minimal inappropriate behavior that does not disrupt the interview)
3: severe (frequent or intense illusions or hallucinations with persistent
inappropriate behavior that disrupts the interview or interferes with
medical care)

Appendices
ITEM 8-DELUSIONS: Rate delusions inferred from inappropriate behavior
during the interview or admitted by the patient, as well as delusions elicited
from nurse/family/chart accounts of the past several hours or of the time
since the previous examination.
0: none (no evidence of misinterpretations or delusions)
1: mild (misinterpretations or suspiciousness without clear delusional
ideas or inappropriate behavior)
2: moderate (delusions admitted by the patient or evidenced by his/her
behavior that do not or only marginally disrupt the interview or interfere
with medical care)
3: severe (persistent and/or intense delusions resulting in inappropriate
behavior, disrupting the interview or seriously interfering with medical
care)

ITEM 9-DECREASED OR INCREASED PSYCHOMOTOR ACTIVITY:

Rate activity over past several hours, as well as activity during interview, by
circling (a) hypoactive, (b) hyperactive, or (c) elements of both present.
0: none (normal psychomotor activity)
a b c 1: mild (hypoactivity is barely noticeable, expressed as slightly
slowing of movement. Hyperactivity is barely noticeable or appears
as simple restlessness.)
a b c 2: moderate (hypoactivity is undeniable, with marked reduction
in the number of movements or marked slowness of movement;
subject rarely spontaneously moves or speaks. Hyperactivity is
undeniable, subject moves almost constantly; in both cases, exam is
prolonged as a consequence.)
a b c 3: severe (hypoactivity is severe; patient does not move or
speak without prodding or is catatonic. Hyperactivity is severe;
patient is constantly moving, overreacts to stimuli, requires
surveillance and/or restraint; getting through the exam is difficult or
impossible.)

Appendices
187
jl
lj
r

ITEM 10-SLEEP-WAKE CYCLE DISTURBANCE (DISORDER O

AROUSAL): Rate patient's ability to either sleep or stay awake at th:
appropriate times. Utilize direct observation during the interview
. patient,
reports from nurses, family, . .
or charts describing , as Well as
sleep-wak
.
disturbance over the past several hours or since e~~e
last examination. Use
observations of the previous night for morning evaluations only.
o: none (at night, sleeps well; during the day, has no trouble staying
awake)

1: mild (mild deviation from appropriate sleepfulness and wakefulness

states: at night, difficulty falling asleep or transient night awakenings,
needs medication to sleep well; during the day, reports periods of
drowsiness or, during the interview, is drowsy but can easily fully awaken
him/herself)

D 2: moderate (moderate deviations from appropriate sleepfulness and

wakefulness states: at night, repeated and prolonged night awakening;
during the day, reports of frequent and prolonged napping or, during the
interview, can only be roused to complete wakefulness by strong stimuli)
3: severe (severe deviations from appropriate sleepfulness and
wakefulness states: at night, sleeplessness; during the day, patient
spends most of the time sleeping or, during the interview, cannot be
roused to full wakefulness by any stimuli)

· es
Append1c
Appendix C. The CAGE-AID Questionnaire

1. Have you ever felt you should cut down on your

drinking or drug use? Yes --- No ___

2. Have people annoyed you by criticizing your drinking

or drug use? Yes - -- No ___

3. Have you ever felt bad or guilty about your drinking or

drug use? Yes --- No ---

4. Have you ever had a drink or used drugs first thing

in the morning to steady your nerves or get rid of a Yes --- No ---
hangover (eye-opener)?

Appendix D. Modified Edmonton Classification System

for Cancer Pain

I. Mechanism of Pain Yes No

A. Nociceptive

B. Neuropathic

II. Incident Pain

Ill. Psychological Distress

IV. Addictive Behavior

V. Cognitive Function

***If unsure, leave blank

Appendices
189
r
Appendix E1: Child 7 years and older
Thinking about the last day (24 hours), please check the bo
describes how much: x that best

Pain bothered you

D Not at all 0 A little bit Kind of 2 D Quite a bit 3 lot

Lack of energy bothered you

Not at all 0 little bit Kind of 2 D Quite a bit 3 lot

4

Feelings of being nervous bothered you

Norat all 0 little bit Kind of 2 Quite a bit 3

4

Nausea or feeling like you could throw up bothered you

Not at all 0 A little bit Kind of 2 Quite a bit 3 4

Hard time sleeping bothered you

D Not at all 0 A little bit Kind of 2 Quite a bit 3 4

Feeling short of breath or trouble breathing bothered you

0 A little bit Kind of 2 Quite a bit 3 4

Not at all

Diarrhea or loose poop bothered you

Quite a bit 3 4
0 A little bit Kind of 2
Not at all

Constipation or pain when trying to poop bothered you

Not at all o I A little bit 1 Kind of 2 I Quite a bit 3 I 4

Feelings of being irritable bothered you

D Not at all o I little bit 1 Kind of 2 I Quite a bit 3 I 4

Do you feel like eating as you normally do

4
2 Quite a bit 3
Not at all 0 A little bit Kind of

Anything else that bothered you: _ 4

2 Quite a bit 3
Not at all 0 little bit Kind of

· es
Append•C

190
1111111
Appendix E2: Parent or Caregiver Assessment
Thinking about the last day (24 hours), please check the box that best
describes how much:

Pain bothered or distressed your child

O Not at all O A little bit Kind of 2 Quite a bit 3 A lot 4

Lack of'energy bothered or distressed your child

O Not at all O A little bit Kind of 2 Quite a bit 3 A lot 4

Feelings of being nervous bothered or distressed your child

Not at all O I A little bit 1 I Kind of 2 I Quite a bit 3 I A lot 4

Nausea or feeling like they could throw up bothered or distressed your child

Not at all O A little bit Kind of 2 Quite a bit 3 A lot 4

Hard time sleeping bothered or distressed your child

Not at all O A little bit Kind of 2 Quite a bit 3 A lot 4

Feeling short of breath or trouble breathing bothered or distressed your child

Not at all O A little bit Kind of 2 Quite a bit 3 A lot 4

Diarrhea or loose poop bothered or distressed your child

Not at all O I A little bit 1 I Kind of 2 I Quite a bit 3 I A lot 4

Feelings of sadness bothered or distressed your child

Not at all O I A little bit 1 I Kind of 2 I Quite a bit 3 I A lot 4

Constipation or pain when trying to poop bothered or distressed your child

0 A little bit Kind of 2 Quite a bit 3 lot 4

Not at all

Feelings of being irritable bothered or distressed your child

Kind of 2 Quite a bit 3 lot 4

Not at all 0 A little bit

Feeling like your child eats as they normally do

2 Quite a bit 3 lot 4

Not at all 0 A little bit Kind of

Anything else that bothered or distressed your child:

D Not at all 0 A little bit Kind of 2 Quite a bit 3 A lot 4

Appendices
191
 111111

Appendix F: Richmond Agitation Sedation scale

Score Term Description

+4 Combative Overtly combative or violent; immediat

danger to staff e

+3 Very agitated Pulls on or removes tube(s) or

catheter(s) or has aggressive behavior
toward staff

+2 Agitated Frequent nonpurposeful movement or

patient-ventilator dyssynchrony

+1 Restless Anxious or apprehensive but

movements not aggressive or vigorous

0 Alert and calm

-1 Drowsy Not fully alert, but has sustained (more

than 10 seconds) awakening, with eye
contact, to voice

-2 Ught sedation Briefly (less than 10 seconds) awakens

with eye contact to voice

-3 Moderate sedation Any movement (but no eye contact) to

voice

-4 Deep sedation No response to voi ce, but any

movement to physica: stimulation

-5 Unarousable No response to voice or physical

stimulation

Procedure for RASS Assessment

1. Observe patient
(Score Oto +4)
a. Patient is alert, restless, or agitated.

2. If not alert, state patient's name and say to open eyes and look at speaker.
(Score -1)
b. Patient awakens with sustained eye opening and eye contact.
(Score-2)
c. Patient awakens with eye opening and eye contact, but not sustained.
(Score-3)
d. Patient has any movement in response to voice but no eye contact.
nd
3. When no response to verbal stimulation, physically stimulate patient by shaking shoulder a /or
rubbing sternum. (Score-4)
e. Patient has any movement to physical stimulation. (Score-5)
f. Patient has no response movement to any stimulation

Append1C
· es

192