American Journal of Hospice and Palliative

Medicine
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Review Article: Palliative Care in Gynecologic Oncology

Youssef Rezk, Patrick F. Timmins and Howard S. Smith
AM J HOSP PALLIAT CARE 2011 28: 356 originally published online 26 December 2010
DOI: 10.1177/1049909110392204

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Review Article
American Journal of Hospice
& Palliative Medicine®
Palliative Care in Gynecologic Oncology 28(5) 356-374
ª The Author(s) 2011
Reprints and permission:
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DOI: 10.1177/1049909110392204
http://ajhpm.sagepub.com
Youssef Rezk, MD1, Patrick F. Timmins III, MD1, and
Howard S. Smith, MD2

Abstract
Patients with advanced gynecologic malignancies have a multitude of symptoms; pain, nausea, and vomiting, constipation, anorexia,
diarrhea, dyspnea, as well as symptoms resulting from intestinal obstruction, hypercalcemia, ascites, and/or ureteral obstruction.
Pain is best addressed through a multimodal approach. The optimum palliative management of end-stage malignant intestinal
obstruction remains controversial, with no clear guidelines governing the choice of surgical versus medical management. Patient
selection for palliative surgery, therefore, should be highly individualized because only carefully selected candidates may derive
real benefit from such surgeries. There remains a real need for more emphasis on palliative care education in training programs.

Keywords
pain, malignant bowel obstruction, nausea and vomiting, palliative care, quality of life, end-of-life care, gynecologic oncology,
gynecologic malignancies

Introduction management.8 Because symptoms are subjective, neither the

behavior nor the vital signs should be used as evidence of their
Despite continued advances in gynecologic oncology, goals
existence or severity.9 When it comes to psychosocial experi-
of therapy are frequently shifted from cure to preserving hope
ences, such as anxiety or depression, there is an even larger dis-
and quality of life (QOL) as the patient enters the terminal
crepancy between caregivers’ and patients’ recognition of the
phase of her illness. Gynecologic oncologists have the obliga-
symptoms.10 Careful symptom assessment, therefore, requires
tion to advocate for and provide such care for women at the end
skill, time, and active listening on the part of the practitioner.11
of life. Data suggest that aggressive interventions, including
Symptoms may be caused by tumor-related factors, therapy-
chemotherapy, continue to be administered until days before
related factors, and/or other factors. Treatment of the individual
death.1-3 It is critical to ensure that the final phase of life is symptoms should be directed at the underlying cause/causes
planned for well in advance along a continuum of care that
whenever possible. Clinicians should be vigilant in assessing
stretches from cure-oriented antineoplastic therapies at one end
for drug side effects and adverse drug interactions resulting
to palliative treatment at the other. This is particularly impor-
from polypharmacy. Elderly patients with terminal cancer are
tant in the current era where changes in societal norms, with
particularly vulnerable and should be carefully monitored.
families spread over wide geographical areas, have led to fewer
Patients with advanced gynecologic malignancies experience
family caregivers available at the close of life. Advance plan-
a great array of symptoms, the most common ones will be
ning avoids the fragmented and choppy approach that is fre-
addressed in a concise manner.
quently seen in these situations.4 This article addresses some
of the common symptoms experienced by this group of patients
in a practical management-oriented approach, removing some
Pain
of the obstacles and encouraging further efforts to improve the
care of women with advanced gynecologic malignancies. It is disturbing that pain control continues to be inadequate in
Because pain management is an integral part of palliation patients with cancer under different settings.5,12 Physicians’
and one that is frequently inadequately treated,5 the section inadequate education and training in cancer pain assessment
on pain alleviation is, therefore, a major component of this
article. A comprehensive review of the topic,6,7 however, is 1
Department of Obstetrics and Gynecology, Division of Gynecologic
beyond the scope of this discussion. Oncology, Albany Medical College, Albany, NY, USA
2
Department of Anesthesiology, Albany Medical College

Symptom Management Corresponding Author:

Patrick F. Timmins, Women’s Cancer Care Associates, 319 South Manning
Whenever gynecologic cancers progress to terminal stages, Blvd., Suite 301, Albany, NY 12208, USA
strategies for supportive care need to focus on symptom Email: PTimmins@womenscancercareassociates.com

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Rezk et al
and management are significant contributing factors. Other
factors include patient underreporting of pain, fear of iatro-
genic opioid addiction (both by the patient and by the treating
physician), fragmentation of care among various providers and
lack of accountability for insufficient pain treatment.13 In order
of priority, the management should aim for control of pain at
night, maintaining sleep, control of pain at rest and, lastly, dur-
ing activity as well. Guidelines for cancer pain management
have been published by the World Health Organization (WHO)
and the American Society of Clinical Oncology (ASCO)
among other organizations.14-18
Common cancer-pain syndromes in patients with gyne-
cologic oncology include peripheral neuropathies (nerve infil-
tration, radiotherapy, or chemotherapy-induced [paclitaxel,
cisplatin, oxaliplatin]), plexopathies, mucositis, abdomino-
pelvic pain, pain due to epidural metastasis with neural com-
pression and metastatic bone pain. Among 4620 patients with
cervical cancer evaluated by Thanapprapasr and colleagues
over a 10-year period, there were 52 patients (1%) with bone
metastases.19 The most common presenting symptom was
pain (78%). Most of the patients had multiple bone lesions and
extrapelvic bone metastases. The lumbar spine was the most
common site (36%). Sixteen patients (39%) received pallia-
tive radiation therapy.19 In addition, painful comorbid condi-
tions, such as osteoarthritis, are common among elderly
patients with cancer.20
Pain Evaluation
The initial assessment of cancer pain begins with a detailed his-
tory including the onset, character, duration, distribution and
severity of pain, trends over time, relieving and aggravating
factors, and response to previous attempts at pain control. This
is followed by a physical examination as well as a psychosocial
assessment. These should lead the clinician to determine the
most likely cause/causes of the patient’s pain and formulate a
management plan. Noteworthy, the natural history of the can-
cer can help determine the most likely operating type of pain.
For example, cervical cancer frequently causes neuropathic
pain due to involvement of the lumbar plexus, while visceral
pain is common in ovarian cancer due to spread of the disease
to the abdominopelvic organs. Accurate documentation of pain
assessment, including its severity, is critical for providing com-
petent pain management.
Practitioners should be familiar with using at least 1 pain
scale, of which several have been developed using 3 funda-
mental approaches: the visual analogue scales, the verbal
descriptor scales, and the numeric rating scales. Although all
3 approaches are roughly equivalent,21 in the elderly popula-
tion, where the ability to use pain-rating scales diminishes
with cognitive impairment22 and advancing age,23 measures
like the hospice approach discomfort scale24 may be consid-
ered. Assessment of the severity of pain is essential for choos-
ing the proper therapeutic modality as well as for monitoring
treatment efficacy. Pain can be graded into mild, moderate,
and severe based on interference with function. These
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357
correspond to grades 1 to 4, 5 to 6, and 7 to 10, respectively,
on the numeric pain rating scales.25 Monitoring response to
therapy and assessment of any new or unrelieved pain should
be an ongoing process.
Specialized assessment tools exist for discomfort from
gynecologic malignancies and their treatment. The 4-item
Functional Assessment of Cancer Therapy/Gynecologic
Oncology Group Abdominal Discomfort (FACT/GOG-AD)
subscale reliably and validly assesses ovarian cancer-specific
abdominal discomfort and captures abdominal symptom
responses to intravenous (iv) and intravenous/intraperitoneal
(iv/ip) cisplatin/paclitaxel treatments.26 A recent report, how-
ever, challenged the common notion that psychological instru-
ments designed to evaluate specific symptoms/conditions are
superior to generic ones. Luckett et al performed a systematic
review of questionnaires used to assess the health-related QOL
of women with gynecologic cancers and their ability to detect
minimal clinically-important differences and change.27 The
evidence they reviewed offered little support for the hypothesis
that disease-, symptom- or treatment-specific instruments are
more sensitive and responsive than cancer-specific or generic
questionnaires.27 However, conclusions were limited by the
small number of head-to-head comparisons available.27
Because pain is a complex state that is influenced by cul-
tural, environmental, social, and psychological factors, psycho-
social evaluation is an important component of pain
assessment. This should include assessment of the social, fam-
ily, and medical support systems, spiritual needs, financial
resources, and any comorbid psychological illnesses such as
depression or anxiety. Addressing each of these individual
issues can have a profound effect on pain control, mostly
through altering the central perception of pain, that is, raising
the pain threshold. Threshold issues should never be addressed
with more analgesics.11
Analgesics, however, remain the cornerstone of cancer
pain treatment due to their rapid action, low cost, and relative
effectiveness. The multimodal approach to pain management
encompasses psychosocial measures, as alluded to earlier, and
more invasive techniques, when appropriate, in addition to
analgesics and other pharmacological agents to achieve opti-
mum pain control.
Pharmacological Treatment Measures
These include 3 major classes of medications: nonsteroidal
anti-inflammatory drugs (NSAIDs)/acetaminophen, opioids,
and adjuvant drugs (co-analgesics). Each of these classes can
be used alone but, more often, in combinations (Tables 1-3).
The analgesic ladder developed by the WHO for cancer pain
management14 provides a simple, effective, and well-vali-
dated36-38 approach for pain control. Patients with mild pain are
started on nonopioid analgesics like acetaminophen or NSAIDs
with or without adjuvant agents (step 1 of the analgesic ladder).
Prostaglandins act as sensitizers for nociception both centrally
and peripherally. Therefore, inhibiting prostaglandin synthesis,
through the use of NSAIDs, can help with pain relief.
358 American Journal of Hospice & Palliative Medicine® 28(5)

Table 1. Commonly Used NSAIDs and Acetaminophena

Drug Dose (oral)b Comments

Acetaminophen 650-1000 mg q 4-6 hours Available OTC. Potential for hepatotoxicity. Lacks periph-
eral antiplatelet and anti-inflammatory activities of
NSAIDs.
Aspirin 650 mg q 4 hour, 975 mg q 6 hours Available OTC. Platelet dysfunction is a concern.
Ibuprofen 400-600 mg q 6-8 hours Available OTC. Ketoprofen has a high degree of renal
Ketoprofen 25-75 mg q 6-8 hours excretion.
Naproxen 250 mg q 6-8 hours
Choline magnesium trisalicylate 1000-1500 mg bid Minimal antiplatelet activity and gastrointestinal toxicity.
Salsalate 500 mg q 8-12 hours (max 4 g/d)
Diflunisal 500 mg q 8-12 hours Absorption may be impaired by antacids.
Etodolac 200-400 mg q 6-8 hours
Fenoprofen 300-600 mg q 6 hours
Flurbiprofen 50-100 mg bid
Indomethacin 25-50 mg tid High doses are not recommended in the elderly individuals.
Ketorolac tromethamine 10 mg q 4-6 hours po (max 40 mg/d), 60 mg Parenteral form available. Total therapy should not exceed 5
initially then 30 mg q 6 hours iv or im days.
Meclofenamate 50-100 mg q 6 hours Long-term use may be associated with Coombs-positive
hemolytic anemia.
Mefenamic acid 250 mg q 6 hours
Meloxicam 7.5-15 mg daily Once daily dosing.
Nabumetone 1-2 g daily
Oxaprozin 1200-1800 mg daily
Sulindac 150-200 mg q 12 hours Relatively less nephrotoxic than other NSAIDs.
Celecoxib 100-200 mg bid COX-2 inhibitors with minimal gastrointestinal toxicity.
Etoricoxib 30-240 mg q d Parecoxib, a parenteral COX-2 inhibitor, is a prodrug of
Lumiracoxib 100-400 mg q d valdecoxib. Etoricoxib, lumiracoxib, and parecoxib are
Parecoxib 20-100 mg iv or im not approved for use in the United States. The COX-2
inhibitors rofecoxib and valdecoxib have been withdrawn
from the US market because of concerns regarding their
thrombotic cardiovascular risk.
Abbreviations: q, every; OTC, over the counter; bid, twice daily; max, maximum; tid, thrice daily; po, oral; iv, intravenous; im, intramuscular; COX-2,
cyclooxygenase-2; NSAIDs, Nonsteroidal anti-inflammatory drugs.
a
Adapted, in part, from N Engl J Med. 1994;330:651-65516 and from Whitecar PS, Jonas AP, Clasen ME. Managing pain in the dying patient. Am Fam Physician.
2000;61:755-764, with permission.
b
Dosage reduction may be necessary in the elderly, renally and/or hepatically-impaired patients as well as in those with altered drug metabolism.

Acetaminophen and NSAIDs, with or without opioids, may be
helpful in certain pain syndromes like postoperative pain, pain
due to bone metastasis, soft tissue infiltration, serositis, and/or
psoas spasm (due to psoas abscess or malignant infiltration),
where they act to reduce the noxious stimulus at the periph-
ery.39-41 Side effects that may be associated with NSAID use
include dyspepsia, gastritis, peptic ulceration, bleeding ten-
dency, diarrhea, constipation, and, occasionally, renal or hepa-
tic failure. Although cyclooxygenase-2 (COX-2) inhibitors
may have a lower side effect profile, particularly with respect
to gastrointestinal toxicity and antiplatelet activity, concerns
regarding their potential thrombotic cardiovascular risk (which
may also be a risk with some of the traditional NSAIDs, partic-
ularly in higher doses)42 have limited their use. Choline magne-
sium trisalicylate, a nonacetylated salicylate, may be an
alternative.43,44 No particular NSAID has been shown to be
superior, in terms of efficacy, over the others for cancer pain.41
A trial of 1 week should be sufficient to test for efficacy.
Unfortunately, NSAIDs have a ceiling effect where dose esca-
lation does not result in additional analgesia beyond a certain
limit. This restricts their use as the sole analgesic agent for
patients with moderate-to-severe pain.
When pain persists (moderate pain), ‘‘weak’’ opioids, better
referred to as opioids for moderate pain, like codeine, hydroco-
done, and oxycodone, used in fixed-dose combinations with
acetaminophen or aspirin, are suggested (step 2 of the analgesic
ladder). Their maximum dose is limited by the acetaminophen
or aspirin in the combination, however.
Step 3 of the analgesic ladder is designed to address severe
pain using ‘‘strong’’ opioids, better referred to as opioids for
severe pain, like morphine, oxymorphone, methadone, oxyco-
done (as a single entity), hydromorphone, and fentanyl. Adju-
vant agents can be used at any step of the ladder. In general,
drugs should be used in the lowest effective dose, in the sim-
plest possible regimen and by the least invasive mode of
administration. However, it should be noted that the WHO

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Rezk et al 359

Table 2. Commonly Used Opioidsa

A. Opioid agonists
Equianalgesic Dose Half-Life Duration
Agonist (mg q hours)b (hours) (hours) Comments

Parenteral Oral
Morphine 10 q 3-4 30 q 3-4 2-3 2-4 Liquid form and rectal suppositories are available.

Morphine CR N/A 90-120 q 12 2-3 8-12 The reported doses are equivalent to ATC dosing of
Morphine ER N/A 180-240 q 24 2-3 24 the IR preparation. For opioid-naive patients, the
usual oral starting dose is 30 mg q 12 hours (CR
preparation) and q 24 hours (ER preparation).

Oxycodone 10 q 4c 20-30 q 4 2-3 3-4 Oral solution is available.

Oxycodone CR N/A 60-90 q 12 2-3 8-12 The reported dose is equivalent to ATC dosing of the
IR preparation. For opioid-naive patients, the usual
oral starting dose is 10-40 mg q 12 hours.
Hydromorphone 1.5 q 3-4 7.5 q 3-4 2-3 2-4 Liquid form, rectal suppositories, and a highly con-
centrated parenteral form are available. The high-
potency parenteral form is for use in opioid-
tolerant patients only.
Oxymorphone 1 q 3-4 10 q 4 2-3 2-4 Rectal suppositories are available.
Oxymorphone ER N/A 30 q 12 2-3 12 The reported dose is equivalent to ATC dosing of the
IR preparation. For opioid-naive patients, the usual
oral starting dose is 5-10 mg q 12 hours.
Fentanyl N/A 7-12 Usually administered as iv or sc infusion. 100 mcg/h is
roughly equivalent to 4 mg/h of iv morphine.
Fentanyl TTS 16-24 48-72 The microgram-per-hour dose of transdermal fentanyl
is roughly equal to one half of the milligram-per-day
dose of oral morphine.
Fentanyl OTFCd 200 mcg 7 For breakthrough pain in opioid-tolerant cancer
(transmucosal) patients only. Contraindicated in the management
of acute or postoperative pain. May repeat the
dose in 15 minutes. Maximum 4 units per day.

Methadone 10 q 6-8 20 q 6-8 12-190 4-12 Not recommended for routine use. Methadone
Levorphanol 2 q 6-8 4 q 6-8 12-15 4-6 accumulates with chronic use requiring large (75%-
Meperidine 100 q 3 300 q 2-3 3 2-4 90%) dosage reduction when converting from high
morphine doses.
B. Opioid Combinations
Drug Usual Starting Dose (oral)
Codeine/aspirin 30 mg/325 mg q 4 hours.
Codeine/acetaminophen 30 mg/325 mg q 4 hours. A liquid form is available.
Hydrocodone/acetaminophen 5 mg/500 mg q 4 hours. A liquid form is available.
Hydrocodone/ibuprofen 7.5 mg/200 mg q 4 hours.
Oxycodone/aspirin 5 mg/325 mg qid.
Oxycodone/acetaminophen 5 mg/325 mg qid. A liquid form is available.
Oxycodone/ibuprofen 5 mg/400 mg qid.
Propoxyphene/acetaminophen 100 mg/650 mg q 4 hours.
Abbreviations: q, every; CR, controlled release; N/A, not available; ER, extended release; ATC, around-the-clock; IR, immediate release; iv, intravenous; sc,
subcutaneous; TTS, transdermal therapeutic system; OTFC, oral transmucosal fentanyl citrate; qid, four times daily.
a
Adapted, in part, from Derby S, Chin J, Portenoy RK. Systemic opioid therapy for chronic cancer pain: practical guidelines for converting drugs and routes of
administration. CNS Drugs. 1998;9:99-109 and from Whitecar PS, Jonas AP, Clasen ME. Managing pain in the dying patient. Am Fam Physician. 2000;61(3):755-764,
with permission.
b
Doses are applicable to opioid-naive patients. For patients with renal and/or hepatic impairment, the elderly and other patients with altered drug metabolism,
dosage reduction may be necessary. Equianalgesic doses are based on a 10-mg parenteral dose of morphine. Because published data on doses equianalgesic to
morphine vary, the dose should be carefully titrated to clinical response. Since cross-tolerance among the various opioids is incomplete, it is usually appropriate
to start with a lower dose than the equianalgesic one when switching from one opioid to the other, particularly in the elderly patients. The intravenous and
intramuscular routes are considered equivalent. The subcutaneous route is frequently utilized in the palliative care setting.
c
Not available in the United States. Parenteral oxycodone is available in some countries.
d
A buccal form of fentanyl citrate is also available. Different products cannot be substituted on a microgram-per-microgram basis due to different
bioavailability.

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360 American Journal of Hospice & Palliative Medicine® 28(5)

Table 3. Selected Adjuvant Agentsa

Class/Drug Dose (Oral)b Indications/Comments

Antidepressants First-line therapy for neuropathic pain especially that with a continuous dull
Amitriptyline 25-150 mg/d component.28 Potentiate analgesic effect of opioids.29 Useful for underly-
Imipramine 20-100 mg/d ing depression or insomnia.29 If one drug is ineffective, switching to
Doxepin 25-150 mg/d another antidepressant can be helpful. Anticholinergic side effects can be
Trazodone 75-225 mg/d problematic especially in the elderly patients.
Anticonvulsants For neuropathic pain especially that with a lancinating component.28 Clona-
Carbamazepine 200-1600 mg/d zepam may be used for opioid myoclonus as well.
Phenytoin 300-500 mg/d
Gabapentin 600-1200 mg/d
Valproate 400-1200 mg/d
Clonazepam 0.5-5 mg/d
Corticosteroids For neuropathic pain, bone pain, pain associated with soft tissue infiltration
Dexamethasone 16-96 mg/d or with brain metastasis and increased intracranial pressure and for
Methylprednisolone 40-125 mg/d appetite stimulation and antiemesis as well. Dexamethasone and methyl-
Prednisone 40-80 mg/d prednisolone are useful for spinal cord compression also.
Benzodiazepines Anxiolytics that can enhance opioid analgesia in the presence of comorbid
Lorazepam 0.5-2 mg tid-qid anxiety. Well tolerated with opioids. Also useful as antiemetics. Diazepam
Diazepam 2-10 mg tid-qid is an effective muscle relaxant.
Analeptics Psychostimulants that improve sedation. May have an analgesic effect.30,31
Methylphenidate 10-15 mg/d
Dextroamphetamine 5-10 mg/d
Antihistamines Adjuvant therapy with opioids for analgesia.32 Antiemetic and anxiolytic.
Hydroxyzine 300-450 mg/d Useful for insomnia as well
Neuroleptics
Methotrimeprazine 40-80 mg/d (im) Analgesic33 and broad-spectrum antiemetic. Very sedating, reserved for the
Miscellaneous final phase of life. No longer available in the United States.
Baclofen 5-20 mg tid Baclofen is a muscle relaxant for muscle pain and/or myoclonus. Pamidronate
Pamidronate 90 mg slowly iv q 30 days and calcitonin are for bone pain34,35 and/or associated hypercalcemia.
Calcitonin 100 IU im or sc q d
Abbreviations: tid, thrice daily; qid, four times daily; im, intramuscular; iv, intravenous; q, every; sc, subcutaneous.
a
Adapted, in part, from Olt GJ. Managing pain and psychological issues in palliative care. Best Pract Res Clin Obstet Gynaecol. 2001;15:235-251, with permission.
b
Dosage reduction may be necessary in patients with hepatic and/or renal disease, the elderly patients and in those with altered drug metabolism.

ladder provides only an outline for guiding cancer pain man-
agement. Tailoring therapy to the individual patient is of
utmost importance. This is particularly true for the elderly
patients with age-related altered drug pharmacokinetics and for
the patients with hepatic and/or renal impairment due to dimin-
ished drug metabolism and/or excretion. These populations
should initially receive smaller and/or less-frequent doses.
Analgesics should be given around the clock to maintain
adequate serum concentrations, with additional doses given
for ‘‘breakthrough’’ pain (BTP).45 The ‘‘baseline’’ analgesia
is usually provided using long-acting agents (eg, controlled-
release (CR) or extended-release (ER) morphine sulfate or
CR oxycodone), while the BTP is addressed with shorter
acting agents (eg, immediate-release (IR) morphine sulfate
or IR oxycodone) that have a rapid onset of action and a rel-
atively short half-life allowing dosing every 3 to 4 hours or
more often as needed.
The prevalence of cancer-related BTP is probably roughly
two third, ranging from 50% to 90%.45-51 Among patients with
cancer, BTP has been associated with more severe chronic
pain,46,47 relatively more impairment in physical functioning
and greater psychologic distress,46,47 reduced responsiveness
to opioids,52,53 and an increased economic burden.54 Portenoy
and colleagues conducted a randomized, double-blind,
placebo-controlled (DBPC) study evaluating the efficacy,
safety, and tolerability of the fentanyl buccal tablet (FBT) in
opioid-treated patients with cancer-related BTP55 and found
that the FBT is efficacious and safe in the treatment of
cancer-related BTP. Other ultra-short-acting opioids for BTP
include oral transmucosal fentanyl citrate (OTFC; Actiq;
lozenge on a stick) and fentanyl buccal film (Onsolis). An
intranasal delivery system is under development. Also, an ion-
tophoretic transdermal system (Ionsys) is available for in-
hospital management of acute postoperative pain.
The iv route, although occasionally used for patients with
acute severe pain, is less desirable for long-term infusions because
it may be associated with drug tolerance that can be difficult to
reverse56 as well as infections secondary to long-term iv access.
Invasive Interventions
With few exceptions, these interventions should be considered
only after simpler, less invasive methods at pain control have
been exhausted. Invasive interventions include intrathecal

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Rezk et al
(IT) or epidural administration of opioids, anesthetic
approaches such as temporary or permanent nerve blocks, and
neurosurgical procedures for pain relief.
Spinal opioids can be administered alone but more
commonly with a local anesthetic (eg, bupivacaine) or an
a2-agonist such as clonidine. Predictable little systemic absorp-
tion occurs with epidural opioid administration, while absorp-
tion is minimal with IT administration. This results in very
low systemic opioid levels and hence marked reduction in the
side effects. In addition, morphine is 10 times more potent
when administered epidurally than iv and the IT route is even
10 times more potent than the epidural one. The result is a
higher degree of analgesia achieved with a much lower mor-
phine dose. Consequently, spinal opioids are generally reserved
for patients with troublesome side effects or inadequate analge-
sia with systemic opioid use.57 Nausea, vomiting, and respira-
tory depression appear to be less common with spinal opioid
administration because tolerance to these side effects usually
has already developed during prior systemic therapy. Spinal
a2-agonists may be particularly helpful in refractory neuro-
pathic pain.58 Neuraxial drug delivery can be intermittent, con-
tinuous, or through patient-controlled analgesia (PCA), via a
percutaneous catheter or an implanted subcutaneous (sc) port
or pump. Long-term adverse effects specific to this route of
therapy include infection, drug toxicity, and mechanical prob-
lems such as catheter occlusion by fibrous sheath formation.
Reasonably strong evidence exists for the use of long-term
IT analgesic therapy in the alleviation of cancer pain.59 Zicono-
tide is a conopeptide IT analgesic, which is approved by the US
Food and Drug Administration (FDA) for the management of
severe chronic pain. It is a synthetic equivalent of a naturally
occurring conopeptide found in the venom of the fish-eating
marine cone snail and provides analgesia via binding to the
N-type voltage-sensitive calcium channels in the spinal cord.60
Side effects of ziconotide, which tend to occur more commonly
at higher doses, may include nausea, vomiting, confusion, pos-
tural hypotension, abnormal gait, reduced level of conscious-
ness, dizziness or lightheadedness, weakness, visual problems
(eg, double vision), elevation of serum creatine kinase, and/
or vestibular side effects. With appropriate usage and very slow
titration, ziconotide has been shown to be a safe and effective
IT analgesic alone or in combination with other analgesics.60
Staats et al conducted a randomized, DBPC trial, from March
1996 to July 1998, at 32 centers in the United States, Australia,
and the Netherlands and concluded that IT ziconotide provided
clinically and statistically significant analgesia in patients with
pain from cancer or AIDS.61 In addition, evidence from DBPC
trials, open-label studies, case series, and case studies suggests
that ziconotide, as either monotherapy or in combination with
other IT drugs, is a potential therapeutic option for patients
with refractory neuropathic pain.62
Neural blockade can be achieved by the injection of a local
anesthetic (temporary) or a neurolytic agent (eg, alcohol) for a
more lasting blockade. The procedure provides partial or
complete relief in as much as 70% to 90% of patients.63-66
However, tumor progression or nerve regeneration can cause
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361
worsening of pain over time, which can then be addressed
with a repeat neurolytic procedure if appropriate.66 There are
several sites for neurolytic blockade of the sympathetic ner-
vous system for the treatment of gynecologic cancer pain. The
more common sites include the celiac plexus, superior hypo-
gastric plexus, and ganglion impar.67 The timing and the
choice of the procedure depend on the exhaustion of other
clinically appropriate options at pain control and the avail-
ability of skilled expertise.
Neurosurgical procedures include ablation of nerves or inter-
ruption of pain pathways, neurostimulatory approaches such as
the implantation of transcutaneous nerve or spinal cord stimula-
tors and/or implantation of drug-infusion devices. Factors to be
considered in selecting the appropriate procedure include the
type (somatic, visceral, or neuropathic) and location (unilateral,
bilateral, etc) of pain, the patient’s clinical condition and life
expectancy, and, lastly, the local expertise available for the pro-
cedure and aftercare. Dorsal rhizotomy (ablation of the dorsal
root fibers) may be useful in unilateral perineal lesions such as
in unilateral vulvar cancer.68 Commissural myelotomy (ablation
of the nociceptive fibers crossing to the opposite spinothalamic
tract) is more appropriate for patients with bilateral pain, includ-
ing visceral pain.69,70 Cordotomy (interruption of the spinothala-
mic tracts) can be done percutaneously or by open surgery and is
used for intractable unilateral nociceptive pain. It is the most
commonly performed ablative procedure with close to 90% of
patients benefiting from the procedure. The complication rate
is low and includes respiratory or bladder dysfunction, motor
paresis or paralysis, and/or sleep apnea.71-73
Terminal sedation may be undertaken only after all other
reasonable attempts for pain palliation have failed or deemed
inappropriate. This is particularly true for the delirious agitated
patient in whom verbal communication is no longer feasible.
Management of Selected Pain Syndromes
The pathophysiology of neuropathic pain involves aberrant
somatosensory processes resulting from a lesion within the
peripheral or the central nervous system.74 In gynecologic
oncology, it may develop as a complication of radiation or che-
motherapy, particularly with cisplatin or paclitaxel therapy, or
due to nerve infiltration such as in lumbar plexopathy resulting
from advanced cervical cancer. Neuropathic pain frequently
presents as an unpleasant ache or may be burning or flashing
in nature. Because symptoms may precede objective evidence
of nerve damage, a high degree of clinical suspicion is needed.
For instance, in patients previously treated for cervical cancer,
new-onset leg pain may be an early sign of disease recurrence.
For the treatment of neuropathic pain, opioid therapy alone is
often inadequate and adjuvant drugs such as antidepressants,
anticonvulsants, and/or corticosteroids are frequently part of the
therapeutic regimen.75 In refractory cases, ketamine may be used
in subanesthetic doses, usually as a sc infusion, to reduce opioid
tolerance and improve analgesia.76-78 Hallucinations can be a
troublesome side effect of ketamine use, however. When pain
is localized to a particular nerve distribution that is readily
362
accessible, neural blockade can be considered. Spinal analgesia
may be used in selected cases. Specialist consultation is usually
needed in these circumstances.79
Malignant psoas syndrome (MPS), first described by
Stevens and Gonet in 1990,39 refers to a constellation of clini-
cal findings that include proximal lumbosacral plexopathy
causing ipsilateral nociceptive or neuropathic pain, painful
fixed flexion of the ipsilateral hip with exacerbation of pain
on attempted extension of the joint (positive psoas sign),
together with radiological or pathological evidence of psoas
major muscle malignant involvement (direct metastasis or
extranodal paraaortic spread). The syndrome represents a con-
tinuum of clinical findings that are related to the degree of
anatomical destruction with its associated inflammation and
muscle spasm.80 Importantly, MPS should be distinguished
from psoas muscle spasm resulting from a psoas abscess, as
the prognosis is quite different. A regimen that includes a nar-
cotic (eg, oxycodone) with a laxative, an NSAID and/or acet-
aminophen, and a muscle relaxant (eg, diazepam) is usually
required. Steroids may be helpful as well. As with neuropathic
pain, opioids alone are insufficient. Measures for local control
of the disease such as palliative chemotherapy, radiotherapy,
or surgery may be appropriate in selected cases.75,80 Spinal
opioids are occasionally used also.
Physical and Psychosocial Interventions
Physical and psychosocial interventions supplement and/or
augment pharmacological measures. Because suffering repre-
sents the culmination of physiological, psychosocial, spiri-
tual, and emotional distress, addressing the pathophysiology
of pain alone without the other aspects contributing to suffer-
ing may be futile. This highlights the importance of the multi-
faceted approach to pain management. Such an approach can
provide the patient with the needed support, knowledge, and
skills to cope with her disease and regain a sense of control
over her illness.81
Physical measures include methods to stimulate cutaneous
nerves through the application of heat, cold, or electricity
(transcutaneous electrical nerve stimulation) and interven-
tions like acupuncture, exercise, and massage. Behavioral
and cognitive psychotherapies are examples of psychosocial
interventions. Behavioral techniques modify physical reac-
tions to pain, such as muscle tension, while cognitive therapy
aims to modify dysfunctional mental processes through alter-
ing dysfunctional thoughts, beliefs, and attitudes.82 Of note,
antidepressants can have a significant role to play in that
setting. They can treat underlying depression, augment opioid
analgesics,83 and may possess an independent analgesic
effect.84 Psychostimulants, such as dextroamphetamine and
methylphenidate, may also have a role in treating depressed
patients with terminal cancer in whom other antidepressants
are contraindicated or ineffective.85,86 Besides their antide-
pressant action, they may also improve the sense of well-
being, appetite, and alertness.
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American Journal of Hospice & Palliative Medicine® 28(5)
Spiritual care is another example of psychosocial interven-
tions. Gynecologic oncologists have both the responsibility and
the privilege to address the spiritual component of end-of-life
care.87 Spiritual care can help with issues like feelings of futi-
lity, loss of control, hopelessness, helplessness, and anguish for
which effective interventions are available. This is an opportu-
nity for deep personal growth both for the patient and for the
physician. Spiritual care can provide the patient with a sense
of healing, peace, and tranquility and the physician with
increased vitality and effectiveness, helping him/her to cope,
thus, avoiding professional burnout.88 Seeking the help of other
members of the palliative care team with skilled expertise in
this field, such as spiritual counselors and pastors, can contrib-
ute significantly to the overall care provided to terminal women
with gynecologic cancer.
Palliative Management of Intestinal Obstruction
Bowel obstruction commonly occurs in advanced gynecologic
malignancies particularly in end-stage ovarian cancer where it
is the most common cause of death. It may be partial or com-
plete and frequently involves multiple segments of the gut.
Obstruction may be caused by occlusion of the intestinal
lumen, tumor infiltrating the muscle layer causing intestinal
‘‘linitis plastica’’, extrinsic extrinsic compression, and/or
intestinal motility disorders secondary to infiltration of the
myenteric nerve plexus. Paraneoplastic effects associated with
autoantibodies have also been described.89 The presence of
constipation and fecal impaction can further aggravate the
problem. Benign causes of obstruction, like incarcerated hernia
or adhesions resulting from prior surgeries or radiation, occur
in a minority of patients with gynecologic cancers.90,91 The
associated symptoms of nausea, vomiting, and abdominal pain
result from a vicious cycle of intestinal secretion-distension-
contractile hyperactivity-secretion,92,93 which may finally lead
to intestinal epithelial damage. In the context of advanced can-
cer, bowel obstruction typically presents with insidious onset
and gradual worsening of symptoms over time.94
The initial management includes restriction of oral intake, iv
fluid resuscitation, antiemetics, and pain control, as needed,
together with gastrointestinal decompression through a naso-
gastric tube if vomiting is copious and/or persistent.95 Mean-
while, radiological investigations should be underway to
evaluate the extent of the disease and define the points and the
highest level of the obstruction and the most likely cause/
causes. At this point, it is prudent to mention that patients with
gut hypomotility secondary to disseminated intraabdominal
carcinomatosis often lack the typical radiological signs of
bowel obstruction and may demonstrate massive fecal loading
instead. This conservative management can continue for a vari-
able period depending on the local institutional policy (often
72-96 hours), then a decision is made between surgical inter-
vention and conservative medical management.
Factors to be considered in making that decision include the
extent of the disease, operability, estimated life expectancy,
chances of response to further antineoplastic therapy, general
Rezk et al
condition of the patient as well as her preferences. The decision
to operate or not should be highly personalized and sufficient
time should be taken to discuss the situation, including opera-
tive risks and alternatives, with the patient and her family to
determine their wishes. Two basic questions should be
considered if surgery is being contemplated: (a) Is the proce-
dure technically feasible with an acceptable morbidity and
mortality risk? (b) Is the procedure likely to improve the
patient’s symptoms and QOL?96 Generally, surgery offers the
best chance at symptom control. However, it has its associated
morbidity and mortality.91,95,97,98 Surgery may be useful in
the minority of patients with a benign cause of obstruction,
in those with limited disease and few sites of obstruction and
in those where postoperative antineoplastic therapy is still an
option. On the other hand, those with limited life expectancy
are generally poor candidates for the surgical approach.
Woolfson et al99 demonstrated that the likelihood for a
benign cause of obstruction increases with increasing the inter-
val since treatment of the primary tumor. None of the patients
who developed bowel obstruction more than 5 years after treat-
ment of the primary tumor had a malignant cause. Other inves-
tigators attempted to define prognostic factors predictive of the
outcome of surgery. These included the extent and the pattern
of the disease, presence of ascites or associated metabolic
derangements, albumin level, interval since primary treatment,
functional level, age, nutritional status, and prior antineoplastic
therapy, among others.100-109 There is no universal consensus,
however, among the various reports regarding many of these
prognostic factors; the evidence being derived mostly from ret-
rospective reviews and survival, rather than QOL or symptom
control, often being the main outcome measured. In view of the
limited data regarding the benefits and the possible deleterious
effects of surgery in the palliative setting, the best management
of these patients, therefore, remains controversial as concluded
by Feuer and colleagues following an elegant review of the lit-
erature.110 When surgery is not an option, symptom control
may be achieved through the insertion of stents or various
decompressive procedures in selected patients and/or by pallia-
tive pharmacotherapy.
Flexible self-expanding metallic stents can be inserted via
endoscopic or radiographic techniques to bypass a localized
segment of obstruction, thus, reestablishing lumenal patency.
Various groups have reported successful relief of the obstruc-
tion with a relatively low complication rate in the majority of
patients.111-117 Complications include bleeding, and bowel
perforation. It should be noted, however, that patients with
multiple levels of obstruction or diffuse carcinomatosis are not
appropriate candidates for stent placement. Because these are
frequent findings in patients with gynecologic malignancies,
this therapeutic modality may only be applicable to a very
select group of patients.
Insertion of a venting gastrostomy tube can be accomplished
endoscopically, through interventional radiology or by laparo-
tomy,118-123 thus avoiding the physical and psychological
distress and potential complications124 associated with pro-
longed nasogastric intubation in patients requiring long-term
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363
gastrointestinal decompression. Successful placement of the
tube results in control of the nausea and vomiting in the great
majority of patients.118-121,123 Noteworthy, patients with portal
hypertension and/or bleeding tendency are less appropriate
candidates for these procedures.125 Possible complications
include stomal-site infection, complications related to the tube,
bleeding and, rarely, peritonitis.
Chi et al reported a prospective outcome analysis of
palliative procedures performed, between 2002 and 2003, for
malignant bowel obstruction (MBO) due to recurrent ovarian
cancer.126 Palliative procedures were operative in 14 (54%)
patients and endoscopic in another 12 (46%).126 Overall,
improvement or resolution of symptoms within 30 days of sur-
gery was achieved in 23 (88%) of 26 patients, with 1 (4%) post-
procedure mortality. At 60 days, 10 (71%) of 14 patients who
underwent operative procedures and 6 of 12 patients who had
endoscopic procedures had symptom control.126 Median sur-
vival from the time of the palliative procedure was 191 days for
those undergoing an operative procedure and 78 days for those
undergoing an endoscopic procedure. Recurrence of symptoms
or death occurred in roughly half of the patients by 90 days
after surgery, however.126
Palliative pharmacotherapy, aimed at symptom control of
MBO, was originally introduced in 1985, by Baines and cow-
orkers at the St. Christopher’s Hospice in London.127 Prior to
their work, the standard approach was either palliative surgery
or prolonged nasogastric suction with parenteral fluids if sur-
gery was not feasible. This often required long-term hospitali-
zation and resulted in distress caused by the prolonged
intubation and inadequate symptom relief. Baines and coinves-
tigators showed that effective symptom control could be
achieved with medical therapy (antiemetics, antispasmodics,
analgesics, etc) in inoperable cases of MBO without reverting
to decompressive techniques. Other groups have demonstrated,
since then, comparable results using a variety of pharmacologi-
cal agents.128-132 This conservative medical approach for the
management of end-stage MBO can be applied both in the
inpatient and outpatient settings and represents a major leap
in the palliative care of such patients.
A trial of a short course of steroids (eg, dexamethasone
4-8 mg sc for 3-5 days) seems prudent in light of current
evidence.133-135 There is no universal consensus, however,
regarding the optimum dose, regimen, or duration of therapy.
Steroids may decrease the associated inflammatory edema,
thus improving the obstruction. Although the morbidity associ-
ated with steroid use appears to be low,135 in such a vulnerable
population, clinicians should be cognizant of the possible side
effects such as worsening glycemic control, infection, gastric
ulceration, and/or emotional lability.
Opioids (eg, sc morphine) are typically used for pain control.
When pain is colicky, the addition of an anticholinergic
agent (eg, hyoscine hydrobromide or butylbromide) may
assist in pain control by reducing intestinal motor activity
and secretions.127 The hydrobromide form has a central
antiemetic effect, in addition. Effective reduction of the gas-
trointestinal secretions, and hence nausea and vomiting, can
364
also be achieved with the use of the anticholinergic agent
glycopyrrolate130 and/or octreotide. The longer acting and
more potent analogue of somatostatin, octreotide, inhibits
several gastrointestinal hormones, reducing gastrointestinal
secretions, motility and splanchnic blood flow, and increas-
ing water and electrolyte absorption,136 thus, breaking the
vicious cycle of secretion distention described earlier. An
indirect, and possibly a direct,137,138 analgesic effect is
achieved through the reduction of intestinal distension and
colic. Animal studies investigating the effect of somatostatin
and octreotide in an experimental comparable setting have
demonstrated their efficacy.139-143 This has been confirmed
in clinical trials131,132,144-148 even when hyoscine therapy
failed.132 Octreotide can be administered sc or iv as a bolus
or as an infusion. A depot form that can be administered
every 4 weeks is also available and may play a bigger role
in this setting in the future.149 Cost and the development
of drug tolerance are potential issues with long-term octreo-
tide use.
Centrally acting antiemetics such as cyclizine, hyoscine
hydrobromide, haloperidol, and prochlorperazine are com-
monly used in MBO. Metoclopramide and other prokinetic
agents (eg, domperidone, etc) are the drugs of choice when
hypomotility of the gut is the likely mechanism of obstruction
and may be used in patients with ‘‘low’’ obstruction to empty
the upper gut and control the nausea and vomiting. They are
contraindicated, however, in patients with ‘‘high’’ obstruction.
Concomitant use of hyoscine hydrobromide and metoclopra-
mide is not recommended either.
The sc route is an appropriate alternative to the oral route for
drug delivery and, occasionally, for hydration in patients with
MBO. It has the advantage of being less costly, easier to handle
at home with less potential complications and, causes less
patient discomfort compared to the iv route. Parenteral hydra-
tion, nevertheless, continues to be a controversial issue in the
setting of end-stage MBO.150,151 Our own policy is to limit par-
enteral fluids when the patient is clearly terminal with goals
focused on promoting the patient’s comfort. Light oral intake
is allowed as desired. Although the patient remains mildly
dehydrated, this helps in controlling the vomiting and is usually
well tolerated. Electrolytes are not checked either, because
electrolyte abnormalities become unavoidable as part of the
natural course of the illness. Finally, exquisite oral hygiene and
supportive counseling are crucial components of the manage-
ment of terminal patients with MBO.
Constipation
Constipation is an extremely common complaint in the
gynecologic oncology palliative care setting. Common
causes include autonomic failure, drug therapy (eg, opioids,
serotonin antagonists, tricyclic antidepressants, etc), bowel
obstruction, decreased activity or fluid intake, and/or associ-
ated hypercalcemia. Massive fecal loading with impaction is
often overlooked as a cause of a multitude of symptoms
including abdominal pain, nausea and vomiting, anorexia,
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American Journal of Hospice & Palliative Medicine® 28(5)
spurious diarrhea (due to bacterial liquefaction of the
stools), and confusion (particularly in the elderly). It may
also interfere with oral drug absorption152 and/or precipitate
intestinal perforation.
A variety of agents are available to address constipation in
the palliative care population (Table 4). The choice of therapy
depends on factors including the most probable underlying
etiology, the side effect profile of the individual agent, the gen-
eral medical condition and functional status of the patient and,
finally, the response to initial therapeutic measures. Bowel
obstruction and impaction should be ruled out before laxative
therapy is initiated. ‘‘Low’’ impaction can be verified by digital
rectal examination, while the diagnosis of ‘‘high’’ impaction,
caused by a hold up at the sigmoid often with a dilated empty
rectum, requires abdominal imaging. Treatment may require
manual disimpaction, stool softeners (eg, docusate sodium),
osmotic laxatives (eg, lactulose), bowel stimulants (eg, senna),
and/or high phosphate or docusate enemas in case of ‘‘high’’
impaction. Adequate fluid intake in addition to moderate activ-
ity (whether active or passive), as tolerated, are important
adjuncts to pharmacological therapy.
One of the most common side effects of opioid treatment is
opioid-induced constipation, which is experienced by 40% to
50% of patients.153-156 In a recent study of patients taking opioids
and laxatives in 6 countries, 33% of patients reported decreasing
the use of their opioids ‘‘in order to make it easier to have a bowel
movement.’’157 Methylnaltrexone (MNTX) is a peripherally-
restricted opioid antagonist that dislodges opioid analgesics from
the gastrointestinal mu-opioid receptor without affecting analge-
sia or precipitating withdrawal. It is FDA approved for the treat-
ment of opioid-induced constipation in patients with advanced
illness receiving palliative care with inadequate response to con-
ventional laxative regimens. Alvimopan158 (indicated in the
United States for the prophylaxis of postoperative ileus) and
methylnaltrexone are better than placebo for the reversal of
opioid-mediated increase of gastrointestinal transit time and con-
stipation.159 The recommended dose for MNTX is 8 mg for
patients weighing 38 to 61 kg and 12 mg for patients weighing
62 to 114 kg, every 2 days. Outside these weight ranges, the dose
should be 0.15 mg/kg. Defecation can be anticipated in roughly
half of the patients administered subcutaneous MNTX within 4
hours after the first dose.160 A small percentage undergoes hepa-
tic metabolism (possibly glucuronidation).161 It is mostly elimi-
nated by renal excretion; about 40% to 50% is excreted
unchanged in urine.162 The most common adverse effects are
abdominal cramping and flatulence. Earnshaw et al concluded
that although the use of MNTX may increase total costs, MNTX
plus standard care is cost-effective in treating advanced-illness
patients with opioid-induced constipation.163
Nausea and Vomiting
Nausea and vomiting are common symptoms in patients with
advanced gynecologic malignancies. They may result from
cancer progression or from the various aspects of therapy.
Common causes of nausea and vomiting in that setting and
Rezk et al 365

Table 4. Pharmacological Management of Constipationa

Class Common Examples Comments

Hydrophilic agents Dietary fiber, psyllium, methylcellulose. Bulk forming agents, retain water in the colon and stimulate the
colonic activity through increasing the volume of its contents.
May precipitate bowel obstruction in patients with ‘‘rib-
bon-like’’ stools.
Osmotic agents Mag hydroxide (MOM), Mag sulfate (Epsom salt), Poorly absorbed ions, disaccharides or alcohols that draw water
Mag citrate, sodium phosphate (phospho-soda), into the intestinal lumen increasing bulk and stimulating
lactulose, sorbitol, glycerin, PEG. peristalsis. Mag-containing agents should be used with caution
in patients with renal impairment. Serious electrolyte
abnormalities and fluid shifts may complicate sodium
phosphate therapy in patients with compromised cardiac or
renal function.
Stimulants Bisacodyl, cascara, senna, castor oil. Stimulate the secretion or inhibit the absorption of water and
electrolytes and/or stimulate colonic motility. Chronic use
may be counterproductive secondary to smooth muscle
atrophy and damage to the myenteric nerve plexus.
Stool softeners Docusate sodium. Surface-active agents that allow mixing of fat and water and fat
penetration of stools increasing stool fat content.
Lubricants Mineral oil, glycerin suppositories. Mineral oil should be avoided in the elderly patients because of
the risk of aspiration causing lipoid pneumonia.
Neuromuscular agents Cholinergic agonists: bethanechol, neostigmine. Stimulate muscarinic or serotoninergic (5-HT4) receptors or
Opioid antagonists: methylnaltrexone. antagonize mu receptors at the level of the gut resulting in
Serotonin (5-HT4) agonists: tegaserod, accelerated transit through the gut. Tegaserod has been
prucalopride. removed from the US market because of concerns regarding
its potential cardiovascular risk. Prucalopride is not currently
available in the United States.
Abbreviations: Mag, magnesium; MOM, milk of magnesia; PEG, polyethylene glycol; 5-HT4, 5-hydroxytryptamine (serotonin) group 4.
a
Adapted, in part, from Sutton LM, Demark-Wahnefried W, Clipp EC. Management of terminal cancer in elderly patients. Lancet Oncol. 2003;4:149-157, with
permission.

Table 5. Management of Nausea and Vomiting Based on the Most Likely Underlying Pathophysiologya

Stimulus Afferent Impulses to Vomiting Center From Treatment

Anxiety and emotional stimuli (eg,
anticipatory chemotherapy-
associated vomiting).
Motion.
Meningeal metastasis.
Intracranial metastasis with raised
intracranial tension.
Gastric stasis, bowel obstruction, fecal
impaction.
Emetogenic drugs (eg, chemotherapeu-
tics, opioids), metabolic derange-
ments (eg, uremia, hypercalcemia).
Abbreviations: GABA, g-amino butyric acid; H1, histamine type 1; 5-HT3, 5-hydroxytryptamine (serotonin) group 3; D2, dopamine type 2.
a
Adapted, in part, from J Palliat Care. 1993;9:42-50, with permission.166
Cerebral cortex (via GABAergic neurons).
Vestibular system (muscarinic and histaminic
[H1] receptors).
Direct stimulation of the vomiting center.
Gastrointestinal tract (muscarinic,
serotoninergic [5-HT3] and dopaminergic
(D2) receptors).
Chemoreceptor trigger zone (dopaminergic
[D2] and serotoninergic [5-HT3] receptors).
Counseling, benzodiazepines (eg, lorazepam).
Antihistamines (eg, cyclizine), anticholinergics (eg,
hyoscine or scopolamine).
Steroids (eg, dexamethasone).
Antihistamines (eg, cyclizine), phenothiazines with
strong antihistaminic activity (eg,
promethazine).
Prokinetic agents such as metoclopramide or
domperidone (contraindicated in ‘‘high’’ bowel
obstruction), serotonin antagonists such as
ondansetron (contraindicated if nausea and
vomiting are due to fecal impaction).
Butyrophenones (eg, haloperidol), serotonin
antagonists (eg, ondansetron).

their likely underlying pathophysiological mechanism are It is responsible for the generation of emesis, receiving several
listed in Table 5. The vomiting center, located in the third ven- input signals from a variety of other centers (Table 5).
tricle, close to the vagal nuclei and inside the blood brain bar- The management of nausea and vomiting begins with
rier, is rich in muscarinic and histaminic (H1) receptors.164,165 identifying the most likely underlying cause/causes. This may

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366
be evident from the pattern of vomiting, associated symptoms
and signs, review of the medication history and, occasionally,
from radiological studies (eg, in case of bowel obstruction or
intracranial metastasis). Iatrogenic Addison’s disease, resulting
from the abrupt withdrawal of corticosteroids or high-dose pro-
gestational agents, is often overlooked as a cause of nausea and
vomiting in this population. The choice of the antiemetic
agent depends on the most likely operating mechanism and
the particular receptors involved, associated comorbidity, side
effect profile and route of administration of the drug, potential
drug interactions, patient’s past experience with a particular
antiemetic drug,166 and, finally, cost particularly in the hos-
pice setting.
Some of the most commonly used antiemetics in the pallia-
tive care setting include dexamethasone, haloperidol, metoclo-
pramide, hyoscine, and cyclizine167 (Table 6). Phenothiazines/
butyrophenones may be combined with either serotonin antago-
nists171,172 or cannabinoids (eg, dronabinol)173 with or without
steroids. Moreover, an improved antiemetic activity has been
reported when combining dexamethasone with each of the sero-
tonin antagonists, metoclopramide or phenothiazines/butyrophe-
nones.174-177 Because of the risk of precipitating extrapyramidal
reactions, the combination of metoclopramide and pheno-
thiazines is undesirable. Little data are available regarding the
treatment of refractory nausea unrelated to intestinal obstruction.
Methotrimeprazine is a sedating phenothiazine with a broad-
spectrum antiemetic activity that can be very helpful in refractory
nausea, particularly in end-stage patients.178-180 Unfortunately, it
is no longer available in the United States, however, olanzapine or
chlorpromazine may be useful substitutes for methotrimeprazine.
Aprepitant (Emend) and Fosaprepitant (Emend for
injection) are neurokinin-1 receptor antagonists indicated for
the prevention of chemotherapy-induced nausea/vomiting. No
significant dose adjustment is needed for mild renal or hepatic
insufficiency. Aprepitant is generally well tolerated with the
most common adverse effect being fatigue. Aprepitant demon-
strated significant activity in patients with nausea/vomiting
refractory to the prophylaxis with 5-HT3 (serotonin) antagonists
and dexamethasone.181 Rapoport and colleagues conducted a
phase III, randomized, gender-stratified, double-blind trial and
concluded that triple-therapy regimen (aprepitant, ondansetron,
and dexamethasone) provided superior efficacy versus a control
regimen (ondansetron and dexamethasone) in the treatment of
chemotherapy-induced nausea and vomiting in a broad range
of patients receiving moderately emetogenic chemotherapy
(MEC) in both no vomiting and complete response (no vomiting
and no rescue medication) end points.182 These results show the
benefit of including aprepitant as part of the standard antiemetic
regimen for patients with cancer receiving MEC.
Anorexia
Anorexia is experienced by the majority of terminally ill
patients and carries a poor prognosis especially when associ-
ated with weight loss. It is a source of distress for patients and
caregivers alike and may interfere with effective palliation by
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American Journal of Hospice & Palliative Medicine® 28(5)
Table 6. Commonly Used Antiemeticsa
Drug Comments
Dexamethasone Antiemetic mechanism of action is not well
understood (may be related to decreasing
permeability of the blood brain barrier). Used
prophylactically for chemotherapy-induced
nausea and vomiting and as an adjunct to other
agents in intractable nausea and vomiting. Appe-
tite stimulant and potential mood elevator.168,169
Can be administered subcutaneously.
Haloperidol Potent dopaminergic (D2) receptor blocker. Less
sedating than prochlorperazine (due to
negligible anticholinergic activity). Useful in
delirious patients with nausea. Relatively safe in
the renally-impaired (not renally-cleared). Can
be administered subcutaneously.
Prochlorperazine Phenothiazine with broader spectrum receptor
blockade (dopaminergic, cholinergic,
histaminergic) than haloperidol. May be helpful if
the mechanism of vomiting is not clear.
Accumulates with chronic use. Akathisia may
occur, particularly in the elderly. Can be
administered rectally and as a buccal tablet.
Subcutaneous administration is not
recommended due to local irritation.
Metoclopramide Prokinetic activity is believed to be mediated via
the cholinergic system in the myenteric
plexus.170 Anticholinergics (eg, hyoscine) can
interfere with this prokinetic action.
Extrapyramidal side effects are a concern. Partic-
ularly helpful in cisplatin-induced delayed nausea
where serotonin antagonists are less effective.
Can be administered subcutaneously or rectally.
Cyclizine Antihistamine that is relatively less sedating than
the other typical antihistamines. May be useful in
bowel obstruction. Anticholinergic side effects
are the main adverse reactions. Can be
administered subcutaneously or rectally.
Hyoscine Anticholinergic that is particularly useful in nausea
and vomiting caused by malignant bowel
obstruction. Anticholinergic adverse effects
include drowsiness and confusion. May be given
subcutaneously.
Ondansetron Serotonin receptor (5-HT3) antagonist that has
synergistic activity with steroids in
chemotherapy-induced nausea. Has a ‘‘ceiling’’
effect. Relatively few side effects notable for
constipation. Useful in radiation-induced nausea
and vomiting and may be helpful when the
underlying mechanism of nausea and vomiting is
not well characterized. May be administered
subcutaneously.
Abbreviations: D2, dopamine type 2; 5-HT3, 5-hydroxytryptamine (serotonin)
group 3.
a
Adapted, in part, from Lickiss N, Philip J. Palliative care and pain management. In:
Berek JS, Hacker NF, eds. Practical Gynecologic Oncology. 4th ed. Philadelphia,
PA: Lippincott Williams & Wilkins; 2005: 835-862, with permission.11
negatively influencing the QOL and functional status. This is
in addition to its contributing role in the development of
decubitus ulcers and other physical impairments. The initial
Rezk et al
management should address potentially reversible causes such
as depression, reversible gastric stasis, and constipation. Nutri-
tional counseling is equally important. Energy-dense small fre-
quent meals,183,184 served in an attractive manner, are
appropriate methods aiming at providing compassionate care
and promoting the patient’s comfort.185 Fatty meals should
be avoided because they can delay gastric emptying.
Caregivers should not express their concern regarding the anor-
exia to the patient.
Pharmacological interventions include high-dose progesta-
gens, such as megestrol acetate or medroxyprogesterone acetate,
which have been shown to improve appetite and nonfluid weight
gain,186-188 corticosteroids,189-192 and cannabinoids.193 The role
of steroids as an appetite stimulant is short-lived, however.194-197
Worth mentioning, the effect of progestagens on appetite is
thought to be, at least in part, due to cytokine downregulation.198
For optimum results, the administration of these agents should
be coordinated with meals.183 Other potential agents for use in
this setting include omega-3 polyunsaturated fatty acids supple-
mented with vitamin E, serotonin antagonists, adenosine tripho-
sphate, melatonin, thalidomide, and others.199-203
Although measures such as parenteral and artificial enteral
feeding would seem appropriate interventions for addressing
anorexia, there is little evidence to suggest that such interven-
tions are helpful in that setting.204,123 Such interventions are
rarely indicated in the management of terminal patients with
advanced cancer in the palliative care setting. Nonetheless,
caregivers should continue to provide small amounts of food,
oral fluids, and ice chips as desired.185,205
Diarrhea
Diarrhea is frequently a sign of fecal impaction in the palliative
gynecologic oncology setting. Other causes include clostridium
difficile enterocolitis, abdominal irradiation, and/or tumor
involvement of the bowel. Clostridium difficile infection is
treated with metronidazole or oral vancomycin. Antidiarrheals
(eg, loperamide) are appropriate agents for nonspecific diar-
rhea. Tenesmus may require the addition of steroids. Impor-
tantly, diarrhea should be differentiated from soiling due to
enterovaginal or rectovaginal fistulae, which can be a source
of significant distress to the patient and may necessitate surgi-
cal correction whenever feasible. When corrective surgery is
not feasible, aggressive local care together with agents to
decrease the fistulous output, such as octreotide in case of small
bowel fistulae206 and bulk-forming agents (eg, methyl cellu-
lose) for colonic fistulae, can be helpful. The addition of metro-
nidazole, given systemically and applied locally, may also
improve the associated odor.
Ascites
Ascites is commonly seen in end-stage ovarian cancer and can
cause considerable distress. Paracentesis should be minimized
to decrease the protein loss, the cardiovascular stress caused
by fluid shifts, and the risk of the tumor seeding the needle
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367
track. Potassium-sparing diuretics (eg, spironolactone), with
or without loop diuretics, may be helpful, initially. Sympto-
matic treatment of the associated discomfort with acetamino-
phen and a low-dose opioid can provide some relief as well.
A more durable control of ascites may be achieved by che-
motherapy if this is still an option.
Dyspnea
Dyspnea, in this setting, often has a multifactorial etiology.
Treatment should be directed toward the underlying cause/
causes whenever possible. Malignant pleural effusion is
addressed by thoracentesis and pleurodesis. Although rather
uncommon in metastatic gynecologic malignancies, a sympto-
matic bronchial lesion may respond to radiation therapy. Dys-
pnea associated with the occasionally reported lymphangitis
carcinomatosis, may improve with steroid therapy.207 When
no specific therapy is available, the management should be
focused on the control of the discomfort associated with the
dyspnea and not the underlying cause. Both opioids (eg, oral
morphine sulfate 2-5 mg every 4 hours) and benzodiazepines
(eg, lorazepam 0.5 mg sublingual) have been used for that
purpose.208-210 For patients in the final phase of their lives, a
low-dose sc infusion of midazolam may help relieving the sen-
sation of uncomfortable breathing. Anticholinergics (eg, glyco-
pyrrolate) may also reduce respiratory secretions and noisy
breathing in patients unable to clear their secretions.
Ureteral Obstruction
Ureteral obstruction, commonly resulting from carcinoma of
the cervix spreading laterally or large pelvic lymphadenopathy
compressing the ureters, may lead to loin pain, hydro/pyone-
phrosis, and, finally, renal failure. When several months of rel-
atively symptom-free survival are anticipated, relieving the
obstruction either through ureteral stenting or through percuta-
neous nephrostomy tube placement seems prudent. However,
when the QOL is severely compromised and other reasonable
treatment options have been exhausted with limited duration
of survival expected, mechanical measures for relief of the
obstruction become rather inappropriate. Short courses of ster-
oids may improve ureteral patency in such situations.211,212
The decision to or not to intervene mechanically should be
highly individualized.211,213
Hypercalcemia
Hypercalcemia may cause a multitude of symptoms in patients
with advanced gynecologic cancers, including weakness,
lethargy, nausea, vomiting, constipation, abdominal pain, and
confusion. It is commonly caused by the tumor secreting
humoral factors (eg, parathormone-related peptide), leading
to accelerated bone resorption. Clear and small-cell carcinomas
of the ovary are common causes of hypercalcemia in these
patients. The elevated calcium level leads to significant volume
depletion resulting from severe polyuria secondary to the
368
interference with the renal urinary concentrating ability. In the
relatively asymptomatic patients, it is prudent to refrain from
aggressive interventions. In symptomatic patients, however,
the principals of management include aggressive hydration
with isotonic fluids (eg, normal saline) in addition to bispho-
sphonate therapy (eg, pamidronate).214 Loop diuretics (eg, fur-
osemide) may be added only after the fluid deficit has been
corrected to enhance calcium excretion. A noticeable response
should be expected within a few days and usually lasts around a
month depending on the clinical scenario. Bisphosphonate
therapy may be repeated if needed. Calcitonin (sc or intramus-
cular) may be used, in addition to bisphosphonates, to effect a
more rapid normalization of serum calcium in refractory cases
or alone in cases with renal failure where bisphosphonate ther-
apy is relatively contraindicated. Antineoplastic therapy, if still
feasible, offers the best chance at a durable response, however.
Summary
In conclusion, the management of women with gynecologic
malignancies in the final phase of their lives continues to be
challenging. Clinicians need more formal training regarding
the care of the terminal woman with an advanced gynecologic
cancer.215 A multimodal approach that addresses all aspects of
suffering is the key to successful palliation. End-of-life discus-
sions should be initiated well in advance. Effective and fre-
quent communication between the health care providers and
the patients and their families cannot be overemphasized. Con-
trolled studies addressing controversial issues such as the pal-
liative surgical management of patients with MBO, and that
use symptom control/QOL as primary end points rather than
survival, have the potential to further optimize the care of such
unfortunate patients.
Declaration of Conflicting Interests
The author(s) declared no conflicts of interest with respect to the
authorship and/or publication of this article.
Funding
The author(s) received no financial support for the research and/or
authorship of this article.
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