JGO-00253; No.

of pages: 12; 4C:

J O U RN A L OF GE RI A T RI C O NC O L O G Y XX ( 20 1 4 ) XX X–XX X

Available online at www.sciencedirect.com

ScienceDirect

Review article

Diffuse large B-cell lymphoma in the elderly: Impact of

prognosis, comorbidities, geriatric assessment, and supportive
care on clinical practice. An International Society of Geriatric
Oncology (SIOG) Expert Position Paper

Vicki A. Morrisona,⁎, Paul Hamlinb , Pierre Soubeyranc , Reinhard Stauder d , Punit Wadhwaa ,
Matti Aaproe , Stuart Lichtman f
a
University of Minnesota, Veterans Affairs Medical Center, Minneapolis MN, USA
b
Memorial Sloan-Kettering Cancer Center, New York, NY, USA
c
University of Bordeaux and Institut Bergonié Bordeaux, France
d
Department of Internal Medicine, V Haematology and Oncology, Innsbruck Medical University, Innsbruck, Austria
e
Institut Multidisciplinaire d'Oncologie, Clinique de Genolier, Genolier, Switzerland
f
Memorial Sloan-Kettering Cancer Center New York and Commack, NY, USA

AR TIC LE I N FO ABS TR ACT

Article history: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin
Received 6 August 2014 lymphoma in the elderly, and is increasing in incidence. Although significant therapeutic
Received in revised form advances have recently been made in the care of older patients with DLBCL, based upon
2 October 2014 results of randomized clinical trials, many older patients are not eligible for such trials due
Accepted 20 November 2014 to comorbidities and functional decline. Pre-treatment evaluation of older patients to
ascertain potential tolerance to therapy is especially important in therapeutic decisions for
this population. Evaluation by performance status alone is insufficient, especially in the
Keywords: elderly, and consideration of the impact of comorbidities and functional/social decline
Large cell lymphoma needs to be included in such assessment. As part of an International Society of Geriatric
Elderly Oncology (SIOG) task force, the issues of prognosis, comorbidities, geriatric assessment, and
Frailty supportive care measures in older patients with DLBCL will be reviewed, and recommen-
Geriatric assessment dations for assessment and allied care made.
Comorbidities Published by Elsevier Ltd.

⁎ Corresponding author at: Sections of Hematology/Oncology & Infectious Disease, 111E, VAMC, One Veterans Dr, Minneapolis, MN 55417,
USA. Tel.: +1 612 467 4135; fax: + 1 612 467 5673.
E-mail address: morri002@umn.edu (V.A. Morrison).

http://dx.doi.org/10.1016/j.jgo.2014.11.004
1879-4068/Published by Elsevier Ltd.

Please cite this article as: Morrison VA., et al, Diffuse large B-cell lymphoma in the elderly: Impact of prognosis, comorbidities,
geriatric assessment, and supportive care on clinical..., J Geriatr Oncol (2014), http://dx.doi.org/10.1016/j.jgo.2014.11.004
2 J O U RN A L OF GE RI A TR I C O NC OLO G Y XX ( 20 1 4 ) XX X–XXX

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2. Demographics and Staging of DLBCL in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3. Prognostic Factors for Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.1. Clinical Prognostic Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.2. Prognostic Biomarkers and Gene Expression Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.3. Immunohistochemical Algorithms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4. Concept of Age-Adjusted Life Expectancy and Individualized Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . 0
5. Comorbidity and Geriatric Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
5.1. Comorbidity and Functional Status. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
5.2. Dementia as Comorbidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
5.3. Endorgan Dysfunction as Comorbidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
5.4. Comprehensive Geriatric Assessment and Frailty Measures (Table 3) . . . . . . . . . . . . . . . . . . . . . . . . 0
6. Supportive Care Issues in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
6.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
6.2. Age as a Risk Factor for Neutropenic Fever . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
6.3. International European Organization for Research and Treatment of Cancer (EORTC) Guidelines . . . . . . . . . 0
6.4. American Society of Clinical Oncology (ASCO) Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
6.5. Red Blood Cell (RBC) Stimulating Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Disclosures and Conflict of Interest Statements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Author Contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

1. Introduction age at diagnosis is between 70–75 years; approximately

Non-Hodgkin's lymphoma (NHL) is common in both genders
with an increasing incidence, especially in those >60 years of
age [1–3]. Diffuse large B-cell NHL (DLBCL) is a common NHL
subtype in the elderly, with poorer prognosis than in younger
patients. Therapy in the older and/or frail population is
complicated by comorbidities, as well as pre-existent alterations
in functional status. Because of these issues as well as the lack
of treatment guidelines for the elderly, under the auspices of the
International Society of Geriatric Oncology (SIOG), an expert
international panel of physicians with academic expertise in
geriatric hematology was convened to review DLBCL in the
elderly, specifically to address prognosis, impact of comorbid-
ities, role of geriatric assessment, and supportive care measures
in the care of this patient population. The issues of treatment
in this patient population, including initial therapy and ap-
proaches to the relapsed and refractory patient, are covered in a
separate manuscript.
2. Demographics and Staging of DLBCL in
the Elderly
With an overall age-adjusted incidence rate between 6 and 8/
100,000 per year in western populations, DLBCL is the most
common subtype of NHL. A greater proportion of elderly
patients are diagnosed with DLBCL, compared to younger
patients [1]. Incidence rates increase dramatically with ad-
vanced age, exceeding 30/100,000 per year in patients > 65–
70 years old [2–4]. In population-based cancer registries, median
two-thirds of DLBCL cases occur in patients ≥ 65 years of age
[3,4]. Incidence rates are higher in males than females, with a
2:1 ratio in the elderly.
Net survival (NS) is the survival that would be observed if
cancer was the only possible cause of death, and constitutes an
interesting indicator in population studies. Recent NS data from
16 French DLBCL registries between 1989–2004 showed that age
at diagnosis was a major prognostic factor [5]. Overall, five-year
NS was 47% (95% CI: 45–49), but 43- and 40-fold decreases in
five- and ten-year NS respectively, were found in young men
(15–45 years old) and men > 75 years of age. Among the oldest
patients (i.e. 65–75, versus >75 years), the five-year NS dropped
in men from 45% (95% CI: 40–50) to 26% (95% CI: 22–31). Similar
observations were found in women, as well as in other
European and American series [2,6,7].
The histologic classification of NHL has evolved from the 1982
International Working Formulation (IWF), to the 1994 REAL
(Revised European American Lymphoma) schema, and lastly the
2001 World Health Organization (WHO) classification (updated
in 2008), which includes morphologic, immunophenotypic, and
genetic features, as well as clinical aspects [8–10]. Diagnostic
material should be submitted for histologic, immunophenotypic,
immunohistochemical, cytogenetic, and molecular analysis.
Non-Hodgkin lymphoma staging recommendations have been
recently updated [11]. Although the division into limited (I–II)
and advanced (III–IV) stage disease remains, the suffixes for A
and B symptoms will no longer be used. Staging evaluation
in the elderly should include physical examination, complete
blood count with differential, lactic dehydrogenase (LDH),
hepatitis B/C serologies, CT scans of chest, abdomen, and other

Please cite this article as: Morrison VA., et al, Diffuse large B-cell lymphoma in the elderly: Impact of prognosis, comorbidities,
geriatric assessment, and supportive care on clinical..., J Geriatr Oncol (2014), http://dx.doi.org/10.1016/j.jgo.2014.11.004
 J O U RN A L OF GE RI A T RI C O NC O L O G Y XX ( 20 1 4 ) XX X–XX X
sites as appropriate, and functional imaging with PET scan (more
sensitive in extranodal sites). In those elderly patients for whom
these scans may not be feasible, CXR and abdominal ultrasound
procedures may be considered. Bone marrow biopsy is no
longer indicated for staging [11]. Assessment of cerebrospinal
fluid cytology should be considered for patients at high risk of
central nervous system involvement. Baseline determination of
cardiac ejection fraction is necessary prior to anthracycline-
based therapy.
3. Prognostic Factors for Outcome
DLBCL is a heterogeneous disease in terms of clinical features,
prognosis and therapeutic response, related to many molecular
pathways and pathogenic mechanisms involved in oncogenic
transformation. Predicting prognosis of patients with DLBCL
has been a “moving target” as new therapies emerge and alter
treatment paradigms. Although earlier studies stratified pa-
tients into different clinical risk groups, recent research has
been directed towards identifying biomarkers, most of which
are for patients of all ages, to refine prognostication (Table 1).
Although very few trials have specifically addressed prognosis
of elderly patients with DLBCL, adverse disease subtypes in-
cluding immunoblastic morphology, activated B-cell (ABC)
subtype, as well as Epstein Barr virus-positive DLBCL are
overrepresented in elderly individuals [12,13]. In addition,
immunosenescence, with deterioration in innate and adaptive
immunity, is observed [14]. Selective depletion of lymphoid-
competent hematopoietic stem cells may explain decreased
lymphopoiesis with age [15,16]. Although such senescence is
now identified in the elderly with cancer, data specific to DLBCL
are lacking [17].
3.1. Clinical Prognostic Models
The International Prognostic Model (IPI) was derived and
validated from a dataset of > 2000 patients treated with
anthracycline-based chemotherapy in the pre-rituximab era
[18]. Five adverse prognostic factors were identified: age >
Table 1 – Prognostic factors for outcome in older patients
with DLBCL.
Clinical factors (age-adjusted International Prognostic Index)
Performance status
Advanced stage disease
>1 extranodal disease site
Elevated LDH
Histologic features
Immunoblastic morphology
Epstein Barr virus-positive variants
Gene expression profile
Germinal center B-cell, activated B-cell subtypes
Stromal-1, stromal-2 signatures
Markers of
Apoptosis (BCL2, survivin, Fas)
Cell-cycle regulation (p53)
Cellular proliferation (Ki-67)
B-cell differentiation (BCL6, FOXP1)
Angiogenesis (HIF-1α, VEGFR2)
Please cite this article as: Morrison VA., et al, Diffuse large B-cell lymphoma in the elderly: Impact of prognosis, comorbidities,
geriatric assessment, and supportive care on clinical..., J Geriatr Oncol (2014), http://dx.doi.org/10.1016/j.jgo.2014.11.004
3
60 years, Eastern Cooperative Oncology Group (ECOG) perfor-
mance status (PS) ≥ 2, stage III/IV disease, > one extranodal
disease site, and elevated LDH. Individual patients were
stratified into four prognostic risk groups (low, low interme-
diate, high intermediate, high) with five-year survival rates of
73%, 51%, 43% and 26% respectively. Subsequently, the
age-adjusted IPI has been utilized for elderly patients. In an
effort to assess its utility in R-CHOP-patients, British Columbia
investigators analyzed registry data of 365 patients (median
age 61 years) [19]. With the traditional IPI scoring system only
two distinct prognostic groups were identified. However,
when IPI scores were redistributed into a revised-IPI (R-IPI)
scoring system, three groups with distinct prognoses were
identified (very good risk, good risk, poor risk, with four-year
survivals of 94%, 79% and 55%, respectively). In subsequent
outcome analysis of 1062 patients receiving rituximab-based
chemoimmunotherapy in three prospective trials, Ziepert
et al., concluded that the IPI score retained its significance
for event-free (EFS), progression-free (PFS), and overall surviv-
al (OS), although rituximab did significantly improve outcome
within each IPI subgroup [20]. Another prognostic model, the
Elderly-International Prognostic Model (E-IPI), utilizing an age
cut-off of 70 (as opposed to 60) years, has been recently
proposed, but needs validation in other datasets of prospec-
tively treated patients > 60 years of age [21].
3.2. Prognostic Biomarkers and Gene Expression Studies
Individual biomarkers have provided insight into molecular
pathways driving lymphomagenesis, and a platform for
rational design of targeted therapy. However, limitations of
prognostic use of biomarkers include: the complexity of
mechanisms involved in transformation to a malignant phe-
notype, the retrospective nature of most biomarker studies,
lack of standardization of methodology used to evaluate the
biomarker, differences in “cut-off” thresholds used to define
“positivity”, and lack of revalidation in patient cohorts treated
prospectively with rituximab-based chemoimmunotherapy. In
a recent review, markers studied in the rituximab era were
specifically addressed [22]. Markers studied most extensively
relate to genes and their protein products involved in apoptosis
(BCL2, survivin and Fas), cell-cycle regulation (p53), markers of
cellular proliferation (Ki-67), markers related to B-cell differen-
tiation (BCL6, FOXP1), and markers germane to angiogenesis
(HIF-1α and VEGFR2) [23–33]. There is considerable interest
in the adverse prognostic outcome associated with MYC
gene rearrangements and myc protein overexpression, as well
as inferior outcome associated with the so-called “double-hit
lymphomas” involving translocations of both MYC and BCL2
[34–39].
Gene expression studies utilize molecular profiling to simul-
taneously study the expression of multiple genes at an mRNA
level. Initial pivotal studies identified two major subtypes of
DLBCL: germinal center B-cell (GCB) and activated B-cell [40–42].
Compared to ABC subtype, patients with GCB subtype had a
significantly better prognosis (five-year survival of 76% versus
16%) with anthracyline-based chemotherapy. The ABC subtype
accounts for 60–70% of DLBCL in patients > 80 years of age
[43–45]. Another seminal gene expression study, in which three
molecular signatures were identified (germinal center B-cell
4 J O U RN A L OF GE RI A TR I C O NC OLO G Y XX ( 20 1 4 ) XX X–XXX
[GCB], stromal-1, stromal-2 signatures) illustrated the im-
portance of tumor microenvironment [43]. The stromal-1
signature, characterized by genes associated with connective
tissue growth factor and cells of monocyte/macrophage lineage,
correlated with significantly superior prognosis compared to
the stromal-2 signature, which was associated with genes
involved in angiogenic pathways.
3.3. Immunohistochemical Algorithms
Major limitations of gene expression studies are that they are
expensive, time-consuming, require fresh vital or fresh
frozen tissue, and are not readily available outside a research
setting. For application in community settings, investigators
have used immunohistochemical (IHC) studies on paraffin-
embedded tissue as surrogates for gene expression, to provide
a semiquantitative assessment of protein expression thought
to be biologically relevant in lymphoma pathogenesis [46–48].
Although these IHC-based tests are more readily available
and easier to perform, there are conflicting results of their
diagnostic utility, and there is currently no consensus about
the best IHC model predictive of prognosis in rituximab-
treated patients.
In summary, the standard of care for prognostication
remains clinical prognostic models as the age-adjusted IPI.
Collaborative research endeavors will allow incorporation of
biomarker-based prognostic models to better stratify patients
in the context of prospective clinical trials, identify novel
therapeutic targets, assure uniform outcome reporting, and
help clinicians individualize therapy for patients based on an
improved understanding of the molecular pathways involved
in lymphomagenesis.
4. Concept of Age-Adjusted Life Expectancy and
Individualized Treatment
To individualize treatment decisions in elderly patients with
DLBCL, decision-making should be based upon risk scoring
and integration of age-related life expectancy, as well as
geriatric assessment, that can aid in classifying patients as fit
or frail [49]. The survival rate of a given patient with DLBCL
should be compared with an age- and sex-matched popula-
tion, which is available in public age statistics in many
western countries (including CDC/NCHS, National Vital Sta-
tistics System [http://www.cdc.gov/nchs/nvss.htm], Statistic
Austria [www.statistik.at]) [50,51]. Even in the elderly, DLBCL
shortens life expectancy dramatically [2,5–7]. This highlights
the need for appropriate, and whenever possible curative,
treatment of DLBCL. An even more precise prognostication of
life expectancy in elderly individuals is based upon integra-
tion of self-reported health, with divisions into upper, middle
and lower quartiles of life expectancy [52]. With the integra-
tion of comorbidities and functional capacities, a scoring
system was developed to predict four-year mortality in elderly
patients [53,54]. These scores are useful in daily practice to
predict life expectancy and develop an individualized thera-
peutic approach. A multidimensional approach to geriatric
assessment, which integrates functional capacities, comor-
bidities, cognitive function, social support, emotional status/
Please cite this article as: Morrison VA., et al, Diffuse large B-cell lymphoma in the elderly: Impact of prognosis, comorbidities,
geriatric assessment, and supportive care on clinical..., J Geriatr Oncol (2014), http://dx.doi.org/10.1016/j.jgo.2014.11.004
depression, nutritional status, and polypharmacy, can aid in
assessing biological–physiologic age, which is more important
than chronological age in developing individualized therapy
approaches, as well as predicting tolerance to therapies.
5. Comorbidity and Geriatric Assessment
Comorbid conditions in the elderly are common, present in 60–
70% of NHL patients > 60 years and associated with poorer
outcome (Table 2) [55]. Consequences of comorbidity include
increased treatment-related mortality and toxicity, leading to
dose reductions with resultant lower dose intensity and higher
rate of treatment failure [56]. Likewise polypharmacy, with
the issues of multiple medications, potential drug interactions,
and patient compliance, is common in elderly patients with
comorbidities. Additionally, comorbidity frequently precludes
clinical trial participation, limiting validity of reported studies in
older NHL patients. Oncology-specific measures of comorbidity
are needed to guide decision-making.
The comorbidity index of the National Institute of Aging/
National Cancer Institute was applied in a Netherlands popula-
tion study of 381 patients with aggressive lymphoma, revealing
high impact comorbidity doubled risk of death, independent of
the IPI [55,57]. The Cumulative Illness Rating Scale (CIRS) has
been employed in the EORTC cooperative group setting to assess
comorbidity in the context of prospective trials targeting frail
DLCL patients [58]. This measure identified severe comorbidities
in 37–47% of patients and was part of the functional definition of
frailty.
As comorbidity is an important consideration in treatment
planning and prognosis, studies have examined its impact. In a
retrospective review of 140 patients with DLBCL > 70 years of
age, treatment outcomes were related to standard IPI risk
stratification [59]. Cardiovascular complications, peripheral
neuropathy and diabetic complications exacerbated by predni-
sone were the most common comorbidities. Lymphoma was
the cause of death in 76% of patients. The Eindhoven Cancer
Registry was examined to determine severity of comorbidity
among older patients (median age, 64 years) in the Netherlands
[55]. Comorbidity was defined as all diseases present at cancer
diagnosis, with severity classified according to the National
Cancer Institute index. For aggressive NHL patients, comorbid-
ities were present in 48% of patients <60 years old and 78% of
older patients. The chance of receiving chemotherapy was only
influenced by age, with the likelihood for those >60 years
only one third that of younger patients (p = 0.05). Severity of
comorbidity had no independent effect on receipt of
Table 2 – Impact of comorbidities on treatment agents for
older patients with DLBCL.
Cardiovascular (anthracyclines)
Renal dysfunction (platinum derivatives)
Pre-existent peripheral neuropathy (platinum derivatives, taxanes,
vinca alkaloids, lenalidomide)
Diabetes (prednisone)
Pre-existent marrow compromise (prior chemotherapy, radiation)
(any myelosuppressive agents)
Dementia (all therapy)
 J O U RN A L OF GE RI A T RI C O NC O L O G Y XX ( 20 1 4 ) XX X–XX X
chemotherapy. However, among patients with aggressive NHL
and cardiovascular comorbidity, the likelihood of receiving
chemotherapy was only 40% compared to those without
comorbidity (p = 0.04). The chance of receiving CHOP-like
chemotherapy was 40% for those >60 years compared with
younger patients, after adjustment for gender, stage and
severity of comorbidity. Dose reductions were not more
common in older patients and did not occur more frequently
among patients with high impact comorbidity. Hematologic
toxicity was the most common reason for dose reduction. There
was no difference in spectrum and incidence of toxicity
comparing older and younger patients. Severity of comorbidity
had no significant impact toxicity occurrence, except for
patients with cardiovascular comorbidity. In aggressive NHL,
three-year crude survival was 62% for patients aged 40–60, and
41% for those >60, years. Survival decreased significantly with
increasing IPI risk score, and was significantly lower for patients
with high impact comorbidity.
Cardiovascular comorbidity is most significant for older
patients. Certain agents, especially the anthracyclines, have
potential cardioxicities, including QT prolongation, myocardial
ischemia, and congestive heart failure (CHF) [60]. Any doxoru-
bicin use was associated with a 29% risk of CHF in a Surveillance,
Epidemiology, and End Results (SEER) Medicare database. CHF
risk increased with number of doxorubicin claims, increasing
age, prior heart disease, comorbidities, diabetes, and hyperten-
sion. Patients with prior heart disease were less likely to receive
doxorubicin. Hypertension was synergistic with doxorubicin for
CHF risk. Patients with hypertension and diabetes had 58% and
27% higher risks of developing CHF. Advanced age was a strong
predictor both of withholding doxorubicin and subsequent CHF.
Those >80 years had more than double the CHF risk as patients
65–70 years old. Older patients who received <six treatments
had no increase of CHF, but had benefit. As such, screening
workup of patients to receive potentially cardiotoxic agents
should include historical assessment of risk factors as hyper-
tension, atherosclerotic cardiovascular disease, diabetes, CHF,
and prior exposure to cardiotoxic drugs or thoracic radiation,
and baseline electrocardiogram and either echocardiogram or
MUGA scan [61]. Cumulative upper doses of anthracyclines
should not be exceeded (i.e., 400–450 mg/m2 for doxorubicin;
140 mg/m2 for mitoxantrone), and serial monitoring of cardiac
function by exam/echocardiogram/MUGA scan should be
done. Relevance of biomarkers as troponins or brain natriuretic
peptide for prediction and follow-up of cardiotoxicity has
not yet been delineated. Use of less cardiotoxic therapy,
particularly liposomal anthracyclines, should be considered
[62]. Potential cardiotoxicity of novel targeted agents also should
be considered.
In another single institution analysis of patients ≥ 80 years
of age, 87% had at least one comorbid illness, with a prior history
of cardiovascular disease being most common [63]. Stratification
of patients according to the Charlson index was 0 (13.7%), 1–2
(36.6%), 3–4 (33.7%), and >4 (15.1%). Anthracycline-based che-
motherapy was administered in 32.2% of patients with aggres-
sive lymphoma. Lymphoma was the predominant cause of
death (57.5%) with comorbidity accounting for 13.7%.
In another evaluation of older NHL patients from
Singapore, there were no significant differences in baseline
demographics and lymphoma characteristics among patients
Please cite this article as: Morrison VA., et al, Diffuse large B-cell lymphoma in the elderly: Impact of prognosis, comorbidities,
geriatric assessment, and supportive care on clinical..., J Geriatr Oncol (2014), http://dx.doi.org/10.1016/j.jgo.2014.11.004
5
aged 60–74 and those > 75 years, except for PS [64]. In
multivariate analysis, lymphoma characteristics as histology,
PS, and stage were useful in predicting survival for patients
<75 years of age. Among patients aged ≥ 75, the only indepen-
dent prognostic factor for survival was PS. The data may be
interpreted that PS, comorbidity, and functional status need
to be independently assessed [65].
5.1. Comorbidity and Functional Status
Comorbidity is important in overall patient survival and may
influence benefits and toxicity of cancer therapy. The associ-
ation between comorbidity and survival was evaluated by
Charlson who determined that number and severity of
comorbid illnesses can predict survival in general medical
patients admitted to an inpatient unit [66]. Although disease
stage is a crucial determinant of survival, comorbidity
increases complexity of management and impacts survival
[58]. Satariano and Ragland assessed the effect of comorbidity
and disease stage on three-year survival in women with
breast cancer, and found comorbidity to be a strong predictor
of survival, independent of disease stage [67]. The association
between functional status and comorbidity was evaluated in
another study of older patients with cancer, which demon-
strated that these factors are independent, thus each needs
separate assessment [65]. Traditional oncology measures as
Karnofsky score (KPS) and PS may not address issues that
would be uncovered with use of geriatric-specific assessment,
as polypharmacy, availability of social support, ability to use
the telephone, and depression. The degree of dependency and
geriatric functional scores can predict survival in older
patients. Future oncology clinical trials would benefit from
incorporation of easy-to-administer functional scales, to aid
in predicting toxicity and outcome [68]. Currently available
functional scales include self-reported measures as ability to
complete activities of daily living (ADL) and instrumental
(I-)ADL, as well as performance-based tests as get up and go
and gait speed.
5.2. Dementia as Comorbidity
Treatment of patients with dementia is a significant issue in
oncology [69]. In a tertiary cancer center, 18% of patients
screened positive on the Mini Mental Status Examination, and
is likely an underestimate of overall incidence [70,71].
Cognitively-impaired patients have markedly reduced surviv-
al compared to nonimpaired patients [72]. Although consid-
eration should be given for potential life-extending therapy,
this should be balanced against potential toxicities. In a SEER
colon cancer database review, patients with dementia are
more significantly less likely to have undergone histologic
diagnosis, be offered surgical resection, or adjuvant chemo-
therapy. Immediate caregiver support is imperative if therapy
is to be offered. The risk of toxicities that can cause delirium,
as diarrhea, dehydration, or febrile episodes, is higher in
impaired patients. Chemotherapy with which these toxicities
are common should be avoided or at least used with extreme
care, paying careful attention to dosing and adjunctive
supportive measures (i.e., growth factors, hydration, etc.).
Delirium may also complicate surgery. Elective surgery is
6 J O U RN A L OF GE RI A TR I C O NC OLO G Y XX ( 20 1 4 ) XX X–XXX
markedly preferred to emergency surgery, with improved
outcome including markedly decreased mortality [73].
5.3. Endorgan Dysfunction as Comorbidity
Patients with endorgan dysfunction are usually excluded
from clinical trials, particularly for new drugs. Assessment of
endorgan dysfunction is critical to guide physicians in cancer
therapy dosing [74–79].
Renal dysfunction is common in the elderly, and impacts
choice of potential therapeutic agents [80]. Recommendations
for chemotherapy dosing of older patients with renal insuffi-
ciency have recently been summarized in International Society
of Geriatric Oncology (SIOG) task force publications [81,82].
When studying a new drug that is not renally excreted, serum
creatinine and/or creatinine clearance requirements may need
to be relaxed. Additional research is needed to determine which
of the available creatinine clearance formulae (modification of
diet in renal disease (MDRD), Cockcroft-Gault) is most accurate in
older patients [83,84]. Depending on methodology utilized,
creatinine clearance can vary and therefore influence clinical
trial eligibility and affect perceptions of safety. Additionally,
evaluation of renal function in extreme obesity or cachexia
is often not valid. Most drugs used in DLBCL treatment as
cyclophosphamide, vincristine, doxorubicin (i.e., CHOP),
bendamustine, or liposomal doxorubicin are characterized by
limited renal elimination, thus dose adjustments are not needed
and use of these agents is feasible in most elderly patients. The
nephrotoxicity of platinum derivatives limits their usage.
Appropriate hydration is warranted and co-administration of
nephrotoxic drugs should be avoided.
Chemotherapy-induced peripheral neuropathy (CIPN) is a
potential side effect of several drugs utilized for DLBCL
therapy, as platinum derivatives, taxanes, vinca alkaloids,
and lenalidomide. General recommendations are to monitor
for neuropathy and hearing loss, and consider alternative
regimens with non-neurotoxic drugs. There are no age-
specific guidelines for dose reduction of these agents in the
elderly/frail. Development of CIPN is influenced by factors as
cumulative dose, co-administration of neurotoxic drugs, and
presence of predisposing factors as diabetes or alcohol abuse.
No agents have proven effectiveness in prevention of CIPN
[85].
5.4. Comprehensive Geriatric Assessment and Frailty
Measures (Table 3)
The comprehensive geriatric assessment (CGA) is a funda-
mental tool in care of geriatric patients, but integration and
application of this tool in oncologic practice are in evolution.
The goals of CGA are to guide selection of interventions to
restore or prevent health decline, recommend an optimal care
environment, and monitor clinical change over time. Compo-
nents of the CGA include functional assessment, comorbid
medical conditions, nutritional status, cognitive function,
psychological state, social support, and medication review.
Unfortunately, complete CGA is time-consuming and often
impractical in a modern oncology practice given logistic and
resource constraints. Hence, there is a pressing need for an
easily, rapidly applied, effective, and validated tool in the
Please cite this article as: Morrison VA., et al, Diffuse large B-cell lymphoma in the elderly: Impact of prognosis, comorbidities,
geriatric assessment, and supportive care on clinical..., J Geriatr Oncol (2014), http://dx.doi.org/10.1016/j.jgo.2014.11.004
Table 3 – Components of a comprehensive geriatric
assessment.
Performance status
Assessment of activities of daily living (ADL), instrumental
ADL (IADL)
Comorbidities
Functional assessment
Fitness/frailty
Nutritional status
Cognitive function
Psychological state
Social support
Polypharmacy
oncologic setting. Current methods, as assessing KPS/PS, ADL,
and IADL, are limited in scope and ability to assess multiple
domains. Screening tools, as the vulnerable elders survey
(VES-13), to identify those at-risk individuals in need of more
formal CGA, require prospective oncologic validation [86].
A SIOG task force concluded that although CGA should
be utilized for elderly oncology patients, with or without
screening, currently a specific CGA tool cannot be recommended
given available data [87]. Multidisciplinary senior adult oncology
programs, as the model program at the Moffitt Cancer Center
(Tampa, FL), have integrated CGA into a team approach and serve
as paradigms for the creation of similar oncogeriatric programs.
Ongoing efforts are resulting in more approachable mechanisms
for general use in the elderly. Hurria et al. have developed a CGA
that is self-administered and feasible in the outpatient setting,
with assessment across multiple domains [88]. This CGA is
currently being validated in both a larger prospective study and
the oncology cooperative group setting [86].
An abbreviated assessment has been used in small NHL
series. Winkelmann et al. evaluated 143 patients, median age
63 years (29% ≥ 70 years), and found that comorbidity and
dependence in IADL were associated with overall survival [89].
However, their results did not account for lymphoma subtype or
therapy. Tucci et al. evaluated patients, aged ≥65 years, with
CGA prior to therapy [90]. As CGA results were blinded, treatment
decisions for aggressive or palliative therapy were made solely
by clinical judgment. As CGA was able to differentiate fit versus
unfit patients better than clinical judgment, they concluded
that CGA is an efficient method to identify which patients
should receive anthracycline-containing chemotherapy. How-
ever, these algorithms need validation in large prospective,
randomized trials before CGA is used to determine whether or
not curative therapy should be administered.
Figuring prominently in the IPI, PS has typically been
assessed with KPS or ECOG PS tools for initial risk assessment.
Unfortunately, these assessments are subjective and not good
predictors in the elderly [63]. In an attempt to utilize com-
ponents of the CGA to better assess PS, Siegel et al. selected
three functional tests validated in older populations: “timed
up and go”, hand grip, and “Tinetti gait and balance test” [91].
These tests, readily applicable in clinic, may improve func-
tional status discrimination. Efforts as these are refining
assessment skills, with the ultimate goal of improving quality
of life and therapeutic outcomes by honing decision-making
processes [86].
 J O U RN A L OF GE RI A T RI C O NC O L O G Y XX ( 20 1 4 ) XX X–XX X 7

Although there is no one precise definition of frailty,
it is important to recognize as such patients are primarily
candidates for supportive care. Suggested inclusion criteria
include age > 85 years, dependence in ADL, exhaustion,
slow gait speed, decreased hand grip, unintentional weight
loss, and decreased physical activity. These patients may
have increased incidence and severity of therapy-related
toxicities and shortened survival. Further research is
needed to precisely define frailty, so not to exclude patients
from active treatment who still have remaining functional
reserve [92–96].
6. Supportive Care Issues in the Elderly
6.1. Introduction
The risk for chemotherapy-related toxicities in older adults has
been examined [88,97]. In one series, 500 patients (mean age
73 years) who received solid tumor chemotherapy completed a
pre-treatment assessment including sociodemographics, tumor/
treatment variables, laboratory tests, and CGA variables [88].
Grade 3–5 toxicities occurred in 53%. Using pre-treatment
variables, a three-tiered risk scoring system was developed for
toxicity occurrence. A chemotherapy risk assessment scale for
high-age patients (CRASH) score was prospectively developed in
another study of 518 patients ≥ 70 years who were to receive
chemotherapy [97]. Such multidimensional risk factor assess-
ments as these are of utility in pre-chemotherapy evaluation of
older patients, to guide dose adjustment and supportive care
measures.
Older patients are likewise at increased risk of hematologic
toxicities with DLBCL therapy. Increased age-related comorbid-
ity predisposes to a greater incidence of febrile neutropenia
with resultant increased morbidity, mortality, dependence,
length of stay, and cost [98,99]. Risk is greatest during early
chemotherapy cycles, warranting consideration of supportive
care measures (Figs. 1, 2) [100,101].
6.2. Age as a Risk Factor for Neutropenic Fever
Hospitalization for chemotherapy-induced febrile neutrope-
nia is associated with substantial cost and may negatively
impact clinical outcome due to associated dose attenuation
[100,102]. In one study, 17% of patients experienced at least
one hospitalization for febrile neutropenia, and more than
half of all initial febrile neutropenia hospitalizations occurred
in cycles 1 or 2. Increased risk of febrile neutropenia
hospitalization, based on Cox proportional hazards models,
was significantly associated with the following baseline
characteristics: age ≥ 65 years (hazard ratio (HR) 1.79; 95%
confidence interval (CI) 1.35–2.37), serum albumin ≤ 3.5 g/dL
(HR 1.34; 95% CI 1.01–1.78), planned average relative dose
intensity ≥ 80% (HR 2.70; 95% CI 1.47–4.98), baseline absolute
neutrophil count < 1500/mm3 (HR 1.98; 95% CI 1.28–3.06), and
presence of hepatic disease (HR 2.18; 95% CI 1.11–4.28). Lack of
early myeloid growth factor usage in cycles 1 and 2 was also
associated with a trend for increased risk of febrile neutrope-
nia hospitalization. A composite risk score based on these
factors effectively distinguished patients at greater risk of
hospitalization for febrile neutropenia (p < 0.001), the major-
ity observed during the first cycle of chemotherapy. This risk
model, including age > 65 years, abnormal liver function
tests, renal insufficiency, and receipt of prior chemotherapy,
can be used to predict febrile neutropenia.
An Oncology Practice Pattern Study reviewed medical
records of intermediate-grade NHL patients who received initial
CHOP chemotherapy and identified risk factors associated with
time to first febrile neutropenic event [103]. Risk of febrile
neutropenia was significantly associated with age ≥ 65 years
(p = 0.001), cardiovascular disease (p = 0.020), renal disease
(p = 0.006), baseline hemoglobin < 12 g/dL (p = 0.018), >80%

Fig. 1 – Time to occurrence of febrile neutropenia with CHOP-like chemotherapy. Hazard function plot displays the distribution
of hazard rates for febrile neutropenia over time in days after chemotherapy initiation for both high-risk and low-risk patients
(from Ref. [100]).

Please cite this article as: Morrison VA., et al, Diffuse large B-cell lymphoma in the elderly: Impact of prognosis, comorbidities,
geriatric assessment, and supportive care on clinical..., J Geriatr Oncol (2014), http://dx.doi.org/10.1016/j.jgo.2014.11.004
8 J O U RN A L OF GE RI A TR I C O NC OLO G Y XX ( 20 1 4 ) XX X–XXX

Fig. 2 – Time to occurrence of febrile neutropenia with CHOP-like chemotherapy by risk group. Kaplan–Meier plot displays the
cumulative proportion of patients who experienced 1 or more episodes of febrile neutropenia over time in days after
chemotherapy initiation for both high-risk and low-risk patients (from Ref. [100]).

planned average relative dose intensity (ARDI) (p = 0.018), and
no prophylactic myeloid growth factor use (p = 0.046). First
febrile neutropenic events occurred by day 14 of cycle 1 in half of
patients experiencing febrile neutropenia. In multivariate
analysis, risk of febrile neutropenia was significantly associated
with age ≥ 65 years (HR 1.65, 95% CI 1.18–2.32), renal disease (HR
1.91, 95% CI 1.10–3.30), cardiovascular disease (HR 1.54, 95% CI
1.02–2.33), baseline hemoglobin < 12 g/dL (HR 1.44, 95% CI 1.04–
2.00), >80% planned CHOP ARDI (HR 2.41, 95% CI 1.30–4.47), and
no myeloid growth factor prophylaxis (HR 2.13, 95% CI 1.20–
3.76). This model can identify patients at greatest risk of febrile
neutropenia, and therefore candidates for elective prophylactic
myeloid growth factor usage.
A prospective, randomized trial of patients > 65 years was
performed evaluating the efficacy of primary prophylaxis in
patients with solid tumors or lymphoma [104]. Proactive
pegfilgrastim use resulted in significantly lower incidence of
febrile neutropenia for solid tumor and NHL patients compared
with reactive use. It also led to fewer hospitalizations resulting
from neutropenia/febrile neutropenia by approximately 50%.
Antibiotic use was lower for solid tumor patients receiving
proactive pegfilgrastim, and equivalent in the two NHL groups.
benefits, prophylactic myeloid growth factor support is recom-
mended. Similarly, if reductions in chemotherapy dose intensity
are associated with poorer prognosis, primary myeloid growth
factor prophylaxis may be used to maintain dose.
6.4. American Society of Clinical Oncology (ASCO) Guidelines
Reduction in febrile neutropenia is an important clinical
outcome that justifies myeloid growth factor use when the
febrile neutropenia risk is ≥20% and no other equally effective
regimen not requiring myeloid growth factor support is available
[106]. Primary prophylaxis is recommended for febrile neutrope-
nia prevention in high-risk patients based on age, medical
history, disease characteristics, and chemotherapy-related
myelotoxicity. Myeloid growth factor use allows modest to
moderate increases in dose-density/intensity of chemotherapy
regimens. Prophylactic myeloid growth factor support for
patients with DLBCL aged ≥ 65 years treated with curative
regimens as rituximab-CHOP should be given to reduce inci-
dence of febrile neutropenia and infections.
6.5. Red Blood Cell (RBC) Stimulating Drugs

6.3. International European Organization for Research and
Treatment of Cancer (EORTC) Guidelines
EORTC recommends that patient-related adverse risk factors as
older age (≥65 years) be evaluated in overall assessment of
febrile neutropenia risk prior to administering each chemother-
apy cycle [105]. When using a chemotherapy regimen associated
with ≥20% risk of febrile neutropenia, prophylactic myeloid
growth factor usage is recommended. With a chemotherapy
regimen associated with 10–20% febrile neutropenia risk, partic-
ular attention should be given to patient-related factors that may
increase overall febrile neutropenia risk. In settings for which
dose-dense/intense chemotherapy strategies have survival
There are no specific recommendations for the use of RBC-
stimulating agents in older patients. ASCO and American Society
of Hematology guidelines recommend that for patients receiving
myelosuppressive chemotherapy with hemoglobin < 10 g/dL,
clinicians should discuss potential harms (i.e., thromboembo-
lism, shorter survival) and benefits (i.e., decreased transfusions)
of erythropoietin stimulating agents (ESAs) and compare these
with potential harms (i.e., serious infections, immune-mediated
adverse reactions) and benefits (i.e., rapid hemoglobin improve-
ment) of RBC transfusions [107,108]. Individual preferences for
assumed risk should contribute to shared decisions on managing
chemotherapy-induced anemia. ESAs should be administered
at the lowest possible dose, and increase hemoglobin to the

Please cite this article as: Morrison VA., et al, Diffuse large B-cell lymphoma in the elderly: Impact of prognosis, comorbidities,
geriatric assessment, and supportive care on clinical..., J Geriatr Oncol (2014), http://dx.doi.org/10.1016/j.jgo.2014.11.004
 J O U RN A L OF GE RI A T RI C O NC O L O G Y XX ( 20 1 4 ) XX X–XX X
lowest level possible to avoid transfusions. These agents
should be discontinued after 6–8 weeks in nonresponders. ESAs
should be avoided in patients with cancer not receiving
concurrent chemotherapy, except for those with lower risk of
myelodysplastic syndromes, and should be used with caution
with chemotherapeutic agents associated with increased risk of
thromboembolic complications.
7. Conclusions
Despite treatment advances for older patients with DLBCL
based upon prospective randomized trials, many patients are
not eligible for such trials based upon underlying comorbid-
ities and functional deficits related to aging. Measures for
more formal evaluation of these patients are being developed,
and include many more facets than PS alone. Although
offering potentially curative therapies to older patients should
be done when possible, pre-treatment evaluation should
include some formalized assessment and consideration not
only of comorbidities, but also of functional, social, and
psychological constraints, such that safety and tolerability of
a given regimen can be determined. Supportive care measures
are of particular importance in the elderly. Routine assess-
ment of these factors in older patients with DLBCL will aid in
identifying those patients for whom curative therapies are
feasible, as well as determining which patients may benefit
most from non-curative supportive regimens, in an effort to
provide meaningful quality and quantity of life.
Disclosures and Conflict of Interest Statements
The authors have no conflicts of interest to disclose.
Author Contributions
Concept and design: V Morrison, P Hamlin, P Soubeyran, R
Stauder, P Wadhwa, M Aapro, S Lichtman
Data collection: V Morrison, P Hamlin, P Soubeyran, R
Stauder, P Wadhwa, S Lichtman
Analysis and interpretation of data: V Morrison, P Hamlin,
P Soubeyran, R Stauder, P Wadhwa, M Aapro, S Lichtman
Manuscript writing and approval: V Morrison, P Hamlin, P
Soubeyran, R Stauder, P Wadhwa, M Aapro, S Lichtman.
Funding
This work was supported by an unrestricted grant from Teva
Pharmaceutical Industries, and from Astellas.
Acknowledgments
Special thanks go to the following for editorial review, com-
mentary, and special contributions: Lodovico Balducci, Cather-
ine Terret, and Gilbert Zulian from SIOG; Alain Monnereau, Irina
Poddubnaya, Verein Seniorenkrebshilfe, and Gayane Tumyan.
Please cite this article as: Morrison VA., et al, Diffuse large B-cell lymphoma in the elderly: Impact of prognosis, comorbidities,
geriatric assessment, and supportive care on clinical..., J Geriatr Oncol (2014), http://dx.doi.org/10.1016/j.jgo.2014.11.004
9
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