2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

What Is the Benefit Versus Cost of Dose Modification
in the Metastatic Setting? Clinical Trial Evidence in
Colorectal Cancer
Depending on the rationale for dose modification, treatment
efficacy may be compromised by an effort to decrease
toxicity. In contrast, quality of life may be substantially
improved by avoiding treatment toxicity. In general, guideline
organizations such as the National Comprehensive
Cancer Network (NCCN) do not recommend dose attenuation
during first-line therapy based on chronologic age if
the patient is “fit.” Many patients seen in clinical practice,
however, are less fit than those enrolled on trials, making
the judgment regarding risks and benefits of standard
treatment much more complicated.
A recently published trial addresses, in part, the issue of
dose reduction of first-line treatment. This study, by Seymour
and colleagues, involved the use of a 2�2 factorial
design to randomly assign 459 frail (considered by their
physician to be unfit for full-dose combination chemotherapy)
older adults with metastatic colorectal cancer to one of
four first-line systemic therapies using an attenuated starting
dose (80% of standard). 26 The study design allowed for
escalation to full-dose therapy after 6 weeks if tolerated.
The four treatments were 48-hour intravenous fluorouracil
(5FU), oxaliplatin plus 5FU, capecitabine alone, or oxaliplatin
plus capecitabine. In addition to a standard quality-oflife
questionnaire, a composite outcome of overall treatment
utility was incorporated in an attempt to capture patient
and physician satisfaction with the outcome of each treatment
decision.
The median age of the patients was 74, and 13% were
older than 80. The primary reason the patients were considered
unfit for standard therapy was frailty or older chronologic
age. During protocol treatment, few patients had dose
escalation and 49% required additional dose reduction (below
the 80% of the standard dose). There was a trend toward
benefit with use of oxaliplatin in this attenuated dosing
schedule, although the primary outcome was not significant
(median progression-free survival, 5.8 months vs. 4.5
months; p � 0.07). No substantial increase in grade 3
toxicity was associated with use of oxaliplatin, but oxaliplatin
was associated with increased overall treatment utility,
suggesting a palliative benefit. Alternatively, capecitabine
was equivalent in efficacy to 5FU but offered no benefit in
quality of life and was also associated with a substantial
increase in toxicity. This study provides evidence for treatment
of unfit older adults with metastatic colorectal cancer
with an attenuated chemotherapy regimen and introduces
additional outcome measures to help quantify the palliative
benefit a patient may receive from therapy.
In addition to dose reduction, questions regarding optimal
dosing schedules, including the option for treatment break,
for older patients are also common. Again, few studies have
addressed this issue specific to older patients, yet older
patients are most likely to have debilitating consequences
from ongoing therapy. For colorectal cancer, some data
can be extrapolated from existing studies. For patients fit
enough to receive combination chemotherapy with an
oxaliplatin-based regimen (FOLFOX), data from randomized
trials support de-escalation to 5FU maintenance after
3 months of oxaliplatin. Although a fraction of patients
enrolled on these studies 27,28 were older than 75, there is
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MOHILE, KLEPIN, AND RAO
suggestion of similar benefit compared with younger patients
when this strategy is used. 29 Additionally, data from
two randomized trials suggest that selected patients may
retain the efficacy of first-line combination therapy with
oxaliplatin- or irinotecan-based regimens despite prescribed
chemotherapy-free intervals. 30,31 Although the evidence is
limited, it is reasonable to incorporate these data into
treatment planning for older patients in an attempt to
minimize the negative consequences of therapy on quality of
life.
Supportive Care Interventions to Maximize Treatment
Efficacy in Older Patients with Advanced Cancer
Several organizations including NCCN and ASCO have
developed guidelines to help manage common side effects.
We focus here on three areas that cause substantial distress
for older patients with cancer and require further research:
cachexia and sarcopenia, chemotherapy-associated peripheral
neuropathy and falls, and cancer-related fatigue. 32,33
Cancer Cachexia and Sarcopenia
Sarcopenia is the progressive generalized loss of skeletal
muscle mass, strength, and function. Cachexia has no uniform
definition and is a complex metabolic syndrome that
is characterized by weight loss of more than 10%, reduced
food intake (�1,500 kcal/d), and systemic inflammation
(C-reactive protein level �10 mg/L). 34 It is estimated that
50% of people older than 80 have sarcopenia. Half of all
patients with cancer lose some body weight; one third lose
more than 5% of body weight, and as many as 20% of all
cancer deaths are caused directly by cachexia. 34
Figure 1 illustrates how the pathophysiology of cancer
cachexia and sarcopenia are intertwined. 35 These syn-
Fig 1. Interaction and consequences between elderly host-tumortherapy.
Abbreviations: ADLs, activities of daily living.