NcXHF

TREATING OLDER ADULTS WITH CANCER
munity practices have shown that increased age is associated
with lower relative-dose intensity during adjuvant chemotherapy.
67,68 An analysis of a multisite cohort study enrolling
older adults starting a new chemotherapy regimen showed
that almost one-third (29%) of the 319 patients with advanced
cancer had a dose reduction with the fırst cycle of chemotherapy.
Factors associated with primary dose reduction
included older age, a primary diagnosis of lung cancer, and
comorbid conditions. 69
INDICATIONS FOR UP-FRONT DOSE ADJUSTMENT
Physiologic changes associated with aging have implications
for chemotherapy toxicity among older adults. Aging is associated
with decreased intestinal absorption, changes in volume
of distribution, decreased hepatic metabolism, and
impaired renal excretion. The degree to which any of these
changes occur in an individual and have clinical signifıcance
varies among patients of the same chronologic age. Among
these, a decline in renal function needs to be considered in
dosing. Many chemotherapy drugs are cleared renally and it
is well documented that relying on serum creatinine alone
will greatly underestimate renal function in older adults. Creatinine
clearance should be calculated for all older adults starting
chemotherapy treatment to inform dose adjustment for renally
cleared drugs. Guidelines exist for recommendations on renal
dose adjustment including a position paper published by the International
Society of Geriatric Oncology. 70
Current guidelines do not recommend up-front dose adjustment
in the adjuvant setting for older adults because of
the potential negative consequences on cancer outcomes and
the goals of therapy. In this setting, the treatment decision
should be framed around the question, “Do I think my patient
can tolerate a standard dose regimen?” Mitigation of
toxicity risk in the adjuvant setting may include a choice between
standard-dose, single-agent chemotherapy compared
with polychemotherapy in certain settings (i.e., colorectal
cancer) or two-drug compared with three-drug combinations
(i.e., breast cancer). Tailoring choice of regimen and
supportive care to the patient’s comorbidity profıle may also
minimize adverse events. For those patients considered unfıt
for standard-dose treatments, no adjuvant therapy is likely
the best alternative. However, in the metastatic setting, our
goals of treatment are to balance disease control and quality
of life. Alterations in dosing and scheduling of treatments become
an important strategy for the management of patients.
A novel randomized trial published by Seymour et al addressed,
in part, the issue of dose reduction in fırst-line treatment
for older adults with advanced stage colorectal cancer.
This study used a 2-by-2 factorial design to randomize 459
frail (considered not fıt for full-dose combination chemotherapy
by their physician) older adults with metastatic colorectal
cancer to one of four fırst-line systemic therapies using
an attenuated starting dose (80% of standard). 71 The study
design allowed for escalation to full-dose therapy after 6
weeks, if tolerated. Patients (median age 74) were randomly
assigned to one of the following arms: (1) 48-hour intravenous
fluorouracil (5-FU), (2) oxaliplatin/5-FU, (3) capecitabine,
or (4) oxaliplatin/capecitabine. In addition to a
quality-of-life questionnaire, a composite outcome termed
overall treatment utility was incorporated in an attempt to
capture patient and physician satisfaction with the outcome
of each treatment decision. Several lessons can be learned
from this study. First, recruiting unfıt patients to a randomized
trial was feasible. Second, few patients achieved dose escalation,
with almost half (49%) requiring additional dose
reductions. Third, the unique trial design, inclusive of
patient-centered endpoints, provided relevant information
suggesting that use of oxaliplatin in this attenuated dosing
schedule may provide a palliative benefıt, whereas, capecitabine
may be associated with more toxicity compared with
5-FU. This study provides evidence for considering up-front
dose attenuation when treating non-fıt older adults with metastatic
colorectal cancer, and introduces additional outcome
measures to help quantify the palliative benefıt of therapy.
Questions regarding optimal dosing schedules, including
treatment breaks, for older patients are also common. Again,
few studies specifıcally have addressed this issue in older patients,
yet, older patients are most likely to suffer debilitating
consequences from ongoing therapy. For colorectal cancer,
some data can be extrapolated from existing studies investigating
chemotherapy-free intervals (CFI). 72-75 For patients fıt
enough to initiate combination chemotherapy, evidence
would suggest that CFI have minimal effect on overall survival
with some potential benefıts in quality of life. Although
only a fraction of patients enrolled in these studies were older
than 75, there is suggestion of similar outcomes among older
compared with younger patients when using this strategy. 74
It is reasonable to incorporate these data into treatment planning
for older patients in an attempt to minimize the negative
consequences of therapy on functional independence and
quality of life.
CLINICAL TRIAL EVIDENCE FOR DOSE
MODIFICATION IN ADVANCED CANCER
Few randomized controlled trials have addressed the risks
and benefıts of up-front dose modifıcation or treatment
schedule modifıcations (i.e., treatment holidays) for non-fıt
older adults with advanced cancer, resulting in a paucity of
guideline-based recommendations. However, several colon
cancer trials directly or indirectly provide some insights into
these approaches.
TOXICITY ASSESSMENT: WHAT ARE WE MISSING?
Prediction of treatment outcomes for older adults is hindered
not only by the limited number of older adults enrolled in
clinical trials, but also by the lack of routine collection of
endpoints that better describes the patient experience.
Outcomes such as functional independence, health care
utilization, psychosocial health, and well-being are typically
not measured in trials. In a review of 127 older
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