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GERIATRIC ONCOLOGY AND CLINICAL TRIALS
SIDEBAR 2. Issues in Clinical Trial Design 5,17
Randomized controlled trial is the standard trial design
Clinical trial eligibility should include a broad range of older
patients of various functional states
Clinical trials specific for older patients should be considered
when standards differ by age
Trials of palliative care should be performed
Randomized phase II trials or single-arm phase II trials in
appropriate clinical settings; studies in older patients after
dose and schedule is determined in a younger population
Observational cohort studies, database analyses, and
evaluation of registries can provide valuable information
Some form of geriatric assessment should be included
Evaluation of new drugs should include evaluation specific for
older patients; regulatory authorities should considering
mandating these studies to determine the spectrum of toxicity
Clinical trials reports should adequately describe the patient
population and results. 9
does not have a renal mechanism of clearance. Limiting offıce
visits and testing will facilitate compliance by allowing patients
with limited social supports to participate and minimizing
caregiver burden. Many older patients have had
previous cancer treatment; therefore, prohibition of a prior
diagnosis of malignancy and treatment needs to be reconsidered.
For diseases in which survival is relatively short, such as
metastatic pancreatic cancer, treatment with localized radiation
5 or 10 years earlier for a localized disease is not relevant.
Less restrictive eligibly criteria will allow a broader range of
patients to participate in trials. These carefully assessed and
monitored patients will yield data that will be applicable to
the general population of older patients and will provide a
degree of safety in terms of dosing and supportive care. It is
fair to state that the doses obtained from phase I trials may
not be broadly applied to the geriatric population without
further exploration in that population, as we currently do in
pediatric populations. A phase I dose should be studied in
older patients with varying degrees of function impairment
and comorbidity.
ENDPOINTS OF CLINICAL TRIALS
The traditional endpoint of survival may not be appropriate
for the older patient and particular care must be must be
taken when overall survival is a study endpoint. A number of
studies determined that cause of death might differ in older
versus younger patient populations. In lymphoma trials,
deaths attributed to tumor or treatment-related toxicity were
similar for patients older than and younger than 60. The observed
differences in survival rate—22% of patients greater
than or equal to 60 years of age but only 2% of patients less
than 60 years—were instead associated with other causes of
death not obviously related to the lymphoma or its therapy.
The inclusion of older patients in clinical trials may
decrease the overall survival secondary to deaths from apparently
unrelated causes. 21,22 Patients with early-stage
breast cancer and comorbidity had a 4-fold higher rate of
all-cause mortality compared with patients who had no
comorbid conditions. 23 This phenomenon is particularly
important in cancers that can have a relatively indolent
course. In prostate cancer studies, it has been shown that
competing causes of death are substantive contributors to
mortality. 24,25 Progression-free survival, time without
symptoms, measuring treatment-free intervals, or maintenance
of independence (or prevention of dependency)
may be more meaningful endpoints.
QUALITY OF LIFE IN CLINICAL TRIALS
Patient quality of life is affected by a number of factors related
to the cancer and treatment, as well as its interaction with
other diseases. Assessment of quality of life is an important
endpoint in clinical trials for older adults; however, the traditional
view of quality of life may be broadened in an older
patient population. For example, the compression of morbidity
and disability to maximize the preservation of “active”
life expectancy is also a potential quality of life endpoint,
particularly in a palliative care setting. 26,27 There are many
parallels between geriatric assessment and quality of life assessment
in that both are multidimensional and broad. They
share many dimensions and focus on issues that are important
to older people, particularly the ability to function fully
in social roles and participate in daily activities. Quality of life
studies have been performed as a predictive marker in non–
small lung cancer and have been analyzed in the context of
the effect of therapy. 28-30
FUNCTION AND CLINICAL BENEFIT
Response rate is one of the standard endpoints of phase II
studies, whereas survival and disease-free survival are endpoints
of phase III studies. Assessment of clinical benefıt has
become an important endpoint, especially in the management
of metastatic disease, and some agents, including gemcitabine
for pancreatic cancer 31 and mitoxantrone for
prostate cancer, 32,33 have been approved for use because of
demonstrated clinical benefıts. In the older population, impaired
functional status is a risk factor for cancer treatment
toxicity and overall survival. Longitudinal changes in functional
status are a potential endpoint of clinical trials. This
was explored in a clinical investigation of infectious syndromes
in older people in which function was used as a risk
factor for infectious syndromes as well as an outcome measure.
34 In older individuals with limited life expectancies, improvement
in survival may be diffıcult to demonstrate and
clinical benefıts may become paramount. In addition to
improvement in pain and other symptoms, the benefıts of
chemotherapy may include prevention of functional dependence
and functional deterioration. As this is one of the most
common complications of diseases in older individuals, it is
surprising that it has not been more commonly explored as
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