Phase 1 and 2 Trials
Older individuals should have access to phase 1 trials, but reserving clinical trials for older individuals alone is not a productive strategy. Due to the increased risk of adverse effects in the older population, phase 1 trials dedicated to older individuals may unnecessarily delay the development and approval of life-saving drugs. Instead, a representation of individuals 70 years or older in phase 2 trials should be adequate to establish the activity and the safety of a new drug among this older population. In my opinion, phase 2 trials represent a convenient way to study the pharmacology of new agents among the elderly without delaying drug development.
Phase 3 Trials
Phase 3 trials dedicated to the elderly may be conducted for 2 reasons: (1) to determine whether the benefits of a treatment strategy decline with age, and (2) whether the use of new drugs may improve the treatment of elderly patients who are not candidates for more aggressive treatment.
In a seminal study of the CALGB, women 65 years of age or older with early-stage breast cancer were randomized to receive combination chemotherapy or single-agent capecitabine.26 The study showed that combination chemotherapy in the adjuvant setting reduced recurrence rates and improved survival among these patients. This study resolved a decade-long controversy of whether adjuvant chemotherapy was beneficial to older women. Other important studies of this type demonstrated that doublet chemotherapy was superior to single-agent chemotherapy in older patients with metastatic non–small-cell lung cancer27 and that full-dose chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone was superior to chemotherapy in reduced doses among elderly patients with large cell lymphoma.28 These trials determined that age alone is not a contraindication to active cancer treatment; however, these trials included healthy elderly patients, and, thus, shed no light on the best treatment options for elderly persons affected by disability and multiple morbidities.
A 2014 study demonstrated that elderly patients with diseases and disability can be studied in randomized controlled trials.29 Individuals with chronic lymphocytic leukemia who were 70 years of age or older and not eligible for more aggressive treatment (eg, combination fludarabine, cyclophosphamide, and rituximab) were randomized to receive chlorambucil or chlorambucil plus rituximab or obinutuzumab. Nearly 1,500 patients were stratified during randomization according to comorbidity severity. Disease-free and overall survival rates were improved in patients treated with obinutuzumab. The results from this recent study represent a model for future randomized controlled studies among older patients with an estimated life expectancy of several years.
Figure1 illustrates how future studies might be conducted. To estimate a patient’s life expectancy, the use of ePrognosis (http://eprognosis.ucsf.edu; University of California, San Francisco) is recommended, which is available free of charge.4 To estimate an older person’s risk of grade 3/4 toxicity, I recommend the Chemotherapy Risk Assessment Scale for High-Age Patients and the Cancer and Aging Research Group instruments, both of which have been validated in older individuals.6,7 Of course, the risk of toxicity that disqualifies an individual from a trial may vary from disease to disease. For example, the threshold may be higher in cases in which the disease is rapidly lethal and the treatment option offers an opportunity for cure or prolonged survival.
Other Studies in Older Patients With Cancer
Clinical trials exclusively dedicated to older patients will still be unable to embrace the diversity of this patient population. The questions that persist include:
- Is the treatment beneficial to the majority of older individuals?
- Which individual factors determine the benefit and risk of treatment in the older population?
Studies that match Surveillance Epidemiology and End Results data with Medicare records may provide a partial answer to the first question above. Because of these data, it was possible to discern that individuals 75 years and older benefit from the adjuvant treatment of colon and rectal cancers30 and that adjuvant chemotherapy is leukemogenic in older women.31 However, it is impossible to establish from these results exactly which patients may benefit and which ones may be harmed by cytotoxic chemotherapy, as it is not possible to analyze certain prognostic factors from these data.
A prospective evaluation of these patients alone is the way to build prognostic models that encompass the variabilities among the older patient population, including all of the factors with the potential to interact with treatment options. Through this process, models were derived to estimate the risk of chemotherapy complications in older individuals.6,7