As reported in The Lancet Oncology by Cunningham and colleagues and reviewed in this issue of The ASCO Post, the AVEX trial was an open-label randomized phase III trial limited to patients over the age of 70 years with previously untreated, unresectable metastatic colorectal cancer who were not deemed candidates for oxaliplatin- or irinotecan-based chemotherapy regimens.1 The primary endpoint was progression-free survival.
A total of 280 patients with a median age of 76 years were included from 10 countries in Europe. Progression-free survival was significantly longer with bevacizumab (Avastin) and capecitabine compared with capecitabine alone (9.1 vs 5.1 months). More patients treated with the combination had grade III or worse toxicity (40% vs 22%), and the most common any-grade adverse event in the bevacizumab group was hemorrhage (25% vs 7%).
Bevacizumab and Older Patients
The role of bevacizumab in treating older patients with malignancy is still uncertain. There has always been concern about the risks of bevacizumab treatment, including thromboembolic events, particularly in those over the age of 65 years and those with comorbidities that may predict their increased chance of adverse outcomes.
Cunningham and colleagues should be commended for performing a prospective trial focusing on patients over the age of 70 years. These kinds of trials have rarely been done and are sorely needed due to the aging of the population, particularly in colorectal cancer, for which the median age of patients is in the early 70s.
Design and Interpretation
This study, however, also raises issues about clinical trial design and clinical trial interpretation that should be considered when evaluating its results. First, despite the fact that the study was limited to patients over the age of 70 years, it did not include any form of geriatric assessment. Even a rudimentary geriatric assessment, such as the activities of daily living or instrumental activities of daily living scales or just a listing of comorbidities, would be helpful in interpreting this trial and what type of patients were studied.
The other issue is that patients who were eligible for the study were those not deemed to be candidates for combination chemotherapy with either irinotecan or oxaliplatin. However, the paper does not address how this decision was made. It is not clear whether these were arbitrary decisions made by the clinician or the decision was based on objective criteria.
Over 90% of the participants had a performance status of 0 or 1. Why were these patients with good performance status not eligible for oxaliplatin or irinotecan? It is well known that the standard performance status measures (ie, Eastern Cooperative Oncology Group or Karnofsky scores) may not be an accurate reflection of the older patient’s functional status,2 but knowing why these patients were considered ineligible for such treatment would help in interpretation of the study results. Moreover, a prospective trial of older patients showed that objective assessment was superior to clinical judgment in predicting toxicity.3
Additional potential issues raised by the study results include questions raised by the fact that the response rates were quite low, with objective response seen in only 10% of patients given capecitabine alone and in 19% given bevacizumab/capecitabine. These rates are lower than previously reported.4-7 Also, two-thirds of the patients did not receive any second-line therapy.
There is also an issue in terms of dosing, with the authors pointing out that the study-mandated dose of capecitabine (2,000 mg/m2) was less than the standard dose used in clinical practice (2,500 mg/m2). This is an interesting comment, since most clinicians in the United States do not use the 2,500-mg/m2 dose in patients of any age, particularly in older patients.
It should be noted that the inclusion criteria required a creatinine clearance of at least 30 mL/minute. This is an important issue in dosing capecitabine and avoiding toxicity.8
Prospective randomized trials of older patients with cancer are important to advancing the field of geriatric oncology. With the aging of the population and increased incidence of malignancies in older patients, studies like the AVEX trial are extremely important. However, to get the most value out of patient participation in these trials, some form of geriatric assessment is critical for clinicians to be able to use the data from such trials in a clinically meaningful fashion. Recently published articles regarding clinical trial design and clinical trial reporting in older patients have presented recommendations that should be followed.9-11
The number of patients—particularly older patients—entering clinical trials is disappointingly low. Therefore, studies should be designed so that the maximum amount of data can be obtained from the patients who do participate. The study of oral anticancer therapy is critically important, as this has become more common in oncology. Cost and compliance are other factors that need to be considered in study design and data acquisition.
It is hoped that prospective trials of older patients will continue to be performed. Study design needs to be adapted to reflect the specific needs of these patients. ■
Disclosure: Dr. Lichtman reported no potential conflicts of interest.
Dr. Lichtman is Attending Physician, 65+ Clinical Geriatric Program, Memorial Sloan-Kettering Cancer Center, and Professor of Medicine, Weill Cornell Medical College, New York.
1. Cunningham D, Lang I, Marcuello E, et al: Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): An open-label, randomised phase 3 trial. Lancet Oncol 14:1077-1085, 2013.
2. Extermann M, Overcash J, Lyman GH, et al: Comorbidity and functional status are independent in older cancer patients. J Clin Oncol 16:1582-1587, 1998.
3. Hurria A, Togawa K, Mohile SG, et al: Predicting chemotherapy toxicity in older adults with cancer: A prospective multicenter study. J Clin Oncol 29:3457-3465, 2011.
4. Feliu J, Safont MJ, Salud A, et al: Capecitabine and bevacizumab as first-line treatment in elderly patients with metastatic colorectal cancer. Br J Cancer 102:1468-1473, 2010.
5. Vrdoljak E, Omrcen T, Boban M, et al: Phase II study of bevacizumab in combination with capecitabine as first-line treatment in elderly patients with metastatic colorectal cancer. Anticancer Drugs 22:191-197, 2011.
6. Hoff PM, Ansari R, Batist G, et al: Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: Results of a randomized phase III study. J Clin Oncol 19:2282-2292, 2001.
7. Van Cutsem E, Hoff PM, Harper P, et al: Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: Integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer 90:1190-1197, 2004.
8. Lichtman SM, Wildiers H, Chatelut E, et al: International Society of Geriatric Oncology Chemotherapy Taskforce: Evaluation of chemotherapy in older patients--an analysis of the medical literature. J Clin Oncol 25:1832-1843, 2007.
9. Lichtman SM: Clinical trial design in older adults with cancer. The need for new paradigms. J Geriatr Oncol 3:368-375, 2012.
10. Lichtman SM: Call for changes in clinical trial reporting of older patients with cancer. J Clin Oncol 30:893-894, 2012.
11. Wildiers H, Mauer M, Pallis A, et al: End points and trial design in geriatric oncology research: A joint European Organisation for Research and Treatment of Cancer–Alliance for Clinical Trials in Oncology–International Society of Geriatric Oncology position article. J Clin Oncol 31:3711-3718, 2013.