Finding the Right Dose of Carboplatin/Pemetrexed for Elderly Lung Cancer Patients
Abstract & Commentary
By William B. Ershler, MD
Synopsis: Carboplatin-pemetrexed doublet chemotherapy is effective primary treatment for patients with nonsquamous non-small cell lung cancer, but the applicability of standard dosing to older or more frail patients was uncertain. This current dose-escalation study in such patients aged 75 years and older finds that a carboplatin dose of AUC5 with pemetrexed at 500 mg/m2 was both efficacious and well tolerated, but a carboplatin dose of AUC6 resulted in unacceptable toxicity.
Source: Tamiya A, et al. Dose escalation study of carboplatin-pemetrexed followed by maintenance pemetrexed for elderly patients with advanced nonsquamous non-small-cell lung cancer. Ann Oncol 2013;24:980-985.
Non-small cell lung cancer (NSCLC) is primarily a disease of older people and its occurrence is increasing with the aging of our population. Whereas combined modality therapy is often considered the standard approach for patients who present with advanced disease, such an aggressive approach is unlikely to be tolerated by very old or frail patients. However, single agent1-4 and doublet5 chemotherapy strategies have been shown to be efficacious in elderly-specific chemotherapy trials. The antifol pemetrexed has demonstrable efficacy in combination with cisplatin for patients with NSCLC, particularly for those with non-squamous histopathology.6 In light of reduced toxicity and increased convenience, carboplatin has gained widespread use as a substitute for cisplatin and may be particularly favored for older, more frail patients.
The current study was designed to determine the recommended dose of carboplatin-pemetrexed in elderly (≥ 75 years old), chemotherapy-naive patients with advanced nonsquamous NSCLC.
Patients received escalated doses of carboplatin (AUC of 4, 5, or 6) and pemetrexed (500 mg/m2) every 3 weeks for four cycles. Patients with an objective response and stable disease continued pemetrexed therapy until disease progression or unacceptable toxicity was observed.
The combination of carboplatin at an area under the concentration-time curve (AUC) of 5 and 500 mg/m2 pemetrexed was determined to be the recommended dose for elderly patients with advanced nonsquamous NSCLC. Of 17 patients, 10 received a median of five cycles of pemetrexed maintenance therapy without unexpected or cumulative toxic effects. The study had an overall response rate of 47.1%. The median progression-free survival time was 142 days (95% confidence interval [CI], 68-216 days) and the median overall survival time was 461 days (95% CI, 168-754 days).
Recommended chemotherapy approaches are often derived from clinical studies that include disproportionately few older patients. Further, those elderly patients who are included on trial may not be representative since they met eligibility criteria that might otherwise exclude the typical patient in this age group. Thus, age-specific inclusive clinical trials are called for, with the goal of establishing reasonable standards of care for typical and frail elderly patients. In such trials, response rates and overall survival might assume lesser importance than quality of life and independence.
In a previous clinical trial with similar methodology from Japan,7 the carboplatin-pemetrexed doublet was examined in nonsquamous NSCLC patients younger than 75 years and the recommended carboplatin dose was an AUC of 6 and pemetrexed was 500 mg/m2. The current study modifies that recommendation for carboplatin at an AUC of 5 for patients over the age of 75. The investigators are to be credited for addressing this important issue and their research concept will hopefully serve as a prototype for the development of standards of care for all tumor types commonly observed in frail elderly patients.
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