ABSTRACT: Despite the fact that elderly patients comprise over 50% of the non-small cell lung cancer (NSCLC) population, our knowledge regarding the efficacy and safety of chemotherapy in this group is suboptimal. The “elderly” (defined as individuals ≥70 years of age) experience physiologically normal aging of their bone marrow and kidneys, which inherently increases toxicity to therapy. Standard practice has often been to discourage the use of combination chemotherapy in these patients; however, general consensus guidelines emphasize that performance status should primarily guide the choice of treatment. Elderly patients with advanced NSCLC treated with platinum doublet therapy demonstrate similar efficacy (but increased toxicity) to their younger counterparts. Patients with metastatic disease in which a targeted and/or biological agent(s) was added to chemotherapy experienced benefits similar to those treated with standard platinum doublets, but with increased morbidity and mortality. In the future, effective testing of molecular targeted therapies will have to include elderly patients among research cohorts or risk excluding a large population of eligible patients. Overall, elderly patients with advanced NSCLC, while experiencing greater toxicity, demonstrate the same response rates and survival benefits as their younger peers.
Introduction
It is estimated that lung cancer will be diagnosed in 222,520 patients in 2010 and that 80% of them will fall into the non-small cell category (NSCLC).[1] Approximately 50% of these patients will be aged 65 years or older.[2] The SEER database indicates that the median age of diagnosis for NSCLC is 69 years of age, with 14% of newly diagnosed patients 80 years old or older—this latter group receives fewer interventions and shows poor survival.[3,4] Furthermore, the age-adjusted incidence of developing lung cancer of any type increases from one in 41 patients from 60 to 69 years of age to 1 in 18 patients at over 70 years of age according to data acquired between 2003 and 2005.[1] In the United States and Europe, 70 is accepted as “elderly”.[5] Patients ≥70 years of age are grossly underrepresented in clinical trials. Historically, only 25% of NSCLC trials included patients 65 years or older.[6] Extrapolating these data to elderly patients in clinical practice represents an obvious clinical dilemma.
However, age alone does not accurately predict patients’ ability to tolerate chemotherapy, and being elderly does not portend poor outcomes. Performance status (PS), rather than age, is a better predictor and should be used to tailor therapy decisions. Furthermore, multiple geriatric assessments have been constructed to better predict which elderly patients can tolerate chemotherapy. Questionnaires, such as ones developed by Hurria and Extermann et al, use a patient’s functional status, which combines nutritional status, mobility assessment, and concurrent health conditions to better predict for morbidity and mortality during treatment.[7,8]
In this article, we aim to demonstrate that elderly patients with advanced (stage III-IV) NSCLC will derive the same benefit from therapy as their younger age-matched controls. Topics to be addressed include toxicity, choice of single-agent or doublet chemotherapy, concurrent chemoradiotherapy, and finally choice of therapy in metastatic disease, with attention paid to toxicity of biological/targeted agents.
Pharmacology and Toxicity
Treatment of elderly cancer patients requires careful regard for potential toxicity. Normal aging results in a decrease in the glomerular filtration rate, which reduces the excretion of many common cytotoxic therapies used in NSCLC such as carboplatin(Drug information on carboplatin) and pemetrexed(Drug information on pemetrexed). The elderly must be careful to avoid dehydration, and nephrotoxic agents such as contrast dye, aspirin(Drug information on aspirin), or NSAIDs must be used with caution.[9, 10] Similarly, aging results in decreased hematopoietic progenitors and increased myelosuppression during chemotherapy.[11]
From 2003 to 2005, advanced-stage NSCLC patients were enrolled in the Cancer Care Outcomes Research and Surveillance [CanCORS] Consortium observational study[12]. Chrischilles et al prospectively evaluated a cohort of 1,371 of these NSCLC patients with age groups of <55, 55 to 64, 65 to 74, and ≥75 for the influence of age on toxicity and choice of therapy.[13] They found that 78% of patients in the <55 group received chemotherapy, while only 60.5% of those in the 65 to 74 group and 42% in the ≥75 group received any therapy (P < .0001). Similarly, older patients were less likely to receive platinum agents. Among those receiving chemotherapy, pre-treatment clinically important acute medical events (as defined in the CanCORS survey) actually occurred in 18.5% of patients age <55 years, but 9.2% of elderly patients. This is in contrast to treatment-related adverse events, which occurred in 42% of patients age 65-74 years, compared to 30.6% of patients <55, which was statistically significant (odds ratio: 1.70, 95% confidence interval: 1.19 to 2.43). Both peripheral neuropathy and neutropenic fever/sepsis occurrences were also associated with increasing age. Some reduction in the incidence of neutropenia may have been achieved via growth factor administration, per the guidelines recommended by the American Society of Clinical Oncology (ASCO).[14]
Doublet vs Single-Agent Therapy
The most recently published expert consensus data did not support the selection of a specific first-line chemotherapy regimen or combination therapy based on age alone, and in fact emphasized that elderly patients derive the same benefit as younger groups, but at the cost of increased toxicity with combination versus single agent first-line chemotherapy.[15, 16]
In the West Japan Thoracic Oncology Group (WJTOG) 9904 trial, in which docetaxel(Drug information on docetaxel) was compared with vinolrelbine in elderly patients with advanced-stage disease (including PS ≤2), docetaxel (5.5 vs 3.1 months, P < .001, and 22.7% vs 9.9%, P < .01, respectively) showed a higher progression-free survival (PFS) and response rate, but also showed higher myelosuppression.[17]
Docetaxel has also been compared to a combination of gemcitabine(Drug information on gemcitabine)-docetaxel in patients >65 years of age. In the combination arm, 39% of patients were >75 years. Time to progression was improved with the combination therapy (4.8 vs 2.9 months; P = .04), but overall survival (OS) results showed no statistical difference. Those with Eastern Cooperative Oncology Group (ECOG) PS of 2 did poorly, and the authors suggested that PS should influence the choice of singlet vs doublet therapy.[18]
Selected Platinum Doublets in Metastatic Disease
A pivotal trial conducted by Quoix et al was recently presented in abstract form (Table 1); this study intended to show that doublet therapy is superior to singlet therapy in the eldest of patients.[19] The trial included only patients aged 70 to 89 years; in addition, patients with ECOG PS of 2 comprised ~27% of the total study population (n = 451). Patients were randomized to 15 weeks of either single-agent weekly gemcitabine or vinorelbine or to a combination of carboplatin, dosed monthly, with weekly paclitaxel(Drug information on paclitaxel) for a total of 16 weeks. Doublet therapy demonstrated an improvement in PFS from 3.0 to 6.1 months for singlet therapy (P < 10-6). OS for doublet therapy was 10.3 months, vs 6.2 months in the single-agent arm (P < .00004). Grade 3 neutropenia occurred in 54% of patients who received doublet therapy and in 38% of those who received singlet therapy (P < 10-5), but no significant differences were shown regarding febrile neutropenia. Toxic deaths were increased with doublet therapy, but overall death rates were higher in the singlet therapy group.
Overall, this trial provides level I evidence for using PS criteria and not age as the most important factor in choosing doublet chemotherapy, since older patients with good PS achieve gains, similar to those seen in their younger counterparts, in PFS and OS with this therapy. This trial provides level I evidence to the ASCO consensus guidelines, which recommend consideration of doublet therapy in fit elderly individuals.[15]
