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Treatment of Advanced Non–Small-Cell Lung Cancer in Special Populations

Treatment of Advanced Non–Small-Cell Lung Cancer in Special Populations

ABSTRACT: The benefits of chemotherapy in non–small-cell lung cancer (NSCLC) patients remains, to some extent, restricted to younger patients with a good performance status (PS). It has long been assumed that chemotherapy is too toxic and of marginal benefit for elderly NSCLC patients and those with a PS of 2. Nevertheless, retrospective analyses and more recent prospective trials have suggested that such patients enjoy longer survival and a better quality of life when treated with chemotherapy. This article will review the data and discuss their clinical implications.

The management of advanced non-small-cell lung cancer (NSCLC) has evolved considerably in the past decade. The positive impact of chemotherapy on the survival and quality of life of advanced NSCLC patients is now accepted by most patients and physicians. However, in practice this benefit remains, to some extent, restricted to younger patients with a good performance status (PS). Physicians have historically approached the treatment of elderly patients with skepticism, based on assumptions that chemotherapy is too toxic and of marginal benefit. Patients with a PS of 2 have also been excluded from chemotherapy trials due to early data indicating an unacceptable rate of chemotherapy-related death and no documented survival benefit. These two subsets of "special populations," which together comprise over 50% of our clinical practice in advanced NSCLC, have recently been the subject of retrospective analyses and prospective trials that have challenged the principles discussed above. In this article, we will review these data and discuss the potential implications for clinical practice. Elderly Patients Approximately two-thirds of newly diagnosed patients with NSCLC are 65 years of age or older, and 40% are older than 70 years.[1] Despite these statistics, elderly patients with advanced NSCLC have been greatly underrepresented in clinical trials. To assess the relationship between age and treatment, Ramsey and colleagues reviewed the Surveillance, Epidemiology, and End Results (SEER) Medicare records from 1994 to 1999.[2] A total of 3,659 patients with stage IIIA/B and 4,067 with stage IV disease were included in their analyses. Chemotherapy was given to only 26.7% of stage IIIA patients, and 21.2% of stage IIIB/IV patients-a much lower frequency than expected for the overall population. The following trials utilizing different single agents and combination regimens have helped reshape the status of chemotherapy for elderly patients with advanced NSCLC. Nonplatinum Agents and Combinations

  • ELVIS Trial-The Elderly Lung Cancer Vinorelbine Italian Study (ELVIS) conducted by Gridelli and colleagues was the first to assess the benefit of modern chemotherapy in elderly patients.[3] The study randomized 154 patients to vinorelbine (Navelbine) at 30 mg/m2 on days 1 and 8 every 21 days or to supportive care alone. Quality of life was evaluated prospectively. Patients treated with vinorelbine showed a significant survival advantage, most notably a 1-year survival rate of 32% compared to 14% for patients managed with supportive care alone (Table 1). In addition, quality-of-life parameters were significantly improved in the chemotherapy arm.
  • MILES Trial-The Multicentre Italian Lung Cancer in the Elderly Study (MILES) was the largest trial ever conducted in elderly patients with advanced NSCLC.[4] Nearly 700 patients were randomized to the three treatment arms (Table 1). The study was designed to compare the overall survival associated with each of the single agents vs the combination regimen. Toxicity was slightly higher in the combination arm, but treatment was well tolerated in general. Response rates were similar in the single- agent and combination arms. Progression- free survival and overall survival were also not significantly different between arms.
Platinum-Based Chemotherapy
Three recent trials from US cooperative groups provided important information about elderly patients treated with platinum-based combination chemotherapy (Table 2).
  • ECOG Trials-Langer and colleagues from the Eastern Cooperative Oncology Group (ECOG) analyzed the outcomes of elderly patients in a randomized trial of cisplatin/etoposide vs cisplatin/paclitaxel (ECOG 5592). Approximately 15% of 584 eligible patients were 70 years or older.[ 5] Elderly patients had more leukopenia and neuropsychiatric complications, but efficacy results, including response and survival, were not significantly different from those in the younger cohort. A similar retrospective analysis was conducted in the more recent ECOG 1594 trial, which randomized 1,139 eligible patients, 20% of whom were age 70 or older, to four different platinum-based regimens.[6] Again, response rates, survival, and toxicity were comparable in younger and older patients across all the arms.
  • SWOG Trials-Kelly and colleagues performed a similar analysis on behalf of the Southwest Oncology Group (SWOG). Patients enrolled in two consecutive randomized trials comparing cisplatin/vinorelbine to cisplatin (SWOG 9308), and to carboplatin (Paraplatin)/paclitaxel (SWOG 9509) were included in this analysis.[7] About 19% of the patient population was age 70 or older. There were no significant differences in outcome, despite a trend toward a lower median survival in the elderly. Severe (grade 3-5) toxicities were more common in older patients, but not unacceptably high.
  • CALGB Trial-The Cancer and Leukemia Group B (CALGB) performed a randomized trial of carboplatin/ paclitaxel vs paclitaxel alone (CALGB 9730). Stratification factors included stage, age, and performance status.[8] A total of 155 elderly patients were enrolled, accounting for 27% of the study population (Table 2). No significant differences in response or survival between the older and younger patients were reported. Toxicity was also similar between the two groups, except for a higher incidence of leukopenia in the elderly.
Summary
The notion that elderly patients are too old to tolerate or benefit from chemotherapy has been conclusively defeated. Age alone should not influence the treatment decision-making process in elderly patients with advanced NSCLC.[9] Those with an acceptable performance status enjoy longer survival and a better quality of life when treated with chemotherapy. Several reasonable treatment options are available, and the decision about which one to recommend is usually based on toxicity profiles and patient preferences. Whether elderly patients should be treated with combination chemotherapy rather than single- agent therapy remains debatable. In practice, when faced with a patient older than 70 years with a good performance status and no major comorbid conditions, the oncologist can refer to the US cooperative group data and recommend a platinum-based doublet. Based on a better therapeutic index, a carboplatin-doublet would be preferable in elderly patients. On the other hand, elderly patients with severe comorbid conditions and a low functional capacity may be better served by single-agent therapy. PS 2 Patients Performance status is the most important prognostic factor in advanced NSCLC.[10] Prospective clinical trials and retrospective analyses in the 1980s suggested that patients with advanced NSCLC and compromised PS experienced substantial toxicity and derived no benefit from systemic chemotherapy. This observation led to the exclusion of PS 2 patients from subsequent cooperative group research. More recent trials, conducted in the late 1990s, started to include PS 2 patients again as a subgroup of the overall study population. Due to more effective and less toxic chemotherapy, the results demonstrated better tolerability to chemotherapy and a trend toward improvement in diseaserelated symptoms. Retrospective Data
  • ECOG Trial-A trial by ECOG published in 1986 was one of the first to illustrate inferior outcomes for PS 2 patients.[11] A total of 486 eligible patients with advanced NSCLC were randomized between 1981 and 1983 to receive one of four platinum-based combination regimens. A total of 92 patients (19%) had a PS of 2. The median survival for PS 0 and PS 1 patients was 36 and 26 weeks, respectively, whereas for PS 2 patients, it was 10 weeks. Furthermore, the incidence of treatment-related deaths in PS 2 patients was 10%-significantly higher than that observed in PS 0-1 patients.
  • European Trials-In a phase III study conducted by Le Chevalier and colleagues, the combination of cisplatin and vinorelbine was superior to cisplatin/vindesine and to single-agent vinorelbine.[12] Approximately 20% of all 612 patients had a PS of 2. A subsequent analysis of prognostic factors indicated no significant interaction between treatment and any of these factors, except a low PS. Specifically in the PS 2 subset, the combination of cisplatin/vinorelbine did not produce any benefit over the other two regimens, and single-agent vinorelbine was suggested as a reasonable treatment approach.[13] Despite these negative survival results, a few investigators reported on symptom improvement in PS 2 patients. Vansteenkiste and colleagues from Belgium compared single-agent gemcitabine (Gemzar) to the combination of cisplatin and vindesine in a phase III trial with clinical benefit as the primary end point.[14] Gemcitabine compared favorably to the combination of cisplatin and vindesine, with longer-lasting clinical benefit (16 vs 10 weeks) and no major differences in survival (6.7 vs 5.5 months). A substantial percentage of PS 2 patients (20%-40%) reported improvement in disease-related symptoms.[15] These findings were similar to those reported by Hickish and colleagues from the UK, who concluded that patients with poor PS experienced symptom relief from chemotherapy.[16]
  • ECOG Subset Analysis-In the United States, ECOG investigators reported a subset analysis of PS 2 patients from trial 1594, which randomized over 1,200 patients to four platinum-based regimens.[17] After the initial 68 PS 2 patients were enrolled, accrual was stopped due to a high incidence of adverse events, including five deaths. However, a subsequent analysis showed that the overall toxicity experienced by PS 2 patients was not significantly different from that experienced by PS 0/1 patients.[18] In fact, only two of the five deaths were directly attributed to toxicity, while the others were thought to be secondary to disease. Efficacy analysis demonstrated an overall response rate of 14% and a median survival time of 4.1 months.[18] The 1-year survival rate was 19%. Based on this subset analysis, the ECOG investigators concluded that patients with advanced NSCLC and a PS of 2 should not be treated with platinum- based combinations-at least not in the doses and schedule utilized in this trial. Their follow-up prospective trial is discussed below.
  • Prospective Data
  • CALGB Trial-The CALGB 9730 trial discussed above enrolled 99 patients with PS 2, the largest number ever accrued to a cooperative group phase III trial in the United States.[8] When compared to PS 0/1 patients, who had a median survival of 8.8 months and a 1-year survival of 38%, the corresponding figures for PS 2 patients were 3.0 months and 14%, respectively. Importantly, however, when PS 2 patients were analyzed by treatment arm, those who received combination chemotherapy had a higher response rate (24% vs 10%), a longer median survival (4.7 vs 2.4 months), and superior 1-year survival (18% vs 10%) compared to those treated with single-agent paclitaxel (Table 3). The difference was statistically significant and, indeed, of greater magnitude than observed between the two arms in PS 0/1 patients. Analysis of quality-of-life parameters showed no detriment in PS 2 patients treated with the combination.
  • ECOG Trial-The only prospective trial dedicated to PS 2 patients was recently completed by Langer and colleagues (ECOG 1599). As a follow- up to the subset analysis of ECOG 1594, the investigators conducted a phase II randomized trial of attenuated doses of cisplatin/gemcitabine, which had yielded the highest efficacy, and carboplatin/paclitaxel, which was the best tolerated regimen, in the first-line treatment of patients with advanced NSCLC and a PS of 2.[19] A total of 47 and 51 eligible patients, respectively, were treated with attenuated doses of cisplatin/gemcitA total of 47 and 51 eligible patients, respectively, were treated with attenuated doses of cisplatin/gemcitabine and carboplatin/paclitaxel. Cisplatin/ gemcitabine yielded a higher response rate (21% vs 10%), but time to progression and median survival time were similar between the two arms. The median survival of approximately 6 months in both arms was longer than expected based on historical controls (Table 4). Toxicity followed the expected pattern for these two regimens: Myelosuppression, particularly thrombocytopenia, was more common with cisplatin/gemcitabine, whereas peripheral neuropathy was more frequent with carboplatin/paclitaxel.
Summary
While it is unlikely that chemotherapy will eliminate the gap in outcome between PS 0/1 and PS 2 patients, the evidence now suggests that PS 2 patients should be offered active treatment. The results of the CALGB subset analysis showed a significant benefit for combination chemotherapy over single-agent therapy in PS 2 patients, with no decrement in quality of life. The most recent ECOG study also demonstrated that PS 2 patients can be administered select platinum- based doublets with reasonable safety.[16] Moreover, independent of a possible impact on survival, chemotherapy leads to a relatively rapid improvement in disease-related symptoms in PS 2 patients. The issue of single-agent vs combination chemotherapy in this particular subset remains unresolved. The CALGB trial, while provocative, should not be considered definitive and further studies are needed. Another important question in PS 2 patients is whether the new molecularly targeted agents have a role in the management of their disease. Gefitinib (Iressa), erlotinib (Tarceva), cetuximab (Erbitux), and bortezomib (Velcade), to name only the drugs with more immediate application in lung cancer, have a favorable toxicity proprofile and seem attractive in this patient population.[20] These agents can be studied alone or in combination with more standard drugs in PS 2 patients. Conclusions The recognition that elderly and PS 2 patients can benefit from chemotherapy is an important contribution to the management of advanced NSCLC. Parallel to the efforts to develop new agents (needed to break through the current plateau), the expansion of the number of patients with advanced NSCLC who can benefit from more active treatment is in itself a great step forward. In fact, the data discussed above should lead to the end of a discriminatory period in clinical research and to the elimination of the denomination "special populations." Although the management of these two subsets requires attention to specific issues that arise less often in younger patients with a good PS, the overall treatment is more similar than dissimilar with respect to the benefits of chemotherapy.

Disclosures

Dr. Lilenbaum receives research grant support, is a consultant and member of the speaker’s bureau for Bristol-Myers Squibb, Lilly, Aventis, and GlaxoSmithKline. He is also a speaker for AstraZeneca, and receives research grant support from Genentech.

References

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