Systemic chemotherapy improves both survival and quality

ORIGINAL ARTICLE Treatment of Elderly Non small Cell Lung Cancer Patients with Three Different Schedules of Weekly Paclitaxel in Combination with Carboplatin: Subanalysis of a Randomized Trial Suresh Ramalingam, MD,* John Barstis, MD, Michael C. Perry, MD, Renato V. La Rocca, MD, Sreenivasa R. Nattam, MD, David Rinaldi, MD, Ray Clark, MD,# Glenn M. Mills, MD,** and Chandra P. Belani, MD* Background: Administration of paclitaxel on a weekly schedule in combination with carboplatin is associated with a lower incidence of neuropathy and myelosuppression. The authors conducted subgroup analysis of their randomized phase II study of three different schedules of weekly paclitaxel with carboplatin to determine the efficacy of each regimen in elderly patients (aged 70 years) with advanced non small-cell lung cancer (NSCLC). Methods: Patients with advanced NSCLC were randomized to one of three different weekly paclitaxel/carboplatin regimens. After four cycles of chemotherapy, those with objective response or stable disease were randomized to weekly paclitaxel or observation as maintenance therapy. Four hundred three patients were enrolled in the study, of whom 111 (28%) were aged 70 years or older. Results: The treatment regimen of weekly paclitaxel (100 mg/m 2 for 3 of 4 weeks) and carboplatin (area under the curve 6 mg/ml/min once every 4 weeks) (arm 1) was associated with the best therapeutic index overall. The median survival and 1-year survival rates were 11.3 months and 50% for patients in the 70 years cohort versus 11.2 months and 46% for the 70 years cohort in arm 1. Efficacy results were comparable between the two groups in the other arms as well. Grade 4 neutropenia and febrile neutropenia occurred in 13.6% and 2.3% in the 70 years cohort compared with 4.5% and 1.1% in the 70 years cohort in arm 1. *University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; University of California at Los Angeles Santa Clarita Cancer Center, Valencia, California; University of Missouri/Ellis Fischel Cancer Center, Columbia, Missouri; Kentuckiana Cancer Center, Louisville, Kentucky; Fort Wayne Medical Oncology-Hematology, Fort Wayne, Indiana; Louisiana Oncology Associates, Lafayette, Louisiana; #Hematology and Oncology Associates, Jackson, Michigan; and **Louisiana State University Medical Center, Shreveport, Louisiana. Presented at the 38th Annual Meeting of the American Society of Clinical Oncology, in Orlando, Florida, May 18 21, 2002. Address for correspondence: Chandra P. Belani, MD, University of Pittsburgh Cancer Institute, 5150 Centre Avenue, Suite 552, Pittsburgh, PA 15232; email: belanicp@upmc.edu. Copyright 2006 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/06/0103-0240 Conclusion: The weekly regimen of paclitaxel administered in combination with carboplatin is tolerated well by elderly NSCLC patients and has comparable efficacy with younger patients. Key Words: Age-specific subanalysis, Carboplatin, Combination therapy, Elderly, Non small-cell lung cancer, Weekly paclitaxel. (J Thorac Oncol. 2006;1: 240 244) Systemic chemotherapy improves both survival and quality of life for patients with advanced non small cell lung cancer (NSCLC). 1 A platinum-based two-drug combination constitutes the current standard of care for the treatment of patients with advanced NSCLC who have a good performance status (PS). However, the efficacy of platinum-based doublets in elderly (aged 70 years) patients with advanced NSCLC has not been studied extensively. Although elderly patients account for approximately 30 to 40% of all cases of NSCLC, they have not been represented in a proportionate manner in clinical trials. 2 Therefore, the safety and efficacy data generated from randomized clinical trials cannot be generalized to elderly NSCLC patients. The choice of chemotherapy regimen for elderly NSCLC patients is influenced by both physician- and patient-related factors. Perception of higher toxicity and lower efficacy in elderly patients by both the treating physician and the patient may result in suboptimal therapeutic selections. It is therefore important that elderly patients are adequately represented in clinical trials, and it is also important to conduct prospective studies exclusively in elderly patients. Treatment of elderly patients with systemic chemotherapy may be limited by various factors such as comorbid illnesses, age-related changes in organ function, and concerns regarding increased toxicity. It is therefore important that elderly patients are adequately represented in clinical trials and that we also conduct prospective elderly-specific studies. Randomized clinical trials have established the utility of single-agent chemotherapy in elderly patients. 3 5 The Elderly Lung Cancer Vinorelbine Study compared treatment with vinorelbine plus best supportive care to best supportive 240 Journal of Thoracic Oncology Volume 1, Number 3, March 2006

Journal of Thoracic Oncology Volume 1, Number 3, March 2006 Treatment of elderly NSCLC patients care alone. 3 Although the study did not complete its planned accrual, both survival and quality-of-life benefits were noted for the elderly patients treated with chemotherapy. The Multicenter Italian Lung Cancer Elderly Study compared singleagent therapy with vinorelbine or gemcitabine with the combination of the same drugs. 4 There was no added benefit when the two drugs were given in combination compared with single-agent therapy alone. However, toxicity was more pronounced with the combination regimen. Because platinumbased doublet regimens are superior to single-agent therapy with either a platinum compound or a novel agent alone, 6 9 there is a need to evaluate platinum-based combination regimens in elderly patients. The combination of carboplatin and paclitaxel is a commonly used regimen for the treatment of patients with advanced NSCLC. The principal toxicities associated with this regimen are myelosuppression and neuropathy. 10 Weekly administration of paclitaxel, however, is associated with a lower incidence of neuropathy and hematologic toxicity. Another potential advantage to administration of paclitaxel at frequent, low dose is its ability to inhibit tumor neoangiogenesis. 11 We conducted a randomized phase II study to evaluate the tolerability and efficacy of weekly administration of paclitaxel in combination with carboplatin for the treatment of patients with advanced NSCLC. 12 The results of this study were reported earlier and demonstrated that a regimen of carboplatin given every 4 weeks in combination with weekly paclitaxel for 3 of 4 weeks was associated with the best therapeutic index among three different weekly schedules. The median survival was 11.3 months and the 1-year survival rate was 47% with this regimen. The incidence of grade 3/4 neuropathy was 5%, compared with 12 to 18% noted with the 3-weekly regimen of carboplatin and paclitaxel. The impressive safety profile of the weekly schedule makes this regimen worthy of evaluation for the treatment of elderly NSCLC patients. Therefore, we performed a subset analysis of our randomized study to determine the efficacy and toxicity of the weekly schedules of paclitaxel in combination with carboplatin for elderly patients with advanced or metastatic NSCLC. PATIENTS AND METHODS Eligibility criteria were as follows: age 18 years or older; histologically or cytologically confirmed stage IIIB (pleural/pericardial effusion) or IV NSCLC; presence of measurable disease; Eastern Cooperative Oncology Group (ECOG) PS of less than or equal to 2; estimated life expectancy of 12 weeks or more; and adequate hematologic, renal, and hepatic function at baseline. The treatment plan for this study included maintenance single-agent paclitaxel after four cycles of initial combination chemotherapy for patients who experienced an objective response or stable disease with initial therapy. The protocol was approved by institutional review boards with jurisdiction over specific sites that registered patients onto the study. Each patient gave written informed consent before enrollment. The treatment scheme was as follows: arm 1, paclitaxel 100 mg/m 2 weekly for 3 of 4 weeks with carboplatin area under the curve (AUC) 6 mg/ml/min on day 1 of each 4-week cycle for a total of four cycles; arm 2, paclitaxel (100 mg/m 2 ) and carboplatin (AUC 2 mg/ml/min) weekly for 3 of 4 weeks of each of four cycles; and arm 3, paclitaxel (150 mg/m 2 for cycle 1 and 100 mg/m 2 for cycle 2) and carboplatin (AUC 2 mg/ml/min) weekly for 6 of 8 weeks for a total of two cycles. Premedication administered 30 to 60 minutes before paclitaxel consisted of dexamethasone 20 mg intravenously (IV), diphenhydramine 50 mg IV, and a histamine 2 blocker (such as cimetidine 300 mg or ranitidine 50 mg IV). After four cycles of therapy, patients who experienced complete response, partial response, or stable disease were randomized to the maintenance phase of therapy with weekly paclitaxel or observation. Each cycle of maintenance chemotherapy consisted of paclitaxel 70 mg/m 2 weekly for 3 of 4 weeks. To evaluate the outcome for elderly NSCLC patients who participated in the study, we compared the baseline characteristics and toxicity and efficacy data for patients aged 70 years or older with those younger than 70 years of age. Subgroup analyses were based on stratification by disease stage (IIIB versus IV) and ECOG PS (0 1 or 2). Toxicity was graded by the National Cancer Institute Common Toxicity Criteria Version 2.0 and responses were assessed by World Health Organization criteria. RESULTS This multicenter study was conducted between May of 1998 and June of 2000. A total of 403 patients were enrolled, and 390 were assessable. Patient baseline characteristics for the initial therapy phase were comparable across treatment arms and age groups (Table 1). Of the 403 enrolled patients, 111 (28%) were aged 70 years or older. The median age for the elderly subset of patients in the three arms of the study was 74 years. The median age for patients younger than 70 years in the three arms of the study were 59, 60, and 59 years, respectively. There was a slightly higher male-to-female ratio for elderly patients enrolled in arm 2 compared with other arms of the study. There was a higher proportion of elderly patients with ECOG PS 2 in arm 2 (29%) compared with the other arms of the study. Efficacy The overall results of the study demonstrated that arm 1 was associated with the best therapeutic index. The response rate was 32% for patients in this arm, and the median survival was 11.3 months. There were 44 patients in the TABLE 1. Baseline Characteristics >70 Yr <70 Yr >70 Yr <70 Yr >70 Yr <70 Yr No. 44 88 34 96 33 95 Median age (yr) 74 59 74 60 74 59 Male/female (%) 57/43 60/40 76/24 60/40 64/36 60/40 Stage IIIB/IV (%) 25/75 23/77 21/79 24/76 27/73 20/80 ECOG PS 2 (%) 11 16 29 8 21 13 Copyright 2006 by the International Association for the Study of Lung Cancer 241

S. Ramalingam et al. Journal of Thoracic Oncology Volume 1, Number 3, March 2006 elderly cohort on this arm compared with 88 patients who were in the 70 years cohort. The median survivals for the 70 years and 70 years cohorts were 11.3 months and 11.2 months, respectively, on arm 1. Time to progression was 6.9 months and 7.2 months, respectively, for the elderly and younger patients. The 1-year survival rates were also comparable. Arm 2 was associated with the least favorable outcome, with median survival duration of 6 months and 7.7 months in the elderly and younger groups, respectively. For the 33 patients who were aged 70 years or older in arm 3, the median survival was 14.4 months compared with 9.1 in the younger group (Table 2). Toxicity There was no evidence of excessive toxicity for elderly patients treated with the combination regimens, with the exception of grade 4 neutropenia (Table 3). The incidence of grade 4 neutropenia in the elderly cohort was 13.6% and 12.1% in arms 1 and 3 versus 4.5% and 9.5%, respectively, for the 70 years age group. Febrile neutropenia rates for the 70 years cohort were 1.1%, 1.0%, and 5.3% for arms 1, 2, and 3, respectively, versus 2.3%, 2.9%, and 3.0% for those in the 70 years cohort. Grade 3/4 thrombocytopenia occurred in 2.3% of patients in the 70 year cohort and was noted only in arm 1. There were no major differences in the nonhematologic toxicity profiles between the two cohorts in arm 1 (Table 4). Neuropathy was more common for patients treated in arm 3, although there was no difference between the two age cohorts in all three arms of the study. There was one episode of grade 4 peripheral neuropathy in arm 3 in the younger group. DISCUSSION Platinum-based chemotherapy has become the cornerstone of therapy for patients with advanced NSCLC. However, the efficacy of platinum-based chemotherapy has not been evaluated adequately in elderly patients by prospective trials. To date, the only prospectively planned evaluation of platinum-based chemotherapy in elderly patients was conducted in the CALGB 9730 trial. 6 This was a randomized comparison between paclitaxel administered alone or in combination with carboplatin for patients with advanced NSCLC. Approximately 27% of the patients who participated in this study were older than 70 years. The study design allowed for stratification of patients by age ( 70 years versus 70 years). The response rate and survival rates noted in the elderly patients were comparable to those of younger patients in this study. There was a higher incidence of leukopenia, TABLE 2. Efficacy >70 Yr <70 Yr >70 Yr <70 Yr >70 Yr <70 Yr Median survival (mo) 11.3 11.2 6.0 7.7 14.4 9.1 1-yr survival rate (%) 50 46 19 35 52 38 2-yr survival rate (%) 23 11 6 11 38 14 Time to progression (mo) 7.2 6.9 5.3 4.2 8.6 6.0 sepsis, and febrile neutropenia in elderly patients. The other toxicities were comparable to that of younger patients. However, because of the smaller number of elderly patients in the study, these observations did not reach statistical significance. Similar observations have been made by retrospective analyses of outcome for elderly patients from randomized trials conducted in advanced NSCLC. 13,14 Langer et al. conducted a subset analysis of patients who participated in the ECOG 1594 trial that evaluated four different chemotherapeutic regimens for the treatment of advanced NSCLC. 14 Of the 1207 patients enrolled to the study, 227 (20%) were older than 70 years and nine patients (1%) were older than 80 years. Delivery of chemotherapy was comparable for the younger than 70 and 70 years or older age groups. Approximately 34% of the younger patients completed the planned six cycles of chemotherapy, compared with 30% of the elderly cohort. The median survival duration was 8.15 and 8.25 months for the younger and elderly cohorts, respectively. On the basis of these results, the authors concluded that elderly patients with a good performance status (ECOG PS 0/1) tolerate and benefit from systemic chemotherapy similar to younger patients. To improve the overall tolerability of the taxanes in the elderly patients, weekly schedules of both paclitaxel and docetaxel have been developed. 15,16 Promising efficacy without an appreciable increase in toxicity was noted from these studies. In a phase II study, Fidias et al. treated elderly NSCLC patients with a weekly dose of paclitaxel (90 mg/m 2 for 6 of 8 weeks). 15 A promising response rate (23%) and median survival (10.2 months) were noted without excessive toxicity. It has also been possible to combine weekly paclitaxel with carboplatin. 17 Favorable efficacy with this combination was noted by a phase II study that was restricted to the elderly and patients with poor performance status. 18 In another phase II study, an attenuated dose of paclitaxel was administered to elderly patients in combination with carboplatin. This regimen resulted in a response rate of 40% and a median time to progression of 5.5 months. 19 In our randomized phase II study that evaluated three different weekly schedules of paclitaxel in combination with carboplatin for patients with previously untreated advanced NSCLC, 12 the regimen with the best therapeutic index was weekly paclitaxel (100 mg/m 2 administered for 3 of 4 weeks) in combination with carboplatin (AUC 6 mg/ml/min every 4 weeks). The subgroup analysis described in this article was derived from this randomized phase II study. 12 The proportion of elderly patients included in this study is higher than that in some of the recently reported clinical trials in advanced NSCLC. 6,20 Because age was not a stratification factor, there were minor differences in the distribution of elderly patients between the three arms of the study. There was a disproportionately higher representation of elderly patients with a PS of 2 in arm 2 of the study. This could be another contributory factor to the inferior survival noted with this treatment arm. Another limitation of our analysis is the lack of information regarding comorbid illness. Efficacy of chemotherapy in the elderly cohort was comparable to the 70 years cohort in all three arms of the study. The higher 242 Copyright 2006 by the International Association for the Study of Lung Cancer

Journal of Thoracic Oncology Volume 1, Number 3, March 2006 Treatment of elderly NSCLC patients TABLE 3. Hematologic Toxicity >70 Yr (%) <70 Yr (%) >70 Yr (%) <70 Yr (%) >70 Yr (%) <70 Yr (%) Neutropenia (grade 4) 13.6 4.5 2.9 1.0 12.1 9.5 Febrile neutropenia (grade 3/4) 2.3 1.1 2.9 1.0 3.0 5.3 Thrombocytopenia (grade 4) 0 2.3 0 0 0 0 Anemia (grade 3) 6.8 6.8 5.9 3.1 3 5.3 TABLE 4. Nonhematologic Toxicity Grade 3 >70 Yr (%) <70 Yr (%) >70 Yr (%) <70 Yr (%) >70 Yr (%) <70 Yr (%) Nausea 0 4.5 0 3.1 6 6.3 Vomiting 0 3.4 0 2.1 0 9.5 Constipation 0 1.1 2.9 3.1 0 2.1 Myalgia 2.3 2.3 0 1 0 0 Neuropathy* 6.9 4.5 2.9 3.1 12.2 12.4 Bone pain 2.3 1.1 0 1 0 3.2 * Includes neuropathy, peripheral neuritis, neuritis, and paresthesia. degree of neutropenia seen in the elderly cohort is consistent with data from other retrospective comparisons between elderly and younger patients with advanced NSCLC. 13,14 The lower incidence of neuropathy with the weekly regimen makes this a more appealing option for the treatment of elderly NSCLC patients. However, such an interpretation is limited by the retrospective nature of this analysis. Furthermore, selection of elderly patients to clinical trials is likely to be associated with an inherent bias. 21 Therefore, the data from elderly patients who participate in clinical trials may not entirely apply to all elderly individuals. Even elderly-specific clinical trials may be associated with such a selection bias. Careful consideration of comorbid illness, functional status, and performance status are critical before treatment decisions are made for elderly patients. Furthermore, no formal statistical analysis was performed in our report to compare the differences in response or toxicity, because the numbers are too small to detect a statistical difference. It is our belief that the weekly regimen is safe and efficacious in elderly patients and therefore warrants evaluation in prospective studies for elderly NSCLC patients. The findings of this analysis are supported by the results of our phase III study that compared the weekly regimen (arm 1 of the study reported here) with the standard 3-weekly regimen of carboplatin-paclitaxel. The study demonstrated comparable efficacy and a favorable nonhematologic toxicity profile with the weekly regimen. In the elderly subset of patients, the weekly regimen was associated with a numerically higher response rate and survival, although the differences did not reach significance. The nonhematologic toxicity profile also favored the weekly regimen in the elderly group. 22 On the basis of this, the weekly regimen may also be more suited to serve as the platform for incorporation of molecularly targeted agents for the treatment of elderly NSCLC patients. Considered together, the results of our analysis add to the growing body of literature that elderly patients with advanced NSCLC tolerate combination chemotherapy as well as younger patients and derive similar benefit. As NSCLC increasingly becomes a disease of the elderly, it is important to develop elderly-specific clinical trials in the future. Efforts should also be undertaken to improve accrual of elderly patients to clinical trials in NSCLC, which will increase the applicability of clinical trial data to elderly patients in routine practice. Another subset of patients who have not been studied in clinical trials is the octogenarians. In the ECOG 1594 trial, only nine patients were older than 80 years. Prospective studies are necessary to define the role of chemotherapy and to identify optimal therapy for advanced NSCLC in the very elderly. ACKNOWLEDGMENTS Supported in part by a grant from Bristol-Myers Squibb Company. REFERENCES 1. Ramalingam S, Belani CP. State-of-the-art chemotherapy for advanced non-small cell lung cancer. Semin Oncol 2004;31:68 74. 2. Bunn PA Jr, Lilenbaum R. Chemotherapy for elderly patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 2003;95:341 343. 3. The Elderly Lung Cancer Vinorelbine Italian Study Group. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 1999; 91: 66 72. 4. Gridelli C, Perrone F, Gallo C, et al. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst 2003;95:362 372. Copyright 2006 by the International Association for the Study of Lung Cancer 243

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