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© 2002 American Society for Clinical Oncology Long-Term Follow-Up of Patients Treated With Paclitaxel/Carboplatin-Based Chemotherapy for Advanced Non–Small-Cell Lung Cancer: Sequential Phase II Trials of the Minnie Pearl Cancer Research NetworkByFrom The Sarah Cannon Cancer Center and Tennessee Oncology, PLLC, Nashville, TN; Oncology Hematology Group of South Florida, Miami, FL; and Comprehensive Cancer Institute, Huntsville, AL. Address reprint requests to John D. Hainsworth, MD, The Sarah Cannon Cancer Center, 250 25th Ave N, Ste 110, Nashville, TN 37203; email: jhainsworth{at}tnonc.com
PURPOSE: To provide long-term follow-up on the survival of patients with advanced non–small-cell lung cancer treated with paclitaxel/carboplatin-based regimens in a multicenter, community-based setting. PATIENTS AND METHODS: Between March 1995 and April 1998, 321 patients with newly diagnosed stage IIIB or IV non–small-cell lung cancer were treated on sequential phase II trials with the following combination regimens: paclitaxel/carboplatin, paclitaxel/carboplatin/gemcitabine, and paclitaxel/carboplatin/vinorelbine. Details of these three regimens and patient populations have been previously reported. Responding and stable patients continued treatment until tumor progression or for a recommended six treatment courses. RESULTS: After a median follow-up of 58 months (minimum follow-up, 40 months), the median survival for the entire group of patients was 8.6 months, with actual 1-, 2-, and 3-year survival rates of 40%, 19%, and 7%, respectively. The actuarial 4-year survival rate for the entire group was 4%. No statistically significant differences in survival were seen among the three regimens. Administration of all three regimens was feasible in a community-based setting; however, myelosuppression and hospitalizations for treatment of neutropenia/fever were more frequent with the three-drug regimens. CONCLUSION: Paclitaxel/carboplatin-based regimens, in addition to prolonging median survival and improving 1-year survival, result in substantial improvements in the 2-year survival of patients with advanced non–small-cell lung cancer when compared retrospectively with supportive care or traditional cisplatin-based regimens. In these sequential phase II trials, we did not demonstrate any advantages of three-drug regimens when compared with paclitaxel/carboplatin. Because few patients remain alive after 4 years with any of these chemotherapy regimens, future treatment improvements will require the introduction of novel agents.
THE INTRODUCTION OF several new antineoplastic agents including the taxanes, gemcitabine, vinorelbine, and irinotecan has resulted in improved treatment for patients with advanced non–small-cell lung cancer. Several of these agents, when combined with either cisplatin or carboplatin, have resulted in improved median and 1-year survivals when compared in randomized trials with either cisplatin alone or older cisplatin-based combination regimens.1-4 One-year survivals with the new regimens are approximately 35% to 40%, markedly improved when compared with the 15% to 20% 1-year survival with supportive care alone.5 In most comparisons, newer regimens have also demonstrated less toxicity than traditional cisplatin-based combinations. To date, relatively little attention has been focused on the long-term results of treatment with the newer, more active chemotherapy regimens for advanced non–small-cell lung cancer. Between March 1995 and April 1998, we evaluated three paclitaxel/carboplatin-based combination regimens in sequential phase II trials containing a total of 321 patients. All of these phase II trials were performed in a multicenter, community-based clinical research network, and preliminary results have been previously reported.6-8 In the first of these trials, we evaluated a now-standard combination of paclitaxel and carboplatin. In the subsequent two trials, we attempted to improve the efficacy of the paclitaxel/carboplatin regimen by adding a third agent, first gemcitabine (second trial) and then vinorelbine (third trial). In this report, we update the results of these large phase II trials, with special attention to the long-term follow-up. Minimum follow-up in this large group of patients is more than 24 months, and actuarial 3- and 4-year survival rates are available. These data provide further documentation of the superiority of the newer regimens, with prolonged palliation in a substantial minority of these patients.
Between March 1995 and April 1998, a total of 321 patients with advanced non–small-cell lung cancer were treated on three sequential phase II trials performed by the Minnie Pearl Cancer Research Network (Appendix). The chemotherapy regimens used in the three trials are listed in Table 1. Preliminary results of all three trials have been previously reported.6-8 The first trial evaluated the combination of paclitaxel and carboplatin, as originally described by investigators at the University of Southern California.9 In the subsequent two trials, gemcitabine and then vinorelbine were added as third drugs to the paclitaxel/carboplatin combination. Preceding each of these phase II trials, we had performed brief phase I trials to identify optimum doses of these three agents when used in combination.7,10
Entry criteria for these three trials were identical. Patients were eligible if they had histologically documented stage IV non–small-cell lung cancer. In addition, patients with stage IIIB disease who were not candidates for radiation therapy (usually because of pleural effusions) were eligible. Previous systemic therapy was not permitted. Patients who had previously received radiation therapy were eligible, provided they had measurable disease outside the previous radiation therapy portal and treatment had been completed more than 4 weeks before initiation of chemotherapy. All patients were required to have unidimensionally or bidimensionally measurable disease by chest radiograph or computed tomographic (CT) scanning. Additional eligibility requirements included age more than 18 years; Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2; life expectancy  12 weeks; adequate bone marrow function (WBC count 3,500/µL, platelets 100,000/µL); adequate liver function (bilirubin  1.5 mg/dL); and adequate renal function (serum creatinine 1.5 mg/dL). Patients with brain metastases were excluded. All patients gave written informed consent before beginning treatment. All three studies were approved by the Investigational Review Board of Centennial Medical Center and by review boards of the participating network affiliates. Before beginning therapy, all patients were evaluated and staged with the following procedures: complete blood count, differential, chemistry profile, chest radiograph, ECG, and CT scan of the chest. CT scans of the abdomen and brain were obtained if clinically indicated. All patients received two courses of therapy, and then were reevaluated for response to treatment. Patients with objective response or stable disease continued treatment until disease progression, or for a total of six courses. Further treatment at the time of disease progression or removal from study was at the discretion of the treating physician. Details of administering these regimens have been previously reported.6-8 In all regimens, paclitaxel was administered by 1-hour intravenous infusion. The dose of carboplatin was calculated using the method of Calvert et al.11 Routine premedication for paclitaxel included dexamethasone 20 mg given orally 12 hours and 4 hours before therapy, and intravenous premedication with dexamethasone 20 mg, diphenhydramine 50 mg, and cimetidine 300 mg immediately preceding paclitaxel administration. Cytokines were not used routinely as part of these regimens, but could be used after the first cycle at the discretion of the treating physician. However, dose reductions on the basis of hematologic and nonhematologic toxicities were specified in each trial, and addition of cytokines could not substitute for adherence to prescribed dose reductions. All patients who received at least two courses of treatment were assigned a response category, using standard definitions. All patients who received at least one dose of treatment were included in the survival analysis. Actuarial survival curves were constructed using the Kaplan-Meier method.12 Duration of survival was calculated from the first day of treatment until the date of death. Survival curves were compared using the Wilcoxon log-rank analysis. The clinical characteristics of the 321 patients are listed in Table 2. There were no major differences in clinical characteristics among the patient groups entered onto these three sequential trials. Seventy-one percent of patients were men; the median age was 62 years. Seventy-two percent of patients had stage IV disease, and a minority (11%) had poor performance status (ECOG 2).
Each of these combination regimens was successfully administered in a multicenter, community-based setting. Patients on each of the three trials received a median of four treatment courses. During the first two courses of treatment, 85% of the planned doses of all drugs was administered with each of the regimens. The efficacy of each of these three regimens and the treatment outcome for the entire group of 321 patients are listed in Table 3. As previously reported, all of these regimens were active; response rates ranged from 37% (paclitaxel/carboplatin) to 44% (paclitaxel/carboplatin/gemcitabine). In all three trials, response rates were similar for patients with stage IV versus stage IIIB disease. Median progression-free survival varied from 3.3 months (paclitaxel/carboplatin) to 5.4 months (paclitaxel/carboplatin/gemcitabine); no significant differences in progression-free survival were observed.
Updated survival curves for patients on each of the three studies are shown in Fig 1. Minimum follow-up for the most recently completed trial (paclitaxel/carboplatin/vinorelbine) is 40 months; therefore, actual 1-, 2-, and 3-year survival rates are available for all three trials. For the entire group of patients, the actual 1-year survival rate was 40%; 1-year survivals ranged from 35% (paclitaxel/carboplatin) to 47% (paclitaxel/carboplatin/gemcitabine). The actual 2-year survival for the entire group was 19% (range, 16% with paclitaxel/carboplatin to 21% with paclitaxel/carboplatin/gemcitabine). There were no statistical differences between the three regimens. The 3- and 4-year survival rates for the entire group were 7% and 4%, respectively.
The 1- and 2-year survival rates for various subgroups in this large patient group are compared in Table 4. Patients with good performance status (ECOG 0 or 1) had markedly better survival than did poor performance status patients (P < .001). In these trials, stage (IIIB vs IV) was not a prognostic factor (P = .71), probably because only an unfavorable subgroup of stage IIIB patients was included. Neither sex nor histologic subtype had any influence on survival in these trials.
A total of 56 patients on these three trials survived longer than 24 months after the initiation of treatment. Characteristics of this subset of patients are listed in Table 5. As expected, these 56 patients had a higher response rate to treatment than did the entire group (72% v 38%, P = .0005). However, the demographic features of this group (median age, sex, performance status, stage) were otherwise similar to those of the group as a whole.
Treatment-related toxicity, previously reported separately for each phase II study, is listed in Table 6. All three regimens were successfully administered in a multicenter, community-based setting. As anticipated, myelosuppression was increased with both three-drug regimens. The paclitaxel/carboplatin/vinorelbine regimen produced the most grade 3/4 leukopenia (90%) and hospitalizations for neutropenia/fever (43% of patients; P < .0001 v paclitaxel/carboplatin). Thrombocytopenia (45%) and platelet transfusion requirement (12% of patients) were most frequent with paclitaxel/carboplatin/gemcitabine. Other than a higher incidence of fatigue with paclitaxel/carboplatin/gemcitabine, nonhematologic toxicities were similar. No significant differences were found in the incidence of treatment-related death, although the 4% rate with paclitaxel/carboplatin/vinorelbine was numerically higher.
The introduction in the early 1990s of several new cytotoxic agents has improved treatment results for patients with advanced non–small-cell lung cancer. Several regimens that pair a new agent with a platinum agent have shown comparable efficacy and have proven more active and less toxic than cisplatin or traditional cisplatin-based regimens.1-4,13-16 In comparing these new regimens with older cisplatin-based regimens and with the results of supportive care alone, attention has appropriately been focused on improvement in patient survival. When compared with previous cisplatin-based regimens, new regimens have prolonged median survival by 6 to 8 weeks and increased the 1-year survival from 25% to 30%, to 35% to 40%. These changes are even more impressive when compared retrospectively with results of supportive care alone, where 1-year survival of 16% was demonstrated in a large meta-analysis.5 To date, relatively little information is available regarding patient survival beyond 1 year after treatment with the newer regimens. Results from randomized trials evaluating new regimens have been published with minimum follow-up of less than 24 months. Therefore, the 2-year survival has always been derived from actuarial calculations, and the 3- and 4-year survival rates have rarely been available.1-3,13-17 In contrast, the minimum follow-up of our patients is 40 months, so that the actual survival rates at 1, 2, and 3 years are available. In these 321 patients treated in a multicenter, community-based setting, we document an actual 2-year survival rate of 19%. A large amount of data is available regarding the outcome of patients with advanced non–small-cell lung cancer treated with best supportive care, often including palliative radiation therapy. In a large meta-analysis, patients randomized to receive best supportive care had a 1-year survival rate of 16%.18 More recently, Mountain19 reviewed treatment results in a group of 5,319 patients with lung cancer treated or reviewed at M.D. Anderson Cancer Center between 1975 and 1988. The 1- and 2-year survival rates in the 1,427 patients with stage IV lung cancer were 20% and 5%, respectively. These previous experiences in large numbers of patients underscore the superiority of current treatment. The 2-year survival rate of 19% in the 321 patients described here is similar to the 1-year survival rate from these historical experiences. In addition, all three regimens described here resulted in 3- and 4-year survival in a small percentage of patients. Survival beyond 2 years has been rare with any previous treatment for advanced non–small-cell lung cancer and is another feature that distinguishes the newer regimens from previously used cisplatin-based combinations. Mature results from these sequential phase II studies do not suggest an incremental benefit from the addition of a third agent in the treatment of advanced non–small-cell lung cancer. However, this question is not answered definitively in these trials, and any benefit with three-drug versus two-drug regimens is likely to be small. Because a large body of information now suggests the equivalence of many two-drug combinations, completion of ongoing randomized trials comparing three-drug and two-drug combinations is important. To date, the paclitaxel/carboplatin (or cisplatin)/gemcitabine regimen has been the most extensively investigated three-drug combination. Results from several phase II trials have demonstrated response rates of more than 40%, with median survivals more than 10 months.7,20-22 Two small randomized trials have also demonstrated high levels of activity with this three-drug combination. Comella et al23 randomized patients to receive paclitaxel/cisplatin/gemcitabine versus cisplatin/epirubicin/vindesine; response rates (57% v 37%) and median survival (12 months v 8 months) were superior in the patients receiving paclitaxel/cisplatin/gemcitabine. A second small trial compared paclitaxel/carboplatin/gemcitabine with paclitaxel/carboplatin; median survival was longer with the three-drug regimen (10.5 v 8 months), but this difference lacked statistical significance because of the small size of the study.24 We recently completed a randomized phase II evaluation of the paclitaxel/carboplatin/gemcitabine and paclitaxel/carboplatin/vinorelbine regimens as two arms of a four-arm randomized trial, which also contains two non–platinum-containing doublets (paclitaxel/gemcitabine and gemcitabine/vinorelbine).25 After randomization of 267 patients, preliminary data analysis showed best results with paclitaxel/carboplatin/gemcitabine (response rate, 37%; median survival, 10 months) and gemcitabine/vinorelbine (response rate, 33%; median survival, 11 months). Accrual to these two regimens is continuing to complete a phase III comparison. However, on the basis of current data, we would not routinely recommend a three-drug regimen for the treatment of stage IV non–small-cell lung cancer except in a clinical trial setting. These long-term treatment results in a large number of patients with advanced non–small-cell lung cancer further emphasize the improved outcome with modern chemotherapy regimens. With currently available treatment, a substantial minority of patients (approximately 20%) will survive for 2 years, an uncommon event with symptomatic treatment or with previous, less effective chemotherapy regimens. Two-year survivors in these trials belong almost exclusively to the subgroup of patients with objective responses to first-line treatment, and demonstrate a change in the natural history of this disease produced by effective treatment. These therapies may have an even greater impact when used as neoadjuvant or adjuvant treatment for patients with early-stage disease. Clinical trials in these patient groups are in progress. In patients with advanced non–small-cell lung cancer, further evaluation of new combinations of currently available cytotoxic agents is unlikely to yield substantial further improvement. Continued therapeutic gains will require incorporation of agents with novel mechanisms of action. The major focus of clinical research should be the evaluation of the multiple promising targeted agents, including epidermal growth factor receptor inhibitors and antiangiogenesis agents.
APPENDIX
Supported in part by Bristol-Myers Squibb, Eli Lilly, and the Minnie Pearl Cancer Research Foundation.
1. Bonomi P, Kim KM, Fairclough D, et al: Comparison of survival and quality of life in advanced non-small cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: Results of an Eastern Cooperative Oncology Group trial. J Clin Oncol 18: 623-631, 2000 2. LeChevallier T, Brisgand D, Douillard JY, et al: Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vindesine alone in advanced non-small cell lung cancer: Results of a European multicenter trial including 612 patients. J Clin Oncol 12: 360-367, 1994[Abstract]
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Sandler AB, Nemunaitis J, Denham C, et al: Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small cell lung cancer. J Clin Oncol 18: 122-130, 2000 4. Wozniak AJ, Crowley JJ, Balcerzak SP, et al: Randomized trial comparing cisplatin with cisplatin plus vinorelbine in the treatment of advanced non-small cell lung cancer: A Southwest Oncology Group study. J Clin Oncol 16: 2459-2465, 1998[Abstract]
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Non-Small Cell Lung Cancer Collaborative Group: Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 5 randomized clinical trials. BMJ 311: 899-909, 1995 6. Hainsworth JD, Urba WJ, Hon JK, et al: One-hour paclitaxel plus carboplatin in the treatment of advanced non-small cell lung cancer: Results of a multicentre, phase II trial. Eur J Cancer 34: 654-658, 1998[Medline] 7. Hainsworth JD, Burris HA, Erland JB, et al: Phase I/II trial of paclitaxel by 1-hour infusion, carboplatin, and gemcitabine in the treatment of patients with advanced non-small cell lung cancer. Cancer 85: 1269-1276, 1999[CrossRef][Medline] 8. Hainsworth JD, Burris HA, Morrissey LH, et al: Paclitaxel, carboplatin, and vinorelbine in the treatment of advanced non-small cell lung cancer: A phase II trial of the Minnie Pearl Cancer Research Network. Cancer J 6: 151-156, 2000[Medline] 9. Vafai D, Israel V, Zaretsky S, et al: Phase I/II trial of combination carboplatin and Taxol in non-small cell lung cancer. Proc Am Soc Clin Oncol 14: 352, 1995 (abstr) 10. Thompson DS, Hainsworth JD, Hopkins LH, et al: Phase I study of vinorelbine, paclitaxel and carboplatin in advanced non-small cell lung cancer. Proc Am Soc Clin Oncol 17: 503a, 1998 (abstr) 11. Calvert AH, Newell DR, Gumbrell LA, et al: Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol 7: 1748-1756, 1989[Abstract] 12. Kaplan ZL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958[CrossRef]
13.
Kelly K, Crowley J, Bunn PA, et al: Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-small cell lung cancer: A Southwest Oncology Group trial. J Clin Oncol 19: 3210-3218, 2001 14. Schiller JH, Harrington D, Sandler A, et al: A randomized phase III trial of four chemotherapy regimens in advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 19: 1a, 2000 (abstr) 15. Scagliotti GV, DeMarinis F, Rinaldi M, et al: Phase III randomized trial comparing three platinum-based doublets in advanced non-small cell lung cancer. Proc Am Soc Clin Oncol 20: 308a, 2001 (abstr 1227) 16. Van Meerbeeck JP, Smit EF, Lianes P, et al: A EORTC randomized phase III trial of three chemotherapy regimens in advanced non-small cell lung cancer. Proc Am Soc Clin Oncol 20: 308a, 2001 (abstr 1228) 17. Giaccone G, Splinter TAW, Debruyne C, et al: Randomized study of paclitaxel-cisplatin versus cisplatin-teniposide in patients with advanced non-small cell lung cancer. J Clin Oncol 16: 2133-2141, 1998[Abstract]
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Non-Small Cell Lung Cancer Collaborative Group: Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 311: 899-909, 1995
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Mountain CF: Revisions in the International System for Staging Lung Cancer. Chest 111: 1710-1717, 1997
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Frasci G, Panza N, Comella P, et al: Cisplatin, gemcitabine and paclitaxel in locally advanced or metastatic non-small cell lung cancer: A phase I-II study. J Clin Oncol 17: 2316-2325, 1999 21. Favaretto A, Paccagnella A, Oniga F, et al: Paclitaxel and carboplatin in combination with gemcitabine (PCG): A phase I-II trial in non-small cell lung cancer. Proc Am Soc Clin Oncol 19: 512a, 2000 (abstr) 22. Paz-Ares L, Sanchez-Rovira P, Gomez-Martin R, et al: A phase II trial of the triplet paclitaxel, cisplatin, and gemcitabine in patients with advanced non-small cell lung cancer. Proc Am Soc Clin Oncol 19: 546a, 2000 (abstr)
23.
Comella P, Frasci G, Panza N, et al: Cisplatin, gemcitabine and vinorelbine combination therapy in advanced non-small cell lung cancer: A phase II randomized study of the Southern Italy Cooperative Oncology Group. J Clin Oncol 17: 1526-1534, 1999 24. Hussein A, Birch R, Waller J, et al: Preliminary results of a randomized study comparing paclitaxel and carboplatin with or without gemcitabine in newly diagnosed non-small cell lung cancer. Proc Am Soc Clin Oncol 19: 504a, 2000 (abstr) 25. Thompson DS, Hainsworth JD, Burris HA, et al: Prospective randomized study of four third-generation chemotherapy regimens in patients with advanced non-small cell lung cancer: A Minnie Pearl Cancer Res Network trial. Proc Am Soc Clin Oncol 20: 314a, 2001 (abstr) Submitted October 15, 2001; accepted March 28, 2002.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
