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Journal of Clinical Oncology, Vol 22, No 1 (January 1), 2004: pp. 127-132 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.06.070 Phase II Trial of Cisplatin/Etoposide and Concurrent Radiotherapy Followed by Paclitaxel/Carboplatin Consolidation for Limited Small-Cell Lung Cancer: Southwest Oncology Group 9713From the University of Maryland Greenebaum Cancer Center, Baltimore, MD; Southwest Oncology Group Statistical Center and Puget Sound Oncology Consortium, Seattle, WA; University of Colorado Health Sciences Center, Denver, CO; University of California Davis Cancer Center, Sacramento, CA; University of Texas Health Science Center, San Antonio, TX; and University of Kansas Medical Center, Kansas City, MO. Address reprint requests to Southwest Oncology Group (S9713), Operations Office, 14980 Omicron Dr, San Antonio, TX 78245-3217
PURPOSE: Limited small-cell lung cancer (LSCLC) is characterized by a high initial response rate to chemoradiotherapy, but local or systemic relapse occurs in the majority of patients. Previous Southwest Oncology Group trials in LSCLC have utilized cisplatin and etoposide (PE) delivered concurrently with thoracic radiotherapy followed by two consolidation cycles. Newer chemotherapy regimens such as paclitaxel and carboplatin are active in small-cell lung cancer and hold the promise of improving both local and systemic control. S9713 evaluated the substitution of paclitaxel and carboplatin for PE consolidation in LSCLC. PATIENTS AND METHODS: Between July 1998 and August 1999, 96 patients were accrued from 43 institutions. Eighty-nine patients were eligible; 87 were assessable for survival and response. Treatment consisted of cisplatin 50 mg/m2 on days 1, 8, 29, and 36, and etoposide 50 mg/m2 on days 1 to 5 and days 29 to 33, with concurrent radiotherapy of 61 Gy beginning on day 1. Consolidation therapy was carboplatin (area under the curve = 6) and paclitaxel 200 mg/m2, both drugs administered on day 1 of a 21 day cycle for three cycles. RESULTS: The response rate was 86% (complete response, 33%; partial response, 53%). Median overall survival was 17 months (95% CI, 12.7 to 19.0). One- and 2-year overall survivals were 61% and 33%, respectively. Median progression-free survival (PFS) was 9 months, 1-year PFS was 40%, and 2-year PFS was 21%. CONCLUSION: Consolidation therapy with paclitaxel and carboplatin in LSCLC resulted in an outcome similar to that seen in prior Southwest Oncology Group trials. This study and others which have tested paclitaxel in small-cell lung cancer dampens enthusiasm for this agent in the primary management of LSCLC.
When treated with combinations of chemotherapy and thoracic radiation, limited stage small cell lung cancer (LSCLC) represents a subset of lung cancer in which long-term survival can be achieved. During the last 15 years, clinical trials have demonstrated that concurrent chemoradiotherapy is superior to sequential treatment and that early use of concurrent radiation is superior to later use [1,2]. Cisplatin and etoposide (PE) has become the standard regimen in the United States because of its ability to be administered concurrently at full dose with thoracic radiotherapy, as well as its possible superiority to other regimens [3]. Yet despite high response rates to initial chemotherapy and radiation, the vast majority of patients with LSCLC subsequently relapse and die of their disease. Although local failure remains a substantial problem, the majority of patients die of distant metastases. Clearly, improved systemic therapy is needed. Attempts by the Southwest Oncology Group (SWOG) to improve outcome by chemotherapy dose intensification, interferon alfa maintenance, and the addition of other drugs to standard PE during induction did not appear beneficial [4-6]. Recently, several newer chemotherapeutic agents with unique mechanisms of action have become available. Early trials have demonstrated substantial activity in extensive stage small-cell lung cancer (SCLC), and it is therefore reasonable to explore their use in LSCLC [7]. In advanced non-small-cell lung cancer, the regimen of carboplatin and paclitaxel has similar response rates and improved tolerability when compared to other platinum/new agent regimens [8,9]. Paclitaxel has also demonstrated activity in SCLC [10]. We therefore undertook a pilot trial of carboplatin and paclitaxel consolidation following induction with cisplatin/etoposide and concurrent radiotherapy.
Eligibility Patients with histologically documented limited stage SCLC defined as disease confined to one hemithorax (including ipsilateral and contralateral supraclavicular nodes and ipsilateral pleural effusion) were entered onto the study. These criteria were identical to those of SWOG trials S8812 and S9229 except that the former study did not permit entry of patients with effusions. Staging consisted of computed tomography scan of the chest, bone scan, bone marrow biopsy, computed tomography or magnetic resonance image of the brain, serum chemistries, and complete blood count. Patients were required to have a SWOG performance status of 0 to 2, and adequate renal, hepatic, and marrow function. No prior chemotherapy or radiotherapy was permitted. The study protocol was approved by the Institutional Review Boards of the participating institutions and all patients provided written informed consent.
Treatment Plan
Statistical Considerations
Patient Characteristics Patient characteristics are detailed in Table 1. Ninety-six patients were enrolled onto the study. Seven patients were ineligible because of non-small-cell histology (one patient); presence of metastases before registration (three patients); failure to undergo required baseline exams within the preregistration time frame (two patients); and inadequate documentation of baseline requirements (one patient). Of the remaining 89 patients, two of them never received protocol treatment and are not analyzable. Other than a slight preponderance of female patients on the current study, the population was typical of patients enrolled on prior SWOG trials for this disease. The baseline demographics for two prior SWOG studies (S9229 and S8812) are provided for comparison.
Adherence to Treatment Plan Overall adherence to the treatment plan was satisfactory. Seventy-two patients (83%) completed concurrent chemoradiotherapy. Fifty-five patients (63%) received all planned treatment. In comparison, 90% of patients on S9229 completed chemoradiotherapy and 50% of patients received all planned therapy. For study S8812, data regarding completion of chemoradiotherapy is unavailable; however, 69% received all planned therapy.
Toxicity
Response and Survival The overall response rate was 86% (CR, 36%; PR, 50%). Eight patients (9% of the total population) who demonstrated a PR during chemoradiotherapy achieved CR with consolidation. Overall and progression-free survival is depicted in Figures 1 and 2. The median progression-free survival was 9 months (95% CI, 7.6 to 10.7 months), and the median overall survival was 17 months (95% CI, 12.7 to 19.0 months). The 24- and 36-month overall survivals were 33% and 20%, respectively. The 12- and 24-month progression-free survivals were 40% and 21%, respectively.
Patterns of Relapse Data on sites of first failure is presented in Table 4. Restaging at the time of relapse was not required and these data should be viewed cautiously. Of 66 patients who have died, 42 (64%) definitely died of progressive disease and an additional eight patients (12%) probably died of progressive disease. Relatively few patients relapsed solely in locoregional sites (n = 9). There were 12 patients whose initial site of relapse was the brain. One patient progressed in the brain during chemoradiotherapy, while the other 11 occurred after completion of treatment. Of these, four patients had been declared complete responders but did not receive PCI. Review of the patient records demonstrated that two of the patients were offered PCI and refused. It is unclear why the other two patients did not receive PCI. The remaining seven patients were partial responders of whom one received PCI.
Despite the potential curability of patients with LSCLC, the majority of patients will relapse and ultimately succumb to their disease. The availability of several new agents in the 1990s with clear activity in this disease, such as paclitaxel, led to optimism that the cure rate could be improved. The combination of carboplatin and paclitaxel is well tolerated in non-small-cell lung cancer and has been utilized as both the primary and salvage therapy in extensive SCLC [12-15]. This trial evaluated the potential of consolidative therapy with carboplatin and paclitaxel to improve the curability of this disease. Unfortunately, sequential administration of paclitaxel-based therapy failed to improve outcome in this study. Based on the results of our trial and others, the role of paclitaxel in the initial treatment of SCLC of either limited or extensive stage is questionable. The Radiation Therapy Oncology Group evaluated a combination of paclitaxel, cisplatin, and etoposide concurrent with radiotherapy. Though initially extremely promising, more mature survival data demonstrate survival comparable to that of the recent Intergroup study. (Ettinger, personal communication, June 2003) [16]. The Eastern Cooperative Oncology Group had disappointing results in a similar trial [17]. In extensive stage disease, the recently reported intergroup study led by the Cancer and Leukemia Group B evaluated the regimen of paclitaxel, etoposide, and cisplatin versus cisplatin and etoposide. This large phase III study failed to demonstrate any advantage in terms of response or survival for the paclitaxel-containing regimen [18]. A European study, however, randomly assigning patients to therapy with either paclitaxel, etoposide, and carboplatin or carboplatin, etoposide, and vincristine did demonstrate an advantage for the paclitaxel-containing arm. This study included both extensive stage and limited stage patients. The median (17.6 months) survival for the paclitaxel-treated limited disease cohort is comparable to this and other SWOG trials as well as to the control arm of the recently reported Intergroup 0096 study [19,20]. Recent studies (most notably the Intergroup 0096 study) have excluded patients with pleural effusions from the category of limited disease. In addition, others have excluded patients with a performance status of 2 from entry. As these factors have been previously evaluated by SWOG and found to be of considerable prognostic importance, we performed an exploratory analysis of patients with pleural effusion (n = 15) or performance status of 2 (n = 7) or both [21]. Surprisingly, there were no differences in terms of median, progression-free, or overall survival. This is most likely the result of small numbers of patients in each of these subsets. When the total S9713 population was divided into prognostic groups as previously defined by SWOG—patients younger than 70 years of age, had normal lactose dehydrogenase, and no pleural effusion versus those with any of those features—no significant difference in survival was found [21]. Again, this was most likely as a result of the small numbers of patients evaluated. Future SWOG studies in LSCLC have excluded patients with pleural effusions. In summary, this trial substituting carboplatin/paclitaxel consolidation for PE after concurrent chemoradiotherapy failed to achieve its prospectively defined survival objective. The results of S9713, in combination with other recently completed studies incorporating paclitaxel into treatment paradigms in SCLC, temper enthusiasm for further study of this agent in this clinical setting. Continued efforts to develop more active agents are needed. In this regard, the results of the Japanese Cooperative Oncology Group phase III trial demonstrating a survival advantage for cisplatin and irinotecan over PE in extensive stage SCLC are of considerable interest and warrants study in LSCLC [22]. A phase I Intergroup study evaluating the utilization of cisplatin and irinotecan with concurrent radiotherapy has been initiated. In addition, the strategy of utilizing cisplatin and irinotecan as consolidation therapy in place of PE has already been evaluated in a phase II trial in Japan and appears promising [23].
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: Christina A. Meyers, Schering-Plough. Received more than $2,000 a year from a company for either of the last 2 years: Martin J. Edelman, BMS; Robert Livingston, BMS.
This investigation was supported in part by the following Public Health Service Cooperative Agreement grant numbers awarded by the National Cancer Institute and the Department of Health and Human Services: CA38926, CA32102, CA22433, CA12644, CA46441, CA35119, CA35261, CA58416, CA67575, CA35128, CA35176, CA35178, CA67663, CA16385, CA35996, CA58861, CA35431, CA37981, CA35192, CA45807, CA04919, CA45377, CA68183, CA58658, CA74647, CA58415, CA14028, CA45450, CA46282, CA76447, CA76448, CA12213, CA63850, CA76132. Portions of this study were presented at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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20. Turrisi AT, Kim Kyungmann K, Blum R, et al: Twice-daily compared with once-daily thoracic radiotherapy in limited small cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 340:265–271, 1999 21. Albain K, Crowley J, LeBlanc M, et al: Determinants of improved outcome in small-cell lung cancer: An analysis of the 2,580 patient Southwest Oncology Group database. J Clin Oncol 8:1563–1574, 1990[Abstract]
22. Noda K, Nishiwaki Y, Kawahara M, et al: Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 346:85–91, 2002 23. Mori K, Kubota K, Nishiwaki Y, et al: Cisplatin and etoposide plus concurrent hyperfractionated thoracic radiotherapy followed by three cycles of irinotecan and cisplatin for the treatment of limited-stage small cell lug cancer: Updated results: JCOG 9903-D1. Proc Am Soc Clin Onc 21:294a, 2002 (abstr 1173) Submitted June 17, 2003; accepted October 31, 2003.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
