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Common arm comparative outcomes analysis of phase 3 trials of cisplatin + irinotecan versus cisplatin + etoposide in extensive stage small cell lung cancer1
Final patient-level results from Japan Clinical Oncology Group 9511 and Southwest Oncology Group 0124
Version of Record online: 24 AUG 2010
Copyright © 2010 American Cancer Society
Volume 116, Issue 24, pages 5710–5715, 15 December 2010
How to Cite
Lara, P. N., Chansky, K., Shibata, T., Fukuda, H., Tamura, T., Crowley, J., Redman, M. W., Natale, R., Saijo, N. and Gandara, D. R. (2010), Common arm comparative outcomes analysis of phase 3 trials of cisplatin + irinotecan versus cisplatin + etoposide in extensive stage small cell lung cancer. Cancer, 116: 5710–5715. doi: 10.1002/cncr.25532
Presented in part at the American Society of Clinical Oncology Annual Meeting, Chicago, Illinois, 2009, and at the World Conference on Lung Cancer, San Francisco, California, 2009.
- Issue online: 3 DEC 2010
- Version of Record online: 24 AUG 2010
- Manuscript Revised: 20 MAY 2010
- Manuscript Accepted: 20 MAY 2010
- Manuscript Received: 1 MAR 2010
- small cell lung cancer;
- extensive stage;
Southwest Oncology Group 0124 was a large North American phase 3 trial that failed to confirm a survival benefit for cisplatin/irinotecan over cisplatin/etoposide in patients with extensive stage small cell lung cancer (SCLC). These results were contrary to Japan Clinical Oncology Group 9511, a phase 3 trial exclusively in Japanese patients. Because 0124 and 9511 used identical treatment regimens and similar eligibility criteria, patient-level data were pooled from both trials, and a common arm analysis was performed to explore potential reasons for the divergent results.
Patients with documented extensive stage SCLC and adequate end-organ function were randomized to intravenously receive either cisplatin 60 mg/m2 Day 1 + irinotecan 60 mg/m2 Days 1, 8, and 15 every 4 weeks or cisplatin 80 mg/m2 Day 1 + etoposide 100 mg/m2 Days 1-3 every 3 weeks. Demographic and outcome data were compared among 805 patients enrolled in 9511 and 0124 receiving identical treatment using a logistic model adjusted for age, sex, and performance status (PS).
Of 671 patients in 0124, 651 eligible patients were included, as were all 154 patients from 9511. Significant differences in sex and PS distribution as well as toxicity were seen between trials. There were also significant differences in response rates (87% vs 60%, P<.001) and median overall survival (12.8 vs 9.8 months, P<.001) when the cisplatin/irinotecan arms from both trials were compared.
Significant differences in patient demographics, toxicity, and efficacy were identified in the 9511 and 0124 populations. These results, relevant in the current era of clinical trials globalization, warrant: 1) consideration of differential patient characteristics and outcomes among populations receiving identical therapy; 2) utilization of the common arm model in prospective trials; and 3) inclusion of pharmacogenomic correlates in cancer trials where ethnic/racial differences in drug disposition are expected. Cancer 2010. © 2010 American Cancer Society.
Lung cancer represents the most common cause of malignant disease globally. Almost 1.4 million new cases of lung cancer are diagnosed annually worldwide, with nearly 1.2 million deaths.1 Small cell lung cancer (SCLC) is a unique subtype of lung cancer that accounts for approximately 15% of all new cases.2 Unfortunately, most SCLC patients die from the disease, due commonly to systemic metastasis (defined as “extensive stage”).3, 4 Over the past 20 years, standard therapy for most patients with extensive stage SCLC has been either carboplatin or cisplatin in combination with etoposide.5
This paradigm was challenged in 2002, when the results of the Japanese phase 3 study Japan Clinical Oncology Group 9511, comparing etoposide/cisplatin with cisplatin/irinotecan in 174 patients, demonstrated that tumor response, progression-free survival (PFS), and overall survival (OS) rates were significantly higher in the cisplatin/irinotecan group.6 It must be noted that 9511 was stopped early at interim analysis by its data safety monitoring board when prospectively prespecified efficacy parameters were met.
Subsequently, the Southwest Oncology Group conducted a large phase 3 trial (0124) involving 671 patients that used virtually the same eligibility criteria and treatment regimens as the Japanese trial to confirm the results of 9511 in North American patients.7 As reported previously, 0124 found no statistical differences in tumor response, PFS, and OS between the 2 arms, contrary to the results of 9511.
To explore potential reasons for the divergent results of these identically designed phase 3 trials, a pooled comparative outcomes analysis inclusive of patient-level data from both trials was conducted.
MATERIALS AND METHODS
Patients in both trials had cytologically or histologically confirmed SCLC and clinical evidence of extensive stage disease (defined by distant metastasis, contralateral hilar-node metastasis, or malignant pleural effusion). Eligibility criteria for both trials were similar and have been previously reported. Patients were randomly assigned to receive either etoposide/cisplatin or cisplatin/irinotecan. The cisplatin/irinotecan regimen consisted of 4 cycles of 60 mg of irinotecan per square meter of body surface area on Days 1, 8, and 15 and 60 mg of cisplatin per square meter on Day 1. Cycle length for this arm was 4 weeks. The etoposide/cisplatin regimen consisted of 4 cycles of 100 mg of etoposide per square meter on Days 1, 2, and 3 and 80 mg of cisplatin per square meter on Day 1. Cycle length for this arm was 3 weeks.
All patients underwent evaluations every cycle that included an assessment of symptoms, a physical examination, a complete blood count, and blood chemistry studies. Tumor response was assessed after every 2 cycles. In the 0124 trial, tumor response was evaluated according to the Response Evaluation Criteria in Solid Tumors, whereas in the 9511 trial, the World Health Organization criteria were used.8 OS was calculated as the time between trial registration and death or date of last contact. PFS was calculated as the time between trial registration and death or progression, with censoring if alive without progression at last contact.
Study Design and Statistical Analysis
The primary objective of both studies was to compare the survival in patients with extensive SCLC treated with etoposide/cisplatin (standard arm) with that in comparable patients treated with the cisplatin/irinotecan (experimental) on an intent-to-treat basis. As 0124 and 9511 protocols used identical treatment regimens and similar eligibility criteria, patient-level data from both trials were pooled to explore potential reasons for the divergent results. Final results of both trials have previously been reported. Of 671 patients in 0124, 651 were eligible and included in this analysis, as were all 154 patients from 9511. Patient demographics, toxicity, and outcomes were compared among 805 patients receiving identical treatment using a common arm analysis. OS and PFS as compared between the Japan and US trials for both treatment arms in the combined sample were analyzed using Cox proportional hazards regression, adjusted for age, sex, and performance status. A logistic model adjusted for age, sex, and performance status was used to compare response to treatment between the 2 trials for the 2 treatment arms. The existence of possible interactions between trial (Japan Clinical Oncology Group vs Southwest Oncology Group) and treatment arm was evaluated for all endpoints, using data pooled over both arms. Significance was set at P<.05.
Median age in 9511 and 0124 was 61 and 62 years, respectively. There were proportionally more men in 9511 (86%, n = 132) compared with 0124 (57%, n = 370). There were more patients with Zubrod performance status 0 in 0124 (211, 32%) compared with 9511 (19, 12%). Demographics are summarized in Table 1.
|Cisplatin + Etoposide||Cisplatin + Irinotecan||Total||Cisplatin + Etoposide||Cisplatin + Irinotecan||Total|
Common arm comparisons of select attributable hematologic toxicities are summarized in Table 2. Regardless of treatment arm, patients in 9511 experienced significantly more hematologic toxicity consisting of neutropenia, leucopenia, and anemia than 0124. Other than a difference in infection rates in the cisplatin/etoposide arm, no differences in nonhematologic toxicities between the 2 trials were seen.
|≥Grade 3 Toxicity||Cisplatin + Etoposide||Cisplatin + Irinotecan|
|Infection||3 (4%)||52 (16%)||.01||4 (5%)||36 (11%)||.23|
|Neutropenia||71 (92%)||220 (68%)||<.001||49 (65%)||107 (34%)||<.001|
|Leukopenia||41 (53%)||109 (34%)||.006||20 (27%)||57 (18%)||.04|
|Anemia||25 (32%)||39 (12%)||<.001||21 (28%)||18 (6%)||<.001|
Treatment Delivery and Dose Intensity
In the original 9511 and 0124 papers, there were no significant differences reported between the 2 arms in terms of treatment delivery. A preliminary common arm comparison of treatment delivery and dose intensity (DI) was performed in the current analysis. These results are summarized in Table 3. There were no clear differences in the proportion of patients completing all 4 cycles of therapy. However, a higher proportion of patients completed all 4 cycles of etoposide/cisplatin in 9511 versus 0124 (38% vs 29%). A more modest difference was seen in the cisplatin/irinotecan arm (29% vs 23%). When comparing the published DI data (9511 vs 0124), there was a numerical difference in the proportion of irinotecan (80.4% vs 66%) and cisplatin (95.3% vs 78%) DI.
|Treatment Arm||P + E||P + I|
|Completed all 4 cycles|
|JCOG-9511||55/77 (71.4%)||53/77 (68.8%)|
|SWOG-0124||218/327 (66.6%)||213/324 (65.8%)|
|Completed 4 cycles without dose modification|
|JCOG-9511||29/77 (38%)||22/77 (29%)|
|SWOG-0124||94/327 (29%)||76/324 (23%)|
|Reported average dose intensitya|
|JCOG-9511||E: 83.9%; P: 84.6%||I: 80.4%; P: 95.3%|
|SWOG-0124||E: 78%; P: 81%||I: 66%; P: 78%|
Common arm comparisons of efficacy endpoints including response rate, PFS, OS are summarized in Table 4 and Figure 1. Ten patients (2 from Japan Clinical Oncology Group and 8 from Southwest Oncology Group) were excluded from the analysis of treatment response because they did not receive treatment. Significant differences in response rates were seen in the common arm comparisons when evaluated in multivariate logistic regression models, which enabled adjustment for age, sex, and performance status. Specifically, for the etoposide/cisplatin arm, response rates were 68% in 9511 and 57% in 0124 (P = .02). For the cisplatin/irinotecan arm, response rates were 87% for the 9511 and 60% in 0124 (P<.001). In an expanded logistic regression model that pooled the data for both treatment arms, there was a significant arm by trial interaction, indicating that the difference in response between the Japanese and US patients is significantly greater in the cisplatin/irinotecan arm patients. (P value for interaction = .03)
|Efficacy Measure||Cisplatin + Etoposide||Cisplatin + Irinotecan|
|Median PFS, mo||4.7||5.2||.18||6.8||5.8||.6|
|Median OS, mo||9.4||9.1||.5||12.8||9.9||<.001|
|One-year survival rate||38%||34%||58%||41%|
There were no differences in PFS and OS for the etoposide/cisplatin arm across trials. However, significant differences were seen for OS for the cisplatin/irinotecan arm. Specifically, median OS was 12.8 months for 9511 and 9.9 months for 0124 (P<.001, adjusted for age, sex, and performance status via Cox proportional hazards regression). Similarly, 1-year survival rates were 58% and 41%, respectively. The 1-month numerical difference in PFS in the cisplatin/irinotecan arm was not statistically significant. Kaplan-Meier survival curves of OS common arm comparisons in the cisplatin/irinotecan arm are shown in Figure 1. In a multivariate proportional hazards regression model including trial (Japan vs United States) treatment arm, age, sex, and performance status, the interaction between trial and treatment arm is significant, confirming that the survival difference by site (Japan vs United States) depends on treatment arm (P value for interaction term = .01). A performance status of 0 (vs 1 or 2) was also independently prognostic for increased survival in multivariate modeling (P<.001). Age and sex were not.
This common arm comparison of 9511 and 0124 using pooled patient-level data provides unique insights into potential reasons for the divergent results of these trials. In addition, this analysis highlights the issue of whether in the current era of clinical trials globalization, the results of randomized oncology studies conducted outside the Unites States are directly translatable to North American populations.9 These issues obviously have regulatory implications.
This analysis is unparalleled because 0124 was designed a priori as a confirmatory trial for 9511, albeit accruing from a different ethnic patient pool. The design of the 0124 protocol was modeled directly on 9511, including similar eligibility criteria and identical treatment dose schedules. The observed differences in demographics, toxicity, and efficacy outcomes between these trials can be attributed to many factors, some of which were previously discussed in the 0124 paper. With the pooled multivariate analysis, we were able to investigate (and rule out) the possibility that the different outcomes between trials in the cisplatin/irinotecan arms were attributable to clear differences in patient populations with respect to sex and performance status. Our analysis of both survival and response showed that although performance status was prognostic for survival, the differences between trials in the cisplatin/irinotecan arm persisted even after adjusting for this imbalance.
Other potential factors included the smaller sample size and/or the early stopping of 9511, which may have overestimated the treatment effect.10
This common arm analysis demonstrates that the principal difference in OS was seen only in the cisplatin/irinotecan arms. The control etoposide/cisplatin arms in both 0124 and 9511 had identical OS results. In the context of irinotecan-based therapy, 1 hypothesis that has been posited is that there are inherent genetic differences related to genes involved in irinotecan drug disposition between patient populations. Although a preliminary pharmacogenomic analysis of specimens from 0124 patients was performed to investigate some of these irinotecan-related genes, no specimens were available from the older 9511 trial for similar pharmacogenomic investigations. Hence, no direct comparison of relevant genotypes between trials is possible. However, insights on this issue can be derived from prior common arm joint collaborations between Southwest Oncology Group and Japanese investigators wherein patients with advanced nonsmall cell lung cancer were enrolled in Southwest Oncology Group and Japanese trials onto a common arm of paclitaxel and carboplatin.11 In that experience, genes relevant to chemotherapy metabolism and transport were analyzed in both American and Japanese populations. Significant differences in toxicity, efficacy, and allelic distribution for genes involved in paclitaxel disposition or DNA repair were observed between Japanese and US patients, supporting the hypothesis that pharmacogenomics may in part be responsible for outcome divergence among patient populations. This may also partly explain the toxicity differences seen between the Japanese and North American populations, wherein Japanese patients apparently had increased hematologic toxicity (neutropenia, leucopenia, and anemia) in both treatment arms when compared with North Americans.
In addition, there appears to be some differences in the delivered DI in the cisplatin/irinotecan arms of both trials (as reported in the published papers). Specifically, more 9511 patients achieved a higher DI for both irinotecan and cisplatin as compared with 0124 patients. Enhanced DI for 9511 patients may potentially explain the differences in toxicity and efficacy between the trials. A more detailed and expansive analysis of dose delivery using individual patient data is required, but is beyond the scope of this article. Finally, it must be noted that other trials comparing similar chemotherapy regimens in SCLC have previously been published.12, 13 Some of us (P.N.L., R.N., and D.R.G.) have previously discussed these trials in the context of 0124 and 9511 in a recent editorial.14 We refer readers to that editorial for additional details.
In conclusion, etoposide/cisplatin remains the reference treatment standard in North America. In Japan, cisplatin/irinotecan remains a standard treatment option. Significant differences in patient demographics, toxicity, and efficacy exist between Japanese and North American SCLC patients receiving identical treatment. These results, relevant in the current era of clinical trials globalization, warrant 1) consideration of differential patient characteristics and outcomes among patients receiving identical therapy, 2) utilization of the common arm model in prospective trials, and 3) inclusion of pharmacogenomic correlates in cancer trials where ethnic/racial differences in drug disposition are expected.
CONFLICT OF INTEREST DISCLOSURES
Grant support for the Southwest Oncology Group: This investigation was supported in part by the following Public Health Service Cooperative Agreement grant numbers awarded by the National Cancer Institute, Department of Health and Human Services: CA32102, CA38926, CA46441, CA58882, CA35261, CA35431, CA35119, CA22433, CA58658, CA11083, CA46441, CA37981, CA45560, CA58861, CA04919, CA67663, CA12644, CA45807, CA67575, CA35281, CA20319, CA45808, CA35178, CA58416, CA14028, CA76448, CA35090, CA52654, CA58882, CA76447, CA76429, CA35128, CA46282, CA63848, CA46113, CA58723, CA63844, CA46368, CA35192, CA68183, CA45450, CA35176, CA76132, CA13612, CA16385, CA45377, CA63850, CA74647, CA58348, CA42777, CA35279; CA25224, CA27525, and CA21115, and in part by Pfizer, Inc. and CA114771 (National Institutes of Health Strategic Partnering to Evaluate Cancer Signatures in Lung Cancer). Grant support for the Japan Clinical Oncology Group: This work was supported in part by the Grants-in-Aid for Cancer Research (5S-1, 8S-1, 11S-2, 11S-4, 14S-2, 14S-4, 17S-2, 17S-5, 20S-2, and 20S-6) and for the Second-Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labor, and Welfare.