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Journal of Clinical Oncology, Vol 24, No 13 (May 1), 2006: pp. 2038-2043 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.8595 Randomized Phase III Trial Comparing Irinotecan/Cisplatin With Etoposide/Cisplatin in Patients With Previously Untreated Extensive-Stage Disease Small-Cell Lung Cancer
From Indiana University; Hoosier Oncology Group, Indianapolis; Michiana Hematology/Oncology, South Bend, IN; University of Colorado Cancer Center, Aurora, CO; Fox Chase Cancer Center, Philadelphia, PA; Baptist Cancer Institute, Jacksonville, FL; Highlands Oncology Group, Springdale, AR; Pfizer Inc, New York, NY; Vanderbilt-Ingram Cancer Center; Vanderbilt-Ingram Community Cancer Center Affiliate Network, Nashville, TN; Juravinski Cancer Centre, Hamilton, Canada; Sir Charles Gairdner Hospital, Nedlands, Australia. Address reprint requests to Nasser Hanna, MD, Indiana University, 535 Barnhill Dr, RT 473, Indianapolis, IN 46202; e-mail: nhanna{at}iupui.edu
PURPOSE: Etoposide and cisplatin (EP) has been a standard treatment for extensive-disease small-cell lung cancer (SCLC). An earlier phase III trial reported improved survival for patients receiving irinotecan plus cisplatin (IP) versus EP. Our trial was designed to determine if a modified weekly regimen of IP would provide superior survival with less toxicity than EP. PATIENTS AND METHODS: The primary objective was to compare overall survival in extensive-disease SCLC patients randomly assigned to receive IP (n = 221) or EP (n = 110). Patients were randomly assigned in 2:1 ratio to cisplatin 30 mg/m2 intravenously (IV) + irinotecan 65 mg/m2 IV on days 1 and 8 every 21 days, or cisplatin 60 mg/m2 IV on day 1, and etoposide 120 mg/m2 IV on days 1 to 3 every 21 days for at least four cycles, until progressive disease, or until intolerable toxicity resulted. RESULTS: Selected grade 3/4 toxicities for IP/EP were: neutropenia (36.2% v 86.5%; P < .01), febrile neutropenia (3.7% v 10.4%; P = .06), anemia (4.8% v 11.5%; P = .02), thrombocytopenia (4.3% v 19.2%; P < .01), vomiting (12.5% v 3.8%; P = .04), and diarrhea (21.3% v 0%; P < .01). There was no significant difference in response rates (48% v 43.6%), median time to progression (4.1 v 4.6 months), or overall survival (median survival time, 9.3 months v 10.2 months; P = .74). CONCLUSION: Treatment with this dose and schedule of IP did not result in improved survival when compared with EP. Fewer patients receiving IP had grade 3/4 anemia, thrombocytopenia, neutropenia, and febrile neutropenia compared with patients receiving EP, but more had grade 3/4 diarrhea and vomiting.
In the United States, approximately 24,000 people are diagnosed with small-cell lung cancer (SCLC) each year, representing approximately 15% of all lung cancer cases.1,2 More than half of these patients are diagnosed with extensive-stage disease (ED) and are most often treated with etoposide and a platinum agent, either carboplatin or cisplatin, resulting in a median survival of 8 to 10 months.3 Newer agents, including the taxanes, vinorelbine, gemcitabine, topotecan, and irinotecan demonstrate significant single agent activity.4-8 In the last decade, a variety of platinum-based combination therapies tested in phase III trials have failed to demonstrate an efficacy superior to that of etoposide plus cisplatin (EP).9-12 In 2002, Noda et al8 reported the results of a phase III trial from the Japanese Cooperative Oncology Group (JCOG) that randomly assigned 154 patients with ED SCLC to either EP (etoposide 100 mg/m2 intravenously [IV] days 1 to 3 with cisplatin 80 mg/m2 IV on day 1, once every 3 weeks) or irinotecan plus cisplatin (IP; irinotecan 60 mg/m2 IV on days 1, 8, and 15 plus cisplatin 60 mg/m2 IV on day 1, once every 4 weeks). Median survival and 1-year survival rates on the IP and EP arms were 12.8 months versus 9.4 months and 58.4% versus 37.7%, respectively. Patients in the EP arm experienced significantly higher rates of grade 3/4 neutropenia and thrombocytopenia, but lower rates of grade 3/4 diarrhea. Only 80.4% of the planned dose intensity of irinotecan was delivered and 50% of the day-15 irinotecan doses were never administered. A confirmatory study was deemed necessary before a change in the standard of care could be recommended. The JCOG study represented a single study with a small sample size (77 patients per arm) for a disease for which no significant survival gains had been seen in 20 years. Furthermore, it was postulated that pharmacogenomic differences might exist between patients in Japan and those in the United States. Therefore, our phase III study, comparing EP with IP in a larger number of ED SCLC patients, was undertaken in the United States, Australia, and Canada. Both the EP and IP regimens in this study were modified compared with the JCOG regimens to improve delivery and reduce toxicity, and to be more consistent with dose and schedules given in the United States, including in the cooperative groups.
Patient Selection Patients with histopathologically or cytologically confirmed ED SCLC were assessed for eligibility. Prior radiation therapy was allowed if the fields did not include the only sites of measurable disease. Patients met the following criteria to be eligible: measurable disease, adequate hematologic function (WBC > 3,000/µL, absolute neutrophil count  1,500 mm3, hemoglobin 9 g/dL, platelet count 100,000/mm3), hepatic function (bilirubin  1.5 mg/dL or 26 µmol/L, AST 2.5x the upper limit of normal [ULN] or 5x ULN if liver metastases were present), and renal function (serum creatinine 1.7 mg/dL or 130 µmol/L). Patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2 were eligible. Patients with known brain metastases were eligible if they were asymptomatic and on a stable or tapering steroid dose if they were on steroids. Patients were excluded if they had received any previous systemic anticancer therapy for SCLC, had a history of significant cardiovascular disease, serious active infection, known Gilbert's disease, National Cancer Institute Common Toxicity Criteria grade 2 peripheral neuropathy, had impaired mental status, or if they were pregnant or breastfeeding. The protocol was approved through institutional ethics review boards, and all patients provided written informed consent before treatment.
Treatment Plan Baseline assessment included a medical history and physical examination, CBC, comprehensive blood chemistries, serum pregnancy test (when applicable), adverse event assessment, and tumor assessment. Staging evaluations included chest x-ray or chest computed tomography (CT) or magnetic resonance imaging (MRI), abdominal CT or MRI (including liver and adrenals), and head CT or MRI. Bone scan and bone marrow evaluation were obtained only if clinically indicated. Tumor assessment was evaluated after every two cycles of therapy.
Statistical Analysis With a planned sample size of 300 patients (IP arm, 200 patients; EP arm, 100 patients), there was an 80% power of detecting a 30% improvement in survival (based on a 30% decrease in each of the hazard functions at 6-month intervals) using a log-rank test assuming that the EP arm hazard function was 0.3 for the first 6 months, 0.7 for the next 6 months, 0.8 for months 12 to 18, and 0.9 for months 18 to 24. A study amendment subsequently excluded PS-2 patients after the first 31 PS-2 patients were enrolled, due to high rates of neutropenic complications and treatment-related deaths. Therefore, the sample size was increased to achieve a total of 300 patients with either PS 0 or 1 only. The expected 1-year survival rates for the IP and EP arms were 50% and 37%, respectively, and the 2-year rates were 15% and 7%, respectively. The primary analysis was conducted 1.5 years after the last patient had been enrolled and when the 220th patient death was recorded.
Survival was defined from date of randomization to date of death and was reported on an intent-to-treat basis. In the absence of a confirmation of death, survival time was censored at the last date of follow-up. Kaplan-Meier method was used to estimate the survival curves of the two treatment arms. Unstratified log-rank test was performed to compare the two survival curves at the .05 level of significance. Survival was characterized in terms of the median and the probability of being alive at 6, 12, 18, and 24 months (based on Kaplan-Meier estimates). Ranges, 95% CI on the treatment estimates, and hazard ratios were computed. Response was measured based on the Response Evaluation Criteria in Solid Tumores guidelines and all responses were confirmed by repeat scans performed no fewer than 4 weeks after the criteria for response were first met. A Toxicity was evaluated using the National Cancer Institute common toxicity criteria version 2.0. An independent data safety monitoring board was implemented to monitor safety parameters during the study. Baseline patient characteristics were summarized with frequency tables for categoric variables and descriptive statistics for continuous variables. All efficacy analyses were done on an intent-to-treat population, whereas all safety analyses were done only on those patients who were actually treated with at least one dose.
From December 2000 through June 2003, 331 patients were randomly assigned to receive either IP (n = 221) or EP (n = 110). The minimum follow-up for all patients was 18 months. The baseline patient and disease characteristics are listed in Table 1. Approximately 45% of patients were at least 65 years old, two thirds of patients had an LDH level higher than ULN, nearly 20% had metastatic disease to the CNS, more than 50% had metastases to the liver, and approximately 25% had metastases to the adrenal glands. More than 60% of patients had four or more sites of disease at baseline. All 331 randomly assigned patients were included in the analysis for response, time to disease progression, and overall survival. Only patients who received at least one cycle of study treatment (n = 322) were assessable for toxicity analysis.
Treatment Administered Table 2 lists the treatment administered. Two hundred sixteen of the 221 patients randomly assigned to the IP arm received at least one dose of study medication and 112 (50.7%) of the 221 treated patients completed at least four courses. The major reasons for not completing study included progressive disease (18.6%), more than a 2-week delay in treatment administration due to toxicities (5.9%), and unacceptable toxicity (9.0%). One hundred six of the 110 patients randomly assigned to the EP arm received at least one dose of the study medication. Sixty-one (55.5%) of the 110 patients completed study. The main reasons for not completing study included progressive disease (21.8%), more than a 2-week delay in treatment administration due to toxicities (3.6%), and unacceptable toxicity (5.5%). The median number of cycles of chemotherapy administered was four in each group; 25.9% of patients on the IP arm received at least one study treatment for six cycles versus 42.5% of patients on the EP arm. The dose intensity delivered on a mg/m2/wk basis exceeded 90% for all drugs. The dose-intensity regimen delivered for irinotecan was 94%, or 39 mg/m2/wk.
Toxicity Results Table 3 lists the toxicity data. Significantly higher rates of grade 3/4 neutropenia, anemia, and thrombocytopenia were observed in the EP arm compared with the IP arm. Higher rates of febrile neutropenia were also experienced in the EP arm compared with the IP arm. Rates of grade 3/4 dehydration, diarrhea, and vomiting were significantly higher on the IP arm compared with the EP arm. Seven patients (22.5%) with PS greater than 1 and 11 patients (3.6%) with PS 0 or 1 died due to treatment-related complications.
Efficacy Results There was no significant difference in response rates (IP, 48% v EP, 43.6%) or stable disease rates (IP, 4.1% v EP, 7.3%) between the IP and EP arms; 28.1% of patients on the IP arm and 29.1% of patients on the EP arm could not be evaluated for tumor response. There was no significant difference between IP and EP in time to disease progression (median, 4.1 v 4.6 months; P = .37; Fig 1), or survival (P = .68; Fig 2). At the time of analysis, 305 (92.1%) of 331 patients had died. Median survival was similar in the two arms (9.3 v 10.2 months). Survival rates at selected time points were similar; 1-year survival rates were 34.95% versus 35.19% and 2-year survival rates were 8.0% versus 7.9%.
Additional Treatment Given After Study More than 60% of patients on each arm of the study received additional treatment once off study (Table 4). More patients on the IP arm received subsequent treatment with etoposide (47.2% v 22.6%), whereas more patients on the EP arm received subsequent treatment with a topoisomerase I inhibitor (33% v 24.1%).
This open label, multicenter, randomized phase III study did not show a statistically significant difference in overall survival between the IP and EP regimens. Rather, the efficacy parameters were similar between the two combinations. The IP arm was associated with significantly lower rates of grade 3/4 neutropenia, anemia, and thrombocytopenia, and a lower rate of febrile neutropenia (P = .06) that was not significant. In contrast, IP was associated with significantly higher rates of diarrhea, vomiting, and dehydration than the EP arm. Routine use of growth factor support and other supportive measures (adequate hydration, antidiarrhea medication) should be considered when treating the PS 2 patient with either regimen as high rates of neutropenia-related deaths were noted in this group. Although both the JCOG study and this study treated patients with ED SCLC, there were significant differences in the disease characteristics between studies. Patients in our trial appeared to have more advanced disease because more than 60% of patients presented with four or more sites of disease at baseline. In the JCOG trial, only 6.5% had adrenal metastases and 18% had liver metastases compared with the 25% and 50% in our study. Why did this study fail to confirm the positive JCOG results? One explanation might be that our study tested a different dose and schedule of IP. The IP regimen in this trial was chosen to increase the dose intensity (changing an every-4-week regimen to every 3 weeks) in response to the lower rates of drug compliance for irinotecan on the JCOG trial (80% of planned dose intensity of irinotecan was delivered with 50% of the day-15 doses omitted). The dose intensity delivered for irinotecan on this trial was 94% or 39 mg/m2/wk, which compares with 80% or 36.2 mg/m2/wk on the IP arm of the JCOG trial. Similar dose intensity delivered for cisplatin was observed in both studies. Cisplatin dose intensification has not yet resulted in significant differences in outcomes in ED SCLC.13 A similar phase III trial recently reported that compared EP with cisplatin plus topotecan, another topoisomerase I inhibitor, also failed to demonstrate a survival difference between the arms.11 It is, therefore, unlikely that the dose and schedule of IP had an adverse impact on outcomes. An ongoing trial by the Southwest Oncology Group in the United States comparing EP and IP using the same schedules from the JCOG study will address this issue. Another possible reason why our study failed to demonstrate superiority for the IP regimen may be related to pharmacogenomic differences that may exist between North American and Japanese patient populations. Specifically, differences in polymorphisms of UDP-glucuronosyltransferase (UGT1A1), an enzyme that metabolizes irinotecan, are observed between patient populations. Low rates (2%) of Gilbert's syndrome, which results in a decreased level of gene transcription of UGT1A1, are recognized in the Asian population compared with European or African populations.14 More or less effective metabolism of irinotecan may result in differences in toxicity, compliance, and chemosensitivity. For example, in one study in non–small-cell lung cancer (NSCLC), patients with Gilbert's syndrome experienced significantly higher rates of severe toxicity when treated with irinotecan and inferior survival outcomes compared with those homozygous for a common allele.15 The ongoing study by the Southwest Oncology Group (SWOG) that compares EP with IP in patients with ED SCLC will be evaluating differences in polymorphisms of UGT1A1 as predictors for response and toxicity to irinotecan. Molecular differences in lung cancer may also exist between Asian and US populations. It is known that a subset of patients with NSCLC have tumors that contain mutations in the epidermal growth factor receptor tyrosine kinase–binding domain.16,17 These mutations predominate in bronchioloalveolar carcinoma type, female sex, never-smokers, and Asian patient populations.17,18 Although the epidermal growth factor receptor does not play a significant role in SCLC, differences in other biologic characteristics may exist that predict for better or worse outcomes within the patient populations treated with the same regimens. One such example of this has recently been demonstrated in a study reported by Gandara et al.19 In a joint effort with investigators from Japan, patients treated with a common arm, carboplatin plus paclitaxel for metastatic NSCLC, in separate but contemporaneous studies from the SWOG and Japan were analyzed. In that comparison, the study designs were very similar and response and toxicity criteria were the same. Despite similar patient characteristics (other than ethnicity), there were significantly higher rates of neutropenia, lower doses of paclitaxel delivered, and inferior survival for those patients treated in the SWOG study. The JCOG trial was the only trial in more than 20 years to demonstrate any significant improvement in survival over the EP regimen. The study was closed early (based on the recommendation of the monitoring committee after an interim analysis found a significant difference between the groups) after only 154 patients had been randomly assigned. Small differences in patient characteristics between the arms may result in differences in outcomes. There was an imbalance in the number of female and PS-2 patients in the JCOG study, thus favoring the IP arm. Furthermore, only 13% of patients on the IP arm had brain metastases versus 22% on the EP arm. It is possible that IP is a better regimen for Japanese patients. In a phase III study reported by Kubota et al,20 patients with advanced NSCLC were treated with one of four different platinum-based chemotherapy regimens. Patients on that trial receiving IP had a median survival of 14.2 months, which far exceeds efficacy seen in the United States, and is similar to what was reported in the JCOG SCLC trial. It is quite likely that in the United States, there are no significant differences in patient outcomes between those treated with IP and EP. In conclusion, advances in the treatment of ED SCLC are clearly needed. Despite decreasing prevalence, SCLC still results in the deaths of approximately 20,000 patients in the United States each year. This figure exceeds that of cancers of the esophagus, stomach, liver, ovary, and bladder, as well as sarcomas, Hodgkin's disease, and most forms of leukemia.2 Although the similar efficacy data from this trial do not suggest that the IP regimen will improve outcomes for the population of SCLC patients, our results suggest that IP represents an equally effective regimen with a different toxicity profile that can be used when it is anticipated that hematologic toxicity will be limiting or when the toxicity is found to be severe during the early cycles of EP.
Although all authors completed the disclosure declaration, the following authors or their immediate family members 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. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amonut Codes (A) < $10,000 (B) $10,000-$99,900 (C)
Supported by Pfizer Inc, New York, NY. Presented in part (abstract and oral presentation) at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005, and at the 11th World Conference on Lung Cancer, Barcelona, Spain, July 3-6, 2005. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Page N, Read W, Tierney R, et al: The epidemiology of small cell lung carcinoma. Proc Am Soc Clin Oncol 21:305a, 2002 (abstr 1216) 2. Jemal A, Murray T, Samuels A, et al: Cancer statistics 2003. CA Cancer J Clin 53:5-26, 2003 3. Roth B, Johnson D, Einhorn L, et al: Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small cell lung cancer: A phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 10:282-291, 1992[Medline] 4. Kakolyris S, Mavroudis D, Tsavaris N, et al: Paclitaxel in combination with carboplatin as salvage treatment in refractory small cell lung cancer (SCLC): A multicenter phase II study. Ann Oncol 12:193-197, 2001 5. Gridelli C, Perrone F, Iannielllo G, et al: Carboplatin plus vinorelbine, a new well-tolerated and active regimen for the treatment of extensive-stage small cell lung cancer: A phase II study. J Clin Oncol 16:1414-1419, 1998 6. Masters G, Declerck L, Blanke C, et al: Phase II trial of gemcitabine in refractory or relapsed small cell lung cancer: Eastern Cooperative Oncology Group Trial 1597. J Clin Oncol 21:1550-1555, 2003 7. von Pawel J, Schiller J, Shepherd F, et al: Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small cell lung cancer. J Clin Oncol 17:658-667, 1999 8. 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 9. Mavroudis D, Papadakis E, Veslemes M, et al: A multicenter randomized clinical trial comparing paclitaxel-cisplatin-etoposide versus cisplatin-etoposide as first-line treatment in patients with small cell lung cancer. Ann Oncol 12:463-470, 2001 10. Sundstrom S, Bremnes R, Kaasa S, et al: Cisplatin and etoposide regimen is superior to cyclophosphamide, epirubicin, and vincristine regimen in small cell lung cancer: Results from a randomized phase III trial with 5 years' follow-up. J Clin Oncol 20:4665-4672, 2002 11. Eckhardt J, von Pawel J, Manikhas G, et al: Comparable activity with oral topotecan/cisplatin (TC) and IV etoposide/cisplatin (PE) as treatment for chemotherapy-naive patients (pts) with extensive disease small cell lung cancer (ED-SCLC): Final results of a randomized phase III trial (389). J Clin Oncol 23:621s, 2005 (suppl; abstr 7003) 12. Smit E, Groen H, Biesma B, et al: Phase III study comparing cyclophosphamide, doxorubicin, and etoposide (CDE) to carboplatin and paclitaxel (CP) in patients (pts) with extensive disease small cell lung cancer (ED SCLC). J Clin Oncol 23:631s, 2005 (suppl; abstr 7045) 13. Ihde D, Mulshine J, Kramer B, et al: Prospective randomized comparison of high-dose and standard-dose etoposide and cisplatin chemotherapy in patients with extensive stage small cell lung cancer. J Clin Oncol 12:2022-2034, 1994 14. Beutler E, Gelbart E, Demina A: Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promote; a balanced polymorphism for regulation of bilirubin metabolism? Proc Natl Acad Sci U S A 95:8170-8174, 1998 15. Font A, Taron M, Rosell R, et al: UGT1a1 genotyping correlates with toxicity and survival in non-small cell lung cancer (NSCLC) patients treated with second-line CPT-11/docetaxel. Proc Am Soc Clin Oncol 20:340a, 2001 (abstr 1357) 16. Lynch T, Bell D, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small cell lung cancer to gefitinib. N Engl J Med 350:2129-2139, 2004 17. Paez J, Janne P, Lee J, et al: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304:1497-1500, 2004 18. Shigematsu H, Lin L, Takahashi T, et al: Clinical and biological features associated with epidermal growth factor gene mutations in lung cancers. J Natl Cancer Inst 97:339-346, 2005 19. Gandara D, Ohe Y, Kubota K, et al: Japan-SWOG common arm analysis of paclitaxel/carboplatin in advanced non-small cell lung cancer (NSCLC): A model for prospective comparison of cooperative group trials. J Clin Oncol 22:618s, 2004 (suppl; abstr 7007) 20. Kubota K, Nishiwaki Y, Ohashi, et al: The four-arm cooperative study (FACS) for advanced non-small cell lung cancer (NSCLC). J Clin Oncol 22:618s, 2004 (suppl; abstr 7006) Submitted November 7, 2005; accepted January 12, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test was performed to compare the response rates between the two treatment groups. Time to progression was defined as the time from date of randomization to first documentation of progressive disease and was reported on an intent-to-treat basis. Treatment administration was recorded and dose intensity (in mg/m2/wk) was defined as the total dose per body-surface area divided by the number of weeks between the start of treatment and the first day of last treatment course plus 21 days. 
