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Journal of Clinical Oncology, Vol 26, No 26 (September 10), 2008: pp. 4261-4267 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.7545 Irinotecan Plus Carboplatin Versus Oral Etoposide Plus Carboplatin in Extensive Small-Cell Lung Cancer: A Randomized Phase III Trial
From the Department of Pulmonary Oncology, Grosshansdorf Hospital, Grosshansdorf, Germany; Department of Chest Medicine, Haukeland University Hospital, Bergen; Institute of Clinical Medicine, University of Tromsø, Tromsø; Department of Medicine, Haugesund Hospital, Haugesund; Departments of Oncology and Medicine, University Hospital, Trondheim, Norway; Department of Respiratory Medicine and Allergology, Sahlgrenska University Hospital, Göteborg; Department of Respiratory Medicine and Allergology, Heart and Lung Division, University Hospital, Lund; Department of Pulmonary Medicine, University Hospital, Linköping; and Department of Pulmonary Medicine, University Hospital, Örebro, Sweden Corresponding author: Andreas Hermes, MD, Grosshansdorf Hospital, Department of Pulmonary Oncology, Wöhrendamm 80, 22927 Grosshansdorf, Germany; e-mail: pahermes{at}hotmail.com
Purpose A Japanese randomized trial showed superior survival for patients with extensive-disease (ED) small-cell lung cancer (SCLC) receiving irinotecan plus cisplatin compared with etoposide plus cisplatin. The present trial evaluated the efficacy of irinotecan plus carboplatin (IC) compared with oral etoposide plus carboplatin (EC). Patients and Methods Patients with ED SCLC were randomly assigned to receive either IC, which consisted of carboplatin (area under the curve = 4; Chatelut formula) and irinotecan (175 mg/m2) intravenously both on day 1, or EC, which consisted of carboplatin as in IC and etoposide (120 mg/m2/d) orally on days 1 through 5. Courses were repeated every 3 weeks with four cycles planned. Doses were reduced by one third in patients with a WHO performance status (PS) of 3 to 4 and/or age older than 70 years. Primary end point was overall survival (OS). Secondary end points were quality of life (QOL) and complete response (CR) rate. Results Of 220 randomly assigned patients, 209 were eligible for analysis (IC, n = 105; EC, n = 104). Thirty-five percent were older than 70 years, and 47% had a PS of 2 to 4. The groups were well balanced with respect to prognostic factors. OS was inferior in the EC group (hazard ratio = 1.41; 95% CI, 1.06 to 1.87; P = .02). Median survival time was 8.5 months for IC compared with 7.1 months for EC. One-year survival rate was 34% for IC and 24% for EC. CR was seen in 18 IC patients compared with seven EC patients (P = .02). There were no statistically significant differences in hematologic grade 3 or 4 toxicity. Grade 3 or 4 diarrhea was more common in the IC group. QOL differences were small, with a trend toward prolonged palliation with the IC regimen. Conclusion IC prolongs survival in ED SCLC with slightly better scores for QOL.
In Norway and Sweden, approximately 5,500 people are diagnosed with lung cancer every year. Fifteen to 20% of patients have small-cell lung cancer (SCLC), of whom approximately two thirds are staged as having extensive disease (ED) at the time of diagnosis. The prognosis of ED SCLC is poor. With standard chemotherapy, usually consisting of a platinum compound and etoposide, median survival is approximately 10 months in patient populations with a good performance status (PS).1 The prognosis had not changed much since the 1970s, until the value of prophylactic brain irradiation in responders was recently demonstrated.2 In a Norwegian randomized study that included 436 patients, cisplatin plus etoposide treatment for SCLC increased survival compared with an older chemotherapy regimen of cyclophosphamide, vincristine, and doxorubicin, but the survival benefit was confined to patients with limited disease.3 In 2000, Japanese investigators reported superior results with the topoisomerase I inhibitor irinotecan combined with cisplatin (IP) compared with standard therapy with etoposide plus cisplatin (EP) in a randomized phase III trial comprising 154 patients with ED SCLC.4 The study was prematurely closed after an interim analysis. Median survival time was 12.8 months in the IP arm compared with 9.4 months in the EP arm (P = .002). However, in a subsequent and larger study comparing a modified weekly IP regimen with the EP regimen in ED SCLC, the superior results with irinotecan were not reproduced.5 The purpose of the present study, which was designed after the first presentation of the Japanese study in 2000, was to compare an irinotecan plus carboplatin (IC) regimen with an oral etoposide plus carboplatin (EC) regimen.
Patients Patients with histologically or cytologically confirmed ED SCLC were considered for eligibility. Patients had to meet the following inclusion criteria: age older than 18 years and adequate hematologic function (WBC > 3,000/µL and platelet count > 100,000/µL), hepatic function (bilirubin < 1.5x the upper limit of normal [ULN] and AST and ALT < 2x ULN), and renal function (serum creatinine < 1.5x ULN). There was no upper age limit and no limitation regarding WHO PS. Brain metastases were not an exclusion criterion. Unimpaired mental status was required. Patients were excluded if they had any previous systemic anticancer therapy, active cancer other than SCLC, or chronic inflammatory bowel disease. Female patients were not included if they were pregnant or breast-feeding. Anticonception was mandatory for fertile participants. The study protocol was approved through institutional ethics review boards and pharmaceutical boards in both Sweden and Norway. All patients provided oral and written informed consent before random assignment.
Baseline Examinations
Random Assignment and Treatment Patients were assigned to receive either IC, which consisted of carboplatin (area under the curve [AUC] = 4 by the Chatelut formula; roughly corresponding to AUC = 5 by the Calvert formula) and irinotecan (175 mg/m2) intravenously on day 1 every 21 days, or EC, which consisted of carboplatin as in IC on day 1 and etoposide (120 mg/m2) orally on days 1 through 5 every 21 days. Four treatment cycles were planned in both treatment arms. Chemotherapy could be terminated earlier in case of objective disease progression, unacceptable toxicity, or if the patient wished to stop treatment. Treatment with the next cycle was not allowed until the WBC count was at least 3,000/µL and the platelet count was 100,000/µL. Treatment could be delayed within reasonable limits until sufficient hematologic function was restored. Dose modifications were made per protocol guidelines, generally resulting in a dose reduction to 75% of calculated doses in case of severe or prolonged hematologic toxicity. A dose reduction was maintained in following cycles. Patients with a PS of 3 or 4 and/or age greater than 70 years received two thirds of the calculated doses through all four treatment cycles. Patients without known hypersensitivity received prophylactic treatment with trimethoprim/sulfamethoxazole 160/800 mg and ofloxacin 200 mg twice a day from day 5 through day 14 during the first chemotherapy cycle.6,7 Loperamide was used for the treatment of irinotecan-induced diarrhea. For patients with chest x-ray findings and clinical examination suggesting a complete response (CR) after four cycles of treatment, a computed tomography scan of thorax and upper abdomen, a computed tomography scan of the brain, a bronchoscopy, and examinations that demonstrated metastatic disease before treatment were recommended to confirm a CR. Repeated examinations for confirmation of CR were not required. All responses were evaluated by the local investigators, and external validation was not performed. For patients with a confirmed CR, the protocol recommended prophylactic brain irradiation. Palliative radiotherapy and further chemotherapy at relapse could be administered at the discretion of the responsible physician.
Assessment of QOL
Statistical Analysis The size of the study was calculated based on the assumption that treatment with the IC regimen would increase median survival time from 0.75 to 1.1 years compared with the EC regimen. With a power of 80%, a level of significance of P = .05, and a one-sided test, the calculated number of patients was 200. The estimated sample size was based on planned interim analyses to be carried out twice yearly. However, interim analyses were not performed. The number of patients was increased to 220 when it became apparent during the study that exclusions as a result of ineligible non–small-cell lung cancer diagnoses approached 10 patients.
Survival curves were calculated using the Kaplan-Meier method and compared using the log-rank test. The Cox proportional hazards model was used for estimation of hazard ratios (HRs). The survival analysis was performed according to the intent-to-treat principle. All patients who received at least one dose of chemotherapy were assessable for toxicity. Hematologic toxicity was reported as maximum toxicity experienced during chemotherapy. The QOL scores were linearly transformed to a 0 to 100 scale in accordance with EORTC guidelines. For functioning and global QOL scales, 100 represents best possible outcome, whereas for symptom scales, 100 represents worst possible symptoms. QOL outcomes were analyzed in the following three ways: group comparison of scale scores at each time point; score changes from baseline; and rates of symptom palliation defined as improvement, control, or prevention, with death counted as nonpalliation.10 Improvement was defined as a change in reported baseline symptom levels from moderate or severe (67 to 100 points) to none or a little (0 to 33 points) or as a little to no symptoms without subsequent deterioration by the time of group comparison. Control of symptoms was defined as stable symptom score levels between 1 and 33 points, whereas prevention of symptoms was assumed when patients reported no symptoms at baseline and subsequent assessments.
Nonparametric tests were used for group comparisons. For illustration, mean scores and mean score changes are presented as well. Group differences that were consistent across methods of analysis or detected with a P
Patients From December 2001 through July 2005, 220 patients were randomly assigned to receive either IC or EC (Fig 1). In accordance with the original study plan, the data set was closed in August 2006, 1 year after random assignment of the last patient. Of the 220 randomly assigned patients, 11 were excluded because of limited disease stage (n = 1), elevated liver enzymes (n = 1), or non-SCLC histology (n = 9). Thus, 209 patients (IC, n = 105; EC, n = 104) were eligible for further analysis.
Baseline characteristics of eligible patients by treatment arm are listed in Table 1. Thirty-five percent of all patients were older than 70 years, and 47% had a PS of 2 or worse. Overall, patient and disease characteristics were well balanced between the arms. Age older than 70 years was somewhat more frequent in the EC than the IC arm, but the difference was nonsignificant (  2 test, P = .074).
Treatment Administered Appendix Table A1 (online only) lists the number of treatment cycles and doses delivered in the two treatment groups. Seventy-eight percent of patients in the IC arm and 77% of patients in the EC arm completed all four scheduled cycles of chemotherapy. The delivered doses of both carboplatin and the adjunct drug were 93% of scheduled doses in both groups. Three patients never commenced chemotherapy because of early deterioration (n = 1) or death (n = 2). Thirty-two patients in the IC group and 29 patients in the EC group were treated with corticosteroids for other reasons than antiemetic purposes.
Efficacy
Toxicity Selected toxicity data are listed in Table 2. Similar rates of grade 3 or 4 anemia and leukopenia were observed in both arms. Thrombocytopenia was more common in the EC arm. As expected, there was a significantly higher rate of grade 3 or 4 diarrhea in the IC group. The incidence of diarrhea (any grade) was significantly higher in the first cycle than in cycles 2, 3, and 4 (26% v 15%, 11%, and 10%, respectively), suggesting a contribution from prophylactic antibiotics administered in the first cycle. Because dose reductions were applied to patients with poor PS and to patients older than 70 years, grade 3 to 4 hematologic toxicities were analyzed for these subgroups (Table 3).
Blood transfusions were administered to 21 IC patients and 29 EC patients (P = .17). Six patients (IC, n = 2; EC, n = 4) received erythropoietin. Infections associated with leukopenia were seen in 19 IC and 20 EC patients. Such infections were somewhat more commonly seen in patients treated with corticosteroids (16 of 61 patients v 23 of 142 patients without corticosteroid treatment; P = .10). Five patients (IC, n = 2; EC, n = 3) had a bleeding event associated with thrombocytopenia. Forty-nine patients (IC, n = 28; EC, n = 21) were admitted to a hospital because of adverse effects. Chemotherapy toxicity was regarded as the cause of death, either alone or in combination with the lung cancer, in three IC patients and nine EC patients (P = .072).
QOL Assessments Outcome. Mean scores for EORTC QLQ-C30 global QOL, functioning, and symptom scales at baseline and key time points during treatment and follow-up are listed by treatment group in Appendix Table A2 (online only). There were no significant group differences in any of the variables before treatment or on treatment. Sleep problems tended to be less frequently reported in the IC group by 20 and 36 weeks (P < .05); otherwise, there were no significant group differences at follow-up assessments. Mean score changes from baseline for core functioning and symptom measures are displayed in Figure 3. A significant improvement was seen with both regimens in several of the functioning and symptom measures, with substantial improvements (ie, > 10 score points) in global QOL, emotional functioning, dyspnea, and pain. However, except for a trend toward a more pronounced improvement in emotional functioning in the IC group by 3 weeks (P < .05), no significant differences between IC and EC patients were observed for change scores during the study period.
Finally, palliation rates for symptom measures were calculated as previously described. Approximately 60% to 70% of all patients were palliated with regard to dyspnea, pain, and sleep problems during some period, whereas palliation of fatigue was less frequently achieved, as indicated in Figure 4. There was a trend toward improved and prolonged palliation with the IC regimen in several of the symptom measures, with significant group differences for dyspnea and sleep problems at several time points (Fig 4).
Additional Treatment Thirteen patients received prophylactic brain irradiation (IC, n = 9; EC, n = 4). Palliative radiotherapy for brain metastases was administered to 50 patients (IC, n = 28; EC, n = 22). Forty-nine patients in the IC arm and 48 patients in the EC arm received second-line chemotherapy. In 13 of the IC patients and 17 of the EC patients, the initial regimen was used as reinduction therapy.
In a time of declining scientific interest in SCLC, the Japanese study showing superior efficacy with irinotecan compared with etoposide in combination with cisplatin in ED SCLC4 gave rise to a series of new trials investigating the role of irinotecan in SCLC. In a subsequent US trial comparing a modified weekly IP regimen with the EP regimen, the superior results with irinotecan were not reproduced, and the survival curves were virtually superimposable.5 In the present trial, we demonstrate increased OS and CR rate for an IC regimen administered every 3 weeks in a Scandinavian population. The survival gain was obtained without increased toxicity, except for diarrhea, which was partly a result of the use of prophylactic antibiotics in the first chemotherapy cycle, and was associated with prolonged symptom palliation. Wide inclusion criteria were applied, without limits for age or PS, resulting in a highly unselected study population, which enhances the external validity of the results. Although poor PS is a strong negative prognostic factor for survival, such patients may experience clinically meaningful responses to chemotherapy and may even return to work.11 They have usually been included in Danish and Swedish clinical trials.12 Almost 50% of the patients had a PS of 2 or worse, and 35% of patients were older than 70 years, which also explains the poorer OS compared with trials comprising more selected groups of patients. In Scandinavian countries, carboplatin is often used in the treatment of SCLC because of less nonhematologic toxicity and easier administration compared with cisplatin in the outpatient setting. Only a few trials directly compared cisplatin with carboplatin in SCLC, without showing any survival differences.12,13 The carboplatin dose used in the present trial (AUC = 4 by the Chatelut formula) roughly corresponds to AUC = 5 by the Calvert formula, which is a standard carboplatin dose in combination chemotherapy used with a palliative intention. The safety and efficacy of IC combinations in the treatment of ED SCLC have been demonstrated in several phase II trials.14,15 Intravenous etoposide is normally used for patients with limited-disease SCLC receiving combined treatment with curative intent. In the palliative setting, the use of oral etoposide in ED SCLC is justified by patient convenience and avoidance of unnecessary hospitalization. Randomized trials comparing intravenous and oral etoposide in combination with platinum compounds in SCLC are lacking. In a Danish phase II study, 106 consecutive unselected patients with SCLC and PS of 0 to 4 were treated with carboplatin and oral etoposide. Sixty-two patients had ED SCLC, and median survival time in this group was 8.5 months, similar to survival after treatment with intravenous etoposide and platinum.16 Oral etoposide has been shown to increase survival in ED SCLC when substituted for methotrexate in combination with older three-drug chemotherapy.17 In pharmacokinetic studies, the bioavailability of oral etoposide is approximately 60%, and interpatient variability of systemic etoposide exposure is increased compared with intravenous administration.18-20 It is customary to compensate for reduced uptake by using approximately the double dose of etoposide when administered by the oral route. This principle will result in similar levels of mean AUC as intravenous treatment.19 The dosage and schedule of irinotecan, with administration once every 3 weeks, differed from the schedules used in other randomized trials in SCLC.4,5 The purpose of the administration schedule of every 3 weeks, which has been established in monotherapy with irinotecan, was to attain a similar structure of intravenous treatment and hospital contacts in both arms to avoid bias in assessment of complications or patient-reported QOL. Overall, there were no major differences between the two regimens in our study with regard to QOL ratings during treatment, but there was a constant trend toward improved and prolonged palliation with the IC regimen, most notably for dyspnea and sleep problems. Because death by the time of scheduled assessment was counted as nonpalliation, part of the group difference could be attributable to the observed prolonged survival in the IC group. Nevertheless, no results indicated a superior QOL outcome with the EC regimen, either on treatment or during follow-up. In conclusion, the present study demonstrated that induction chemotherapy with IC in ED SCLC prolongs OS compared with oral EC without compromising QOL. The results support the use of an irinotecan-platinum combination as standard induction regimen for treatment of ED SCLC.
The author(s) indicated no potential conflicts of interest.
Conception and design: Andreas Hermes, Bengt Bergman, Christer Sederholm, Sverre Sörenson Provision of study materials or patients: Andreas Hermes, Bengt Bergman, Roy Bremnes, Lars Ek, Sverre Fluge, Christer Sederholm, Stein Sundstrøm, Lars Thaning, Jan Vilsvik, Ulf Aasebø, Sverre Sörenson Collection and assembly of data: Andreas Hermes, Bengt Bergman, Sverre Sörenson Data analysis and interpretation: Andreas Hermes, Bengt Bergman, Sverre Sörenson Manuscript writing: Andreas Hermes, Bengt Bergman, Sverre Sörenson Final approval of manuscript: Andreas Hermes, Bengt Bergman, Roy Bremnes, Lars Ek, Sverre Fluge, Christer Sederholm, Stein Sundstrøm, Lars Thaning, Jan Vilsvik, Ulf Aasebø, Sverre Sörenson
We acknowledge Randi Eikeland, Centre of Clinical Cancer Research, Haukeland University Hospital, for excellent data processing; Geir Egil Eide, Biostatistician, Centre for Clinical Research, Haukeland University Hospital, Bergen, Norway, for statistical advice when the study was planned; and the following investigators at the participating centers: V. Lejlic, Arendal Hospital; Ø. Fløtten, Haukeland University Hospital, Bergen; T. Tollåli, Nordland Hospital, Bodø; J.-E. Varildengen, Borås Hospital; Dr Fosså, Bærum Hospital; T. Brezicka, Sahlgrenska University Hospital, Göteborg; K. Aronsen, Hammerfest Hospital; A. Totland, Haugesund Hospital; I. Skog, Helsingborg Hospital; G. Hoven, Kristiansand Hospital; R. Kibsgaard, Levanger Hospital; A. Vikström, University Hospital, Linköping; R. Öhman, University Hospital, Lund; Dr Petersen, Molde Hospital; R. Hatlevoll, Norwegian Radium Hospital, Oslo; F. Stornes, Ullevål University Hospital, Oslo; H. Strøm, Sandnessjøen Hospital; T. Månsson, Skövde Hospital; T. Børvik, University Hospital, Tromsø; H. Hjelde and B. Grønberg, St Olav Hospital, Trondheim; I. Eskeland, Volda Hospital; F. Wammer, Ålesund Hospital; and A. Kihlgren, Örebro University Hospital.
Supported by the Norwegian Cancer Society and by unrestricted grants from Sanofi-Aventis and Pfizer Inc. Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL, and at the 12th World Conference on Lung Cancer, September 2-6, 2007, Seoul, South Korea. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Simon GR, Turrisi A: Management of small cell lung cancer: ACCP evidence-based clinical practice guidelines, 2nd edition. Chest 132:324S-339S, 2007 (suppl 3)[CrossRef][Medline] 2. Slotman B, Faivre-Finn C, Kramer G, et al: Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 357:664-672, 2007 3. Sundstrøm S, Bremnes RM, 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 4. 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 5. Hanna N, Bunn PA Jr, Langer C, et al: Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol 24:2038-2043, 2006 6. de Jongh CA, Wade JC, Finley RS, et al: Trimethoprim/sulfamethoxazole versus placebo: A double-blind comparison of infection prophylaxis in patients with small cell carcinoma of the lung. J Clin Oncol 1:302-307, 1983[Abstract] 7. Nagatomo A, Watanabe K, Kunikane H, et al: A randomized controlled trial of sulfamethoxazole/trimethoprim plus norfloxacin versus sulfamethoxazole/trimethoprim alone for the prophylaxis of bacterial infection during chemotherapy for lung cancer. Lung Cancer 19:121-125, 1998[CrossRef][Medline] 8. Aaronson NK, Ahmedzai S, Bergman B, et al: The European Organization for Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365-376, 1993 9. Bergman B, Aaronson NK, Ahmedzai S, et al: The EORTC QLQ-LC13: A modular supplement to the EORTC Core Quality of Life Questionnaire (QLQ-C30) for use in lung cancer clinical trials—EORTC Study Group on Quality of Life. Eur J Cancer 30A:635-642, 1994[CrossRef] 10. Stephens RJ, Hopwood P, Girling DJ: Defining and analysing symptom palliation in cancer clinical trials: A deceptively difficult exercise. Br J Cancer 79:538-544, 1999[CrossRef][Medline] 11. Bergman B, Sörenson S: Return to work among patients with small cell lung cancer. Eur J Respir Dis 70:49-53, 1987[Medline] 12. Lassen U, Kristjansen PE, Østerlind K, et al: Superiority of cisplatin or carboplatin in combination with teniposide and vincristine in the induction chemotherapy of small-cell lung cancer: A randomized trial with 5 years follow up. Ann Oncol 7:365-371, 1996 13. Skarlos DV, Samantas E, Kosmidis P, et al: Randomized comparison of etoposide-cisplatin vs. etoposide-carboplatin and irradiation in small-cell lung cancer. Ann Oncol 5:601-607, 1994 14. Schmittel A, Fischer von Weikersthal L, Sebastian M, et al: A randomized phase II trial of irinotecan plus carboplatin versus etoposide plus carboplatin treatment in patients with extended disease small-cell lung cancer. Ann Oncol 17:663-667, 2006 15. Kinoshita A, Fukuda M, Soda H, et al: Phase II study of irinotecan combined with carboplatin in previously untreated small-cell lung cancer. Br J Cancer 94:1267-1271, 2006[CrossRef][Medline] 16. Pfeiffer P, Sørensen P, Rose C: Is carboplatin and oral etoposide an effective and feasible regimen in patients with small cell lung cancer? Eur J Cancer 31A:64-69, 1995[Medline] 17. Hirsch FR, Hansen HH, Hansen M, et al: The superiority of combination chemotherapy including etoposide based on in vivo cell cycle analysis in the treatment of extensive small-cell lung cancer: A randomized trial of 288 consecutive patients. J Clin Oncol 5:585-591, 1987 18. Hande K, Messenger M, Wagner J, et al: Inter- and intrapatient variability in etoposide kinetics with oral and intravenous drug administration. Clin Cancer Res 5:2742-2747, 1999 19. Kroschinsky FP, Friedrichsen K, Mueller J, et al: Pharmacokinetic comparison of oral and intravenous etoposide in patients treated with the CHOEP regimen for malignant lymphomas. Cancer Chemother Pharmacol 61:785-790, 2008[CrossRef][Medline] 20. Würthwein G, Krümpelmann S, Tillmann B, et al: Population pharmacokinetic approach to compare oral and i.v. administration of etoposide. Anticancer Drugs 10:807-814, 1999[Medline] Submitted December 13, 2007; accepted April 16, 2008.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
.01 were interpreted as probable treatment effects. 
