Annals of Oncology Advance Access originally published online on January 19, 2006
Annals of Oncology 2006 17(4):663-667; doi:10.1093/annonc/mdj137
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© 2006 European Society for Medical Oncology
A randomized phase II trial of irinotecan plus carboplatin versus etoposide plus carboplatin treatment in patients with extended disease small-cell lung cancer
Department of 1 Hematology, Oncology and Transfusion Medicine; 2 Department of Biostatistics and Clinical Epedimiology and 3 Cardiology and Pneumology, Charité, Campus Benjamin Franklin, Berlin; 4 Department of Hematology and Oncology, St. Marien Hospital, Amberg; 5 Department of Pneumology, University of Mainz; 6 Department of Hematology and Oncology, Westpfalz-Clinic, Kaiserslautern, Germany
* Correspondence to: Alexander Schmittel M.D., Charité, Campus Benjamin-Franklin, Dept. of Hematology, Oncology and Transfusion Medicine, Hindenburgdamm 30, 12200 Berlin, Germany. Tel: +49-30-8445-3090; Fax: +49-30-8445-4468; E-mail: alexander.schmittel{at}charite.de
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Abstract |
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Background: Superiority of irinotecan/cisplatin over etoposide/cisplatin was suggested in small-cell lung cancer (SCLC). This trial investigated irinotecan/carboplatin (IP) versus etoposide/carboplatin (EP).
Patients and methods: The interim analysis at the phase II/phase III transition point of the multicenter trial is reported. Extensive disease SCLC patients were randomized to receive carboplatin AUC 5 mg • min/ml either in combination with 50 mg/m2 of irinotecan on days 1, 8 and 15 (IP) or with etoposide 140 mg/m2 days 1–3 (EP). The primary end point was response rate and the secondary end points were toxicity and progression-free survival.
Results: Seventy patients were randomized. Significant differences in grade 3 and 4 thrombopenia (17% IP versus 48% EP, P = 0.01) and neutropenia (26% IP versus 51% PE, P < 0.01) were found. Grade 3 and 4 diarrhea was more frequent with IP (18%) than with EP (6%) (P = 0.133). Response rates were 67% and 59% (P = 0.24) in the IP versus EP arm, respectively. Median progression-free survival (PFS) was 9 months (95% CI 7.1–10.9) in the IP arm and 6 months (95% CI 4.1–7.9) in the EP arm (P = 0.03).
Conclusions: IP is active, less toxic and appears to improve PFS. Based on the phase II results the trial has been extended to phase III to assess the impact on overall survival.
Key words: irinotecan, etoposide, carboplatin, SCLC, extensive disease, phase II
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Etoposide in combination with platinum-based chemotherapy has been the standard treatment for extensive disease small-cell lung cancer. Other regimens like the combination of cyclophosphamide, adriamycin and vincristine (CAV) are equally effective [1
] and have been employed in alternation with etoposide plus platinum for first-line therapy [2] or for treatment of relapse [3]. More recently, a randomized phase III trial performed in Japan was terminated early after 154 patients, because of a superior survival in the irinotecan/cisplatin treatment arm when compared with standard etoposide/cisplatin [4]. In addition, high efficacy of irinotecan-based chemotherapy has been demonstrated in two phase II trials in relapsed or refractory disease [5, 6].
These data resulted in the initiation of further trials in SCLC. In North America, one randomized phase III trial comparing irinotecan/cisplatin to etoposide/cisplatin in a 2:1 randomization in 331 patients has recently been reported. This trial confirmed lower myelotoxicity and a significantly increased frequency of diarrhea in the irinotecan arm, but failed to show a significant difference in overall survival [7]. Since many oncologists in Europe prefer carboplatin over cisplatin because of its favourable toxicity profile and equal efficacy [8, 9], we initiated this randomized phase II/III trial to compare irinotecan/carboplatin with standard etoposide/carboplatin. Previously, we had performed a phase I dose escalation study and found irinotecan 50 mg/m2 on days 1, 8 and 15 and carboplatin AUC 5 on day 1 to be the maximum tolerated dose (MTD) in our patient population [10]. This was the basis for the experimental treatment arm investigated in the trial presented here. The dose is similar to results of a phase I study in the Asian population, which demonstrated grade IV thrombopenia and grade IV neutropenia lasting for more then 3 days and grade III or IV diarrhea to be dose-limiting toxicities (DLTs) of this treatment regimen [11]. One additional phase I trial conducted in North America defined a maximum tolerated dose (MTD) in two dose schedules of carboplatin plus irinotecan in heavily pretreated patients with a variety of solid tumors: the first schedule administered carboplatin AUC 4 on day 1 plus 60 mg/m2 of irinotecan on days 1 and 8 every 3 weeks, the second schedule administered carboplatin AUC 2 plus 90 mg/m2 of irinotecan both on days 1 and 8 every 3 weeks [12].
Because of the very limited data on toxicity and efficacy of the irinotecan/carboplatin combination, we designed a randomized phase II trial to allow for response and toxicity analysis before proceeding into phase III. We report here on the results from the randomized phase II section of the trial, which triggered the decision to proceed into phase III.
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patients and methods |
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patient selection
Patients with pathologically proven small-cell lung cancer (SCLC) extensive disease, defined as malignant effusion or supraclavicular lymph node metastases or visceral metastases, were eligible. Staging procedure consisted of CT scans of brain, chest and abdomen. Inclusion criteria were: no prior chemotherapy, life expectancy of >3 months, Karnofsky performance status
60%, measurable lesions, adequate hematologic function (leucocyte count >4000/mm3, platelet count >100 000/mm3, hemoglobin >9 g/dl), no severe hepatic or renal dysfunction with a bilirubine <1.25 x UNL and creatinine <1.25 x UNL. Criteria for exclusion were: second active malignant disease, chronic diarrhoea CTC grade 1, chronic inflammatory bowel disease, severe cardiac dysfunction (NYHA II), pregnancy, lactation, inadequate contraception. All patients gave written informed consent. The trial was approved by the local ethics committee.
trial design
Randomization was stratified by center. A two-step design was chosen. In the first step a total of 70 patients were randomized and response and stabilization rate were determined as a descriptive primary end point. A response rate exceeding 50% in each arm and acceptable toxicity were the criteria for extension into the phase III section of the trial with a switch to overall survival as the primary end point and response rate, progression-free survival and toxicity as secondary end points. The number of patients included into the phase III trial was estimated as follows: a 2-year survival of 10% would be expected in the standard treatment arm. An increase in 2-year survival from 10% to 20% would be clinically relevant. To detect such a difference with a power of 80% and an alpha-error of 5% in a two-sided test, a total of 296 patients (148 patients/arm) would be needed. Evaluation can be performed after 245 events.
treatment schedule and dose reduction
In arm A (IP) chemotherapy included irinotecan at a dose of 50 mg/m2 administered on days 1, 8 and 15 in 250 ml NaCl 0.9% i.v. over 30 min. In arm B (EP) etoposide 140 mg/m2 was administered on days 1, 2 and 3 in 1000 ml NaCl 0.9% i.v. over 90 min. Carboplatin was given in both treatment arms at a dose of AUC 5 mg • min/ml in 500 ml 5% glucose over 1 h on day 1. The individual dose of carboplatin was determined using Calvert's formula [13]: dose (mg) = AUC x [glomerular filtration rate (GFR) + 25]. GFR was determined using Jelliffe's formula [14]. Cycles were repeated on day 29 in arm A (IP) and on day 22 in arm B (EP). All patients received antiemetic therapy consisting of 5-HT3 antagonist intravenously, before starting the infusion of chemotherapy. In case of diarrhea, patients were instructed to take 4 mg of loperamide followed by 2 mg every 2 h until termination of diarrhea.
Dose reduction in case of thrombopenia <20 000/mm3 was performed as follows: if thrombopenia occurred before day 15 in arm A (IP) irinotecan infusion was omitted on day 15 and in all subsequent cycles. If thrombopenia <20 000/mm3 occurred after day 15 in arm A (IP) or any time in arm B (EP) or leucopenia <1.000/mm3 occurred carboplatin dose was reduced to AUC 4, if thrombopenia <20 000/mm3 or leucopenia <1000/mm3 still reoccurred after the first dose reduction carboplatin was further reduced to AUC 3.
In case of diarrhoea grade 2 persisting for >3 days despite treatment with loperamide and neomycin or in case of grade 4 diarrhea, irinotecan dose was reduced by 20% for subsequent cycles.
response and toxicity evaluation
CT-based response evaluation according to the RECIST criteria [15] was performed before initiation of chemotherapy and after two, four and six cycles of chemotherapy. The time points varied, because of differences in cycle duration. However, all patients had a radiographic assessment scheduled in week 16 after completion after four treatment cycles. In the follow-up period CT scans were performed every 3 months. Toxicity assessment was performed once weekly.
statistical analysis
All analyses were performed on an intent-to-treat basis considering all patients randomized. Progression-free survival (PFS) was estimated by using the Kaplan–Meier method. The log-rank test was used to determine statistical significance. To analyse differences in toxicity and response rate the 
2-test was used. The statistical analysis was carried out using the SPSS software (release 9.0).
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results |
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patient characteristics
A total of 70 patients were accrued in six institutions and all were found to fulfil eligibility criteria. Thirty-five patients were randomized into each arm. Median age was 59 and 63 years in the IP and EP arms, respectively. In both arms, 25 patients were male (Table 1).
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dose reduction and treatment delivered
In arm A (IP), 11 out of 35 (31.4%) patients had a dose reduction because of thrombopenia, diarrhea or febrile neutropenia. In arm B (EP), 10 of 35 (28.6%) patients had dose reduction because of thrombopenia and/or febrile neutropenia. The median number of cycles administered in both treatment arms was four. In the IP arm the mean dose of carboplatin administered per week was AUC 1.21 mg • min/ml and 35.94 mg/m2/week of irinotecan, which was 97% and 95.8% of the planned dose per week (Table 2). In the EP arm the mean dose administered per week was AUC 1.59 for carboplatin (95.4% of the planned dose) and 135.48 mg/m2/week (96.1% of the planned dose) for etoposide (Table 2).
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response analysis
In the IP arm, the response rate was 67% with four and 18 of 33 evaluable patients achieving a confirmed complete or partial remission, respectively. In the EP arm, response rate was 59% with 20 of 34 evaluable patients having a confirmed partial remission according to the RECIST criteria (Table 3). Three patients in each arm had stable disease, 24% and 32% progressed in the IP or EP arm, respectively. Two patients in the IP arm and one in the EP arm were not evaluable for response assessment, because of early death (Table 3).
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Until week 16 of therapy three patients progressed and four patients died in the IP arm, whereas eight patients progressed and six died in the EP arm (P = 0.068) (Table 3).
toxicity analysis
Grade 3 and 4 leucopenia, neutropenia and thrombopenia were significantly more frequent in the standard arm (EP) (Table 4). In contrast, no significant differences were observed for febrile neutropenia or treatment-related death. Grade 3 and 4 diarrhea were more frequent in the IP arm (n = 6) than in the EP arm (n = 2). However, this difference was not significant (P = 0.133). Grade 3 and 4 dehydration was rare with 6% in the IP arm and 0% in the EP arm (P = 0.15) (Table 4).
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Two patients in the IP arm and one in the EP arm died after the first cycle of chemotherapy (Table 4). In the IP arm one patient, who had received radiation to a sacral spine lesion between cycles one and two, developed toxic colitis, followed by fatal septic multi-organ failure during cycle 2. Another patient in the IP arm had a fatal endocarditis of the aortic valve during neutropenia after the second cycle of chemotherapy. One patient in the EP arm developed septic multi-organ failure in neutropenia after the first treatment cycle.
progression-free survival analysis
At the time of the analysis the median potential follow-up interval from randomization was 21 months and 25 patients (71.4%) had progressed in each arm allowing for mature PFS analysis. Median PFS was 9 months (95% CI 7.1–10.9) in the IP arm and 6 months (95% CI 4.1–7.9) in the EP arm (P = 0.03) (Table 3, Figure 1). One-year PFS was 26.5% (95% CI 9.1–43.9) in the IP arm and 10.6% (95% CI 0–24.2) in the EP arm. Median response duration of patients achieving a complete or partial remission was 7 months (95% CI 5.4–8.6 months) in the IP arm and 5.5 months (95% CI 4.5–6.5 months) in the EP arm (P = 0.44) (Table 3). All patients had a radiographic evaluation scheduled for week 16 after completion of four treatment cycles. At that time point, 28 patients (80%) in the IP arm were alive and without disease progression, compared with 21 patients (60%, P = 0.068) in the EP arm (Table 3).
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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The standard chemotherapy regimen for treatment of extensive disease small cell lung cancer (SCLC) has been the combination of etoposide plus cisplatin or carboplatin [8
, 9, 16]. Recently, a randomized phase III trial was terminated early after 154 patients because of a significant survival benefit in the irinotecan/cisplatin group, when compared with the etoposide/cisplatin group [4]. In this trial the median survival was 12.8 months in the irinotecan/cisplatin arm and 9.4 months in the etoposide/cisplatin arm. The 1- and 2-year survival was 58.4% and 19.5% in the irinotecan/cisplatin arm and 37.7% and 5.2% in the etoposide/cisplatin arm [4]. Since the number of patients treated within this trial was rather low, a similar trial in 331 patients has been conducted in North America and reported very recently [7]. This second trial did not show a benefit of a different schedule of IP over EP, as it demonstrated a comparable overall survival with a median of 9.3 months and a 1-year survival of 35.4% in the IP arm and a median survival of 10.2 months and a 1-year survival of 36.7% in the EP arm [7]. In addition, the SWOG is currently performing a randomized phase III trial comparing exactly the same regimens already investigated by the Japanese group [4]. This trial will provide additional important information.
We initiated the current randomized phase II/III trial in Germany to evaluate the efficacy of the irinotecan/carboplatin regimen compared with the frequently used etoposide/carboplatin regimen. The data presented here are the results from the phase II part of the trial. We could observe a response rate in excess of 50% in both study arms and an acceptable toxicity, triggering the transition from the phase II part of the trial into the phase III part, which is expected to complete accrual by the end of 2006 and will analyze overall survival as a primary end point. The comparison of both treatment arms revealed a non-significant trend towards an improved response rate of 67% in the IP and 59% in the EP arm. The response rate observed in the control arm of our trial is comparable to earlier trials [8, 9, 16] and the somewhat higher response rate with IP is similar to the observations made by Noda et al., who reported a significantly increased response rate of 84.4% in the irinotecan/cisplatin compared with 67.5% in the etoposide/cisplatin group [4]. In contrast the disappointing response rates were only 48% in the IP and 43.6% in the EP arm in the North American trial, despite the exclusion of patients with an ECOG performance status of above 1 after enrolment of the initial 30 patients [7]. In our trial we observed a significant improvement of median PFS of 9 versus 6 months in the IP versus EP arm, which should be interpreted with caution, since this was not the primary end point of the current phase II trial. Consistent with our results, Noda et al. [4] reported a significant difference in PFS. Median PFS was 6.9 months in the irinotecan/cisplatin arm and 4.8 months in the etoposide/cisplatin arm. The North American trial did not reveal a difference in TTP between the IP and EP arm. Median TTP was 4.1 months in the IP and 4.6 months in the EP arm [7]. We now have to await the overall survival results of the phase III part of our trial in order to draw final conclusions.
Both cisplatin-based randomized trials comparing IP with EP [4, 7] demonstrated a lower frequency of grade 3 and 4 hematologic toxicity of IP, which is similar to the myelotoxicity observed in our trial. Sixteen per cent of patients in the IP arm of the Japanese trial and 21.3% of patients in the IP arm of the North American trial had grade 3 or 4 diarrhea [4, 7]. This is similar to the 18% grade 3 and 4 diarrhea observed in our trial. However, our trial is the only trial without significant differences in the rate of diarrhea between the IP and the EP arm, because of an increased frequency of 6% grade 3 diarrhea in the standard arm (EP), which might be caused by a higher dose intensity of etoposide in our study. The planned dose intensity of etoposide was 140 mg/m2/week in our trial and 120 mg/m2/week in the American and 100 mg/m2/week in the Japanese trial [7, 4]. Management of diarrhea is critical when using irinotecan. Early loperamide and fluid replacement has to be employed in case severe diarrhea develops to prevent dehydration [17]. Secondary prophylaxis with neomycin has been shown to effectively prohibit the development of diarrhea in subsequent treatment cycles [18]. Following these measures, dehydration could be prohibited in almost all patients in our trial despite the occurrence of grade 3 diarrhea.
Three treatment-related deaths occurred in our trial and four in the trial reported by Noda et al. [4]. One treatment-related death that occurred in the IP arm in our trial deserves special attention, as it was caused by toxic colitis after irradiation of a spinal sacral metastasis, a complication, which has not yet been reported in lung cancer patients. This observation demonstrates that concurrent radiotherapy of bony metastases that may include parts of the intestine should not be performed with irinotecan-based chemotherapy in lung cancer patients.
The results of the first step of our randomized phase II/III trial reported here justify the extension into phase III, which is currently ongoing, to investigate further the impact of IP on survival.
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Acknowledgements |
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The authors thank Susanne Beier for excellent data management.
Received for publication October 26, 2005. Revision received November 30, 2005. Accepted for publication December 14, 2005.
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References |
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