1 Department of Internal Medicine, National Cancer Center Hospital, Tokyo; 2 Division of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa; 3 Division of Internal Medicine, Kanagawa Cancer Center, Yokohama; 4 First Department of Internal Medicine, Osaka City University Medical School, Osaka; 5 Department of Internal Medicine, Kinki University School of Medicine, Osaka; 6 Division of Internal Medicine, Tochigi Prefectural Cancer Center, Utsunomiya; 7 Department of Pulmonary Medicine, Osaka City General Hospital, Osaka; 8 Division of Internal Medicine, Niigata Cancer Center Hospital, Niigata; 9 Department of Internal Medicine, Osaka Prefectural Habikino Hospital, Osaka; 10 First Department of Medicine, Asahikawa Medical College, Asahikawa; 11 Third Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
Received 7 October 2002; revised 9 December 2002; accepted 23 January 2003
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Abstract |
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The purpose of this study was to evaluate the toxicity and antitumor effect of cisplatin, irinotecan and etoposide combinations on two schedules, arms A and B, for previously untreated extensive small-cell lung cancer (E-SCLC), and to select the right arm for phase III trials.
Patients and methods:
Sixty patients were randomized to receive either arm A (cisplatin 25 mg/m2 day 1, weekly for 9 weeks, irinotecan 90 mg/m2 day 1, on weeks 1, 3, 5, 7 and 9, and etoposide 60 mg/m2 days 13, on weeks 2, 4, 6, 8), or arm B (cisplatin 60 mg/m2 day 1, irinotecan 60 mg/m2 days 1, 8, 15, and etoposide 50 mg/m2 days 13, every 4 weeks for four cycles). Prophylactic granulocyte colony-stimulating factor support was provided in both arms.
Results:
Full cycles were delivered to 73% and 70% of patients in arms A and B, respectively. Incidences of grade 34 neutropenia, anemia, thrombocytopenia, infection and diarrhea were 57, 43, 27, 7 and 7%, respectively, in arm A, and 87, 47, 10, 13 and 10%, respectively, in arm B. A treatment-related death developed in one patient in arm A. Complete and partial response rates were 7% and 77%, respectively, in arm A, and 17% and 60%, respectively, in arm B. Median survival time was 8.9 months in arm A, and 12.9 months in arm B.
Conclusions:
Arm B showed a promising complete response rate and median survival with acceptable toxicity in patients with E-SCLC, and should be selected for the investigational arm in phase III trials.
Key words: cisplatin, etoposide, irinotecan, randomized phase II, small-cell lung cancer
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Introduction |
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Irinotecan, a water-soluble camptothecin derivative, has been shown to exhibit excellent antitumor activity against SCLC in monotherapy and in combination with cisplatin [6, 7].
A previous phase III trial of the PE regimen versus a combination of cisplatin and irinotecan (PI) in patients with extensive SCLC showed that the PI regimen produced an MST of 12.8 months and a 2-year survival of 21%, which were significantly better than the results with the PE regimen [8]. However, since etoposide is still considered one of the key drugs for the treatment of SCLC, a combination of these three drugs, cisplatin, irinotecan and etoposide (PIE), seemed to be a promising strategy for advanced SCLC. We previously determined the recommended doses of the PIE regimens for two schedules, weekly and every 4 weeks, independently [9, 10]. In this phase II study, we evaluated the two PIE regimens.
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Patients and methods |
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Patient selection
Patients were enrolled in this study if they met the following criteria: (i) a histological or cytological diagnosis of SCLC; (ii) no prior treatment; (iii) measurable disease; (iv) extensive disease, defined as having distant metastasis or contralateral hilar lymph node metastasis; (v) performance status of 0 to 2 on the Eastern Cooperative Oncology Group (ECOG) scale; (vi) predicted life expectancy of 3 months; (vii) age between 20 and 70 years; (viii) adequate organ function as documented by a WBC count
4.0 x 109/l, neutrophil count
2.0 x 109/l, hemoglobin
9.5 g/dl, platelet count
100 x 109/l, total serum bilirubin
1.5 mg/dl, hepatic transaminases
100 IU/l, serum creatinine
1.2 mg/dl, creatinine clearance
60 ml/min, and PaO2
60 Torr; and (ix) written informed consent.
Patients were not eligible for the study if they had any of the following: (i) uncontrollable pleural, pericardial effusion or ascites; (ii) symptomatic brain metastasis; (iii) active infection; (iv) contraindications for the use of irinotecan, including diarrhea, ileus, interstitial pneumonitis and lung fibrosis; (v) synchronous active malignancies; (vi) serious concomitant medical illness, including severe heart disease, uncontrollable diabetes mellitus or hypertension; or (vii) pregnancy or breast feeding.
Pretreatment evaluation
Pretreatment assessment included a medical history, physical examination, complete blood cell count, differential counts, routine chemistry measurements, creatinine clearance, blood gas analysis, electrocardiogram, chest X-ray, chest computed tomography (CT) scan, brain CT scan or magnetic resonance imaging, abdominal CT scan or ultrasound sonography, and if patients complained of symptoms suggesting bone metastasis, a radionuclide bone scan.
Treatment schedule
In arm A, cisplatin 25 mg/m2 was administered intravenously (i.v.) over 60 min on day 1 and at 1-week intervals for 9 weeks; irinotecan 90 mg/m2 was administered i.v. over 90 min on day 1 on weeks 1, 3, 5, 7 and 9; and etoposide 60 mg/m2 was administered i.v. over 60 min on days 13 of weeks 2, 4, 6 and 8. Hydration (2000 ml) and 5HT3-antagonist were given on day 1, followed by an additional infusion if indicated. Granulocyte colony-stimulating factor (G-CSF) was administered prophylactically on days when the cytotoxic drugs were not given, unless the WBC count exceeded 10.0 x 109/l (Figure 1). In arm B, cisplatin 60 mg/m2 was administered i.v. over 60 min on day 1; irinotecan 60 mg/m2 was administered i.v. over 90 min on days 1, 8 and 15; and etoposide 50 mg/m2 was administered i.v. over 60 min on days 13. Hydration (2500 ml) and 5HT3-antagonist were given on day 1, followed by an additional infusion if indicated. G-CSF was subcutaneously injected from day 5 to the day when the WBC count exceeded 10.0 x 109/l. This treatment was repeated every 4 weeks for a total of four cycles (Figure 1).
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Response evaluation
Objective tumor response was evaluated according to the World Health Organization (WHO) criteria issued in 1979 [12].
Study design, data management and statistical considerations
This study was designed as a multi-institutional, prospective, randomized phase II trial by 20 institutions in the Lung Cancer Study Group of JCOG. The protocol and consent form were approved by the Clinical Trial Review Committee of JCOG and the Institutional Review Board of each institution. Registration and randomization was conducted at the Registration Center. Data management, periodical monitoring and the final analysis were performed by the Study Coordinator. Simons randomized phase II selection design was used to determine the sample size. Assuming response rates of a poor and better arm of 70% and 85%, respectively, and a correct selection probability of 90%, the estimated required number of patients was 26 for each arm [13]. Accordingly, 30 patients for each arm and their accrual period of 24 months were planned for this study.
The dose intensity of each drug was calculated for each patient who received at least two cycles of chemotherapy by using the following formula:
Dose intensity (mg/m2/week) = Total milligrams of a drug in all cycles per body surface area/[(Total days of therapy)/7]
where total days of therapy is the number of days from day 1 of cycle 1 to day 1 of the last cycle plus 7 days for arm A or 28 days for arm B [14]. The median dose intensity was then calculated.
The survival distribution was estimated by the KaplanMeier method [15]. The final analysis was planned 15 months after the last patient accrual. The investigational arm in a phase III trial was proposed based on the response rate, survival, toxicity and compliance data in the final analysis.
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Results |
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Discussion |
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Randomized phase II trials are a useful method of selecting one arm for subsequent phase III trials [13]. It is not always easy, however, to determine the right arm on the basis of the results of this kind of study, because the sample size is not large enough to detect statistically significant differences between the arms. The response rate, the primary endpoint of this study, was slightly higher in arm A (83% in arm A and 77% in arm B), but the CR rate and MST were both higher in arm B (7% and 8.9 months in arm A, and 17% and 12.9 months in arm B, respectively). Since patients with various characteristics were equally distributed in the two arms, it seems reasonable to attribute the difference in survival to the difference in treatment arms. We therefore concluded that arm B should be selected for future phase III studies. The CR rate and MST in arm B were more promising than the historical control data [38].
The reasons for the difference in survival between the arms are unknown. The proportion of patients who discontinued treatment because of severe toxicity did not differ between the arms. The cumulative total doses of cisplatin, irinotecan and etoposide were comparable in both arms. Since the dose intensity of the three agents in arm A was higher than in arm B, the dose intensity did not contribute to the better survival in arm B. Because of the negative results of recent phase III studies comparing dose intens- ive versus standard chemotherapy [1618], increasing dose intensity is not considered a major strategy for the treatment of extensive SCLC.
Although compliance with the treatment cycles appeared good in arm B, irinotecan administration often needed to be skipped, especially on day 15. Thus, a 3-week schedule in which irinotecan is administered only on days 1 and 8 and the chemotherapy cycle is repeated every 3 weeks may improve treatment delivery and antitumor efficacy. A recent randomized phase II study of cisplatin and gemcitabine chemotherapy in patients with non-small cell lung cancer showed that a 3-week schedule was better than a 4-week schedule [19].
In conclusion, combinations of cisplatin, irinotecan and etoposide on two schedules were effective against extensive SCLC with acceptable toxicity. Arm B, in which these agents were administered on a 4-week basis, was considered to be more appropriate as the investigational arm in phase III trials.
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Acknowledgements |
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Footnotes |
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References |
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