Journal of Clinical Oncology, Vol 17, Issue 1
(January), 1999: 319
© 1999 American Society for Clinical Oncology
Phase II Study of a Combination of Irinotecan and Cisplatin Against Metastatic Gastric Cancer
Narikazu Boku,
Atsushi Ohtsu,
Yasuhiro Shimada,
Kuniaki Shirao,
Shigeki Seki,
Hiroshi Saito,
Yuh Sakata,
Ichinosuke Hyodo
From the Department of Gastrointestinal Oncology and Gastroenterology, National Cancer Center Hospital East, Kashiwa; Department of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo; Department of Internal Medicine, Saku Central Hospital, Minami-Saku; Department of Internal Medicine, Yamagata Prefectural Central Hospital, Yamagata; Department of Gastroenterology, Aomori Prefectural Central Hospital, Aomori; and Department of Internal Medicine, National Shikoku Cancer Center Hospital, Matsuyama, Japan.
Address reprint requests to Narikazu Boku, Department of Gastrointestinal Oncology and Gastroenterology, National Cancer Center Hospital East, 6–5-1 Kashiwanoha, Kashiwa, Chiba 277–8577, Japan.
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ABSTRACT
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PURPOSE: A phase II study of a combination chemotherapy regimen of cisplatin (CDDP) and irinotecan (CPT-11) was conducted to assess its efficacy and feasibility in patients with metastatic gastric cancer.
PATIENTS AND METHODS: Eligibility criteria included the following: (1) histologically proven gastric cancer with measurable metastatic lesions, (2) performance status of 2 or less, (3) age of 75 years or younger, (4) one or no prior chemotherapy regimens, (5) adequate bone marrow, liver, renal, and cardiac functions, and (6) written informed consent. The treatment consisted of CPT-11 (70 mg/m2) on day 1 and day 15 and CDDP (80 mg/m2) on day 1, repeated every 4 weeks.
RESULTS: Forty-four patients were entered onto the study. The overall response rate was 48% (21 of 44 patients, 95% confidence interval [CI], 33% to 63%) and included one complete remission (2%). The response rate of the patients who had not received prior chemotherapy was 59% (17 of 29 patients, 95% CI, 39% to 77%). The median survival time was 272 days for all patients and 322 days for the 29 patients who had not received prior chemotherapy. Grade 4 neutropenia was observed in 25 patients (57%), and grade 3 or 4 diarrhea was observed in nine patients (20%). Other adverse reactions were mild. No treatment-related deaths occurred.
CONCLUSION: This combination chemotherapy regimen is active and well tolerated. It may be an appropriate regimen for future phase III trials.
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INTRODUCTION
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CISPLATIN (CDDP) IS an antineoplastic agent that is active against gastric cancer,1 and some chemotherapy regimens that include CDDP have been reported to show high response rates.2-5 However, because the survival benefit of these regimens has not yet been demonstrated,6-8 new and active chemotherapy regimens are needed. Irinotecan hydrochloride (CPT-11) is a water-soluble, semisynthetic derivative of camptothecin (CPT) that retains the original antitumor activity of CPT but has less toxicities.9 The antitumor effects of CPT-11 are due to the inhibition of DNA topoisomerase I,10,11 and CPT-11 has activity against various experimental tumors.12 Against gastric cancer, the response rate of CPT-11 alone has been reported to be 18% in phase II studies, regardless of prior chemotherapy.13 Marked synergism, lack of cross-resistance, different mechanisms of action, and relatively different profiles of adverse reactions of CPT-11 and CDDP have been recently recognized.14 Furthermore, the combination of CDDP and CPT-11 has been reported to be effective with acceptable adverse reactions in phase II studies of lung cancer.15,16 In our previous phase I/II study of CPT-11 and CDDP against metastatic gastric cancer, the recommended dose and schedule was 70 mg/m2 of CPT-11 on day 1 and day 15 and 80 mg/m2 of CDDP on day 1, repeated every 4 weeks.17 The response rate at the recommended dose was 44% (four of nine patients), and the major adverse reaction was neutropenia. Therefore, we conducted a multicenter phase II study to confirm the activity and feasibility of this regimen at the recommended dose and schedule in patients with metastatic gastric cancer.
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PATIENTS AND METHODS
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Eligibility Criteria
Patients entered onto this study were required to fulfill the following eligibility criteria: (1) histologically proven gastric cancer with measurable metastatic lesions; (2) Eastern Clinical Oncology Group scale performance status of 2 or less; (3) age of 75 years or younger; (4) one or no prior chemotherapy regimens completed 4 weeks before entry; (5) adequate functions of bone marrow (WBC count  4,000/µL and platelet count 10,000/µL), liver (serum bilirubin level  2.0 mg/dL and serum transaminase level three times the upper limit of normal range), and renal (serum creatinine level 1.5 mg/dL, blood urea nitrogen level 25 mg/dL, and creatinine clearance 50 mL/min); (6) normal cardiac function; (7) no other severe medical conditions; (8) no other active malignancy; and (9) provision of written informed consent in accordance with government guidelines ("Good Clinical Practice" by the Ministry of Health and Welfare of Japan). This study was approved by the institutional review boards of all participating hospitals.
Treatment Schedule
On day 1, CPT-11 (70 mg/m2) was administered by intravenous infusion for 90 minutes; this was followed by a 2-hour interval, after which intravenous infusion of CDDP (80 mg/m2) was administered over 2 hours with adequate hydration. The same dose of CPT-11 was administered on day 15. This treatment was repeated every 4 weeks until disease progression, patient refusal, or unacceptable adverse reactions. On day 15, if the patient had leukopenia or thrombocytopenia of grade 2 or higher, diarrhea of grade 1 or higher, or an episode of infection, then the second dose of CPT-11 was postponed until recovery from these adverse reactions. If the adverse reactions continued beyond day 22, then the second dose of CPT-11 was not administered. If a hematologic adverse reaction or diarrhea was grade 4, then the second dose of CPT-11 was not administered, and the subsequent dose of CPT-11 was reduced to 60 mg/m2. Granisetron was used routinely before administration of CPT-11. Granulocyte colony-stimulating factor (G-CSF) was used when necessary.
Evaluation
Objective response to chemotherapy in measurable lesions was evaluated by the standard World Health Organization criteria.18 The response of the primary lesions was not counted for overall response. The Eastern Cooperative Oncology Group common toxicity criteria were applied to evaluate the adverse reactions. The eligibility and suitability for assessment of the subjects and the response to treatment were reviewed extramurally.
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RESULTS
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Patient Characteristics
Forty-four patients were enrolled from April 1995 to May 1996, and all were eligible and assessable for response and adverse reactions. The patient characteristics are listed in Table 1. The median age of the patients was 56 years (range, 26 to 72 years). Forty-two patients (96%) had performance status 0 or 1. Histologically, 28 patients (64%) had intestinal type of adenocarcinoma, and 16 patients (36%) had diffuse type. Thirty-three patients (75%) had primary foci. All patients had measurable metastatic lesions, and metastatic sites were located in the liver in 30 patients (68%), the lymph nodes in 27 patients (61%), the lung in four patients (9%), and other areas in four patients (9%). Twenty-nine patients (66%) had received no prior chemotherapy; the other 15 patients received prior chemotherapy that was completed 4 or more weeks before entry. The best response to the prior chemotherapy is listed in Table 1, and all of these patients showed progressive disease before entry onto this study.
Response and Survival
There was one complete remission and 20 partial responses, which results in a response rate of 48% (21 of 44 patients, 95% CI, 33% to 63%). The response rate of the 29 patients without prior chemotherapy was 59% (17 of 29 patients, 95% CI, 39% to 77%). The response rates of patients with metastases in liver, lymph node, lung, and others were 40% (12 of 30 patients), 37% (10 of 27 patients), 50% (two of four patients), and 25% (one of four patients), respectively (Table 2). The median time to response was 40 days (range, 22 to 103 days), and median response duration was 176 days (range, 41 to 323 days). The median survival time of all patients was 272 days; median survival time of the 29 patients without prior chemotherapy was 322 days (Fig 1).
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Fig 1. Survival curves of all patients and patients without prior chemotherapy. —: Survival curve of all patients (median survival time, 272 days). - - - : Survival curve of patients without prior chemotherapy (median survival time, 322 days).
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Adverse Reactions
The total number of treatment courses was 146 (median, three courses per patient; range, one to seven courses). The adverse reactions to this regimen are summarized in Table 3. The most frequent adverse reaction was neutropenia, and grade 4 neutropenia was observed in 25 patients (57%) and in 35 courses (24%). The median nadir of neutropenia was observed on day 16 (range, 5 to 22 days). Granulocyte colony-stimulating factor was administered in 25 (17%) courses. With G-CSF support, grade 4 neutropenia was resolved promptly (median duration, 4 days; range, 2 to 24 days), and grade 3 or 4 infection was observed in only two patients (5%). Other hematologic adverse reactions were mild.
Diarrhea was observed on day 6 (range, 1 to 24 days), and grade 3 or 4 diarrhea was observed in three patients (7%) during the first course and in nine patients (21%) during all courses. It was resolved with the use of loperamide or other antidiarrheal drugs with adequate hydration (median, 3 days; range, 1 to 13 days). Six of the nine patients received subsequent courses of chemotherapy; in the subsequent courses, with five patients undergoing dose reduction of CPT-11, none of these six patients had complications of grade 3 or 4 diarrhea. Other nonhematologic adverse reactions were mild. There was no cessation of treatment because of adverse reactions, and there were no treatment-related deaths.
Dose-Intensity
Twenty (20%) of 102 subsequent courses were delayed longer than 4 weeks because of adverse reactions, and the median course interval was 5 weeks (range, 4 to 8 weeks). The second dose of CPT-11 was postponed in 82 (56%) courses and was not given in 34 (23%) courses of all 146 courses. The median interval between the first and second dose of CPT-11 was 19 days (range, 14 to 28 days). The dose was reduced in 21 (14%) courses. Leukopenia and/or diarrhea were the most common reasons for not giving the second CPT-11 dose (16 of 34 courses; 47%) and for dose reduction (17 of 21 courses; 81%). Thus, the actual administered dose of CPT-11 in the first two courses was 28.5 mg/m2/wk and that of CDDP was 18.0 mg/m2/wk, which corresponded to 81.4% and 89.9% of the planned doses.
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DISCUSSION
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This phase II study was initiated to confirm the antitumor effects in the previous phase I/II study.17 The overall response rate to the combination of CPT-11 and CDDP was 48% (21 of 44 patients), which was comparable to the response rate at the recommended dose in the previous phase I/II study (44%; four of nine patients). The response rate of CPT-11 as a single agent against gastric cancer was reported to be 18%9 and that of CDDP was reported to be approximately 20%.1 Our results suggest synergistic antitumor effects of CDDP and CPT-11. The response rate of the 29 patients without prior chemotherapy was 59% (17 of 29 patients) and the median survival time was 322 days. Compared with the treatment regimens examined in recent phase II studies for gastric cancer,2-5,19,20 the combination of CPT-11 and CDDP may be quite active against gastric cancer.
Diarrhea is a major toxicity of CPT-11. The incidence of grade 3 or 4 diarrhea was 20% (9 of 44 patients) in this study, which was lower than that in the studies of CPT-11 alone.21-28 Because the incidence of diarrhea was dose- and schedule-related,29 the actual dose intensity of CPT-11 in this study, which was less than one half of the dose intensity of CPT-11 alone,29 may explain the lower incidence of severe diarrhea. In the phase II study of a combination of CPT-11 and CDDP against lung cancer in which CPT-11 (60 mg/m2) was administered on days 1, 8, and 15 and CDDP (80 mg/m2) was administered on day 1, the incidence of grade 3 or 4 diarrhea was approximately 20%.15,16 We used a schedule of CPT-11 every 2 weeks to decrease the incidence of diarrhea. The incidence of grade 3 or 4 diarrhea during the first course was 7% (3 of 44 patients) in this study and 19% (19 of 100 patients) in the phase II study of lung cancer (detailed data were obtained from the researchers16). This may reflect the difference in schedule of CPT-11 dose. Moreover, grade 3 or 4 diarrhea did not reappear in subsequent courses. These results suggest that the dose and schedule of this regimen may succeed in reducing the incidence of severe diarrhea.
The incidence of grade 4 neutropenia (57%) was relatively high, and it was a major cause for delay and elimination of the second CPT-11 dose and dose reduction. However, the incidence of grade 4 leukopenia (9%) in this study was comparable to that identified in the recent phase II studies,2-5,19,20 some of which did not refer to neutropenia. Moreover, it was recovered promptly with G-CSF support, and grade 3 or 4 infection was observed in only two patients (5%). There was no cessation of the study due to adverse reactions, and no treatment-related deaths occurred. From these results, this regimen is considered to be tolerable.
In conclusion, the combination of CPT-11 and CDDP is active and feasible, and can be a potential candidate regimen in future phase III trials. We are now planning a phase III study of a combination of CPT-11 and CDDP with adequate G-CSF support versus the regimen that will be proved to be standard in the ongoing phase III trial of the Japanese Clinical Oncology Group (fluorouracil alone v uracil-futrafur + mitomycin v fluorouracil + CDDP).
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ACKNOWLEDGMENTS
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Supported in part by Daiichi Pharmaceutical Co, Ltd, and Yakult Honsha Co, Ltd, Tokyo, Japan
We thank Akira Sahashi, Masanori Suzuki, and Tomiaki Zama for assistance in data collection and analysis. We are also grateful to Drs Akira Wakui, Nagahiro Saijo, and Yasuo Ohashi for kind advice during the study, and to Drs Noriyuki Masuda and Nagao for giving us detailed data of the phase II study of CPT-11 and CDDP against lung cancer.
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Submitted January 8, 1998;
accepted September 9, 1998.
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TOP
ABSTRACT
INTRODUCTION
