Japanese Journal of Clinical Oncology 31:419-423 (2001)
© 2001 Foundation for Promotion of Cancer Research
Phase II Evaluation of Protracted Infusion of Cisplatin and 5-Fluorouracil in Advanced Squamous Cell Carcinoma of the Esophagus: a Japan Esophageal Oncology Group (JEOG) Trial (JCOG9407)
1Department of Surgery, Tokyo Women’s Medical University, Tokyo, 2Department of Surgery, School of Medicine, Keio University, Tokyo, 3Department of Surgery, National Cancer Center Hospital, Tokyo, 4First Department of Surgery, School of Medicine, Tokyo Medical and Dental University, Tokyo, 5First Division of Surgery, Kanagawa Cancer Center, Yokohama, 6Department of Surgery, National Shikoku Cancer Center Hospital, Matsuyama, 7First Department of Surgery, Iwate Medical University, Morioka, 8Second Department of Surgery, School of Medicine, Chiba University, Chiba, 9Department of Surgery, School of Medicine, Tokai University, Isehara, 10Department of Surgery and Surgical Basic Science, School of Medicine, Kyoto University, Kyoto, 11Department of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya, 12Department of Surgery, National Tokyo Medical Center, Tokyo, 13Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, 14Department of Surgery, Faculty of Medicine, Kurume University, Kurume, 15Japan Clinical Oncology Group Data Center, Cancer Information and Epidemiology Division, National Cancer Center Research Institute, Tokyo, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONOBJECTIVEPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Background: Surgery for advanced esophageal carcinoma has its limits as regards aggressiveness and therapeutic effect, therefore effective multimodality treatment is required to obtain better survival. The objective of this study was to evaluate whether daily continuous infusion of CDDP could achieve a higher clinical response rate with less toxicity than its drip infusion in the previous phase II study that we had conducted.
Methods: Patients with primary extensive or relapsed esophageal carcinoma after esophagectomy, which had distant organ metastasis and histologically proven SCC, were eligible for this study. A dose of 20 mg/m2 of cisplatin and 800 mg/m2 of 5-fluorouracil was given by continuous infusion for 24 h on days 1–5. This treatment was repeated every 4 weeks for up to four cycles. A total of 36 men and six women with a median age of 64 (range 39–75) years were registered and 36 patients were eligible.
Results: The overall response rate of the registered patients was 33.3% (12/36) and the median response duration was 175 days. Median survival time was 201.5 days and the 1-year survival rate was 27.8%. Change from bolus to continuous infusion of cisplatin affected neither the type nor the degree of toxicity.
Conclusion: Daily continuous infusion of cisplatin was not associated with higher response or lower toxicity than those seen with the high-dose bolus or multibolus treatment regimens. We conclude that this regimen in this setting is not worthy of further phase III trials. JEOG is now evaluating other drug combination regimens.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONOBJECTIVEPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Surgery for advanced or recurrent esophageal carcinoma has been disappointing because of low resectability and a high risk of distant metastasis. Owing to the anatomical location of the esophagus and the degree of surgical aggressiveness, surgical outcome is inferior to those of other gastrointestinal malignancies. Even with three-field lymphadenectomy (neck, mediastinum and abdomen) on esophagectomy, the 5-year survival for these patients is <50% and thus they are in a very sorry plight (1,2). About 40% of initially relapsed patients have organ metastasis and the extent of lymph node metastasis correlates closely with the patient survival (3). Surgery has its limits as regards aggressiveness and therapeutic effect, and therefore effective multimodality treatment is urgently required to obtain better survival of these patients.
The Japan Esophageal Oncology Group (JEOG) has conducted two phase II studies for advanced or recurrent squamous cell carcinoma (SCC) of the esophagus. Unlike Western countries, most of the histology of the esophageal cancer is SCC in Japan, and therefore the clinical trials are generally focused on SCC of the esophagus.
The combination of CDDP (cisplatin) and vindesine showed a 16.1% response rate (4) and a later study using bolus CDDP and continuous 5-fluorouracil (5-FU) infusion achieved 35.9% (5), which was relatively higher than that of the CDDP/vindesine study, but was far from satisfactory in terms of prolongation of survival. Since we have no innovative new drugs at present, we must improvise as best we can with the administration of currently available agents.
The efficacy of a combination chemotherapy consisting of cisplatin and 5-FU on esophageal carcinoma has been reported previously, with response rates ranging from 35 to 66% (6–8), but still there seems room for argument about the administration schedule of CDDP. Several clinical trials have been conducted for evaluating various administration methods with the aim of increasing the intravenous or intratumor concentration of CDDP without increasing toxicity. Drewinko et al. (9) reported that the cytotoxic effect of CDDP at low concentrations and with long-term exposure was greater than that with high concentration and short-term exposure in in vitro studies. Therefore, we set up a new phase II study of daily continuous infusion of cisplatin and 5-FU for far-advanced or recurrent SCC of the esophagus.
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OBJECTIVE |
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TOPABSTRACTINTRODUCTIONOBJECTIVEPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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The objective of this study was to evaluate the efficacy and safety of the chemotherapy regimen with 5FU plus CDDP both in a daily continuous infusion mode in order to determine whether this regimen is worthy of further investigation by a phase III trial. The clinical criteria were whether this regimen could achieve a higher tumor response and less toxicity than its drip infusion in the previous phase II study that we had conducted. The planned end-points were objective tumor response rate and toxicity. Response duration in responders and overall survival in all eligibles were also estimated as secondary end-points.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONOBJECTIVEPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Patient Selection
Patients with primary extensive or relapsed esophageal carcinoma after esophagectomy, which had distant organ metastasis and was histologically proven SCC, were eligible for this study. They underwent no prior chemotherapy for esophageal SCC and were younger than 75 years. The Eastern Cooperative Oncology Group performance status (PS) (10) of eligible patients was 0–3. They had a complete medical history, blood chemistry, chest X-ray, barium esophagogram, abdominal ultrasonography and computed tomography (CT). The examinations were performed initially and were repeated after every treatment course. They had not had any treatment during the preceding 4 weeks. Eligible patients were required to have two-dimensionally measurable lesions and adequate renal (
1.2 mg creatinine/dl, 
60 ml creatinine clearance/min) and hepatic (<1.5 mg bilirubin/dl, 2.0 x normal GOT value, 2.0 x normal GPT value) functions and also 10 mg Hb/dl, 4000 WBC/ml and 100 000 platelets/ml. Written or oral informed consent was obtained from all patients before registration with the documentation and the date in the patients’ records.
Evaluation
Responses were assessed by chest X-ray, barium esophagogram, abdominal ultrasonography and CT in accordance with the response criteria given by the Japan Society of Clinical Oncology and the evaluation of the primary lesion followed the ‘Guide Lines for Clinical and Pathological Studies on Carcinoma of the Esophagus’ issued by the Japanese Society for Esophageal Disease: complete response (CR), the complete disappearance of clinical evidence of existing lesions for over 4 weeks; partial response (PR), a >50% reduction in the sum of the products of two perpendicular measurements taken of all measurable lesions lasting for over 4 weeks; no change (NC), change in tumor size 50% for over 4 weeks; progressive disease (PD), a >25% increase in the sum of the products of two perpendicular measurements taken of an evaluable lesion or the appearance of new lesions. All responses (CR + PR) were centrally reviewed and confirmed using X-ray and CT scan films at the regular JEOG meetings.
Statistical Analysis
The confidence intervals for the response rate were based on the exact binomial distribution. Overall survival was calculated from the date of registration until death due to any cause. Response duration was measured from the date of registration until progression or death due to any cause, whichever came first. In the case of survivors with no progression, response duration was censored at the date of last follow-up. Overall survival and response duration were calculated by the Kaplan–Meier method and confidence intervals were based on Greenwoods’ equation (11). Toxicity was graded according to Japan Clinical Oncology Group Toxicity Criteria (12). All analyses were performed with SAS software version 6.12 (SAS Institute, Cary, NC) by the JCOG Data Center (JCOG DC).
Sample size was calculated using Simon’s two-stage optimal design (13). The lower activity level (p0) was set at 0.20 and the target activity level (p1) of interest was 0.40. The 
and ß error levels were both set at 0.1. The first-stage decision was planned to stop the trial if 3 responders out of 17 eligible patients were observed and overall decision was planned to reject the regimen if 10 responders out of 37 eligible patients were observed. The planned accrual period was 2 years and the follow-up period was set as 2 years after the completion of accrual.
Treatment
A dose of 20 mg/m2 of cisplatin and 800 mg/m2 of 5-FU was given by continuous infusion for 24 h on days 1–5. This treatment was repeated every 4 weeks for up to four courses unless the response was PD on the first course and NC or PD on the other courses. The dose of CDDP in subsequent courses was halved if creatinine reached 1.2–1.5 mg/dl and/or creatinine clearance reached 40–60 ml/min and was halted if creatinine became >1.5 mg/dl or creatinine clearance <40 ml/min. At 2000–4000 WBC/ml and/or 50 000–100 000 platelets/ml both 5-FU and CDDP were halved and were terminated if there were <2000 WBC/ml and/or 50 000 platelets/ml. If WBC recovered to >4000/ml and platelets increased to >100 000/ml, the administration halt was revoked and each drug was re-administered at a 20% reduced dose.
This study protocol was approved by the Clinical Trial Review Committee of the JCOG and the institutional review board in each participating institution before study activation and the JCOG Data Center was in charge of the data management.
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RESULTS |
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TOPABSTRACTINTRODUCTIONOBJECTIVEPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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A total of 42 patients, 36 men and six women with a median age of 64 (range 39–75) years, were registered in this study between September 5, 1994 and June 27, 1997. Among the 42 patients registered, six were ineligible: three had no organ metastasis, one was misdiagnosed as having lung and another renal metastasis, and in one case the target metastatic lesion on the skin had been totally removed by the initial biopsy before registration. The characteristics of the patients are given in Table 1. Twenty-one patients were unresectable because of metastasis to lung (seven patients), lung and lymph nodes (four), liver and lymph nodes (four), lung, liver and lymph nodes (two), lung, liver, bone and lymph node (one), liver and stomach (one), liver (one) and bone (one). Also, 15 patients had relapse after surgery in the lung (four), liver (one), lung and liver (two), lung and lymph nodes (two), liver and lymph nodes (two), lung and skin (one), lung, liver and lymph nodes (one), lung, skin and lymph node (one), liver, bone and lymph nodes (one). Three patients had been treated by radiotherapy before registration and 33 had no prior treatment. Six out of 36 eligible patients completed four courses of chemotherapy. Thirty patients received three or fewer courses of the treatment: 23 due to disease progression, four due to toxicities, two because of patient refusal and one due to intercurrent death. By the end of February 1996, there were four PR out of 17 patients and the first stage decision was made to continue this study pursuant to Simon’s two-stage design. As for protocol deviations, among 11 courses in eight patients, no dose reduction of 5-FU and/or CDDP was made despite of leukocytepenia or decreased creatinine clearance, and among three courses in two patients, a dose reduction was made although toxicity had not met the dose reduction criterion. Among 10 courses in six patients, the course intervals were prolonged to more than a week, ranging from 7 to 73 days.
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Objective tumor responses among the 36 eligible patients were 1 CR, 11 PR, 11 NC and 13 PD. The overall response rate (Table 2) was 33.3% [12/36, 95% confidence interval (CI) = 18.6–54.6]. The response rates were 33.3% (7/21 lesions) for primary tumor, 36% (9/25) for lung metastasis, 12.5% (2/16) for liver, 33% (1/3) for bone, 50% (1/2) for skin and 24% (4/21) for lymph node.
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The median response duration for the responders (CR + PR) was 175 days. Two out of the 12 (16.6%) responding patients achieved a response duration longer than 1 year, but all cases relapsed within 400 days. The overall survival curves for all registered and all eligible cases are shown in Fig. 1. The median survival time (MST) of all patients was 227 days (95% CI = 144–308) and the 1-year survival rate was 33.3% (95% CI = 19.1–47.6%). The MST and 1-year survival rate of eligible patients were 201.5 days (95% CI = 123–274 days) and 27.8% (95% CI = 13.2–42.4%), respectively.
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Toxicities associated with this chemotherapy regimen are summarized in Table 3. Hematological and gastrointestinal toxicities were the most common. Among 42 registered patients, two with no chemotherapy were excluded in the toxicity assessment. Grade 3 anemia was observed in two patients, grade 3 neutropenia in six, grade 3 thrombocytopenia in one, grade 4 thrombocytopenia in one, grade 3 bilirubinemia and grade 3 fever in one. Renal dysfunction was not serious and there was no case with nephrotoxicity of grade 3 or higher. A 62-year-old woman died of hypovolemic shock due to severe watery diarrhea 20 days after the second course and this was considered to be a treatment-related death. This patient had also suffered from grade 4 hematotoxicity.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONOBJECTIVEPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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In the last decade, several trials involving combined chemotherapy with CDDP and 5-FU in patients with squamous cell carcinoma of the esophagus have resulted in improved tumor response compared with those of single drug treatment. The JEOG also previously reported the efficacy of a combination of CDDP and 5-FU on squamous cell carcinoma of the esophagus, with a response rate of 35.9% (5). In that CDDP–5-FU phase II study, 70 mg/m2 of CDDP were administered by slow drip infusion for 120 min and 700 mg/m2 of 5-FU by continuous infusion.
Recently, some investigators have attempted to establish an optimal therapeutic schedule for this combination. Reece et al. (14) mentioned that repeated courses of CDDP raised the free platinum area under the time–concentration curve (AUC) with less renal toxicity. Ikeda et al. (15), members of our multi-center group, reported that when CDDP is administered by daily continuous infusion, the total platinum AUC increased over three times, with less renal toxicity, compared with a single short-term infusion schedule. The optimal dose of low-dose daily CDDP infusion has not yet been established, although several papers reported that it could range from 6 to 20 mg/body/day (16–18).
The aim of this JEOG phase II study was to determine whether daily continuous CDDP infusion could achieve a higher clinical response rate with less toxicity than applying a bolus infusion. The treatment regimen followed our multi-center group study and in this study CDDP was expected to act either as a carcinostatic agent or modulator for 5-FU.
In this study, the objective response rate of daily continuous infusion of CDDP–5-FU was 33.3% (12/36 cases) in primary extensive or relapsed esophageal carcinoma after esophagectomy. This response rate was almost the same as in our previous phase II study using bolus CDDP and continuous 5-FU infusion and the results were not as good as we had expected based on the results of in vitro studies (14,15). The response duration and overall survival resembled those in the previous study and there was no target organ specificity about tumor response in this study either.
Hematological and/or gastrointestinal toxicities have commonly been reported in chemotherapy with CDDP plus 5-FU, but this study suggests that changing from bolus to continuous infusion of CDDP affected neither the type nor the degree of toxicity. Most of all, these toxicities appeared in the same manner as in our bolus CDDP and continuous 5-FU phase II study. Among 40 patients in this study, serious adverse reaction appeared in only one patient, who experienced grade 4 hematotoxicity. After the second course, she experienced dehydration from severe diarrhea and subsequently suffered fatal multiple organ failure during her stay at home. As for protocol compliance, deviations with possibility of overdosing occurred in eight patients and of underdosing in eight patients. Therefore, protocol deviations were unlikely to cause a strong bias for estimating efficacy and safety end-points.
Pharmacokinetic and pharmacodynamic studies have suggested that daily continuous infusion of CDDP would be associated with a higher response and lower toxicity than those seen with high-dose bolus or multibolus treatment regimens. Nevertheless, there were no superior outcomes in daily continuous CDDP infusion in terms of administration compliance, tumor response or toxicities. The same or a lower modulatory effect of CDDP compared with 5-FU could be expected when CDDP was continuously administered. In other respects it seemed to be an advantage that the management of continuous CDDP administration was easier with regard to hydration, but a disadvantage was that precise drip control was intricate.
We still cannot explain this discrepancy between in vitro and in vivo results and cannot conclude that continuous CDDP administration is more favorable clinically. Daily continuous infusion of cisplatin was not associated with a higher response and lower toxicity than those seen with the high-dose bolus or multibolus treatment regimens. We also cannot ascribe this low response rate to the strict dose modification of this protocol, because the protocol compliance itself was within the allowable range and there existed eight protocol deviations of unreduced cases, which could improve the response rate. At present there seem to be no positive reasons to move to a continuous CDDP–5-FU regimen from bolus CDDP–continuous 5-FU in the treatment of squamous cell carcinoma of the esophagus. We conclude that this regimen in this setting is not worthy of further phase III trials. JEOG is now evaluating other drug combination regimens.
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Acknowledgments |
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TOPABSTRACTINTRODUCTIONOBJECTIVEPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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The Japan Esophageal Oncology Group (JEOG) is a subgroup of the Japan Clinical Oncology Group (JCOG), which is organized with support by Grants-in-Aid for Cancer Research from the Ministry of Health and Welfare of Japan. We are greatly appreciative of all the members for their excellent cooperation in this long-term follow-up study. This was JCOG 9407 study supported by Grants-in-Aid for Cancer Research from the Ministry of Health and Welfare of Japan (5S-1, 8S-1, 11S-3, 11S-4). We thank Ms Yukiko Fujikura, Data Manager assigned to JEOG, for data management.
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FOOTNOTES |
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+ For reprints and all correspondence: Kazuhiko Hayashi, Department of Surgery, Institute of Gastroenterology, Tokyo Women’s Medical University, 8–1, Kawada-cho, Shinjuku-ku, Tokyo,162-8666, Japan. E-mail: hayashi@hosp.net
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TOPABSTRACTINTRODUCTIONOBJECTIVEPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Received October 30, 2000; accepted May 18, 2001.
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