Cis-diammine-glycolatoplatinum (Nedaplatin) and

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1 å ORIGINAL ARTICLE D A NewCombination Chemotherapy with Cis-diammine-glycolatoplatinum (Nedaplatin) and 5-fluorouracil for Advanced Esophageal Cancers Takashi Yoshioka, Makio Gamoh, Ryusaburo Shineha*, Satoru Ishibashi*, Hiroyuki Shibata, Takao Suzuki, Yasuko Murakawa, Syunsuke Kato, Hideki Shimodaira, Satoshi Kato, Chikashi Ishioka and Ryunosuke Kanamaru Objective The efficacy of a new chemotherapeutic combination consisting of Cis-diammineglycolatoplatinum (Nedaplatin), a derivative of cisplatin (CDDP), and 5-fluorouracil (5FU) was evaluated in patients with advanced esophageal carcinomas. Methods Nedaplatin was administered at a dose of 80 or 100 mg/m2 with 500 ml of saline by slow drip infusion for 120 minutes on day 1. 5FU at a dose of 350 or 500 mg/m2 was mixed with 1,000 ml of saline and administered by continuous infusion for 24 hours on days 1 to 5. Patients or Materials This combination chemotherapy was tried in 17 patients with metastatic, recurrent, or bulky unresectable esophageal cancers. Of these, 15 evaluable patients received at least two courses of chemotherapy. Results The response rates in assessable and all patients were 60%and 52.9%, respectively. Cases with lymph node and liver metastases, as well as primary lesions, showed excellent response to the therapy with positive response rates of 54.5% (6/ll), 100% (5/5) and 58.4% (7/12), respectively. The median response duration was 7 (range 3 to 37+) months for patients who achieved a partial response. Adverse drug reactions were limited to three cases of grade 3 toxicity, including allergy, and decreased hemoglobin and platelets, which were well tolerated by the patients. Conclusion The present study thus indicated the combination chemotherapy of Nedaplatin and 5FU to be safe and efficacious for advanced esophageal cancer. Further investigations are clearly warranted. (Internal Medicine 38: , 1999) Key words: antineoplastic agents, drug effects, cisplatin derivative, squamous cell, undifferentiated carcinoma Introduction Esophageal cancer remains a difficult and most often terminal cancer. In recent years, several strategies involving presurgical chemotherapy, either alone or with radiotherapy, or chemoradiotherapy without surgery have been tried to improve this prognosis (1-5). However, the obtained improvement was limited to local esophageal cancers, and the response to therapy and prognosis of patients with metastases, recurrent, or bulky unresectable carcinomas of the esophagus has remained generally poor (6). Cisplatin (CDDP) -based combinations are well reported to show high response rates, varying from 15 to 76% (7). Among the various combinations tested, that with 5-flurouracil (5FU) has proved to be a most effective and safe regimen (1). However, because CDDPitself has substantial toxicity, there has been a keen interest in newer platinum analogues. Oneexample is cis-diammine-glycolatoplatinum (Nedaplatin), which was developed with the aim of decreasing renal and gastrointestinal toxicity but maintaining the effectiveness of CDDP(8). Numerous single agents have been tested for esophageal cancer and the overall response rate typically has ranged from 23%to 38%(1), while the response rate for Nedaplatin as a single agent was 42.9% in a phase II study, with little toxicity (9). It has been shown in vitro that, like CDDP,Nedaplatin may exert synergic effects with 5FU (10). Based on these findings, we planned a pilot study of the Nedaplatin and 5FUcombination for patients with metastatic, From the Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai and *the Second Department of Surgery, Tohoku University, Sendai Received for publication January 27, 1999; Accepted for publication June 28, 1999 Reprint requests should be addressed to Dr. Takashi Yoshioka, the Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Aoba-ku, Sendai

2 recurrent, or bulky unresectable esophageal cancers. The first purpose of this study was to determine the efficacy of this combination therapy. The second was to determine the recommended doses in this combination because these two drugs might interact to worsen some adverse drug reactions like gastrointestinal toxicity or myelo-suppression. Patients and Methods Nedaplatin and 5FU in Esophageal Cancer Between December 1995 and September 1997, 17 patients with advanced esophageal cancer cared for at the Department of Clinical Oncology, Hospital of Institute of Development, Aging and Cancer, Tohoku University were eligible and gave informed consent for the study. All patients had biopsy-proven squamous cell carcinomas or undifferentiated carcinomas of the esophagus or gastroesophageal junction, and they had either metastatic disease, bulky unresectable tumors, or recurrent disease after surgical resection of esophageal cancer. All patients had evaluable or measurable disease by computed tomographic scanning, esophagography, or endoscopic examination. Two had been given postoperative chemoradiation but had no treatment during the six months immediately preceding this study, and the others had not received previous chemotherapy or radiotherapy. Eligible patients were required to have an Eastern Cooperative OncologyGroup performance status (PS) of 0 to 3, and adequate renal function (<1.2 mg creatinine/dl, >50 ml creatinine clearance/min) and bone marrow reserve (leukocyte count>3,000/ il, and platelet count > 100,000/ Mi). Nedaplatin was administered at a dose of 80 or 100 mg/m2 with 500 ml of saline by slow drip infusion for 120 minutes on day 1. 5FU at a dose of350 or 500 mg/m2was mixed with 1,000 ml of saline and administered by continuous infusion for 24 hours on days 1 to 5. The first five patients in this study received 80 mg Nedaplatin/m2 and 350 mg 5FU/m2, and the others received 80 mg Nedaplatin/m2 and 500 mg 5FU/m2. Seven patients received 100 mg Nedaplatin/m2 in subsequent cycles because they were relatively young (<70) and tolerated the therapy well in the first cycle. Serotonine receptor antagonist was preventively given as an antinauseant just before the administration of Nedaplatin. This schedule was repeated more than twice at four-week intervals. After three cycles, it was performed in every two to four months. After four cycles, if the responder's primary tumor was residual, irradiation of the primary site was additionally performed. Whenonly one administration was carried out, the case was regarded as being incomplete. The World Health Organization criteria were used to define the following: complete response (CR), the disappearance of all known disease for at least four weeks; partial response (PR), 50%or more decrease in total tumor load of the lesions estimated by two observations no less than four weeks apart; no change (NC), no significant change for at least four weeks, which includes stable disease, estimated decrease of less than 50%, and lesions with estimated increase of less than 25%; progressive disease (PD), appearance of any new lesions not previously identified or estimated increase of existing lesions by 25%or more (1 1). For reference, minor response (MR) was also described, which was a 25 to 50%reduction in the sum of the products of two perpendicular measurementstaken of all measurable lesions with at least a four-week interval. Response duration wascalculated from the first day of treatment to the date of first observation of progressive disease (1 1). Toxicity was graded according to the World Health Organization scales (ll). Results The characteristics of the 17 patients entered into this study are given in Table 1. All were menand the median age was 65 years (range, 51 to 74). The tumors were 14 squamous cell and 3 undifferentiated carcinomas. All patients had distant metastases and were Stage IV. Metastatic sites were 3 cervical, 5 mediastinal, 6 abdominal lymph nodes, 5 liver, 4 lung, 1 kidney and 2 others. Amongthese 17 patients, two could not be evaluated, one because of an allergic response to Nedaplatin at the second administration and the other because of cerebral infarction caused by atrial fibrillation. Seven patients underwent two courses of treatment, 3 three, 2 four, 3 five, and 1 Table 1. Patient Characteristics ECOG: Eastern Cooperative Oncology Group, SCC: squamouscell carcinoma. Internal Medicine Vol. 38, No. 1 1 (November 1999) 845

3 Yoshioka et al eight. The results were 9 PR, one MR, one NCand 4 PD (Table 2). The response rates in assessable and all patients were 60%(95% CI= %) and 52.9% (95% CI= %), respectively. All the responses were obtained within four weeks after the first cycle of administration. Data for response according to tumor site are shown in Table 3. Primary lesions and, lymph node and liver metastases proved very responsive to the therapy, with response rates of 58.4, 54.5 and 100%, respectively. The median duration of the response was 7 (range 3 to 37+) months. Four patients received more than five cycles of chemotherapy. Except for one postoperative case whohad only multiple liver metastases, the primary sites demonstrated small residual lesions and received irradiation after four courses of chemotherapy. One achieved CR, but the other two remained PR with tumor recurrence in the primary sites after the fifth course of chemotherapy. Toxicity grades for the 17 patients entered in the present study are shown in Table 4. There was no Grade 3 or 4 toxicity with the 80 mg Nedaplatin/m2 and 350 mg 5FU/m2. In the upper dose group, there was one case demonstrating an allergic response (grade 3), which occurred 30 minutes after the start of the second administration of Nedaplatin, but it disappeared immediately after the discontinuance of chemotherapy and administration of steroid. There was one case of cerebral infarction and we could not overlook the probability of relationship with the administration of 5FU, but the details were unclear. Grade 3 thrombocytopenia and anemia were also each observed in one case. Although grade 2 renal toxicity was apparent in one individual, no patients needed to have Nedaplatin discontinued because of renal toxicity and there was no chemotherapy-related death. Discussion Patients with advanced esophageal cancer rarely benefit from chemotherapy. Several kinds of combination therapy have been employedbut the reported objective response rates have been 15% with CDDPand bleomycin (12), 42% CDDPand mitomycin (13), 29% with CDDP, bleomycin and vindesine (14), and 35 to 60% with CDDPand 5FU (1, 15-18), respectively. Cure is not possible and the prognosis for esophageal carcinomapatients remains unsatisfactory. Wedesigned the present study to evaluate the efficacy of combined Nedaplatin and 5FUfor advanced esophageal carcinomas, confirming and extending the original finding of a high Table 2. Response to Therapy Assess pts: responders/assessable patients, All pts: responders/all patients. Table 3. Response According to the Disease Site 846

4 Nedaplatin and 5FU in Esophageal Cancer Table 4. Toxidty Group A; patients who received 80 mg/nedaplatin/m2 and 350 mg 5FU/m2. Group B; patients who received mg/nedaplatin/m2 and 500 mg 5FU/m2. response rate for Nedaplatin alone in esophageal cancer patients in a phase II study (9) and the suggestion of synergic effects of Nedaplatin and 5FU in vitro (10). The CDDPand 5FU combination has been considered the standard regimen for patients with esophageal carcinomas ( 1 ), and Kies et al (15) andajani et al (16) have both reported high response rates of about 60%for resectable or localized tumors. However, for patients with metastatic, recurrent, or bulky unresectable cancer, Iizuka et al reported a response rate of only 35.9% (17), similar to the 36% of Bleiberg et al (18). With the present Nedaplatin and 5FUcombination chemotherapy, a response rate of 60%in assessable patients was achieved with a duration time of 7 (range 3 to 37+) months for advanced esophageal carcinomas. Moreover, this combination appeared especially effective for liver metastases, as well as primary tumors and lymph node metastases (Table 3), without unacceptable side effects (Table 4). From our dose finding study, we recommend100 mg Nedaplatin/m2 and 500 mg 5FU/m2. Although the possibility of allergic responses should be taken into account, Nedaplatin has only limited nephrotoxicity and the patients did not need hydration (9); several were able to receive the combination therapy as outpatients via an infusion pump. In this study, three responders received additional radiotherapy in the late period of their therapy, but the merits were unclear due to the small number. A phase II study of the combination of Nedaplatin and 5FU for advanced esophageal cancers should be planned. Further studies of the combination of Nedaplatin and 5FUfor early stage disease are also warranted, as well as investigations of their efficacy in conjunction with radiotherapy and/or surgery. In conclusion, the Nedaplatin and 5FU combination appears promising for treatment of advanced esophageal cancers. References 1) Ajani AJ. Contributions of chemotherapy in the treatment of carcinoma of the esophagus: results and commentary. Semin Oncol 21: , ) Herskovic A, Martz K, al-sarraf M, et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 326: , ) Bates BA, Detterbeck FC, Bernard SA, Qaqish BF, Tepper JE. Concurrent radiation therapy and chemotherapy followed by esophagectomy for localized esophageal carcinoma. J Clin Oncol 14: , ) Stahl M, Wilke H, Fink U, et al. Combined preoperative chemotherapy and radiotherapy in patients with locally advanced esophageal cancer: Interim analysis of a phase II trial. J Clin Oncol 14: , ) al-sarraf M, Martz K, Herskovic A, et al. Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an intergroup study. J Clin Oncol 15: , ) Urba SG, Turrisi III AT. Split-course accelerated radiation therapy combined with carboplatin and 5-fluorouracil for palliation of metastatic or unresectable carcinoma of the esophagus. Cancer 75: , ) Leichman L, Berry BT. Experience with cisplatin in treatment regimens for esophageal cancer. Semin Oncol 18: 64-72, ) Totani T, Aono K, Komura M. Synthesis of (Glycolato-o, o') diammine platinum (II) and its related complexes. Chemistry Letters, 1986: ) Taguchi T, Wakui A, Nabeya K, et al. A phase II clinical study of cisdiammine glycolato platinum, 254-S, for gastrointestinal cancers. Jpn J Cancer Chemother 19: , ) Furukawa S, Yoshida T, Tukuda M, et al. Experimental study on combination chemotherapy with platinum compounds and 5-fluorouracil. Jpn J Cancer Chemother 16: , ) Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 47: , ) Coonley CJ, Bains M, Hilaris B, Chapman R, Kelsen DP. Cisplatin and bleomycin in the treatment of esophageal carcinoma, a final report. Can- 847

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