Longterm survival of a Western patient with metastatic gastric cancer ...

Gastric Cancer (2006) 9: 140–143 DOI 10.1007/s10120-006-0363-x

” 2006 by International and Japanese Gastric Cancer Associations

Case report Longterm survival of a Western patient with metastatic gastric cancer treated with S-1 plus cisplatin Eric D. Tetzlaff, Josephine Faust, and Jaffer A. Ajani Department of Gastrointestinal Medical Oncology, Box 426, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA

Abstract The prognosis for patients with metastatic gastric cancer is poor. Fewer than 10% of patients with metastatic gastric cancer live beyond 2 years. Chemotherapy is offered with a palliative intent. We report the case of a Western patient with metastatic gastric cancer successfully treated with S-1 plus cisplatin. S-1 was administered orally every 12 h at a dose of 30 mg/m2 (60 mg/m2 daily) for 21 consecutive days, followed by 7 days of recovery. Cisplatin was administered intravenously on day 1, at a dose of 60 mg/m2. The cycles were repeated every 28 days. The patient first received seven cycles of S-1 plus cisplatin; however, cisplatin was discontinued secondary to nephrotoxicity, and S-1 was administered alone for an additional five cycles. The patient achieved a clinical complete response to S-1 plus cisplatin. The complete response has now been maintained for 12 months without any chemotherapy. A total of 28 months have elapsed since the date of registration on the study and the patient currently has no symptoms. This patient exemplifies the strategy of maintenance therapy with S-1 alone and shows a prolonged and excellent response to S-1 and cisplatin. Key words Cisplatin · Complete response · Gastric cancer · Metastases · S-1

Introduction The American Cancer Society estimated that there would be 21 860 new cases of gastric cancer diagnosed in the United States in 2005 [1]. Many of these cases would have been diagnosed after the cancer had already metastasized, when the relative 5-year survival rate is 3.1% [2]. Chemotherapy is offered to patients with metastatic gastric cancer for palliative purposes, and there is improvement in overall survival as compared to best

Offprint requests to: J.A. Ajani Received: October 27, 2005 / Accepted: January 18, 2006

supportive care [3,4]. Several chemotherapy agents are considered active in advanced gastric cancer; they include fluorouracil (FU), cisplatin, irinotecan, oxaliplatin, and taxotere [5]. Combination chemotherapy regimens have been developed in hopes of improving the response rate and overall survival. Unfortunately, the benefits of combination chemotherapy have been modest and no regimen is considered standard worldwide [5]. New chemotherapy regimens and agents are needed for the treatment of metastatic gastric cancer. S-1 is a fourth-generation oral fluoropyrimidine that is a formulation of tegafur (FT), 5-chloro-2-4dihydroxypyridine (CDHP), and potassium oxonate (oxo) [6]. FT is the prodrug for fluorouracil (FU) and CDHP prevents its degradation, and in animal models oxo is protective against FT-induced diarrhea [7]. S-1 is active as a single agent in gastric cancer, with response rates ranging from 26% to 45% [8–10]. Dramatic responses have been reported, such as the eastern patient with a complete response to S-1 alone [11]. However, the combination of S-1 and cisplatin appears more promising, and in a Japanese study, it resulted in a response rate of 76% [12]. The experience with S-1 plus cisplatin in Western patients is limited. A phase I pharmacokinetic study of S-1 plus cisplatin in Western patients defined the maximum tolerated dose of S-1 plus cisplatin [13]. This study found that the dose of S-1 tolerated by Western patients was lower than that for Japanese patients. It was proposed that the lower tolerated dose of S-1 was related to polymorphic differences in the key CYP2A6 gene. A follow up phase II study of S-1 plus cisplatin has been performed; the interim overall response rate was 65% and the median survival had not been reached [14]. Longterm survivals of Western patients with metastatic gastric cancer treated with S-1 plus cisplatin have not been reported. Herein we report the long-term survival of a patient in the Western hemisphere with metastatic

E.D. Tetzlaff et al.: Longterm survival with S-1 + cisplatin of Western patient with metastatic GC

gastric cancer who participated in the phase I study of S-1 plus cisplatin.

Case report Staging and classification The American Joint Committee on Cancer (AJCC) staging classification for carcinoma of the stomach was utilized for staging [15]. The toxicity to S-1 plus cisplatin was classified using the National Cancer Institute Common Toxicity Criteria version 2.0 (NCI CTC) and the Response Evaluation Criteria in Solid Tumors was used to assess response [16,17]. Initial presentation and evaluation A 60-year-old African American man presented with dyspepsia, nausea, and anemia. An esophagogastroduodenoscopy revealed a large fungating mass in the body of the stomach. Histological examination revealed poorly differentiated adenocarcinoma. Computed tomography (CT) of the chest, abdomen, and pelvis revealed a large lobulated gastric mass; large peritoneal implants abutting the gastric antrum, transverse mesocolon, and within the ileocolic mesentery; and gastrohepatic lymphadenopathy (Fig. 1). No thoracic metastatic disease was identified. The baseline staging was determined to be stage IV metastatic gastric cancer based on the AJCC staging criteria. Baseline laboratory studies revealed anemia, with a hemoglobin level of 10.8 g/dl, normal liver function tests, and a creatinine clearance of 96 ml/min. The serum carcinoembryonic antigen (CEA) was 1.6 ng/ml. Combination chemotherapy and adverse events The patient was enrolled in a phase I pharmacokinetic study of S-1 plus cisplatin. The protocol was approved by the institutional review board and the patient signed

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B

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the written informed consent. S-1 was administered orally every 12 h at a dose of 30 mg/m2 (60 mg/m2 daily) for 21 consecutive days, followed by 7 days of rest. Cisplatin was administered intravenously on day 1 at a dose of 60 mg/m2 over 120 mins. Standard premedications and hydration were used. The dose of cisplatin was reduced by 25% to 45 mg/m2 after cycle 4 and further reduced by 50% after cycle 5, to 22.5 mg/m2, secondary to nephrotoxity (creatinine clearance decreased to 38.4 ml/min and 49.2 ml/min during cycles 4 and 5, respectively). Following cycle 7, cisplatin was discontinued secondary to persistent nephrotoxicity and S-1 was continued as single-agent chemotherapy. Dose reductions in S-1 were not required during treatment. After an additional five cycles of S-1 alone he was taken off the study, because a clinical complete response was maintained. Overall, he received seven cycles of S-1 plus cisplatin, and an additional five cycles of S-1 alone. Overall, treatment was well tolerated. The patient did not experience any grade 3 or 4 adverse events while on combination chemotherapy or S-1 alone. Grade 1 and 2 adverse events were easily managed in the outpatient setting. Adverse events during any cycle of therapy are presented in Table 1.

Table 1. Adverse events during treatment Adverse events

NCI CTC Grade

Nausea/Vomiting Diarrhea Mucositis Anorexia Weight loss Fatigue Abdominal (cramping/pain) Neuropathy Ocular (sensitivity/tearing) Anemia Neutropenia Serum creatinine Hand-foot syndrome

2/2 1 1 1 1 1 1/2 2 2/2 2 2 2 2

Fig. 1A,B. Computed tomography at baseline. A A large and lobulated gastric carcinoma. B Metastatic peritoneal implant

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Radiographic response At baseline, two target lesions were identified to assess the response to S-1 plus cisplatin; a gastrohepatic lymph node that measured 2.2 × 2.0 cm and a peritoneal mass that measured 2.5 × 2.8 cm. The radiographic response was evaluated following cycle 1, and revealed a partial response. The baseline gastrohepatic lymph node decreased from 2.2 × 2.0 cm to 1.2 × 1.0 cm and the peritoneal mass that measured 2.5 × 2.8 cm at baseline was not visualized on the restaging CT scan. The lobulated mass in the stomach was not visualized, but circumferential thickening in the body and antrum of the stomach remained. A partial response was confirmed following cycle 2, as the gastrohepatic lymph node measured 1.0 × 1.0 cm and the peritoneal mass was again not seen (Fig. 2). Further improvement in the gastric primary was again noted. Following cycle 10, the gastrohepatic lymph node was no longer visualized, all target and nontarget lesions were not seen, and there was no evidence of new metastases. A pathological complete response has not been confirmed and is not expected. His most recent staging evaluation did not reveal any evidence of metastatic disease within the chest, abdomen, or pelvis. As of this writing, 28 months have elapsed since the start of S-1 plus cisplatin and the patient has maintained a clinical complete response for more than 12 months since discontinuing all anticancer therapy.

Discussion There is a significant survival benefit of fluorouracil (FU)-based chemotherapy for unresectable advanced gastric cancer compared with best supportive care [3,4]. To improve on the results of FU-based chemotherapy, several combination chemotherapy regimens have been examined. Unfortunately, the results of various combination chemotherapy regimens have been disappoint-

Fig. 2A,B. Computed tomography following cycle 2. A The lobulated gastric mass has resolved, but gastric thickening remains. B The peritoneal mass is not visualized

ing and few patients with metastatic gastric cancer enjoy longterm survival. New agents need to be developed. There is considerable interest in the oral agent S-1 in the treatment of advanced gastric cancer. The S-1 compound was logically engineered to reduce the degradation of the active cytotoxic FU and potentially reduce the associated gastrointestinal toxicity. In Japan and Korea, S-1 is commercially available (Taiho Pharmaceuticals, Tokyo, Japan). There have been reports of patients in Japan with advanced gastric cancer effectively treated with S-1 with longterm survival. Yoshimizu et al. [18] reported the case of a patient with advanced gastric cancer treated with preoperative S-1 plus cisplatin with concurrent radiotherapy. The patient had a pathological complete response to chemoradiotherapy and was alive without recurrence 17 months following the initiation of chemotherapy. Hamada et al. [19] reported similar success in which they treated a patient with peritoneal dissemination from gastric cancer with neoadjuvant S-1 followed by total gastrectomy. The peritoneal disease disappeared by the time of surgery and the patient was living 23 months after the date of the resection without evidence of recurrence. Similar results have not been reported in Western patients treated with S-1. In the present report, we have described a Western patient who presented with a massive primary gastric tumor, distant lympadenopathy, and peritoneal implants. He was successfully treated with the oral agent S-1 plus cisplatin and achieved a complete clinical response. He enjoys longterm survival exceeding 28 months. Unlike the patients described in previous reports, the present patient was not treated with surgery or radiotherapy. In our patient, the decision to stop chemotherapy was made based on increasing toxicity (skin toxicity only) and the patient’s desire to have a chemotherapy-free interval. However, the point at which to discontinue systemic chemotherapy after a complete or partial response is not clear. The inconvenience, toxicity, and


expense of intravenous chemotherapy will strongly influence the decision to discontinue treatment in patients who obtain a complete response or are treated to maximum response. However, the concept of maintenance therapy with an oral agent such as S-1 is a very appealing option when one considers the schedule and toxicity of treatment. We should consider the new paradigm of treating with combination therapy until patients achieve maximum objective response and then maintain that response with the use of low-dose, minimally toxic maintenance therapy. By identifying potentially therapeutic molecular targets, such a concept can become reality. In conclusion, longterm survival was demonstrated in a patient with metastatic gastric cancer after treatment with S-1 plus cisplatin. A multicenter phase III study comparing S-1 plus cisplatin with cisplatin and fluorouracil is now accruing patients. Acknowledgments Supported in part by Taiho Pharmaceutical, New Jersey, United States.

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