Japanese Journal of Clinical Oncology 33:584-588 (2003)
© 2003 Foundation for Promotion of Cancer Research
Histological Complete Response in a Case of Advanced Gastric Cancer Treated by Chemotherapy with S-1 Plus Low-dose Cisplatin and Radiation
1 Department of Surgery, 2 Department of Internal Medicine, 3 Department of Radiology, and 4 Center for Diagnostic and Therapeutic Endoscopy, School of Medicine, Keio University, Tokyo, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONCASE REPORTDISCUSSIONREFERENCES |
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A 76-year-old male was diagnosed with stage IV (cT4, cN2, cP0, cH0, cM0) gastric carcinoma with a type 3 tumor in the cardia with lymph node metastases, determined by gastrofiberscope and abdominal computed tomography (CT). The patient was treated with chemotherapy consisting of S-1 and low-dose cisplatin (CDDP) during the first cycle (3 weeks). S-1 was orally administered at a dose of 100 mg/day (60 mg/m2/day) on days 1–21. CDDP was infused at a dose of 10 mg/day (6 mg/m2/day) on days 1–5, 8–12 and 15–19. After this cycle, the clinical response was evaluated as no change (NC). In the second cycle, radiation therapy (2 Gy/day for 5 days/week) was initiated along with the chemotherapy. The CDDP dose was decreased to 7.5 mg/day because of the grade 3 thrombocytopenia and grade 2 leukocytopenia that occurred during the first cycle. The second cycle was stopped at a total radiation dose of 48 Gy due to grade 3 thrombocytopenia and grade 2 leukocytopenia. Examination after this treatment showed remarkable reduction of tumor volume in the primary lesion and lymph nodes, which was defined as a partial response (PR). The patient then underwent total gastrectomy with D1 lymph node dissection. The postoperative course was uneventful without surgical complications. At this time, no gastric cancer cells were detected in the resected specimen, including the primary lesion and lymph nodes, confirming a pathological complete response (CR grade 3). Thus, the chemo-radiation treatment regimen described here may be a potent tool to control advanced gastric carcinoma.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONREFERENCES |
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According to the Japanese Gastric Cancer Association guidelines, surgery is currently the only recommended treatment for patients with gastric cancer (1). Stage I early gastric cancer is cured by surgery, with high certitude. However, for stage III and IV advanced gastric cancer, surgical treatment alone is not regarded as the definitive standard treatment, since the 5-year survival rates of stage III and IV patients were reported to be less than 50% even when a curative operation was performed (2,3). While several regimens of adjuvant chemotherapy reportedly improve patient survival, a standard chemotherapy regimen for gastric cancer has not yet been established. Thus, new effective regimens are sought for, which could be used pre or postoperatively.
S-1 is an oral 5-fluorouracil (5-FU) derivative consisting of tegafur, gimeracil and oteracil. Gimeracil (5-chloro-2,4-dihydropyrimidine) is a dihydropyrimidine dehydrogenase (DPD) inhibitor. DPD degrades 5-FU. Oteracil (monopotassium 1,2,3,4-tetrahydro-2,4-dioxo-1,3,5-triazine-6 carboxylate) reduces gastrointestinal toxicity by phosphorylating 5-FU (4–6). Previous reports have shown an approximately 50% response rate in advanced gastric cancer patients treated with S-1 (7–9). S-1 used in combination with other drugs is expected to provide an even better response rate. Indeed, CDDP used in combination with S-1 shows a more effective response rate. This combination shows high efficacy in advanced gastric cancer patients without severe adverse effects, and it maintains the patient’s quality of life (10,11).
The effectiveness of preoperative radiation still remains unclear, as several reports have shown conflicting results (12,13). Recently, radiation has been shown to achieve loco-regional control of cancer cells and may improve the prognosis of gastric cancer patients (14–16). In this report, we describe a preoperative chemo-radiotherapy regimen which could achieve a pathological complete response (pCR; grade 3) in a stage IV gastric cancer patient.
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CASE REPORT |
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Definitions and Drugs
We evaluated the effect of combination chemotherapy with S-1 and low dose CDDP (TSLD). The definitions of the Japanese Gastric Cancer Association (1) were utilized in staging and in both radiological and histological evaluation of the treatment effects. The toxicity of TSLD was classified using the CTC v: Cancer Therapy Evaluation Program version 2.0 (17). S-1 (Taiho Pharmaceutical, Tokyo, Japan) was prescribed as an orally administered drug, and CDDP was purchased from Nihon Kayaku Co. Ltd., Tokyo, Japan.
Evaluation before Therapy
A 76-year-old male visited our hospital with complaints of epigastric pain. His hemoglobin level was 9.3 g/dl. His serum levels of Carcinoembryonic Antigen (CEA) and CA19-9 were 2.1 U/ml and 21 U/ml, respectively. Endoscopy of the upper gastrointestinal tract (GIF) showed type 3 advanced gastric carcinoma that had invaded the esophagus (Fig. 1a, b). A biopsy specimen revealed moderately to poorly differentiated adenocarcinoma. Abdominal computed tomography (CT) showed that the tumor had invaded the stomach wall, the esophagus and the diaphragm (Fig. 2a). Metastases were present in the lymph nodes around the stomach and along the left gastric artery (Fig. 2b). The patient was diagnosed with stage IV (cT4, cN2, cH0, cP0, cM0) advanced gastric carcinoma according to the Japanese classification of gastric carcinoma. Resection of the tumor along with the diaphragm might be an alternative surgery without any preoperative therapy. On the other hand, it is well-known that the prognosis of stage IV gastric cancer is very poor by means of surgery alone. We regarded the case as a stage IV case incurative by surgery; therefore, we attempted a novel approach with chemo-radiotherapy, to obtain a better prognosis. The patient’s informed consent was obtained after providing him with detailed information on stage IV gastric cancer and its prognosis.
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), and the lesion surrounded the abdominal esophagus (
), incurative surgery was predicted as a result of cancer invasion into the diaphragm (T4). (b) Abdominal CT before chemo-radiotherapy showed the wall-thickness of the stomach and lymph nodes metastases. Arrows indicate suspected metastatic lymph nodes around the celiac axis. (c) Abdominal CT after chemo-radiotherapy revealed reduced mass formation around the cardia (The First Cycle of Combination Chemotherapy
The chemotherapy schedule consisted of one cycle every 3 weeks. S-1 was administered orally at a dose of 100 mg/day (60 mg/m2/day) every day on days 1–21. CDDP was infused at a dose of 10 mg/day (6 mg/m2/day) for 1 hour on days 1–5, but was not infused on day 6 and 7. This was repeated three times; on days 1–5, 8–12 and 15–19. After 3 weeks (one cycle), endoscopy and imaging examinations were performed to evaluate the clinical response to the chemotherapy. Endoscopic findings revealed no change (NC) in the primary lesion. Similarly, abdominal CT revealed no change in lymph node size compared with the previous size. The patient’s CEA and CA19-9 was 2.5 U/ml and 12 U/ml, respectively. Adverse reactions (grade 3 thrombocytopenia and grade 2 leukocytopenia) were observed during the first cycle.
Addition of Radiation Therapy
The second cycle of chemotherapy was initiated along with radiation therapy. Radiation was targeted at the primary tumor (in the cardia of the stomach and in the lower part of the thoracic and abdominal esophagus) and to the surrounding lesions, including the lymph nodes. The irradiation was performed using 6MV Linac. Radiation therapy was planned using a CT simulator for two rectangular portals (anterior and left lateral) with a pair of 45-degree wedge filters. The spinal cord and left kidney were not included in the left lateral field, and they were irradiated at <40% of the maximum iso-dose. Due to adverse reactions (grade 3 thrombocytopenia and grade 2 leukocytopenia) during the first cycle, the dose of CDDP was decreased to 7.5 mg/day. Radiation therapy (5 days/week) at 2 Gy/day was started concurrently with chemotherapy. The chemo-radiotherapy was stopped on day 18 of the cycle due to toxicity (grade 3 thrombocytopenia, grade 2 leukocytopenia and grade 2 dermatitis). The final total doses of S-1 and CDDP were 3900 mg and 255 mg, respectively, and the total dose of radiation was 28 Gy.
Clinical Evaluation of the Treatment
The clinical response was evaluated at the end of chemo-radiotherapy. GIF showed that the ulcerative lesion in the cardia was smaller and no tumor was present in the esophagus (Fig. 1c, d). Moreover, no viable cancer cells were detected in specimens endoscopically biopsied from the ulcerative lesion in the cardia. Abdominal CT revealed reduced thickness of the cardia walls and no observable tumor in the diaphragm (Fig. 2c). The gastric regional lymph nodes were not detectable (Fig. 2d). The patient’s CEA and CA19-9 were 2.7 U/ml and 10 U/ml, respectively. This clinical response was classified as a partial response (PR) according to World Health Organization (WHO) criteria (18).
Surgical Treatment
Surgery was performed on the 18th day after chemo-radiotherapy. Laparotomy revealed neither ascites nor peritoneal dissemination, and cytological examination of the peritoneal washes was negative. The primary tumor was located at the lesser curvature of the esophago-cardiac junction and had formed a giant mass involving the esophagus, diaphragm and marginal lymph nodes. Fibrous changes were observed around the tumor, and partial resection of the diaphragm was needed for mobilization of the tumor. Lymph nodes along the lesser curvature and around the cardia were considerably swollen, while the lymph nodes along the left gastric artery were not palpable. Total gastrectomy with D1 lymph node dissection was performed.
Histopathological Findings
The macroscopic appearance of the primary tumor showed an irregular depressed lesion with erosive changes in the mucosa of the lesser curvature of the cardia (Fig. 3a). The tumor was classified as a 0-III type tumor. The increased wall thickness was attributed to fibrosis (Fig. 3b). Microscopically, no gastric cancer cells were detected in the resected specimen, including tissues from the primary lesion and lymph nodes, confirming the pCR observed after preoperative chemo-radiotherapy. Fibrosis with marked lymphocytic infiltration was observed in the primary tumor, but no residual cancer cells were observed (Fig. 3c).
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Postoperative Course
The postoperative course was uneventful with no surgical complications. The patient was hospitalized for 122 days for treatment with preoperative chemo-radiotherapy and surgery, and was discharged 30 days after surgery. The patient received no adjuvant chemotherapy and is alive without recurrence, 8 months after surgery and 11 months after the initial chemotherapy.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONREFERENCES |
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The prognosis of advanced gastric cancer is poor, even in patients who have successfully undergone curative surgery (2,3). In highly advanced gastric cancer with regional lymph node metastases, surgery may remove visible tumor masses but microscopic cancer cells may still exist in the blood, lymphatic system or peritoneal cavity, resulting in local recurrence, distant metastases or peritoneal dissemination after macroscopically curative surgery. Although a number of researchers and clinicians have attempted to control such microscopic cancer cells by means of adjuvant chemotherapy after surgery, a consistent, efficacious regimen has not yet been established.
The novel anticancer drug S-1 has demonstrated an approximately 50% response rate in patients with advanced gastric cancer (7–9). S-1 is a 5-FU derivative consisting of tegafur, gimeracil (which inhibits the 5-FU degradation enzyme) and oteracil (which reduces gastrointestinal toxicity). The antitumor effects of 5-FU are reportedly modulated by CDDP, and in clinical practice, 5-FU/CDDP combination chemotherapy is a standard therapy for gastric cancer (19,20). Therefore, combination S-1/CDDP is also expected to show favorable antitumor activity. Low-dose CDDP is as effective as high-dose CDDP and is less toxic. Therefore, we used S-1 and low-dose CDDP (TSLD) to treat our patient. We have previously reported a clinical pilot study using TSLD for nine patients with unresectable or incurable stage IV gastric cancer (10). Of the nine patients who received TSLD, five showed histological effectiveness evaluated as greater than grade 1b. However, no patient achieved grade 3 effectiveness (10).
While the role of preoperative radiation for gastric cancer has been controversial in previous studies (12,13), some studies in highly advanced gastric cancer patients have shown a measurable survival benefit with this treatment (14–16). Although S-1/CDDP regimen showed a high response rate, we could not obtain a histological grade 3 response by chemotherapy alone. After observing the postoperative course of patients with grade 2 histology, it became evident that the patients with a grade 2 response did suffer from cancer recurrence and death. Macdonald et al. reported the clinical efficacy of chemo-radiotherapy in improving the survival of advanced gastric cancer patients (16). We have thus attempted to supplement the S-1/CDDP regimen with radiation therapy to obtain higher antitumor activity, which was proven in this case with a histological grade 3 response. Regarding the toxicity of this regimen, the patient experienced grade 3 thrombocytopenia and grade 2 leukocytopenia. The patient recovered from myelosuppression with the use of granulocyte-colony stimulating factor and surgery was successfully completed without any postoperative complications. Thus, the TSLD regimen appears to be relatively well tolerated.
In the present case, a histological examination of the resected specimen showed no detectable cancer cells. Therefore, we believe that radiation therapy combined with systemic chemotherapy eradicated both the primary tumor and all the metastases in this patient. These encouraging results suggest that this regimen is an effective strategy for the treatment of advanced gastric cancer. Given the generally poor prognosis of these patients, our regimen should be further evaluated to determine its efficacy and toxicity in a larger patient population. We are currently conducting a phase I study for stage IV patients with the aim of achieving complete response in stage II, stage III and a part of stage IV gastric cancer patients using preoperative chemo-radiotherapy.
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FOOTNOTES |
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+ For reprints and all correspondence: Yoshiro Saikawa, Department of Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail: saiky{at}sc.itc.keio.ac.jp
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REFERENCES |
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Received June 14, 2003; accepted October 6, 2003
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