Abstract
Background: The prognosis for advanced gastric cancer is poor, with surgery as the only treatment for resectable advanced gastric cancer. Therefore, treatment options that might improve the prognosis are needed. To that end, neoadjuvant chemoradiotherapy with S-1 and cisplatin (CDDP) was investigated. Patients and Methods: The chemotherapy schedule included one cycle repeated after 6 weeks. S-1 was administered orally every day on days 1-21 and CDDP was infused on days 1, 8 and 15. Radiation therapy was started concurrently with chemotherapy and repeated daily on days 1-5, 8-12, 15-19, and 22-26. Results: A total of 10 patients were recruited. The first four patients were entered into level 1 (CDDP, 20 mg/m2 ). The next six patients were entered into level 0 (15 mg/m2 ), because of dose-limiting toxicity (delaying the second course of chemotherapy in two patients) that had been observed at level 1. The maximum tolerated dose (MTD) of CDDP was 20 mg/m2 . Seven patients underwent surgery and all had an R0 (no residual tumor) resection without surgical complications. Conclusion: Neoadjuvant chemoradiotherapy with S-1 and CDDP may cause surgery to be delayed, but shows promise for resectable advanced gastric cancer.
Surgery plays the most important role in the treatment of patients with resectable gastric cancer. The prognosis for a patient with early gastric cancer who undergoes curative surgery is favorable, with a 5-year survival rate of approximately 90% (1, 2). However, the prognosis for advanced gastric cancer remains poor because of a high rate of metastasis or recurrence. In western countries, adjuvant chemoradiotherapy with fluorouracil plus leucovorin, along with radiation, has been one of the standard therapies, after curative surgery for patients with advanced gastric cancer (3), while in Japan, adjuvant chemotherapy with S-1 is recommended in this setting (4). Recent clinical trials had shown survival benefits of adjuvant chemotherapy after curative resection compared with surgery alone (4, 5). However, there is still a great need for further treatment improvements for patients with advanced gastric cancer, especially highly advanced local cases. It is necessary for these patients to receive more potent adjuvant chemotherapy, such as a combination regimen, to prolong survival. However, it is difficult for postoperative patients to receive such potent adjuvant chemotherapy and compliance is low. Therefore, neoadjuvant chemotherapy has been highlighted in the last decade (6-10). Neoadjuvant chemotherapy has several potential advantages including reducing the viability of micrometastasis, increasing the rate of curability, enhancing treatment compliance and allowing evaluation of chemosensitivity. The most important potential benefit of neoadjuvant chemotherapy is high therapeutic efficacy against the primary tumor and regional lymph node metastases, resulting in prevention of local recurrence and distant metastasis.
Recently, combination chemotherapy with S-1 and cisplatin (CDDP) was shown to be well tolerated and to have high efficacy in a randomized phase III trial, and was recognized as one of the standard regimens for first-line treatment for highly advanced gastric cancer (11). Since 2002, we have treated unresectable and recurrent gastric cancer patients with chemoradiotherapy consisting of S-1 and CDDP and reported high efficacy and tolerable toxicity (12-14). Based on these experiences, chemoradiotherapy with S-1 and CDDP is a promising candidate for evaluation as a preoperative therapy for highly advanced gastric cancer.
In the present phase I study, chemoradiation therapy for the treatment of resectable advanced gastric cancer was evaluated to determine the maximum-tolerated dose (MTD) and recommended dose (RD) of CDDP, and also to examine the preliminary therapeutic effect of this combination therapy.
Patients and Methods
Eligibility criteria. Eligibility criteria included: histological confirmation of gastric adenocarcinoma; curable clinical Stage III or IV disease according to the criteria of the Japanese Research Society for Gastric Cancer (15); age >20 and <80 years; performance status (PS) 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Scale; no prior chemotherapy; adequate liver and renal function and the ability to take medications orally. All the eligible patients provided written informed consent to participate.
Schedule of neoadjuvant chemoradiotherapy. S-1 and CDDP were purchased from Taiho Pharmaceutical Co. Ltd. (Tokyo, Japan) and Yakult Honsya Co. Ltd. (Tokyo, Japan), respectively. The chemotherapy schedule consisted of one cycle repeated after 6 weeks. S-1 was administered orally every day on days 1-21 and the total dose was based on the patient's body surface area (BSA) as follows: less than 1.25 m2, 80 mg; 1.25-1.5 m2, 100 mg and greater than 1.5 m2, 120 mg. CDDP was infused on days 1, 8 and 15 as a 1 h intravenous infusion without hydration. The dose range of CDDP selected for possible administration in the study was 15 mg/m2 to 30 mg/m2. The starting dose of CDDP, given to the first three patients enrolled, was 20 mg/m2 (defined as level 1). Dose levels of CDDP, which could be given to subsequent cohorts of patients depending of safety results observed in the previous cohort (detailed in the next paragraph), were as follows: 15 mg/m2 (level 0); 20 mg/m2 (level 1); 25 mg/m2 (level 2); and 30 mg/m2 (level 3). Radiation therapy (5 days/week) at 2 Gy/day was started concurrently with chemotherapy and repeated daily on days 1-5, 8-12, 15-19 and 22-26. Irradiation was planned using a computed tomography (CT) simulator for two rectangular portals (anterior and left lateral) with a pair of 45-degree wedge filters and was targeted at the primary tumor and surrounding lesions, including lymph nodes. After the initial chemoradiation therapy, the chemotherapy with S-1 and CDDP was repeated within 2 weeks after the termination of radiotherapy. The treatment schedule is summarized in Figure 1.
Determination of maximum tolerated dose (MTD) and recommended dose (RD). Toxicity was evaluated by Common Terminology Criteria for Adverse Events (v 3.0) (16). The dose limiting toxicity (DLT) was defined as: Grade 4 neutropenia; Grade 4 leukocytopenia; Grade 4 thrombocytopenia; higher than Grade 3 febrile neutropenia; higher than Grade 3 non-hematological toxicity excluding anorexia, nausea and vomiting; delay of more than 10 days for initiation of the second course of chemotherapy; delay of more than 10 days for the day 8 and day 15 infusions of CDDP; failure to complete radiation within 45 days or surgery not performed within 42 days after completion of the second cycle of chemotherapy. At each dose level beginning with level 1 (20 mg/m2), three patients were enrolled. If DLT was recognized in one of the three patients, three additional patients were to be evaluated at that dose level. If two patients experienced DLT at the same dose level, that level was defined as the MTD. The RD was defined as the dose level below the MTD.
Patient characteristics.
Clinical evaluation. Abdominal CT and upper gastrointestinal (UGI) endoscopy were evaluated during each treatment cycle. The clinical response to preoperative treatment was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) for metastatic lesions and the Japanese Research Society for Gastric Cancer criteria for the primary lesion (17).
Surgery. After the second cycle of preoperative treatment, radiological and endoscopic examinations were carried out to evaluate efficacy, resectability and curability. Surgery was scheduled to take place within 6 weeks after completion of the second cycle of chemotherapy. If surgical findings revealed nothing to indicate incurability such as peritoneal dissemination or positive lavage cytology, gastrectomy was performed with D2 lymph node dissection. All the resected specimens, including the lymph nodes, were examined to evaluate pathological response to the preoperative treatment according to the Japanese Research Society for Gastric Cancer criteria for primary lesions (15).
Results
Patient characteristics. Between March 2010 and January 2011, 10 patients were entered into this study and underwent preoperative chemotherapy. The patient characteristics are summarized in Table I. All the patients had regional lymph node metastases but no distant metastasis except para-aortic lymph node metastasis.
Maximum tolerated dose (MTD) and recommended dose (RD). The hematological and non-hematological toxicity of chemoradiotherapy are summarized in Table II. The main toxicity was hematological, especially leukocytopenia and neutropenia. No patient experienced higher than Grade 2 non-hematological toxicity. Among the first three patients enrolled at level 1, one patient was unable to complete the first treatment cycle because of myelosuppression (Table III). The next additional patient enrolled at level 1 was unable to complete radiotherapy because of leukocytopenia. Therefore, the next cohort of three patients was enrolled at a lower dose level (level 0), with one of these patients unable to complete the first treatment cycle because of myelosuppression. Among the next three additional patients entered at level 0, none experienced DLT. According to these results, MTD and RD were determined at level 1 (20 mg/m2) and level 0 (15 mg/m2), respectively.
Treatment schedule.
Adverse events.
Dose limiting toxicity.
Clinical outcomes. The clinical outcomes are summarized in Table IV. The clinical response was evaluated after two courses of preoperative treatment. Three out of the four patients at level 1 and four out of the six patients at level 0 were evaluated as having a partial response (PR). There was no patient with either a complete response (CR) or progressive disease (PD). The overall response rate was 70%. Seven out of the 10 patients enrolled in the study completed the preoperative treatment without DLT and underwent surgery; all seven of these patients achieved curative resection with negative results after lavage cytology. Six patients had a total gastrectomy and one had a distal gastrectomy. The median operating time was 257 min and the median blood loss was 625 ml. Postoperative complications developed in two patients. There were no major surgical complications such as anastomotic leakage or pancreatic fistula. The pathological examination of resected specimens showed that the grades of histological therapeutic effect were Grade 1a in two patients, Grade 1b in two patients and Grade 2 in two patients. One patient had no viable cancer cells either in the primary tumor or lymph nodes, which is classified as a Grade 3 histological therapeutic effect and represented a pathological CR to chemoradiotherapy.
Discussion
The RD of CDDP was defined as 15 mg/m2 weekly (level 0). High incidences of leukocytopenia and neutropenia, more severe than Grade 3, were observed when CDDP was administered at 20 mg/m2 (level 1). In two out of four patients at level 1, the second course of chemotherapy could not be started within the protocol specified schedule because of these hematological adverse events. Although one out of the first three patients receiving CDDP at 15 mg/m2 (level 0) required a delay before starting the second course of preoperative therapy because of hematological adverse events, the next three patients at level 0 received preoperative therapy as scheduled. No non-hematological toxicity more severe than Grade 3 or treatment-related deaths were observed. These results support the safety and feasibility of chemoradiotherapy consisting of S-1 and CDDP (15 mg/m2) as preoperative treatment for patients with resectable advanced gastric cancer.
Clinical outcomes.
Previously, we observed high efficacy and tolerability of chemoradiotherapy consisting of S-1 and CDDP in patients with incurable advanced gastric cancer (12-14). Radiation is a potent therapy for the primary tumor and regional lymph node metastases, and is expected to improve the rate of curable resection and local recurrence (3, 18). In the current study, although highly advanced local cases with serosal invasion and metastases of the regional lymph nodes were included, all the patients who underwent surgery were able to receive a curative resection. Five out of the seven patients who underwent surgery showed at least a Grade 1b histological therapeutic effect, with one of these patients showing a Grade 3 effect for both the primary tumor and lymph nodes. Thus, chemoradiotherapy consisting of S-1 and CDDP appears to be a promising strategy for preoperative treatment.
However, some concerns have surrounded neoadjuvant treatment including the possibility of missing an opportunity for surgery and uncertainty regarding treatment safety and possible association with surgical complications. In the current study, seven out of 10 patients underwent curative surgery after preoperative chemoradiotherapy according to the treatment plan. So, in terms of allowing an opportunity for surgery, neoadjuvant chemoradiotherapy seems feasible. Surgical complications were tolerable and no major surgical complications such as anastomotic leakage or pancreatic fistula occurred. Postoperative complications occurred in two cases. One patient developed pneumonia and recovered with antibiotics. Another patient showed chylous ascites, which resolved without additional intervention. In addition, there were no treatment-related deaths in this study.
In conclusion, the recommended dose of CDDP is 15 mg/m2 weekly and its safety and feasibility as a preoperative therapy are supported in this study. Although it is necessary to address myelosuppression especially during simultaneous chemotherapy and radiotherapy, neoadjuvant chemoradiotherapy of highly locally advanced gastric cancer can provide remarkable shrinkage of tumors; increases in curability rate would be expected to follow. Further clinical trials in a larger number of patients are recommended to evaluate the feasibility of neoadjuvant chemoradiotherapy with S-1 and CDDP as a standard treatment strategy for resectable advanced gastric cancer.
- Received May 19, 2011.
- Revision received July 6, 2011.
- Accepted July 7, 2011.
- Copyright© 2011 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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