We included all eligible patients from two clinical trials (JCOG0210 and JCOG0405) that were conducted by the JCOG. These phase II trials aimed to evaluate the efficacy and safety of neoadjuvant S-1 plus cisplatin in gastric cancer patients [7, 8]. The eligibility criteria of the JCOG0210 trial included linitis plastica (Borrmann type 4) and ulcero-invasive-type (Borrmann type 3) tumors. In the case of ulcero-invasive tumors, the size of the primary tumor was required to be 8 cm or larger. Between March 2003 and December 2003, 49 eligible patients were enrolled in the JCOG0210 trial. Responses to neoadjuvant chemotherapy were evaluated using JCGC criteria. After preoperative chemotherapy, 41 patients could undergo gastrectomy, which provided tissue samples for use in assessing the histological response to preoperative chemotherapy. Six patients failed in simple laparotomy because of the presence of incurable lesions. Two patients did not undergo surgery for reasons of chemotherapy-related death in one patient and refusal of any protocol treatment in one patient.
The eligibility criteria for the JCOG0405 trial included gastric cancer with paraaortic nodal metastases or bulky lymph nodes. Between February 2005 and June 2007, 51 eligible patients were enrolled in the JCOG0405 trial. Responses to neoadjuvant chemotherapy were evaluated with RECIST. After preoperative chemotherapy, 48 patients could undergo gastrectomy, which provided material to evaluate the histological response to preoperative chemotherapy. Three patients did not undergo surgery because of progressive tumor.
All patients in the JCOG0210 and the JCOG0405 trials gave written informed consent. These trials were approved by the JCOG Clinical Trial Review Committee and the institutional review board of each institution involved. Permission for the secondary use of trial data was included in patients’ informed consent for JCOG0210 and JCOG0405. The protocol of this correlative study (JCOG0507-A) was approved by the JCOG Protocol Review Committee. JCOG0405 is registered with UMIN-CTR (http://www.umin.ac.jp/ctr/), identification number C000000094.
The same chemotherapy regimen was used in each of the two trials. S-1 was given orally at 80 mg/m2 for the first 3 weeks of a 4-week cycle. Cisplatin was given as an intravenous infusion of 60 mg/m2 on day 8 of each cycle. Patients received two 4-week cycles of neoadjuvant S-1 plus cisplatin and then underwent gastrectomy with D2 (in the JCOG0210 trial) or D2 plus paraaortic lymphadenectomy (in the JCOG0405 trial). If curative resection was considered difficult after the second course, addition of a further course of chemotherapy before surgery was permitted only in the JCOG0405 trial. After surgery, no further treatment was given until tumor recurrence.
After the second course of neoadjuvant chemotherapy, tumor response was evaluated with JCGC criteria based on computed tomography (CT), barium X-ray, and endoscopic examination findings in the JCOG0210 trial, whereas response evaluation using RECIST in the JCOG0405 trial was based only on CT findings. These evaluations were performed by the central reviewers. Response evaluations based on RECIST were not conducted in the JCOG0210 trial because many patients did not have measurable lesions. We could not evaluate the JCGC response in the JCOG0405 trial because barium X-rays and endoscopic examinations were not performed after neoadjuvant chemotherapy.
With the JCGC criteria, overall tumor response depends on the combined responses of primary gastric lesions and metastatic lesions. The details of the JCGC criteria have been described elsewhere . Briefly, morphological changes of gastric lesions are evaluated by X-ray or endoscopic examinations, and the overall responses are classified into four categories: complete response (CR), partial response (PR), no change (NC), or progressive disease (PD). Measurable lesions with at least a 50 % decrease in total tumor size in two dimensions and at least a 30 % decrease in total tumor size in one dimension are classified as PR. Evaluable but nonmeasurable lesions with flattening on X-ray or endoscopic examination, or diffusely infiltrating lesions with at least 50 % enlargement of the gastric lumen in the tumor area by X-ray examination, are also classified as PR. CR or PR cases were treated as responders.
Surgical specimens were assessed histologically, and tumor response was evaluated according to the histological criteria of the JCGC . Briefly, histological evaluations were classified into five categories according to the proportion of the tumor affected by degeneration or necrosis: grade 3, no viable tumor cells remain; grade 2, viable tumor cells remain in less than 1/3 of the tumorous area; grade 1b, viable tumor cells remain in more than 1/3 but less than 2/3 of the tumorous area; grade 1a, viable tumor cells occupy more than 2/3 of the tumorous area; grade 0, no evidence of treatment effect. A histological responder was defined as a patient in whom one third or more of the tumor was affected (grade 1b, 2, or 3). Because the definition of histological responder is controversial, we also evaluated the results when a histological responder was classified as grade 2 or 3. Patients who did not undergo surgery were regarded as non-responders. These evaluations were performed by the pathologists at each institution.
The data from all eligible patients were analyzed in this study. Cases in which the tumor was not resected or could not be evaluated were treated as non-responders. With the methods used in this study, a comparison of the overall survival between responders and non-responders was said to have a pitfall because early death cases were classified into the non-responder group. In our study, however, there were no early deaths during the protocol treatment, which implies that minimal bias was induced by the classification system employed in our study.
The relationship of response and overall survival was evaluated using hazard ratios (HRs). The HR for death of responders to non-responders was estimated using the Cox proportional hazard model, and survival distributions were compared using the log-rank test. The difference in response rates between short- and long-term survivors was estimated and tested with Fisher’s exact test. Statistical analysis was performed with SAS version 9.2 (SAS Institute, Cary, NC, USA).