A phase II study of preoperative chemotherapy with S-1 plus cisplatin followed by D2/D3 gastrectomy for clinically serosa-positive gastric cancer (JACCRO GC-01 study)
Introduction
Gastric cancer remains the second leading cause of cancer death in the world and is the most frequent malignancy in Japan, South America, and Eastern Europe.1 Complete resection is essential for cure,2 and because more than half of T3 and T4 tumors have metastasized to lymph nodes along the major branch arteries or in the para-aortic area, complete resection has involved D2 or D3 dissection in Japan.3, 4 However, despite resection of these tumors with curative intent, prognosis has been limited.5 To improve the survival of these patients, new treatment strategies must be developed.
Most clinical trials of postoperative adjuvant chemotherapy have failed to prove a survival benefit.6 However, a large phase III trial recently demonstrated that adjuvant chemotherapy with S-1 (1 M tegafur–0.4 M gimestat–1 M ostat potassium) significantly improved survival after D2 curative gastrectomy in Japanese patients with T2N+ or T3 disease.7 Based on this, D2 surgery and postoperative S-1 chemotherapy has been established as a standard treatment in Japan. Nonetheless, even with adjuvant S-1 chemotherapy, the prognosis for T3 tumors was not satisfactory.
Preoperative chemotherapy followed by extended surgery has some theoretical benefits when compared with postoperative chemotherapy.8 If bulky tumors are reduced in size by chemotherapy, complete tumor removal could theoretically be easily achieved by extended surgery. If distant micrometastases are eliminated by chemotherapy, complete resection by extended surgery may improve survival and result in cure in some cases. However, preoperative chemotherapy followed by extended surgery has not been confirmed in phase III trial.
A high response rate and relatively low toxicity are required for preoperative chemotherapy, because target tumors are resectable or marginally resectable and the patients must receive potentially curative surgery after chemotherapy. Combined chemotherapy with S-1 plus cisplatin is an attractive regimen for preoperative chemotherapy for gastric cancer. A previous phase II trial of this regimen in metastatic gastric cancer reported a high response rate of 76% and acceptable toxicities.9 Recently, a Japanese phase III trial of chemotherapeutic regimens for metastatic gastric cancer (SPIRITS trial) demonstrated that S-1 plus cisplatin led to significantly longer median overall survival than S-1 alone (13 months vs. 11 months).10 Moreover, in the recent international phase III trial (FLAGS), S-1 plus cisplatin had lower toxicity but achieved equally overall survival compared with 5-FU plus cisplatin (CF) (Ajani JA, et al. presented at the 2009 Gastrointestinal Cancers Symposium). Triplet chemotherapy of CF plus epirubicin (ECF) or CF plus docetaxel (DCF) is effective but more toxic than CF.11
However, the influence of preoperative chemotherapy on D2 or D3 surgery has not been fully evaluated, although D2 and D3 gastrectomy are safe procedures in Japan.12 Unlike D0 or D1 surgery, D2 or D3 gastrectomy involves nodal dissection along the pancreas, which can cause pancreatic fistula or abdominal abscess. These complications can be lethal and might be increased by preoperative chemotherapy. The effect of preoperative chemotherapy on surgical mortality or morbidity with these procedures has not been fully clarified. Recently, preoperative chemotherapy of CPT-11 plus cisplatin followed by D3 dissection was tested in phase II trial to evaluate the efficacy and toxicity in Japan.13 However, this trial has been terminated due to high treatment-related death during the accrual. A safe and effective regimen before extended surgery has yet to be reported.
The Japan Clinical Cancer Research Organization (JACCRO) therefore, conducted a multi-institutional phase II trial (JACCRO GC-01) to evaluate the feasibility and safety of preoperative chemotherapy with S-1 plus cisplatin followed by curative D2 or D3 gastrectomy for clinically serosa-positive (T3–4) gastric cancer.
Section snippets
Eligibility criteria
Eligibility criteria were: (1) histologically proven gastric adenocarcinoma; (2) stage clinically assessed as T3–4, N0–N3 which is classified according to 2nd English Edition of Japanese Classification of Gastric Carcinoma,14 and M0; (3) age 20–75 years; (4) Eastern cooperative oncology group (ECOG) performance status 0–1; (5) no prior therapy; (6) sufficient organ function [white blood cell count (WBC) 4000–12,000 mm3, platelet count (PLT) >100,000/mm3, glutamic oxaloacetic transaminase (GOT)
Patients
Between February 2004 and January 2005, 50 patients were enrolled and the study was terminated. During the accrual, unpredicted severe adverse events or treatment-related death was not observed. One of these patients declined to participate, while the other 49 were eligible and received the treatment protocol. Table 1 shows patient demographics and tumor characteristics. Clinically apparent nodal disease was observed in 40 patients.
Preoperative chemotherapy and toxicities
Of all 49 eligible patients, 3 did not receive cisplatin
Discussion
This multi-institutional phase II prospective trial demonstrated neither treatment-related death nor severe adverse events by preoperative chemotherapy of S-1 plus cisplatin followed by extended surgery, suggesting that this multi-modality treatment was safe and feasible.
Acknowledgment
This study was supported by the Japan Clinical Cancer Research Organization (JACCRO).
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