Surg Today DOI 10.1007/s00595-015-1276-2
ORIGINAL ARTICLE
Feasibility of neoadjuvant S‑1 and oxaliplatin followed by surgery for resectable advanced gastric adenocarcinoma Yoshitaka Honma1 · Yasuhide Yamada1 · Tetsuji Terazawa1 · Atsuo Takashima1 · Satoru Iwasa1 · Ken Kato1 · Tetsuya Hamaguchi1 · Yasuhiro Shimada1 · Masaki Ohashi2 · Shinji Morita2 · Takeo Fukagawa2 · Nozomu Machida3 · Hitoshi Katai2
Received: 28 August 2015 / Accepted: 26 October 2015 © Springer Japan 2015
Abstract Purpose In Japan, the administration of S-1 following D2 gastrectomy is a standard treatment for stage II/III gastric cancer (GC). However, the survival of stage IIIB/IIIC GC remains unsatisfactory. To improve this, we conducted a multicenter phase II study to evaluate the safety and efficacy of a neoadjuvant S-1 and oxaliplatin regimen (SOX) followed by surgery targeted at stage III GC. Methods Oxaliplatin was administered intravenously (130 mg/m2) on day 1, and S-1 was administered orally (40 mg/m2, twice a day) for 14 days followed by a sevenday rest period. After three cycles of therapy, D2 gastrectomy was performed. Results A total of 14 patients were enrolled and completed the protocol treatment. Grade 3/4 toxicities included thrombocytopenia (21.4 %), anorexia (14.3 %), and diarrhea (7.1 %). Seven patients (50 %) underwent total gastrectomy, and seven patients underwent distal gastrectomy. Grade 3/4 surgical complications included pancreatic fistula (21.4 %) and lung infection (7.1 %). The pathological response rate was 85.7 %. Conclusion Although our data are limited and preliminary, neoadjuvant SOX followed by surgery can be performed safely with a high pathological response rate in
* Hitoshi Katai [email protected] 1
Gastrointestinal Oncology Division, National Cancer Center Hospital, 5‑1‑1 Tsukiji, Chuo‑ku, Tokyo 104‑0045, Japan
2
Gastric Surgery Division, National Cancer Center Hospital, 5‑1‑1 Tsukiji, Chuo‑ku, Tokyo 104‑0045, Japan
3
Division of Gastrointestinal Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi‑cho, Sunto‑gun, Shizuoka 411‑8777, Japan
patients with resectable advanced GC. Further investigation of this neoadjuvant approach is warranted. Keywords Gastric cancer · Neoadjuvant chemotherapy · S-1 · Oxaliplatin
Introduction Adjuvant chemotherapy is intended to eradicate micrometastases after curative surgery to improve patient outcomes [1]. In Japan, the administration of S-1 for one year following D2 gastrectomy is a standard treatment for stage II or III gastric cancer (GC) according to the results of the ACTS-GC trial [2]. However, the five-year overall survival (OS) rate in patients with stage IIIB disease was 50.2 % in the S-1 group and 44.1 % in the surgery-only group, suggesting that there is still some room for improvement [2]. To improve the survival of patients with resectable advanced GC, several phase II studies have been conducted to evaluate the efficacy of doublet chemotherapy after surgery. However, some patients experienced severe toxicities in previous studies [3–5]. After gastrectomy, patients often experience a loss of appetite and decreased food intake, resulting in severe toxicities that might influence compliance with adjuvant chemotherapy [6]. Moreover, several previous reports indicated the importance of preoperative induction chemotherapy for far advanced disease, such as GC with para-aortic lymph node metastases or positive lavage cytology [7, 8]. Therefore, neoadjuvant chemotherapeutic strategies have been developed for advanced GC, especially for high-risk patients with postoperative recurrence. Conversely, in Japan, regimens containing standarddose cisplatin (CDDP) have been generally administered
13
as inpatient chemotherapy because the regimen is highly emetic and requires intensive hydration. A previous report recommended that outpatient chemotherapy with standarddose CDDP can be safely and effectively administered with appropriate patient selection and supportive treatment [9]. Therefore, to improve the survival, less toxic but intensive treatments that can be administered as outpatient chemotherapy are needed. Oxaliplatin is a third-generation platinum compound that was developed to improve the tolerability and ease of administration compared with CDDP [10]. The non-inferiority of oxaliplatin-based regimens to CDDP-based regimens was demonstrated in the REAL -2 and G-SOX phase III trials for unresectable or metastatic GC [11, 12]. A comparison of safety between the S-1 and oxaliplatin regimen (SOX) and the S-1 and CDDP regimen (CS), which is the standard treatment for unresectable or metastatic GC in Japan, as reported in the G-SOX phase III trial revealed lower incidences of grade 3/4 neutropenia and febrile neutropenia [12]. Furthermore, SOX does not require intensive hydration, and it can be administered as outpatient chemotherapy. These findings indicate that SOX may have greater utility than CS in terms of safety. For this reason, we conducted a multicenter phase II study to evaluate the safety and efficacy of neoadjuvant SOX followed by surgery targeted at pathological stage III GC.
Materials and methods Patient eligibility The eligibility criteria were as follows: (1) histologically proven and clinically resectable advanced gastric adenocarcinoma (cT3–4, cN0–3, cM0); (2) the HER2 status was examined before registration; (3) negative lavage cytology was confirmed by previous laparoscopy; (4) 20–75 years of age; (5) ECOG performance status 0–1; (6) no prior chemotherapy, radiation therapy, or operation for GC; (7) adequate oral intake without any active bleeding or intestinal obstruction; (8) sufficient organ function; and (9) written informed consent. The key exclusion criteria were as follows: (1) bulky nodal involvement around major branched arteries to the stomach and/or para-aortic nodal metastases and (2) thoracotomy necessary for curative resection (transhiatal approach is acceptable). The study was approved by the institutional review boards of each of the four institutions involved and was monitored for its entirety by an independent data and safety monitoring committee; it was also conducted in accordance with the Helsinki Declaration and Japanese Ethical Guidelines for Clinical Studies. This study is registered with the University Hospital Medical
13
Surg Today
Information Network Clinical Trials Registry (UMINCTR), Number 000007589. Immunohistochemical staining In this study, the HER2 status was examined in all patients using endoscopic biopsy specimens obtained before registration. The HER2 status was tested in each institution. Immunohistochemistry (IHC) for HER2 was graded on a scale of 0–3 as follows: 0 = no reactivity or membranous reactivity in
ORIGINAL ARTICLE
Feasibility of neoadjuvant S‑1 and oxaliplatin followed by surgery for resectable advanced gastric adenocarcinoma Yoshitaka Honma1 · Yasuhide Yamada1 · Tetsuji Terazawa1 · Atsuo Takashima1 · Satoru Iwasa1 · Ken Kato1 · Tetsuya Hamaguchi1 · Yasuhiro Shimada1 · Masaki Ohashi2 · Shinji Morita2 · Takeo Fukagawa2 · Nozomu Machida3 · Hitoshi Katai2
Received: 28 August 2015 / Accepted: 26 October 2015 © Springer Japan 2015
Abstract Purpose In Japan, the administration of S-1 following D2 gastrectomy is a standard treatment for stage II/III gastric cancer (GC). However, the survival of stage IIIB/IIIC GC remains unsatisfactory. To improve this, we conducted a multicenter phase II study to evaluate the safety and efficacy of a neoadjuvant S-1 and oxaliplatin regimen (SOX) followed by surgery targeted at stage III GC. Methods Oxaliplatin was administered intravenously (130 mg/m2) on day 1, and S-1 was administered orally (40 mg/m2, twice a day) for 14 days followed by a sevenday rest period. After three cycles of therapy, D2 gastrectomy was performed. Results A total of 14 patients were enrolled and completed the protocol treatment. Grade 3/4 toxicities included thrombocytopenia (21.4 %), anorexia (14.3 %), and diarrhea (7.1 %). Seven patients (50 %) underwent total gastrectomy, and seven patients underwent distal gastrectomy. Grade 3/4 surgical complications included pancreatic fistula (21.4 %) and lung infection (7.1 %). The pathological response rate was 85.7 %. Conclusion Although our data are limited and preliminary, neoadjuvant SOX followed by surgery can be performed safely with a high pathological response rate in
* Hitoshi Katai [email protected] 1
Gastrointestinal Oncology Division, National Cancer Center Hospital, 5‑1‑1 Tsukiji, Chuo‑ku, Tokyo 104‑0045, Japan
2
Gastric Surgery Division, National Cancer Center Hospital, 5‑1‑1 Tsukiji, Chuo‑ku, Tokyo 104‑0045, Japan
3
Division of Gastrointestinal Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi‑cho, Sunto‑gun, Shizuoka 411‑8777, Japan
patients with resectable advanced GC. Further investigation of this neoadjuvant approach is warranted. Keywords Gastric cancer · Neoadjuvant chemotherapy · S-1 · Oxaliplatin
Introduction Adjuvant chemotherapy is intended to eradicate micrometastases after curative surgery to improve patient outcomes [1]. In Japan, the administration of S-1 for one year following D2 gastrectomy is a standard treatment for stage II or III gastric cancer (GC) according to the results of the ACTS-GC trial [2]. However, the five-year overall survival (OS) rate in patients with stage IIIB disease was 50.2 % in the S-1 group and 44.1 % in the surgery-only group, suggesting that there is still some room for improvement [2]. To improve the survival of patients with resectable advanced GC, several phase II studies have been conducted to evaluate the efficacy of doublet chemotherapy after surgery. However, some patients experienced severe toxicities in previous studies [3–5]. After gastrectomy, patients often experience a loss of appetite and decreased food intake, resulting in severe toxicities that might influence compliance with adjuvant chemotherapy [6]. Moreover, several previous reports indicated the importance of preoperative induction chemotherapy for far advanced disease, such as GC with para-aortic lymph node metastases or positive lavage cytology [7, 8]. Therefore, neoadjuvant chemotherapeutic strategies have been developed for advanced GC, especially for high-risk patients with postoperative recurrence. Conversely, in Japan, regimens containing standarddose cisplatin (CDDP) have been generally administered
13
as inpatient chemotherapy because the regimen is highly emetic and requires intensive hydration. A previous report recommended that outpatient chemotherapy with standarddose CDDP can be safely and effectively administered with appropriate patient selection and supportive treatment [9]. Therefore, to improve the survival, less toxic but intensive treatments that can be administered as outpatient chemotherapy are needed. Oxaliplatin is a third-generation platinum compound that was developed to improve the tolerability and ease of administration compared with CDDP [10]. The non-inferiority of oxaliplatin-based regimens to CDDP-based regimens was demonstrated in the REAL -2 and G-SOX phase III trials for unresectable or metastatic GC [11, 12]. A comparison of safety between the S-1 and oxaliplatin regimen (SOX) and the S-1 and CDDP regimen (CS), which is the standard treatment for unresectable or metastatic GC in Japan, as reported in the G-SOX phase III trial revealed lower incidences of grade 3/4 neutropenia and febrile neutropenia [12]. Furthermore, SOX does not require intensive hydration, and it can be administered as outpatient chemotherapy. These findings indicate that SOX may have greater utility than CS in terms of safety. For this reason, we conducted a multicenter phase II study to evaluate the safety and efficacy of neoadjuvant SOX followed by surgery targeted at pathological stage III GC.
Materials and methods Patient eligibility The eligibility criteria were as follows: (1) histologically proven and clinically resectable advanced gastric adenocarcinoma (cT3–4, cN0–3, cM0); (2) the HER2 status was examined before registration; (3) negative lavage cytology was confirmed by previous laparoscopy; (4) 20–75 years of age; (5) ECOG performance status 0–1; (6) no prior chemotherapy, radiation therapy, or operation for GC; (7) adequate oral intake without any active bleeding or intestinal obstruction; (8) sufficient organ function; and (9) written informed consent. The key exclusion criteria were as follows: (1) bulky nodal involvement around major branched arteries to the stomach and/or para-aortic nodal metastases and (2) thoracotomy necessary for curative resection (transhiatal approach is acceptable). The study was approved by the institutional review boards of each of the four institutions involved and was monitored for its entirety by an independent data and safety monitoring committee; it was also conducted in accordance with the Helsinki Declaration and Japanese Ethical Guidelines for Clinical Studies. This study is registered with the University Hospital Medical
13
Surg Today
Information Network Clinical Trials Registry (UMINCTR), Number 000007589. Immunohistochemical staining In this study, the HER2 status was examined in all patients using endoscopic biopsy specimens obtained before registration. The HER2 status was tested in each institution. Immunohistochemistry (IHC) for HER2 was graded on a scale of 0–3 as follows: 0 = no reactivity or membranous reactivity in
