Phase I study of neoadjuvant chemoradiotherapy with S-1 for clinically resectable type 4 or large type 3 gastric cancer in elderly patients aged 75 years and older (OGSG1303)

Phase I study of neoadjuvant chemoradiotherapy with S-1 for clinically resectable type 4 or large type 3 gastric cancer in elderly patients aged 75 years and older (OGSG1303) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Phase I study of neoadjuvant chemoradiotherapy with S-1 for clinically resectable type 4 or large type 3 gastric cancer in elderly patients aged 75 years and older (OGSG1303) Masayuki Shinkai, Motohiro Imano, Masaki Yokokawa, Jin Matsuyama, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5267297/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 19 Dec, 2024 Read the published version in Medical Oncology → Version 1 posted 10 You are reading this latest preprint version Abstract Purpose The prognosis for type 4 and large type 3 gastric cancer (GC) is extremely poor, especially in elderly patients (≥ 75 years). To improve the prognosis of these types of GC, we performed a phase I study to determine the recommended dose (RD) of S-1 combined with neoadjuvant radiotherapy. Methods Patients with clinically resectable type 4 and large type 3 GC were enrolled to successive cohorts in a conventional 3 + 3 design. Three dose levels were designed, as follows: level 0: S-1 60 mg/m 2 /day on Days 1–14; level 1: S-1 80 mg/m 2 /day on Days 1 − 14; level 2: S-1 80 mg/m 2 /day on Days 1–14 and Days 22–35. The starting dose was level 1. Radiotherapy was delivered at a total dose of 40 Gy in fractions for 4 weeks. Results Ten patients were enrolled from July 2014 to August 2018. Six patients were registered at level 1, and one patient developed a dose limiting toxicity as gastric stenosis (grade 3). Two of four patients enrolled at level 2 developed dose limiting toxicity (inability to receive S-1 for hematological reasons). Therefore, the RD was determined as level 1. All patients underwent the protocol surgery; one patient underwent R1 resection because of positive peritoneal washing cytology. There were no treatment-related deaths, and the pathological response rate was 80%. The 5-year overall- and progression-free survival rates were both 60.0%. Conclusion The RD was determined as level 1. A phase II trial using the RD should be initiated. Gastric cancer Chemoradiotherapy Type 4 Large Type 3 S-1 elderly Figures Figure 1 Figure 2 Introduction The proportion of elderly people in the Japanese population is increasing. Cancer is the leading cause of death among Japanese people, and according to a report by the Cancer Control and Information Center of Japan’s National Cancer Center, the percentage of patients over 75 years of age among the total number of newly diagnosed gastric cancer (GC) cases is increasing annually [ 1 ]. Among GC, type 4 GC has a particularly poor prognosis. The 5-year overall survival (OS) rate of patients with type 4 GC ranges from 12.5–27.6% [ 2 , 3 ]. To improve the prognosis of type 4 GC, Furukawa et al. performed extended resection surgery (left upper abdominal exenteration plus the Appleby procedure) [ 4 ]. However, this extended surgery has not become common owing to the high incidence of pancreatic fistula. The JCOG 0002 trial using S-1 as neoadjuvant chemotherapy (NAC) to improve the prognosis of scirrhous GC (also known as type 4 GC) showed a pathologic response rate (Grade > 1b) of 32% and no improvement in prognosis compared with historical controls [ 5 ]. Therefore, we considered it necessary to develop a treatment method other than extended surgery or NAC by S-1 to improve the prognosis of type 4 GC. Saikawa et al. investigated the efficacy of chemoradiotherapy (CRT) with S-1 plus low-dose cisplatin for unresectable GC and reported a high response rate (65.5%) [ 6 ]. Additionally, a phase I trial of neoadjuvant CRT consisting of S-1 and low-dose cisplatin for patients with resectable advanced GC reported no major surgical complications and a pathologic complete response rate of 10% [ 7 ]. Thus, CRT with S-1 and cisplatin may be a promising treatment for advanced GC. However, the feasibility, safety, and efficacy of neoadjuvant CRT for resectable type 4 GC, especially for elderly patients, remain unknown. Considering these previous reports, we performed this prospective study to determine the feasibility, safety, and efficacy of neoadjuvant CRT for type 4 GC and large type 3 GC, which is considered to have the same biological behavior as type 4 GC, such as a high incidence of peritoneal dissemination [ 8 ]. Additionally, because this study included elderly GC patients aged ≥ 75 years, cisplatin was excluded from the chemotherapy regimen because of age-related declines in renal function [ 9 ]. This phase I study was designed to determine the dose-limiting toxicity (DLT) of S-1, with concurrent radiotherapy, and to define the recommended dose (RD) for a subsequent phase II study. Materials and Methods Patients The eligibility criteria for this study were as follows: (1) histologically proven and clinically resectable GC; (2) age > 75 years; (3) macroscopic type of carcinoma as type 4 or type 3 GC; (4) in type 3 GC, tumor size > 8 cm in diameter; (5) Eastern Cooperative Oncology Group performance status of 0 or 1; (6) tumor invasion of the esophagus < 1 cm, with no involvement of the duodenum; (7) lymph node metastasis limited to the regional lymph nodes; (8) no evidence of distant metastases, no peritoneal metastasis, and negative lavage cytology confirmed by staging laparoscopy; (9) no prior abdominal surgery; (10) no previous chemotherapy or radiotherapy; (11) no other previous or concurrent malignancies; (12) no bleeding from the main lesion or intestinal stenosis; and (13) adequate bone marrow function (white blood cell count ≥ 3000/mm 3 , neutrophil count ≥ 1500/mm 3 , hemoglobin ≥ 8.0 g/dL, platelet count ≥ 100 × 10 3 /mm 3 ), adequate liver function (total serum bilirubin level ≤ 2.0 mg/dL, serum alanine transaminase and aspartate transaminase < 100 U/L), and adequate renal function (creatinine clearance ≥ 40 mL/min). Written informed consent was obtained from all patients prior to their participation in the study. The exclusion criteria were as follows: (1) other major medical disease or malignancy other than GC; (2) history of severe drug hypersensitivity; (3) treatment with a major tranquilizer, steroids, flucytosine, phenytoin, or warfarin; (4) lung fibrosis, intestinal pneumonitis, bowel obstruction, or ischemic heart disease; and (5) patients determined to be inappropriate for inclusion in this study. The present trial was performed in accordance with the World Medical Association Declaration of Helsinki and the Japanese Good Clinical Practice guidelines. This study was approved by the ethics committee in each institution or hospital and registered in the University Hospital Medical Information Network Clinical Trial Registry (UMIN000013821). Study design The primary objective of this phase I study was to determine the RD of S-1 combined with neoadjuvant radiation therapy in elderly patients with type 4 and large type 3 GC using a conventional dose-escalation design. The secondary objectives were to evaluate the pathological response rate and the treatment safety profile. Treatment Schedule The treatment schedule is summarized in Figure 1. Combined CRT consisted of S-1 and radiotherapy. S-1 was administrated orally from Days 1 to 14 followed by rest for 14 days at levels 0 and 1. At level 2, S-1 was administered from Days 1 to 14 and Days 22 to 35. The dose of S-1 administered at level 0 was 60 mg/m 2 /day. At levels 1 and 2, the dose of S-1 was 80 mg/m 2 /day. Radiotherapy was delivered using megavoltage (6–15 MV) X-rays and a multi-field technique. Patients received 2 Gy/day of radiation 5 days per week from the initiation of chemotherapy, with a total radiation dose of 40 Gy. Three-dimensional computed tomography (CT) simulation was required. CT simulation and daily radiation therapy were performed with the patient’s stomach empty, 3 hours after dietary intake. The gross volumes of the primary tumor (GTV primary) and the metastatic lymph nodes (GTV node) were defined by CT and positron emission tomography, with reference to an upper gastrointestinal series. The clinical target volume was calculated as the GTV primary and GTV node plus a 1-cm margin to account for subclinical extension. The planned target volume was the CTV plus 1–2 cm longitudinally and 0.5–1 cm transversely and vertically to account for setup variation and visceral motion. All patients were evaluated by abdominal and pelvic CT 4 weeks after completion of CRT to evaluate the possibility of R0 resection. The surgical criteria were as follows: (1) achievable R0 resection; (2) white blood cell count ≥ 2500/mm 2 ; and (3) platelet count ≥ 100,000/mm 2 . Surgery was performed between 7 and 9 weeks after the end of radiotherapy. Determination of DLT, maximum-tolerated dose, and RD This study followed a standard 3+3 dose escalation protocol. Level 1 was the starting dose; if DLT developed, three additional patients were needed. Once DLT development was confirmed in 3/6 patients at level 1, the next step comprised level 0. In principle, the RD was one level down from the maximum-tolerated dose (MTD). However, if the MTD was not expressed at level 2 in this study, we would recommend level 2 as the RD. Toxicity was graded in accordance with the Common Toxicity Criteria for Adverse Events version 4.0 [10]. DLT was defined as follows: (1) grade 4 neutropenia; (2) grade 4 thrombocytopenia; (3) grade 3 febrile neutropenia lasting 4 days; (4) grade 3 non-hematologic toxicity except for appetite loss and general fatigue; and (5) inability to receive S-1 for > 10 days at levels 0 and 1 and > 19 days at level 2. Surgery and postoperative chemotherapy Surgery consisted of total or distal gastrectomy, depending on the location of the primary tumor. D2 lymphadenectomy was routinely performed, while splenectomy was performed only for tumor involvement in the upper one-third of the greater curvature or with nodal metastases in the splenic hilum. If resectable M1 disease (hepatic, peritoneal, and/or lymphatic metastases) was found during surgery, the affected nodes were removed to achieve R0 resection. If R0 resection was impossible, the protocol treatment was terminated. Following R0 resection, 1 year of adjuvant chemotherapy with S-1 monotherapy was administered within 6 weeks after gastrectomy. Postoperative follow-up After treatment, in accordance with the protocol, patients were followed-up every 3 months for the first 2 years, then every 6 months for the next 5 years. Assessment and statistical analysis The tumor-node-metastasis categories were in accordance with the Japanese Classification of Gastric Carcinoma (3 rd English edition) [11]. The pathological response rate was evaluated and graded by pathologists in accordance with the Japanese Classification of Gastric Carcinoma (3 rd English edition) as grade 0 (no evidence of effect), grade 1a (viable tumor cells remain in more than two-thirds of the tumorous area), grade 1b (viable tumor cells remain in more than one-third but less than two-thirds of the tumorous area), grade 2 (viable tumor cells remain in less than one-third of the tumorous area), or grade 3 (no viable tumor cells). A pathological response was defined as a response greater than grade 1b. Toxicity and adverse events were described in accordance with the National Cancer Institute Common Toxicity Criteria grading version 4.0 [10]. Intra-and postoperative complications were graded in accordance with the Clavien–Dindo classification [12]. OS and progression-free survival (PFS) were calculated from the date of the initial staging laparoscopy to death or the date of the most recent follow-up, respectively. OS and PFS were estimated using the Kaplan–Meier method, with 95% confidence intervals (CI) determined using Greenwood’s formula. All statistical analyses were performed using SAS version 9.2 (SAS Institute Inc., Cary, NC, USA). Results Patient characteristics Between July 2014 and August 2018, 10 patients were enrolled in this study and underwent neoadjuvant CRT. The patients’ characteristics are summarized in Table 1. The median age was 78.5 years (range: 75–81 years). The numbers of patients with large type 3 and type 4 tumors were 4 and 6, respectively. MTD and RD All 10 patients started treatment and could be evaluated for toxicity. The details of toxicity in levels 1 and 2 are shown in Table 2. Six patients were registered at level 1. The main toxicity was hematological and comprised anemia (50.0%) and leukopenia (33.3%). Additionally, three patients (50.0%) developed hypoalbuminemia. No patients experienced higher than grade 3 hematological toxicity. Regarding non-hematologic toxicity, two patients developed grade 2 anorexia, and one patient (16.7%) developed DLT as gastric stenosis (grade 3). During dose level 2, two of four patients (50.0%) developed grade 2 leukemia and neutropenia, and one patient (25.0%) developed grade 2 anemia. The leukemia and neutropenia failed to respond to therapy, and as a result, the two patients (50.0%) were unable to continue the specified amount of S-1 for ≥ 19 days Therefore, the RD was determined as level 1. Surgery and postoperative complications All patients underwent the protocol surgery. The operation transition rate was 100% (95% CI, 69.2%–100%). Total gastrectomy was performed in nine patients, while distal gastrectomy was performed in one patient. Peritoneal cytology positive for carcinoma cells (CY1) was observed in one patient. Therefore, the rate of R0 resection was 90% (9/10) (95% CI, 55.5%–96.7%). Other surgical findings are shown in Table 3. Surgical complications were observed in one patient (10%) and comprised transverse colonic necrosis (Grade IIIb), which required reoperation. There were no surgery-related deaths. Pathological findings The pathological effects of neoadjuvant CRT were as follows: grade 0 in 0 (0%) patients, grade 1a in two (20%), grade 1b in one (10%), grade 2 in seven (70%), and grade 3 in 0 (0%) patients. The pathological response rate, the secondary endpoint, was 80% (Table 4). Postoperative chemotherapy S-1 postoperative adjuvant chemotherapy was initiated in 7 of the 10 patients who underwent surgery. The remaining three patients declined postoperative adjuvant chemotherapy. Survival OS and PFS were evaluated in the 10 eligible patients. At the time of analysis (September 2023), six patients were alive without recurrence; three patients had died as a result of recurrence. Another patient died of other disease 16 months after surgery. The 3- and 5-year OS rates were both 60.0% (95% CI, 25.3%–82.7%). The 3- and 5-year PFS rates were also both 60.0% (95% CI, 25.3%–82.7%) (Fig. 2a and b). Discussion This phase I study was designed to evaluate neoadjuvant concurrent CRT in elderly patients with resectable type 4 or large type 3 GC and it determined the RD of S-1 as 80 mg/m 2 /day on Days 1–14. The predominant adverse events in this study were anemia (40%), leukopenia (40%), and neutropenia (20%). No patients developed grade 3 or 4 hematologic toxicity at the two dose levels evaluated in this study. These adverse event results were consistent with those in several previous studies that examined the safety of S-1 in elderly patients with advanced GC [13, 14]. The chemotherapy completion rate was 80% (8/10), similar to that observed in the JCOG 0002 trial (clinical trial for scirrhous GC) using S-1 for NAC (94%) [5]. In comparison, the radiotherapy completion rate was 100%, and eventually, 9 of the 10 (90%) patients underwent R0 resection. As a result, the lower limit of the 95% CI was 55.5%, suggesting that our neoadjuvant CRT regimen is feasible. However, CY1 was identified in one (10%) patient after neoadjuvant CRT. This may have resulted from the inadequate diagnostic accuracy of peritoneal lavage examination. The accuracy of conventional peritoneal lavage cytology for peritoneal metastasis diagnosis is still limited, with a sensitivity of < 60% [15, 16]. Therefore, in the affected patient in our study, CY1 might have been latent at the time of the initial staging laparoscopy. Recently, the usefulness of the cell block technique has been reported [17], and this technique is covered by insurance in Japan. Therefore, the cell block technique may increase the accuracy of peritoneal cytological diagnosis in the future. Regarding surgical complications, the postoperative morbidity rate was low (10%) in our study compared with that of previous studies [18], and there were no surgery-related deaths in this study. However, colonic necrosis developed in one patient as a postoperative adverse event (Grade ≥ 3). Ischemic changes due to irradiation are considered to occur several years after irradiation when the total irradiation dose exceeds 55–60 Gy [19, 20]. There have been no reports of colonic necrosis following low doses of radiation, such as 40 Gy. The necrosis in the patient in our study occurred during the acute phase of radiation damage, and we believe it was caused by an additional complication, such as infection or an intraoperative procedure. The low rate of surgical complications made it possible for 7 of the 10 patients (70%) to receive adjuvant chemotherapy as scheduled. Therefore, our neoadjuvant CRT regimen was considered safe. Regarding therapeutic efficacy, our study achieved a pathological response rate of 80%, which was better than that of the JCOG 0002 trial (32%) [5]. It is assumed that the high pathological response rate in this study may be associated with the addition of concurrent radiation therapy. The prognostic outcome and pathological response rate are generally used as indicators to evaluate the effect of preoperative therapy [21]. The JCOG 0002 trial indicated that the 3-year survival rate for type 4 GC was < 40% [5]. Although our sample size was small, the 5-year OS and PFS rates in our study were both 60.0%. Therefore, neoadjuvant CRT might provide a favorable prognosis for elderly patients with type 4 or large type 3 GC. In conclusion, the safety and efficacy of this regimen (S-1 80 mg/m 2 /day from Days 1 to 14 with concurrent radiotherapy at 40 Gy) will be evaluated in a phase II study with larger numbers of patients. Declarations Acknowledgements The authors are grateful to the members of the OGSG Data Center and OGSG Operations Office for their support in this study. We would also like to thank Ying-Feng Peng, and Jane Charbonneau, DVM, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript. Author contributions Study concept: MI and HF; study design: MI, MY, and HF; acquisition of data: MS, MI, JM, and YK; statistical analysis of the data: TS; analysis and/or interpretation of the data: MS, MI, and TS; drafting the manuscript: MS and MI; revising the manuscript critically for important intellectual content: HK, TS, TY, and HF. All authors approved the final version of the manuscript. Ethics approval All procedures were performed in accordance with the ethical standards of the committee on human experimentation and with the Helsinki Declaration of 1964 and later versions. This study was approved by the institutional review and ethics board of each participating hospital and registered in the University Hospital Medical Information Network (UMIN) database (UMIN000013821). Funding This study was supported by the Osaka Gastrointestinal Cancer Chemotherapy Group (OGSG). Consent to participate Informed consent or substitute consent was obtained from all patients included in the study. Conflict of interest statement The authors declare no competing interests. Consent for publication statement The authors have approved publication. Data availability statement Not applicable References Vital Statistics Japan (Ministry of Health, Labour and Welfare). http://www.mhlw.go.jp/english/database/db-hw/index.html An JK, Kang TH, Choi MG, Noh JH, Sung T, Kim S (2008) Borrmann type IV: an independent prognosis factor for survival in gastric cancer. 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Patient characteristics (n=10) Characteristic Number Age, years Median (range) 78.5 (75–81) Sex Male 5 Female 5 ECOG performance status 0 10 1 0 Macroscopic findings (JGCA) Type 3 4 Type 4 6 Tumor location in the stomach Upper 1 Middle 8 Lower 1 Histological subtype Tubular adenocarcinoma 5 Poorly differentiated adenocarcinoma 2 Signet-ring cell carcinoma 3 Clinical T stage T3 4 T4a 5 T4b 1 Clinical N stage N0 7 N1 0 N2 3 N3 0 Peritoneal metastasis P0 10 P1 0 Peritoneal lavage cytology CY0 10 CY1 0 Clinical M stage M0 10 M1 0 Clinical TMN stage IA 0 IB 0 IIA 3 IIB 4 IIIA 1 IIIB 1 IIIC 1 IV 0 ECOG: Eastern Cooperative Oncology Group, JGCA: Japan Gastric Cancer Association, P0: No peritoneal metastasis, P1: Peritoneal metastasis, CY0: Peritoneal cytology negative for carcinoma cells, CY1: Peritoneal cytology positive for carcinoma cells, M0: No distant metastasis, M1: Distance metastasis, T: Tumor, N: Node Table 2. Adverse events (n=10) Toxicity Grade 1 Grade 2 Grade 3 Grade 4 % Grade 3/4 Level 1 (n=6) Hematologic Leukopenia 1 1 0 0 0 Neutropenia 0 0 0 0 0 Thrombocytopenia 1 0 0 0 0 Anemia 2 1 0 0 0 Hypoalbuminemia 2 1 0 0 0 AST elevated 0 0 0 0 0 ALT elevated 1 0 0 0 0 Hyperbilirubinemia 1 1 0 0 0 Hypercreatininemia 1 0 0 0 0 Hyperkalemia 0 0 0 0 0 Hypernatremia 1 0 0 0 0 Hyponatremia 1 0 0 0 0 Gastrointestinal Anorexia 0 2 0 0 0 Nausea 1 0 0 0 0 Vomiting 0 0 0 0 0 Diarrhea 1 0 0 0 0 Fatigue 1 0 0 0 0 Malaise 1 0 0 0 0 Rash 0 0 0 0 0 Gastric stenosis 0 0 1 0 16.7 Level 2 (n=4) Hematologic Leukopenia 0 2 0 0 0 Neutropenia 0 2 0 0 0 Thrombocytopenia 1 0 0 0 0 Anemia 0 1 0 0 0 Hypoalbuminemia 1 2 0 0 0 AST elevation 1 1 0 0 0 ALT elevation 1 1 0 0 0 Hyperbilirubinemia 0 0 0 0 0 Hypercreatininemia 0 0 0 0 0 Hyperkalemia 1 0 0 0 0 Hypernatremia 0 0 0 0 0 Hyponatremia 1 0 0 0 0 Gastrointestinal Anorexia 0 1 1 0 16.7 Nausea 0 3 0 0 0 Vomiting 2 0 0 0 0 Diarrhea 0 0 0 0 0 Fatigue 0 0 0 0 0 Malaise 0 1 0 0 0 Rash 1 0 0 0 0 Gastric stenosis 0 0 0 0 0 ALT: alanine transaminase, AST: aspartate transaminase Toxicities were graded in accordance with the National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0. Table 3. Surgical findings and postoperative complications (n=10) Finding Number Peritoneal lavage cytology CY0 9 CY1 1 Peritoneal metastasis P0 10 P1 0 Type of resection Total gastrectomy 9 Distal gastrectomy 1 Combined resection Transverse colon 1 Pancreatic tail 1 Diaphragm 1 Lymph node dissection D2 10 Residual tumor R0 9 R1 1 R2 0 Postoperative complications Anastomotic leakage 0 Pancreatic fistula 0 Intra-abdominal abscess 0 Wound infection 0 Transverse colonic necrosis 1 ( Gr. IIIb) 30/60-day mortality 0/0 CY0: Peritoneal cytology negative for carcinoma cells, CY1: Peritoneal cytology positive for carcinoma cells, P0: No peritoneal metastasis, P1: Peritoneal metastasis, Gr. Toxicity grade in accordance with the Clavien–Dindo classification Table 4. Pathological findings (n=10) Finding Number Depth of tumor (T) invasion T0 0 T1a 0 T1b 1 T2 1 T3 5 T4a 1 T4b 2 Lymph node (N) metastasis N0 5 N1 2 N2 3 JCGA stage IA 1 IB 1 IIA 2 IIB 2 IIIA 1 IIIB 1 IIIC 1 IV 1 JCGA histological response Grade 0 0 Grade 1a 2 Grade 1b 1 Grade 2 7 Grade 3 0 JCGA: Japanese Classification of Gastric Carcinoma (3 rd English edition) Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 19 Dec, 2024 Read the published version in Medical Oncology → Version 1 posted Editorial decision: Revision requested 23 Nov, 2024 Reviews received at journal 16 Nov, 2024 Reviews received at journal 08 Nov, 2024 Reviewers agreed at journal 08 Nov, 2024 Reviewers agreed at journal 08 Nov, 2024 Reviewers agreed at journal 07 Nov, 2024 Reviewers invited by journal 07 Nov, 2024 Editor assigned by journal 16 Oct, 2024 Submission checks completed at journal 16 Oct, 2024 First submitted to journal 15 Oct, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5267297","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":381788666,"identity":"a200c910-83ba-4ee1-866e-896b72ac8f44","order_by":0,"name":"Masayuki Shinkai","email":"","orcid":"","institution":"Kindai University Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Masayuki","middleName":"","lastName":"Shinkai","suffix":""},{"id":381788667,"identity":"e4ad2545-ded4-4332-82bf-f9259bb1c177","order_by":1,"name":"Motohiro Imano","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8ElEQVRIiWNgGAWjYBACNjBZAcQH2BgOALk8YAEJglrOkKIFDBjbIFpgJuAHfGKHnz34OG+bHN8BtsTDBWV2Mgzshx8wWO7A4zDpNHPDmdtuG0seYDtweMa5ZB4GnjQDBskz+LQkmEnzbruduOEAe8Nh3jZmoF9yGBgk2/BpSf8mzTvndj1USz0PA/8bQlpygLY03E4wADmMt+0wD4MEQVtyyiRnHLttOPMwW8JhnnPHedgknhkcwOcX+dnp2yQ+1NyW5zveZvyZp6zanp8/+eFjSTwhhgDMMHuB+LBkAzFakAHjR5K1jIJRMApGwTAGAGsjSmteypKDAAAAAElFTkSuQmCC","orcid":"","institution":"Kindai University Faculty of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Motohiro","middleName":"","lastName":"Imano","suffix":""},{"id":381788668,"identity":"b22d2003-68c6-44cc-9a17-38599c1f6da0","order_by":2,"name":"Masaki Yokokawa","email":"","orcid":"","institution":"Kindai University Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Masaki","middleName":"","lastName":"Yokokawa","suffix":""},{"id":381788669,"identity":"29ea61ab-2156-4ecd-b183-5469bc7b4eb7","order_by":3,"name":"Jin Matsuyama","email":"","orcid":"","institution":"Higashiosaka City Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Jin","middleName":"","lastName":"Matsuyama","suffix":""},{"id":381788670,"identity":"b43daf9f-728f-41a3-81d3-0c8e0f9dfc4c","order_by":4,"name":"Yutaka Kimura","email":"","orcid":"","institution":"Sakai City Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Yutaka","middleName":"","lastName":"Kimura","suffix":""},{"id":381788672,"identity":"e156f517-48ff-4480-9f19-7d1cb4fe6352","order_by":5,"name":"Toshio Shimokawa","email":"","orcid":"","institution":"Wakayama Medical University","correspondingAuthor":false,"prefix":"","firstName":"Toshio","middleName":"","lastName":"Shimokawa","suffix":""},{"id":381788673,"identity":"c727afaf-be31-4a87-9783-16dcb2d85a98","order_by":6,"name":"Hisato Kawakami","email":"","orcid":"","institution":"Kindai University Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hisato","middleName":"","lastName":"Kawakami","suffix":""},{"id":381788675,"identity":"ed44c078-ddab-4c50-b3dd-3cf4022beb44","order_by":7,"name":"Taroh Satoh","email":"","orcid":"","institution":"Osaka University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Taroh","middleName":"","lastName":"Satoh","suffix":""},{"id":381788677,"identity":"8a2af27f-c0db-4b92-aa03-710f3b097c42","order_by":8,"name":"Takushi Yasuda","email":"","orcid":"","institution":"Kindai University Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Takushi","middleName":"","lastName":"Yasuda","suffix":""},{"id":381788679,"identity":"5ed3b4d0-5ce8-49a2-b94d-101af179ca1e","order_by":9,"name":"Hiroshi Furukawa","email":"","orcid":"","institution":"Kindai University Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hiroshi","middleName":"","lastName":"Furukawa","suffix":""}],"badges":[],"createdAt":"2024-10-15 09:08:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5267297/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5267297/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12032-024-02583-3","type":"published","date":"2024-12-19T15:57:07+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":71481010,"identity":"9d554f5c-6bcf-4fac-933d-6d03f3aaba29","added_by":"auto","created_at":"2024-12-16 06:00:03","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":652987,"visible":true,"origin":"","legend":"\u003cp\u003eThe schema of dose escalation\u003c/p\u003e","description":"","filename":"Fig1shinkai.png","url":"https://assets-eu.researchsquare.com/files/rs-5267297/v1/d27a48b44d4c44b9f5e1510b.png"},{"id":71480988,"identity":"5a2d5bad-60db-4574-8d9d-b781f604874a","added_by":"auto","created_at":"2024-12-16 05:59:54","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":377548,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier analyses of (a) overall survival and (b) progression-free survival for the 10 patients in this study\u003c/p\u003e","description":"","filename":"Fig2shinkai.png","url":"https://assets-eu.researchsquare.com/files/rs-5267297/v1/03c49d5a6f95a5319ca0f94d.png"},{"id":72201657,"identity":"9de3302f-bb07-4b2a-9f50-27048069dd11","added_by":"auto","created_at":"2024-12-23 16:09:05","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1890584,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5267297/v1/d7f8964a-4b87-464a-bc76-88f9226d0207.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Phase I study of neoadjuvant chemoradiotherapy with S-1 for clinically resectable type 4 or large type 3 gastric cancer in elderly patients aged 75 years and older (OGSG1303)","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe proportion of elderly people in the Japanese population is increasing. Cancer is the leading cause of death among Japanese people, and according to a report by the Cancer Control and Information Center of Japan\u0026rsquo;s National Cancer Center, the percentage of patients over 75 years of age among the total number of newly diagnosed gastric cancer (GC) cases is increasing annually [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAmong GC, type 4 GC has a particularly poor prognosis. The 5-year overall survival (OS) rate of patients with type 4 GC ranges from 12.5\u0026ndash;27.6% [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. To improve the prognosis of type 4 GC, Furukawa et al. performed extended resection surgery (left upper abdominal exenteration plus the Appleby procedure) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, this extended surgery has not become common owing to the high incidence of pancreatic fistula.\u003c/p\u003e \u003cp\u003eThe JCOG 0002 trial using S-1 as neoadjuvant chemotherapy (NAC) to improve the prognosis of scirrhous GC (also known as type 4 GC) showed a pathologic response rate (Grade\u0026thinsp;\u0026gt;\u0026thinsp;1b) of 32% and no improvement in prognosis compared with historical controls [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Therefore, we considered it necessary to develop a treatment method other than extended surgery or NAC by S-1 to improve the prognosis of type 4 GC.\u003c/p\u003e \u003cp\u003eSaikawa et al. investigated the efficacy of chemoradiotherapy (CRT) with S-1 plus low-dose cisplatin for unresectable GC and reported a high response rate (65.5%) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Additionally, a phase I trial of neoadjuvant CRT consisting of S-1 and low-dose cisplatin for patients with resectable advanced GC reported no major surgical complications and a pathologic complete response rate of 10% [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Thus, CRT with S-1 and cisplatin may be a promising treatment for advanced GC. However, the feasibility, safety, and efficacy of neoadjuvant CRT for resectable type 4 GC, especially for elderly patients, remain unknown.\u003c/p\u003e \u003cp\u003eConsidering these previous reports, we performed this prospective study to determine the feasibility, safety, and efficacy of neoadjuvant CRT for type 4 GC and large type 3 GC, which is considered to have the same biological behavior as type 4 GC, such as a high incidence of peritoneal dissemination [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Additionally, because this study included elderly GC patients aged\u0026thinsp;\u0026ge;\u0026thinsp;75 years, cisplatin was excluded from the chemotherapy regimen because of age-related declines in renal function [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. This phase I study was designed to determine the dose-limiting toxicity (DLT) of S-1, with concurrent radiotherapy, and to define the recommended dose (RD) for a subsequent phase II study.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e\u003cstrong\u003ePatients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe eligibility criteria for this study were as follows: (1) histologically proven and clinically resectable GC; (2) age \u0026gt; 75 years; (3) macroscopic type of carcinoma as type 4 or type 3 GC; (4) in type 3 GC, tumor size \u003cu\u003e\u0026gt;\u003c/u\u003e 8 cm in diameter; (5) Eastern Cooperative Oncology Group performance status of 0 or 1; (6) tumor invasion of the esophagus \u003cu\u003e\u0026lt;\u003c/u\u003e 1 cm, with no involvement of the duodenum; (7) lymph node metastasis limited to the regional lymph nodes; (8) no evidence of distant metastases, no peritoneal metastasis, and negative lavage cytology confirmed by staging laparoscopy; (9) no prior abdominal surgery; (10) no previous chemotherapy or radiotherapy; (11) no other previous or concurrent malignancies; (12) no bleeding from the main lesion or intestinal stenosis; and (13) adequate bone marrow function (white blood cell count \u0026ge; 3000/mm\u003csup\u003e3\u003c/sup\u003e, neutrophil count \u0026ge; 1500/mm\u003csup\u003e3\u003c/sup\u003e, hemoglobin \u0026ge; 8.0 g/dL, platelet count \u0026ge; 100 \u0026times; 10\u003csup\u003e3\u0026nbsp;\u003c/sup\u003e/mm\u003csup\u003e3\u003c/sup\u003e), adequate liver function (total serum bilirubin level \u0026le; 2.0 mg/dL, serum alanine transaminase and aspartate transaminase \u003cu\u003e\u0026lt;\u003c/u\u003e 100 U/L), and adequate renal function (creatinine clearance\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u0026ge; 40 mL/min). Written informed consent was obtained from all patients prior to their participation in the study.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The exclusion criteria were as follows: (1) other major medical disease or malignancy other than GC; (2) history of severe drug hypersensitivity; (3) treatment with a major tranquilizer, steroids, flucytosine, phenytoin, or warfarin; (4) lung fibrosis, intestinal pneumonitis, bowel obstruction, or ischemic heart disease; and (5) patients determined to be inappropriate for inclusion in this study.\u003c/p\u003e\n\u003cp\u003eThe present trial was performed in accordance with the World Medical Association Declaration of Helsinki and the Japanese Good Clinical Practice guidelines. This study was approved by the ethics committee in each institution or hospital and registered in the University Hospital Medical Information Network Clinical Trial Registry (UMIN000013821).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary objective of this phase I study was to determine the RD of S-1 combined with neoadjuvant radiation therapy in elderly patients with type 4 and large type 3 GC using a conventional dose-escalation design. The secondary objectives were to evaluate the pathological response rate and the treatment safety profile.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment Schedule\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe treatment schedule is summarized in Figure 1. Combined CRT consisted of S-1 and radiotherapy. S-1 was administrated orally from Days 1 to 14 followed by rest for 14 days at levels 0 and 1. At level 2, S-1 was administered from Days 1 to 14 and Days 22 to 35. The dose of S-1 administered at level 0 was 60 mg/m\u003csup\u003e2\u003c/sup\u003e/day. At levels 1 and 2, the dose of S-1 was 80 mg/m\u003csup\u003e2\u003c/sup\u003e/day.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRadiotherapy was delivered using megavoltage (6\u0026ndash;15 MV) X-rays and a multi-field technique. Patients received 2 Gy/day of radiation 5 days per week from the initiation of chemotherapy, with a total radiation dose of 40 Gy. Three-dimensional computed tomography (CT) simulation was required. CT simulation and daily radiation therapy were performed with the patient\u0026rsquo;s stomach empty, 3 hours after dietary intake. The gross volumes of the primary tumor (GTV primary) and the metastatic lymph nodes (GTV node) were defined by CT and positron emission tomography, with reference to an upper gastrointestinal series. The clinical target volume was calculated as the GTV primary and GTV node plus a 1-cm margin to account for subclinical extension. The planned target volume was the CTV plus 1\u0026ndash;2 cm longitudinally and 0.5\u0026ndash;1 cm transversely and vertically to account for setup variation and visceral motion. All patients were evaluated by abdominal and pelvic CT 4 weeks after completion of CRT to evaluate the possibility of R0 resection.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe surgical criteria were as follows: (1) achievable R0 resection; (2) white blood cell count \u0026ge; 2500/mm\u003csup\u003e2\u003c/sup\u003e; and (3) platelet count \u0026ge; 100,000/mm\u003csup\u003e2\u003c/sup\u003e. Surgery was performed between 7 and 9 weeks after the end of radiotherapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDetermination of DLT, maximum-tolerated dose, and RD\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study followed a standard 3+3 dose escalation protocol. Level 1 was the starting dose; if DLT developed, three additional patients were needed. Once DLT development was confirmed in 3/6 patients at level 1, the next step comprised level 0. In principle, the RD was one level down from the maximum-tolerated dose (MTD). However, if the MTD was not expressed at level 2 in this study, we would recommend level 2 as the RD.\u003c/p\u003e\n\u003cp\u003eToxicity was graded in accordance with the Common Toxicity Criteria for Adverse Events version 4.0 [10]. DLT was defined as follows: (1) grade 4 neutropenia; (2) grade 4 thrombocytopenia; (3) grade 3 febrile neutropenia lasting 4 days; (4) grade 3 non-hematologic toxicity except for appetite loss and general fatigue; and (5) inability to receive S-1 for \u0026gt; 10 days at levels 0 and 1 and \u0026gt; 19 days at level 2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSurgery and postoperative chemotherapy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSurgery consisted of total or distal gastrectomy, depending on the location of the primary tumor. D2 lymphadenectomy was routinely performed, while splenectomy was performed only for tumor involvement in the upper one-third of the greater curvature or with nodal metastases in the splenic hilum. If resectable M1 disease (hepatic, peritoneal, and/or lymphatic metastases) was found during surgery, the affected nodes were removed to achieve R0 resection. If R0 resection was impossible, the protocol treatment was terminated.\u003c/p\u003e\n\u003cp\u003eFollowing R0 resection, 1 year of adjuvant chemotherapy with S-1 monotherapy was administered within 6 weeks after gastrectomy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePostoperative follow-up\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter treatment, in accordance with the protocol, patients were followed-up every 3 months for the first 2 years, then every 6 months for the next 5 years.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssessment and statistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe tumor-node-metastasis categories were in accordance with the Japanese Classification of Gastric Carcinoma (3\u003csup\u003erd\u003c/sup\u003e English edition) [11]. The pathological response rate was evaluated and graded by pathologists in accordance with the Japanese Classification of Gastric Carcinoma (3\u003csup\u003erd\u003c/sup\u003e English edition) as grade 0 (no evidence of effect), grade 1a (viable tumor cells remain in more than two-thirds of the tumorous area), grade 1b (viable tumor cells remain in more than one-third but less than two-thirds of the tumorous area), grade 2 (viable tumor cells remain in less than one-third of the tumorous area), or grade 3 (no viable tumor cells). A pathological response was defined as a response greater than grade 1b. Toxicity and adverse events were described in accordance with the National Cancer Institute Common Toxicity Criteria grading version 4.0 [10]. Intra-and postoperative complications were graded in accordance with the Clavien\u0026ndash;Dindo classification [12]. OS and progression-free survival (PFS) were calculated from the date of the initial staging laparoscopy to death or the date of the most recent follow-up, respectively. OS and PFS were estimated using the Kaplan\u0026ndash;Meier method, with 95% confidence intervals (CI) determined using Greenwood\u0026rsquo;s formula. All statistical analyses were performed using SAS version 9.2 (SAS Institute Inc., Cary, NC, USA).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatient characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBetween July 2014 and August 2018, 10 patients were enrolled in this study and underwent neoadjuvant CRT. The patients\u0026rsquo; characteristics are summarized in Table 1. The median age was 78.5 years (range: 75\u0026ndash;81 years). The numbers of patients with large type 3 and type 4 tumors were 4 and 6, respectively.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMTD and RD\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll 10 patients started treatment and could be evaluated for toxicity. The details of toxicity in levels 1 and 2 are shown in Table 2. Six patients were registered at level 1. The main toxicity was hematological and comprised anemia (50.0%) and leukopenia (33.3%). Additionally, three patients (50.0%) developed hypoalbuminemia. No patients experienced higher than grade 3 hematological toxicity. Regarding non-hematologic toxicity, two patients developed grade 2 anorexia, and one patient (16.7%) developed DLT as gastric stenosis (grade 3). During dose level 2, two of four patients (50.0%) developed grade 2 leukemia and neutropenia, and one patient (25.0%) developed grade 2 anemia. The leukemia and neutropenia failed to respond to therapy, and as a result, the two patients (50.0%) were unable to continue the specified amount of S-1 for \u0026ge; 19 days Therefore, the RD was determined as level 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSurgery and postoperative complications\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients underwent the protocol surgery. The operation transition rate was 100% (95% CI, 69.2%\u0026ndash;100%). Total gastrectomy was performed in nine patients, while distal gastrectomy was performed in one patient. Peritoneal cytology positive for carcinoma cells (CY1) was observed in one patient. Therefore, the rate of R0 resection was 90% (9/10) (95% CI, 55.5%\u0026ndash;96.7%). Other surgical findings are shown in Table 3.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSurgical complications were observed in one patient (10%) and comprised transverse colonic necrosis (Grade IIIb), which required reoperation. There were no surgery-related deaths.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePathological findings\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe pathological effects of neoadjuvant CRT were as follows: grade 0 in 0 (0%) patients, grade 1a in two (20%), grade 1b in one (10%), grade 2 in seven (70%), and grade 3 in 0 (0%) patients. The pathological response rate, the secondary endpoint, was 80% (Table 4).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePostoperative chemotherapy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eS-1 postoperative adjuvant chemotherapy was initiated in 7 of the 10 patients who underwent surgery. The remaining three patients declined postoperative adjuvant chemotherapy. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSurvival\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOS and PFS were evaluated in the 10 eligible patients. At the time of analysis (September 2023), six patients were alive without recurrence; three patients had died as a result of recurrence. Another patient died of other disease 16 months after surgery. The 3- and 5-year OS rates were both 60.0% (95% CI, 25.3%\u0026ndash;82.7%). The 3- and 5-year PFS rates were also both 60.0% (95% CI, 25.3%\u0026ndash;82.7%) (Fig. 2a and b).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis phase I study was designed to evaluate neoadjuvant concurrent CRT in elderly patients with resectable type 4 or large type 3 GC and it determined the RD of S-1 as\u0026nbsp;80 mg/m\u003csup\u003e2\u003c/sup\u003e/day on Days 1\u0026ndash;14. The predominant adverse events in this study were anemia (40%), leukopenia (40%), and neutropenia (20%). No patients developed grade 3 or 4 hematologic toxicity at the two dose levels evaluated in this study. These adverse event results were consistent with those in several previous studies that examined the safety of S-1 in elderly patients with advanced GC [13, 14]. The chemotherapy completion rate was 80% (8/10), similar to that observed in the JCOG 0002 trial (clinical trial for scirrhous GC) using S-1 for NAC (94%) [5].\u003c/p\u003e\n\u003cp\u003eIn comparison, the radiotherapy completion rate was 100%, and eventually, 9 of the 10 (90%) patients underwent R0 resection. As a result, the lower limit of the 95% CI was 55.5%, suggesting that our neoadjuvant CRT regimen is feasible.\u0026nbsp;However, CY1 was identified in one (10%) patient after neoadjuvant CRT. This may have resulted from the inadequate diagnostic accuracy of peritoneal lavage examination. The accuracy of conventional peritoneal lavage cytology for peritoneal metastasis diagnosis is still limited, with a sensitivity of \u0026lt; 60% [15, 16]. Therefore, in the affected patient in our study, CY1 might have been latent at the time of the initial staging laparoscopy. Recently, the usefulness of the cell block technique has been reported [17], and this technique is covered by insurance in Japan. Therefore, the cell block technique may increase the accuracy of peritoneal cytological diagnosis in the future.\u003c/p\u003e\n\u003cp\u003eRegarding surgical complications, the postoperative morbidity rate was low (10%) in our study compared with that of previous studies [18], and there were no surgery-related deaths in this study. However, colonic necrosis developed in one patient as a postoperative adverse event (Grade \u0026ge; 3). Ischemic changes due to irradiation are considered to occur several years after irradiation when the total irradiation dose exceeds 55\u0026ndash;60 Gy [19, 20]. There have been no reports of colonic necrosis following low doses of radiation, such as 40 Gy. The necrosis in the patient in our study occurred during the acute phase of radiation damage, and we believe it was caused by an additional complication, such as infection or an intraoperative procedure.\u003c/p\u003e\n\u003cp\u003eThe low rate of surgical complications made it possible for 7 of the 10 patients (70%) to receive adjuvant chemotherapy as scheduled. Therefore, our neoadjuvant CRT regimen was considered safe.\u003c/p\u003e\n\u003cp\u003eRegarding therapeutic efficacy, our study achieved a pathological response rate of 80%, which was better than that of the JCOG 0002 trial (32%) [5]. It is assumed that the high pathological response rate in this study may be associated with the addition of concurrent radiation therapy. The prognostic outcome and pathological response rate are generally used as indicators to evaluate the effect of preoperative therapy [21]. The\u003c/p\u003e\n\u003cp\u003eJCOG 0002 trial indicated that the 3-year survival rate for type 4 GC was \u0026lt; 40% [5]. Although our sample size was small, the 5-year OS and PFS rates in our study were both 60.0%. Therefore, neoadjuvant CRT might provide a favorable prognosis for elderly patients with type 4 or large type 3 GC.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn conclusion, the safety and efficacy of this regimen (S-1\u0026nbsp;80 mg/m\u003csup\u003e2\u003c/sup\u003e/day from Days 1 to 14 with concurrent radiotherapy at 40 Gy) will be evaluated in a phase II study with larger numbers of patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are grateful to the members of the OGSG Data Center and OGSG Operations Office for their support in this study. We would also like to thank Ying-Feng Peng, and Jane Charbonneau, DVM, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudy concept: MI and HF; study design: MI, MY, and HF; acquisition of data: MS, MI,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eJM, and YK; statistical analysis of the data: TS; analysis and/or interpretation of the data: MS, MI, and TS; drafting the manuscript: MS and MI; revising the manuscript critically for important intellectual content: HK, TS, TY, and HF. All authors approved the final version of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u0026nbsp;\u003c/strong\u003eAll procedures were performed in accordance with the ethical standards of the committee on human experimentation and with the Helsinki Declaration of 1964 and later versions. This study was approved by the institutional review and ethics board of each participating hospital and registered in the University Hospital Medical Information Network (UMIN) database (UMIN000013821). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003eThis study was supported by the Osaka Gastrointestinal Cancer Chemotherapy Group (OGSG).\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u0026nbsp;\u003c/strong\u003eInformed consent or substitute consent was obtained from all patients included in the study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest statement\u0026nbsp;\u003c/strong\u003eThe authors declare no competing interests.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication statement\u0026nbsp;\u003c/strong\u003eThe authors have approved publication.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e Not applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eVital Statistics Japan (Ministry of Health, Labour and Welfare). http://www.mhlw.go.jp/english/database/db-hw/index.html\u003c/li\u003e\n \u003cli\u003eAn JK, Kang TH, Choi MG, Noh JH, Sung T, Kim S (2008) Borrmann type IV: an independent prognosis factor for survival in gastric cancer. J Gastrointest Surg 12:1364-1369. https://doi.org/10.1007/s11605-008-0516-9\u003c/li\u003e\n \u003cli\u003eLi C, Oh SJ, Kim S, Hyung WJ, Yan M, Zhu ZG, Noh SH (2009) Macroscopic Borrmann type as a simple prognostic indicator in patients with advanced gastric cancer. Oncology 77:197-204. https://doi.org/10.1159/000236018\u003c/li\u003e\n \u003cli\u003eFurukawa H, Hiratsuka M, Iwanaga T, Imaoka S, Ishikawa O, Kabuto T, Sasaki Y, Kameyama M, Ohigashi H, Nakamori S, Yasuda T (1997) Extended surgery-left upper abdominal extension plus Appleby\u0026rsquo;s method-for type 4 gastric carcinoma. Ann Surg Oncol 4:209-214\u003c/li\u003e\n \u003cli\u003eKinoshita T, Sasako M, Sano T, Katai H, Furukawa H, Tsuburaya A, Miyashiro I, Kaji M, Ninomiya M (on behalf of the Gastric Cancer Surgery Study Group of the Japan Clinical Oncology group) (2009) Phase II trial of S-1 for neoadjuvant chemotherapy against scirrhous gastric cancer (JCOG 0002). Gastric Cancer 12:37-42. https://doi.org/10.1007/s10120-008-0496-1\u003c/li\u003e\n \u003cli\u003eSaikawa Y, Kubota T, Kumagai K, Nakamura R, Kumai K, Shigematsu N, Kubo A, Kitajima M, Kitagawa Y (2008) Phase II study of chemoradiotherapy with S-1 and low-dose cisplatin for inoperable advanced gastric cancer. Int J Radiat Oncol Biol Phys 71:173-179. https://doi.org/10.1016/j_ijrohp.2007.09.010\u003c/li\u003e\n \u003cli\u003eTakahashi T, Saikawa Y, Takaishi H, Takeuchi H, Wada N, Oyama T, Fukuda K, Fukada J, Kawaguchi O, Shigematsu N, Kitagawa Y (2011) Phase I study of neoadjuvant chemoradiotherapy consisting of S-1 and cisplatin for patients with resectable advanced gastric cancer (KOGC-01). Anticancer Res 31:3079-3084\u003c/li\u003e\n \u003cli\u003eYamashita K, Ema A, Hosoda K, Mieno H, Moriya H, Katada N, Watanabe M (2017) Macroscopic appearance of Type IV and giant Type III is a high risk for a poor prognosis in pathological stage II/III advanced gastric cancer with postoperative adjuvant chemotherapy. World J Gastrointest Oncol 9:166-175. https://doi.org/10.4251/wjgo.v9.i4.166\u003c/li\u003e\n \u003cli\u003ePeterson LI, Hurria A, Feng T, Mohile SG, Owusu C, Klepin HD, Gross CP, Lichtman SM, Gajra A, Glezerman I, Katheria V, Zavala L, Smith DD, Sun CL, Tew WP (2017) Association between renal function and chemotherapy-related toxicity in older adults with cancer. J Geriatr Oncol 8:96-101. https://doi.org/10.1016/j.jgo.2016.10.004\u003c/li\u003e\n \u003cli\u003eU.S. Department of Health and Human Survices. National Eventns (CTCAE) version 4.0. (2009)\u003c/li\u003e\n \u003cli\u003eJapanese Gastric Cancer Association (2011) Japanese classification of gastric carcinoma: 3\u003csup\u003erd\u003c/sup\u003e English edition. Gastric Cancer 14:101-112. https://doi.org/10.1007/s10120-011-0041-5\u003c/li\u003e\n \u003cli\u003eDindo D, Demartines N, Clavien PA (2004) Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 240:205-213. https://doi.org/10.1097/01.sla.0000133083.54934.ae\u003c/li\u003e\n \u003cli\u003eKoizumi W, Akiya T, Sato A, Sakuyama T, Sasaki E, Tomidokoro T, Hamada T, Fujimori M, Kikuchi Y, Shimada K, Mine T, Yamaguchi K, Sasaki T, Kurihara M (2010) Phase II study of S-1 as first-line treatment for elderly patients over 75 years of age with advanced gastric cancer: the Tokyo Cooperative Oncology Group study. Cancer Chemother Pharmacol 65:1093-1099. https://doi.org/10.1007/s00280-009-1114-6\u003c/li\u003e\n \u003cli\u003eImamura H, Kishimoto T, Takiuchi H, Kimura Y, Morimoto T, Imano M, Iijima S, Yamashita K, Maruyama K, Otsuji T, Kurokawa Y, Furukawa H (2014) Phase II study of S-1 monotherapy in patients over 75 years of age with advanced gastric cancer (OGSG0404). J Chemother 26:57-61. https://doi.org/10.1179/1973947813Y.0000000116\u003c/li\u003e\n \u003cli\u003eHoskovec D, Varga J, Dytrych P, Konecna E, Matek J (2017) Peritoneal lavage examination as a prognostic tool in cases of gastric cancer. Arch Med Sci 13:612-616. https://doi.org/10.5114/aoms.2016.64044\u003c/li\u003e\n \u003cli\u003eKang KK, Hur H, Byun CS, Kim YB, Han SU, Cho YK (2014) Conventional cytology is not beneficial for predicting peritoneal recurrence after curative surgery for gastric cancer: results of a prospective clinical study. J Gastric Cancer 14:23-31. https://doi.org/10.5230/jgc.2014.14.1.23\u003c/li\u003e\n \u003cli\u003eTaffon C, Giovannoni I, Mozetic P, Capolupo GT, La Vaccara V, Cinque C, Caricato C, Rainer A, Zelano G, Crescenzi A (2019) Seriate cytology vs molecular analysis of peritoneal washing to improve gastric cancer cells detection. Diagn Cytopathol 47:670-674. https://doi.org/10.1002/dc.24165\u003c/li\u003e\n \u003cli\u003eTerashima M, Iwasaki Y, Mizusawa J, Katayama H, Nakamura K, Katai H, Yoshikawa T, Ito Y, Kaji M, Kimura Y, Hirao M, Yamada M, Kurita A, Takagi M, Boku N, Sano T, Sasako M, Stomach Cancer Study Group, Japan Clinical Oncology Group (2019) Randomized phase III trial of gastrectomy with or without neoadjuvant S-1 plus cisplatin for type 4 or large type 3 gastric cancer, the short-term safety and surgical results: Japan Clinical Oncology Group Study (JCOG0501). Gastric Cancer 22:1044-1052. https://doi.org/10.1007/s10120-019-00941-z\u003c/li\u003e\n \u003cli\u003eEmami B, Lyman J, Brown A, Coia L, Goitein M, Munzenrider JE, Shank B, Solin LJ, Wesson M (1991) Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 21:109-122. https://doi.org/10.1016/0360-3016(91)90171-y\u003c/li\u003e\n \u003cli\u003eTimmerman R (2022) A story of hypofractionation and the table on the wall. Int J Radiat Oncol Biol Phys 112:4-21. https://doi.org/10.1016/j.ijrobp.2021.09.027\u003c/li\u003e\n \u003cli\u003eTomasello G, Petrelli F, Ghidini M, Pezzica E, Passalacqua R, Steccanella F, Turati L, Sgroi G, Barni S (2017) Tumor regression grade and survival after neoadjuvant treatment in gastro-esophageal cancer: a meta-analysis of 17 published studies. Eur J Surg Oncol 43:1607-1616. https://doi.org/10.1016/j.ejso.2017.03.001\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Patient characteristics (n=10)\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"561\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003eNumber\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003eAge, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e78.5 (75\u0026ndash;81)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003eSex\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003eECOG performance status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003eMacroscopic findings (JGCA)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Type 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Type 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003eTumor location in the stomach\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Upper\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Middle\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Lower\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003eHistological subtype\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Tubular adenocarcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Poorly differentiated adenocarcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Signet-ring cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003eClinical T stage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;T3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;T4a\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;T4b\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003eClinical N stage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; N0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; N1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; N2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; N3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003ePeritoneal metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e P0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e P1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003ePeritoneal lavage cytology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;CY0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;CY1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003eClinical M stage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;M0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;M1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003eClinical TMN stage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;IA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;IB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;IIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;IIB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;IIIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;IIIB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;IIIC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;IV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eECOG: Eastern Cooperative Oncology Group, JGCA: Japan Gastric Cancer Association,\u003c/p\u003e\n\u003cp\u003eP0: No peritoneal metastasis, P1: Peritoneal metastasis, CY0: Peritoneal cytology negative for carcinoma cells, CY1: Peritoneal cytology positive for carcinoma cells, M0: No distant metastasis, M1: Distance metastasis, T: Tumor, N: Node\u003c/p\u003e\n\u003cp\u003eTable 2. Adverse events (n=10)\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"576\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003eToxicity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003eGrade 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003eGrade 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003eGrade 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003eGrade 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e% Grade 3/4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003eLevel 1 (n=6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003eHematologic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; Leukopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; Neutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; Thrombocytopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; Anemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; Hypoalbuminemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; AST elevated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; ALT elevated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; Hyperbilirubinemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; Hypercreatininemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003eHyperkalemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003eHypernatremia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003eHyponatremia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003eGastrointestinal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Anorexia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Nausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Vomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Diarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003eMalaise\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003eRash\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003eGastric stenosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e16.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003eLevel 2 (n=4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003eHematologic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; Leukopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; Neutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; Thrombocytopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; Anemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; Hypoalbuminemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; AST elevation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; ALT elevation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; Hyperbilirubinemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; Hypercreatininemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; Hyperkalemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; Hypernatremia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; Hyponatremia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003eGastrointestinal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Anorexia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e16.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Nausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Vomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Diarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003eMalaise\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003eRash\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003eGastric stenosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eALT: alanine transaminase, AST: aspartate transaminase\u003c/p\u003e\n\u003cp\u003eToxicities were graded in accordance with the National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0.\u003c/p\u003e\n\u003cp\u003eTable 3. Surgical findings and postoperative complications (n=10)\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"561\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003eFinding\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003eNumber\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003ePeritoneal lavage cytology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;CY0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;CY1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003ePeritoneal metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;P0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;P1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003eType of resection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Total gastrectomy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Distal gastrectomy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003eCombined resection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Transverse colon\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Pancreatic tail\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Diaphragm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003eLymph node dissection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;D2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003eResidual tumor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;R0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;R1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;R2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003ePostoperative complications\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003eAnastomotic leakage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003ePancreatic fistula\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003eIntra-abdominal abscess\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003eWound infection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003eTransverse colonic necrosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 1 (\u003cem\u003eGr.\u003c/em\u003e IIIb)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 297px;\"\u003e\n \u003cp\u003e30/60-day mortality\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 265px;\"\u003e\n \u003cp\u003e0/0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCY0: Peritoneal cytology negative for carcinoma cells, CY1: Peritoneal cytology positive for carcinoma cells, P0: No peritoneal metastasis, P1: Peritoneal metastasis, \u003cem\u003eGr.\u003c/em\u003e Toxicity grade in accordance with the Clavien\u0026ndash;Dindo classification\u003c/p\u003e\n\u003cp\u003eTable 4. Pathological findings (n=10)\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"561\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 287px;\"\u003e\n \u003cp\u003eFinding\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 274px;\"\u003e\n \u003cp\u003eNumber\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 287px;\"\u003e\n \u003cp\u003eDepth of tumor (T) invasion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 274px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 287px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u0026nbsp; \u0026nbsp;T0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 274px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 287px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; T1a\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 274px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 287px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u0026nbsp; \u0026nbsp;T1b\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 274px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 287px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u0026nbsp; \u0026nbsp;T2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 274px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 287px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u0026nbsp; \u0026nbsp;T3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 274px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 287px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u0026nbsp; \u0026nbsp;T4a\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 274px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 287px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u0026nbsp; \u0026nbsp;T4b\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 274px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 287px;\"\u003e\n \u003cp\u003eLymph node (N) metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 274px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 287px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; N0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 274px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 287px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; N1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 274px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 287px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u0026nbsp; \u0026nbsp;N2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 274px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 287px;\"\u003e\n \u003cp\u003eJCGA stage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 274px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 287px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u0026nbsp; \u0026nbsp;IA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 274px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 287px;\"\u003e\n \u003cp\u003eIB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 274px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 287px;\"\u003e\n \u003cp\u003eIIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 274px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 287px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; IIB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 274px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 287px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; IIIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 274px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 287px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; IIIB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 274px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 287px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; IIIC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 274px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 287px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; IV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 274px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 287px;\"\u003e\n \u003cp\u003eJCGA histological response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 274px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 287px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Grade 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 274px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 287px;\"\u003e\n \u003cp\u003eGrade 1a\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 274px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 287px;\"\u003e\n \u003cp\u003eGrade 1b\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 274px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 287px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Grade 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 274px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 287px;\"\u003e\n \u003cp\u003eGrade 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 274px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eJCGA: Japanese Classification of Gastric Carcinoma (3\u003csup\u003erd\u003c/sup\u003e English edition)\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"medical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"medo","sideBox":"Learn more about [Medical Oncology](https://www.springer.com/journal/12032)","snPcode":"12032","submissionUrl":"https://submission.nature.com/new-submission/12032/3","title":"Medical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Gastric cancer, Chemoradiotherapy, Type 4, Large Type 3, S-1, elderly","lastPublishedDoi":"10.21203/rs.3.rs-5267297/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5267297/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003ePurpose\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe prognosis for type 4 and large type 3 gastric cancer (GC) is extremely poor, especially in elderly patients (\u0026ge;\u0026thinsp;75 years). To improve the prognosis of these types of GC, we performed a phase I study to determine the recommended dose (RD) of S-1 combined with neoadjuvant radiotherapy.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003ePatients with clinically resectable type 4 and large type 3 GC were enrolled to successive cohorts in a conventional 3\u0026thinsp;+\u0026thinsp;3 design. Three dose levels were designed, as follows: level 0: S-1 60 mg/m\u003csup\u003e2\u003c/sup\u003e/day on Days 1\u0026ndash;14; level 1: S-1 80 mg/m\u003csup\u003e2\u003c/sup\u003e/day on Days 1 \u0026minus;\u0026thinsp;14; level 2: S-1 80 mg/m\u003csup\u003e2\u003c/sup\u003e/day on Days 1\u0026ndash;14 and Days 22\u0026ndash;35. The starting dose was level 1. Radiotherapy was delivered at a total dose of 40 Gy in fractions for 4 weeks.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eTen patients were enrolled from July 2014 to August 2018. Six patients were registered at level 1, and one patient developed a dose limiting toxicity as gastric stenosis (grade 3). Two of four patients enrolled at level 2 developed dose limiting toxicity (inability to receive S-1 for hematological reasons). Therefore, the RD was determined as level 1. All patients underwent the protocol surgery; one patient underwent R1 resection because of positive peritoneal washing cytology. There were no treatment-related deaths, and the pathological response rate was 80%. The 5-year overall- and progression-free survival rates were both 60.0%.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe RD was determined as level 1. A phase II trial using the RD should be initiated.\u003c/p\u003e","manuscriptTitle":"Phase I study of neoadjuvant chemoradiotherapy with S-1 for clinically resectable type 4 or large type 3 gastric cancer in elderly patients aged 75 years and older (OGSG1303)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-16 05:59:36","doi":"10.21203/rs.3.rs-5267297/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-11-23T19:45:14+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-16T11:34:19+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-08T19:22:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"248858954697256497896460803103321948248","date":"2024-11-08T14:25:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"77897874778782824571740977993553642446","date":"2024-11-08T08:50:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"84804207205771327939872274477311669750","date":"2024-11-08T04:22:03+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-11-08T04:17:14+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-16T05:58:41+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-10-16T05:56:26+00:00","index":"","fulltext":""},{"type":"submitted","content":"Medical Oncology","date":"2024-10-15T09:05:41+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"medical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"medo","sideBox":"Learn more about [Medical Oncology](https://www.springer.com/journal/12032)","snPcode":"12032","submissionUrl":"https://submission.nature.com/new-submission/12032/3","title":"Medical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"786632bf-eb80-4617-baf9-9cd79ac9697c","owner":[],"postedDate":"December 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-12-23T16:00:16+00:00","versionOfRecord":{"articleIdentity":"rs-5267297","link":"https://doi.org/10.1007/s12032-024-02583-3","journal":{"identity":"medical-oncology","isVorOnly":false,"title":"Medical Oncology"},"publishedOn":"2024-12-19 15:57:07","publishedOnDateReadable":"December 19th, 2024"},"versionCreatedAt":"2024-12-16 05:59:36","video":"","vorDoi":"10.1007/s12032-024-02583-3","vorDoiUrl":"https://doi.org/10.1007/s12032-024-02583-3","workflowStages":[]},"version":"v1","identity":"rs-5267297","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5267297","identity":"rs-5267297","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}