Protocol digest of a phase III trial to evaluate the efficacy of preoperative chemotherapy with S-1 plus oxaliplatin followed by D2 gastrectomy with postoperative S-1 in locally advanced gastric cancer: Japan Clinical Oncology Group study JCOG1509 (NAGISA Trial)

Abstract

In Japan, postoperative chemotherapy is a standard care for stage II/III gastric cancer after curative resection with D2 lymph node dissection, and the clinical outcomes of patients with stage III gastric cancer are unsatisfactory. A combination of oral S-1 and oxaliplatin, that is the standard chemotherapy regimen for unresectable advanced/recurrent gastric cancer associated with a high response rate, was considered the most promising preoperative chemotherapy regimen. This randomized phase III trial was started in September 2016 to confirm the superiority of preoperative chemotherapy with S-1 plus oxaliplatin followed by D2 gastrectomy with postoperative chemotherapy compared with D2 gastrectomy with postoperative chemotherapy for patients with clinical T3–4N1–3 M0 locally advanced gastric cancer in terms of overall survival. A total of 470 patients will be enrolled from 63 hospitals in Japan for 8.5 years. This trial has been registered in the Japan Registry of Clinical Trials as jRCTs031180350 [https://jrct.niph.go.jp/latest-detail/jRCTs031180350].

Introduction

Gastric cancer is the fifth most common type of cancer and the fourth leading cause of cancer-related deaths worldwide (1). Perioperative treatment for locally advanced gastric cancer has been inconsistent between Japan and the Western countries (2–4). Perioperative chemotherapy is considered a standard care in Western countries (5–7). Meanwhile, D2 gastrectomy followed by S-1 postoperative chemotherapy for 1 year was the standard treatment for patients with a pathological stage (pStage) II/III gastric cancer [except for pT1 (M,SM) N2–3 and pT3 (SS) N0] in Japan based on the ACTS-GC trial (8). However, the 5-year survival for patients with pStage IIIA and IIIB gastric cancer according to the Japanese gastric cancer classification 13th edition (9) was 67 and 50%, respectively (10). Thus, room for improvement and intensification of chemotherapy remains. However, administering chemotherapy with sufficient intensity is challenging after gastrectomy.

Preoperative chemotherapy is an expectedly effective treatment for locally advanced gastric cancer with a poor prognosis due to its preoperative administration, which allows better compliance with chemotherapy and early chemotherapy administration for micrometastases. The Japan Clinical Oncology Group (JCOG) has conducted several phase II trials for patients with gastric cancer with extensive lymph node metastasis, including JCOG0405, which showed survival benefits of preoperative chemotherapy with S-1 + cisplatin (SP) (11). JCOG1002 for the same target investigated the efficacy of a triplet regimen (S-1 + cisplatin + docetaxel); however, the response rate was not high enough to justify its superior efficacy over SP regimen (12,13). The G-SOX study for metastatic gastric cancer confirmed the non-inferiority of S-1 plus oxaliplatin to SP in terms of progression-free survival (14). Oxaliplatin administration does not require hydration, thus S-1 plus oxaliplatin with its lesser treatment burden was more convenient than SP. S-1 plus oxaliplatin was adopted as the most promising regimen in JCOG1509 considering the results of JCOG0405, JCOG1002 and the G-SOX study.

One of the problems with the preoperative chemotherapy was the possible inclusion of patients with pStage I gastric cancer who may experience unnecessary adverse events due to chemotherapy because the accuracy of clinical diagnosis of the preoperative stage was limited to 70–80%. The patient selection criteria to maximize the sensitivity of patients with pStage III gastric cancer with poor prognosis and minimize the contamination of patients with pStage I gastric cancer who do not need preoperative chemotherapy are important to select patients for preoperative chemotherapy. Therefore, the JCOG Stomach Cancer Study Group conducted JCOG1302A, a prospective diagnostic accuracy study to identify appropriate patient selection criteria by endoscopy, endoscopic ultrasonography and computed tomography (CT) for preoperative chemotherapy (15). Clinical T3–4 (SS, SE, SI) and N1–3 (positive lymph node was defined as that with a long-axis diameter of ≥10 mm or short-axis diameter of ≥8 mm) were selected as optimal candidates for intensive preoperative chemotherapy as the criteria included 6.5% overdiagnosed patients with pStage I and accounted for 52.6% of all patients with pStage III gastric cancer.

Therefore, we have designed and started this randomized phase III trial to confirm the superiority of preoperative chemotherapy with S-1 plus oxaliplatin followed by D2 gastrectomy with postoperative chemotherapy compared with D2 gastrectomy with postoperative chemotherapy for patients with clinical T3–4 (SS, SE, SI) N1–3M0 locally advanced gastric cancer in terms of overall survival.

The JCOG Protocol Review Committee approved this study protocol in December 2015, and this study was activated in September 2016. This trial was registered at the Japan Registry of Clinical Trials with the number jRCTs031180350 [https://jrct.niph.go.jp/latest-detail/jRCTs031180350].

Protocol digest of the JCOG1509

Unless otherwise noted, the notation in the text is described according to the Japanese Classification of Gastric Carcinoma 14th edition.

Purpose

This study aims to confirm the superiority of the addition of preoperative chemotherapy with S-1 plus oxaliplatin followed by D2 gastrectomy and postoperative chemotherapy to the standard treatment, D2 gastrectomy and postoperative chemotherapy for patients with clinical T3–4 (SS, SE, SI) N1–3M0 gastric cancer.

Study setting

A multi-institutional (63 specialized centers), randomized controlled phase III trial.

Resources

This study is supported in part by the National Cancer Center Research and Development Funds (26-A-4, 29-A-3, 2020-J-3) and the AMED under Grant Numbers JP17ck0106310 and JP20ck0106591.

Endpoints

The primary endpoint is overall survival, which is defined as the time from randomization to death of any cause and censored on the last contact day for a surviving patient. The secondary endpoints are progression-free survival, preoperative chemotherapy response rate as assessed according to the Response Evaluation Criteria in Solid Tumors version 1.1, pathological response rate, R0 resection proportion, surgical completion proportion, protocol treatment completion proportion, preoperative chemotherapy dose intensity, the proportion of patients undergoing postoperative chemotherapy at 3, 6, 9 and 12 months after surgery and adverse events. Progression-free survival is defined as the time from randomization to the first event of either progress, relapse or death from any cause and censored at the last date of contact for a progression-free surviving patient. The patients are not consediered as an event for progression-free survival if tumor progression or clicanil progression is not observed after initiating preoperative chemotherapy but R0/R1 resection is not achieved. Also, the patient is not considered as an event for progression-free survival if the R0/R1 resection is achieved even when tumor progression or clinical progression is observed during preoperative chemotherapy. The patient is considered as an event for progression-free survival on the surgical date if tumor progression or clinical progression is observed after preoperative chemotherapy initiation and the surgery falls into R2 resection. The definition of progression-free survival is the same regardless of resectability for patients randomized to D2 gastrectomy followed by postoperative chemotherapy arm. The pathological response rate is defined as the proportion of Grade 1b, 2 and 3 according to the Japanese Classification of Gastric Carcinoma 3rd English edition among all eligible patients in the preoperative chemotherapy arm (16). Adverse events are evaluated according to the Common Terminology Criteria for Adverse Events version 4.0 and Clavien–Dindo classification for surgical complications (17).

Inclusion criteria

Patients who meet all of the following criteria are enrolled in this trial:

• 1) Histologically proven gastric adenocarcinoma.

• 2) Clinical T3 (SS) or T4 (SE, SI) by imaging.

• 3) No tumor invasion to the pancreas head of the primary tumor and/or metastatic lymph node.

• 4) Enlarged lymph node (≥8 mm in minor axis or ≥ 10 mm in major axis) by contrast-enhanced abdominal CT.

• 5) No bulky lymph nodes (>3 cm × 1 or > 1.5 cm × 2 on the major axis) along with the celiac, splenic, common or proper hepatic arteries or the superior mesenteric vein by contrast-enhanced abdominal CT.

  • Irrespective of human epidermal growth factor receptor 2 (HER2). Initially, HER2 negative had to be confirmed in patients with enlarged lymph nodes of 15 mm in the minor axis due to the priority of patient accrual in JCOG1301C which was a study of preoperative chemotherapy with trastuzumab targeting HER2-positive gastric cancer, but was excluded in October 2021 due to the end of accrual in JCOG1301C (18,19).

• 6) No distant metastasis based on contrast-enhanced thoracic, abdominal and pelvic CT.

• 7) The macroscopic tumor type is neither Borrmann type 4 (linitis plastica) nor large (≥8 cm) type 3.

• 8) No esophageal invasion or an invasion of ≤3 cm.

• 9) No gastric stump cancer.

• 10) No non-curable factors other than positive lavage cytology revealed in a staging laparoscopy before registration.

• 11) Sufficient oral intake.

• 12) No prior chemotherapy, radiotherapy or endocrine therapy for any malignancies within 5 years.

• 13) Ages between 20 and 79 years.

• 14) Eastern Cooperative Oncology Group performance status of 0 or 1.

• 15) Sufficient organ function as follows:

  • Neutrophil ≥1500/mm³

  • Hemoglobin ≥8.0 g/dL

  • Platelet ≥100 000/mm³

  • Total bilirubin ≤2.0 mg/dL

  • AST ≤ 100 IU/L

  • ALT ≤100 IU/L

  • Creatinine ≤1.3 mg/dL

  • CCr ≥ 60 mL/min/body

• 16) Written informed consent.

Exclusion criteria

Patients who have any of the following criteria are excluded from this trial:

• 1) Synchronous or metachronous (within 5 years) malignancies except cancer with a 5-year relative survival rate of ≥95%, such as carcinoma in situ, intramucosal tumor or early-stage cancers

• 2) Infectious diseases requiring systemic treatment

• 3) Body temperature of ≥38°C

• 4) Pregnant female, female within 28 days of post-parturition, or during lactation. Males with partners planning conception shortly

• 5) Severe psychological disease

• 6) Receiving continuous systemic corticosteroid or immunosuppressant treatment

• 7) Under flucytosine, phenytoin or warfarin treatments

• 8) History of unstable angina pectoris within 3 weeks or myocardial infarction within 6 months before registration

• 9) Poorly controlled diabetes

• 10) Interstitial pneumonia, pulmonary fibrosis or severe emphysema based on chest CT

Randomization

Patients will be randomized (1:1) to either the postoperative (D2 gastrectomy followed by postoperative chemotherapy) or perioperative chemotherapy arm (preoperative chemotherapy with S-1 plus oxaliplatin followed by D2 gastrectomy with postoperative chemotherapy) following the confirmation of patient eligibility using the web-based system to the JCOG Data Center. The minimization method will be used for the randomization with clinical T factors (cT3 [SS] vs. cT4 [SE, SI]), planned surgical procedures (total gastrectomy versus distal gastrectomy) and the institution.

Treatment Methods

Preoperative chemotherapy

Patients in the perioperative chemotherapy arm receive an oxaliplatin infusion (130 mg/m²/day) on Day 1 and oral S-1 (40 mg/m², twice, daily) for 2 weeks from Days 1 to 14 followed by a 1-week rest period. Three courses of preoperative chemotherapy are administered unless unequivocal progression or unacceptable toxicities are observed. The tumor response and feasibility of R0 resection are evaluated after the third course. The protocol treatment is terminated when R0 resection is considered difficult regardless of tumor shrinkage after the third course.

Surgery

Total or distal gastrectomy with D2 lymph node dissection is performed in both arms. Total gastrectomy with splenectomy when the tumor invaded upper stomach was recommended if at least one of the following conditions are met: (i) tumor invades at the great curvature of the upper stomach; (ii) the macroscopic tumor type is Borrmann type 4 (linitis plastica) and (iii) lymph node metastasis is suspected in the splenic hilar lymph node (No. 10). The omentum is removed, as well as any involved adjacent organ(s) to achieve R0 resection. A laparoscopic or robotic gastrectomy was not allowed. However, three randomized phase III trials from Korea, China and Japan compared laparoscopic distal gastrectomy with open distal gastrectomy and showed the non-inferiority of laparoscopic distal gastrectomy to open distal gastrectomy in patients with locally advanced gastric cancer after trial initiation (20–22). The study protocol was revised in April 2022 considering the results of JCOG1401 (23) and LOC-A study, in which the feasibility of laparoscopic total gastrectomy was demonstrated (24), to allow a laparoscopic distal or total gastrectomy. Resectable M1 disease (hepatic, peritoneal and/or lymphatic metastases) found during surgery is resected if achieve R0 resection is expected. The protocol treatment is terminated if R0 resection is impossible. The protocol treatment is terminated after the operation is completed when total gastrectomy with thoracotomy, left upper abdominal exenteration, pancreaticoduodenectomy or Appleby’s operation is required to achieve the R0 resection. Patients in the postoperative chemotherapy arm undergo surgery within 21 days after the randomization. When possible, the patient in the perioperative chemotherapy arms undergoes surgery within 56 days (preferably 28 days) after the last S-1 treatment.

Postoperative chemotherapy

At the study initiation, postoperative chemotherapy with S-1 was initiated within 42 days postoperatively after the R0 resection for patients with pStage II/III gastric cancer. However, the JACCRO GC-07 (START-2) trial showed that the addition of docetaxel to S-1 improved relapse-free survival compared with S-1 for pStage III gastric cancer following R0 resection (25). Postoperative chemotherapy with docetaxel plus S-1 is applied to pStage III/IV and ypStage III/IV with R0 or R1 with only CY1 as a non-curative factor after the protocol amendment in June 2018. A 3-week course that consists of 2 weeks of daily oral S-1 administration at 40 mg/m², twice daily followed by a 1-week rest is repeated during the first to seventh courses. Patients receive an infusion of docetaxel (40 mg/m²) on Day 1 during the second to seventh courses. A 6-week course consisting of 4 weeks of daily oral S-1 administration at 40 mg/m², twice daily followed by a 2-week rest is repeated from the 8th to the 12th course. Postoperative chemotherapy with S-1 is applied to the R0 resection for pStage II gastric cancer in the postoperative chemotherapy arm and ypStage 0–II in the perioperative chemotherapy arm. A 6-week course consisting of 4 weeks of daily oral S-1 administration at 40 mg/m², twice daily followed by a 2-week rest is repeated during the first year postoperatively.

Follow-up

All enrolled patients are followed up for 5 years. Physical, blood examinations and tumor markers, such as carcinoembryonic antigen and carbohydrate antigen 19–9, are conducted every 3 months for the first 3 years and every 6 months for the past 2 years. An abdominal CT is performed every 6 months for the first 3 years and every year for the past 2 years. Chest X-ray and upper gastrointestinal endoscopy (only for distal gastrectomy cases) are conducted every year.

Study design and statistical analysis

We intended to enroll 470 patients for 3 years to observe 195 deaths for a hazard ratio of 0.70, assuming 5-year overall survival of 60% in the postoperative chemotherapy arm with a one-sided alpha of 5%, power of 80% and a follow-up period of 5 years by Schoenfeld and Richter’s method (26). However, we recalculated the sample size to consider the improvement of the addition of docetaxel to S-1 for postoperative chemotherapy. The expected 5-year overall survival was increased from 60 to 65% in the postoperative chemotherapy arm. The planned sample size remained at 470 patients because the planned accrual period was extended from 3.5 to 5.5 years, considering the suspension period for patient registration to amend the protocol and poor accrual in 2018, to observe 195 deaths with a power of 80% and one-sided alpha of 5% for a hazard ratio of 0.70. In October 2021, the accrual period was again extended from 5.5 to 8.5 years due to poor accrual.

Overall survival will be compared by the stratified log-rank test according to clinical T factors and planned surgical procedures as strata. The stratified Cox proportional hazard model is used to estimate the hazard ratio between the arms. All statistical analyses will be conducted at the JCOG Data Center.

Interim analysis and monitoring

Two interim analyses are planned. The first will be conducted after enrolling half of the planned number of patients and the second after achieving the planned patient accrual and completing the patients’ protocol treatment. The Lan–DeMets α-spending function with the O’Brien and Fleming type will be used to adjust the multiplicity (27). Study termination will be considered due to efficacy if the primary endpoint was higher in the perioperative chemotherapy arm than in the postoperative chemotherapy arm with a P value less than the adjusted significance level. The conditional power (28) and predictive probability (29) for the primary endpoint will be used to judge whether the study should terminate or not due to futility. The Data and Safety Monitoring Committee of the JCOG will review the interim analysis report independently from the group investigators and group statistician.

Participating institutions

1. Hakodate Goryoukaku Hospital

2. Keiyukai Sapporo Hospital

3. Iwate Medical University

4. National Hospital Organization, Sendai Medical Center

5. Miyagi Cancer Center

6. Yamagata Prefectural Central Hospital

7. Southern Tohoku General Hospital

8. Tochigi Cancer Center

9. Saitama Cancer Center

10. Saitama Medical University International Medical Center

11. National Cancer Center Hospital East

12. Chiba Cancer Center

13. National Cancer Center Hospital

14. Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital

15. Tokyo Medical and Dental University Hospital

16. Cancer Institute Hospital of Japanese Foundation for Cancer Research

17. Toranomon Hospital

18. Tokai University Hachioji Hospital

19. Kanagawa Cancer Center

20. Kitasato University School of Medicine

21. Yokohama City University Medical Center

22. Niigata Cancer Center Hospital

23. Nagaoka Chuo General Hospital

24. Toyama Prefectural Central Hospital

25. Ishikawa Prefectural Central Hospital

26. Gifu University School of Medicine

27. Gifu Municipal Hospital

28. Ogaki Municipal Hospital

29. Shizuoka General Hospital

30. Shizuoka Cancer Center

31. Aichi Cancer Center Hospital

32. Nagoya University School of Medicine

33. National Hospital Organization Kyoto Medical Center

34. Osaka University Graduate School of Medicine

35. Osaka Metropolitan University Hospital

36. Kindai University Hospital

37. Osaka International Cancer Institute

38. National Hospital Organization Osaka National Hospital

39. Osaka General Medical Center

40. Osaka Medical and Pharmaceutical University

41. Toyonaka Municipal Hospital

42. Sakai City Medical Center

43. Kansai Medical University Hospital

44. Osaka Rosai Hospital

45. Kobe University Graduate School of Medicine

46. Kansai Rosai Hospital

47. Hyogo Cancer Center

48. Itami City Hospital

49. Himeji Red Cross Hospital

50. Wakayama Medical University, School of Medicine

51. Shimane University Faculty of Medicine

52. Okayama University Hospital

53. Hiroshima University Hospital

54. Hiroshima City Hiroshima Citizens Hospital

55. NHO Fukuyama Medical Center

56. Hiroshima City North Medical Center Asa Citizens Hospital

57. Fukuyama City Hospital

58. Tokushima Red Cross Hospital

59. Kagawa Prefectural Central Hospital

60. National Hospital Organization Shikoku Cancer Center

61. Kurume University School of Medicine

62. Oita University Hospital

Conflict of Interest Statement

All authors received grants from the Japan Agency for Medical Research and Development, and the National Cancer Center Research and Development Fund.

J.M. reports honoraria from Chugai pharmaceutical, Taiho pharmaceutical outside the submitted work; spouse is an employee from Pfizer.

M.T. reports honoraria from Lilly, Taiho pharmaceutical, Ono pharmaceutical, Yakult outside the submitted work;

N.M. reports honoraria from MSD, Taiho, Ono, Daiichi-Sankyo, Yakult, BMS, Lilly, Merck Bio, Takeda outside the submitted work;

T.K. reports honoraria from Taiho, Ono, BMS, Lilly, Chugai outside the submitted work;

H.F. reports honoraria from Chugai pharmaceutical, m3 inc outside the submitted work;

N.B. reports grants or contracts from Ono,Takeda to the institution outside the submitted work; reports honoraria from Taiho, Ono, Bristol Myers Aquibb, Daiichi Sankyo outside the submitted work;

M.T. reports honoraria from Taiho Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical.

BMS, Yakult Honsha, Takeda Pharmaceutical, Eli Lilly Japan, Pfizer Japan, Daiichi-Sankyo, Johnson and Johnson, Medtronic Japan, Intuitive Surgical Japan, Olympus outside the submitted work;

N.Y., R.K., H.I., T.N., S.N., K.T., H.K., T.Y. declares no conflict of interests.

References