Surgery Plus Chemo Versus Chemoradiotherapy Followed by Surgery Plus Chemo for Locally Recurrent Rectal Cancer (JCOG1801)

JCOG1801: A Phase III Randomized Controlled Trial Comparing Surgery Plus Adjuvant Chemotherapy With Preoperative Chemoradiotherapy Followed by Surgery Plus Adjuvant Chemotherapy for Locally Recurrent Rectal Cancer (RC-SURVIVE Study)

JCOG1801 is a randomized phase III trial which was initiated in Japan in August 2019 to confirm the superiority of preoperative chemoradiotherapy followed by surgery plus adjuvant chemotherapy for local relapse-free survival over standard treatment, i.e. surgery plus adjuvant chemotherapy, for previously non-irradiated locally recurrent rectal cancer.

Study Overview

• Status: Recruiting
• Conditions: Rectal Cancer Recurrent
• Intervention / Treatment: Drug: Chemotherapy; Radiation: Preoperative radiotherapy; Other: Procedure

Detailed Description

In all, 110 patients from 43 Japanese institutions will be recruited over a period of 6 years. Eligible patients would be registered and randomly assigned to each group with an allocation ratio of 1:1. The primary endpoint is local relapse-free survival. The secondary endpoints are overall survival, relapse-free survival, proportion of local relapse, proportion of distant relapse, proportion of patients with pathological R0 resection, response rate of preoperative chemoradiotherapy (preoperative chemoradiotherapy arm), pathological complete response rate (preoperative chemoradiotherapy arm), proportion of patients who completed the protocol treatment, incidence of adverse events (adverse reactions), and quality of life after surgery.

• Study Type: Interventional
• Enrollment (Anticipated): 110
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Yuichiro Tsukada, MD,PhD; Phone Number: +80-4-7133-1111; Email: yutsukad@east.ncc.go.jp
• Study Contact Backup: Name: Masaaki Ito, MD, PhD; Phone Number: +80-4-7133-1111; Email: maito@east.ncc.go.jp

Study Locations

• Japan
  • Chiba, Japan
    • Recruiting
    • Chiba Cancer Center
    • Contact: Nobuhiro Takiguchi
  • Gifu, Japan
    • Recruiting
    • Gifu University School of Medicine
    • Contact: Kazuhiro Yoshida
  • Hidaka, Japan
    • Not yet recruiting
    • Saitama Medical University International Medical Center
    • Contact: Shigeki Yamaguchi
  • Hirakata, Japan
    • Not yet recruiting
    • Kansai Medical University Hospital
    • Contact: Mitsugu Sekimoto
  • Hiroshima, Japan
    • Recruiting
    • Hiroshima City Asa Citizens Hospital
    • Contact: Mamoru Shimomura
  • Hiroshima, Japan
    • Recruiting
    • Hiroshima City Hospital
    • Contact: Masazumi Okajima
  • Izumo, Japan
    • Recruiting
    • Shimane University Faculty of Medicine
    • Contact: Yoshitsugu Tajima
  • Kanazawa, Japan
    • Recruiting
    • Ishikawa Prefectural Central Hospital
    • Contact: Hiroyuki Bando
  • Kashiwa, Japan
    • Recruiting
    • National Cancer Center Hospital East
    • Contact: Masaaki Ito
  • Kawagoe, Japan
    • Recruiting
    • Saitama Medical Center, Saitama Medical University
    • Contact: Hideyuki Ishida
  • Kochi, Japan
    • Recruiting
    • Kochi Health Sciences Center
    • Contact: Ryo Inada
  • Kumamoto, Japan
    • Recruiting
    • Kumamoto University Hospital
    • Contact: Hideo Baba
  • Kurashiki, Japan
    • Recruiting
    • Kurashiki Central Hospital
    • Contact: Kazuyuki Kawamoto
  • Kurume, Japan
    • Recruiting
    • Kurume University School of Medicine
    • Contact: Yoshito Akagi
  • Matsuyama, Japan
    • Recruiting
    • National Hospital Organization Shikoku Cancer Center
    • Contact: Takaya Kobatake
  • Mitaka, Japan
    • Recruiting
    • Kyorin University Faculty of Medicine
    • Contact: Tadahiko Masaki
  • Morioka, Japan
    • Not yet recruiting
    • Iwate Medical University
    • Contact: Koki Otsuka
  • Nagoya, Japan
    • Not yet recruiting
    • Nagoya University Graduate School of Medicine
    • Contact: Keisuke Uehara
  • Niigata, Japan
    • Recruiting
    • Niigata Cancer Center Hospital
    • Contact: Yasumasa Takii
  • Nishinomiya, Japan
    • Recruiting
    • Hyogo College of Medicine
    • Contact: Naohiro Tomita
  • Okayama, Japan
    • Recruiting
    • Okayama Saiseikai General Hospital
    • Contact: Yoshihiro Akazai
  • Osaka, Japan
    • Recruiting
    • Osaka City General Hospital
    • Contact: Kiyoshi Maeda
  • Osaka, Japan
    • Recruiting
    • National Hospital Organization Osaka National Hospital
    • Contact: Takeshi Kato
  • Saitama, Japan
    • Recruiting
    • Saitama Cancer Center
    • Contact: Yusuke Nishizawa
  • Sapporo, Japan
    • Recruiting
    • Sapporo-Kosei General Hospital
    • Contact: Hideki Yamagami
  • Sendai, Japan
    • Recruiting
    • Miyagi Cancer Center
    • Contact: Kou Miura
  • Shizuoka, Japan
    • Recruiting
    • Shizuoka Cancer Center
    • Contact: Akio Shiomi
  • Suita, Japan
    • Recruiting
    • Osaka University Graduate School of Medicine
    • Contact: Tsunekazu Mizushima
  • Suita, Japan
    • Recruiting
    • Suita Municipal Hospital
    • Contact: Shu Okamura
  • Takatsuki, Japan
    • Recruiting
    • Osaka Medical College
    • Contact: Junji Okuda
  • Tokorozawa, Japan
    • Recruiting
    • National Defense Medical College
    • Contact: Hideki Ueno
  • Tokyo, Japan
    • Recruiting
    • National Cancer Center Hospital
    • Contact: Yukihide Kanemitsu
  • Tokyo, Japan
    • Recruiting
    • Tokyo Medical University Hospital
    • Contact: Akihiko Tsuchida
  • Tokyo, Japan
    • Recruiting
    • Toho University Ohashi Medical Center
    • Contact: Yoshihisa Saida
  • Tokyo, Japan
    • Not yet recruiting
    • Toho University Omori Medical Center
    • Contact: Kimihiko Funahashi
  • Tokyo, Japan
    • Recruiting
    • Tokyo Medical and Dental University Hospital
    • Contact: Yusuke Kinugasa
  • Tokyo, Japan
    • Recruiting
    • Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital
    • Contact: Keiichi Takahashi
  • Utsunomiya, Japan
    • Recruiting
    • Tochigi Cancer Center
    • Contact: Shin Fujita
  • Yamagata, Japan
    • Recruiting
    • Yamagata Prefectural Central Hospital
    • Contact: Toshihiko Sato
  • Yokohama, Japan
    • Recruiting
    • Yokohama City University Medical Center
    • Contact: Jun Watanabe
  • Yokohama, Japan
    • Recruiting
    • Kanagawa Cancer Center
    • Contact: Manabu Shiozawa
  • Yokohama, Japan
    • Recruiting
    • Saiseikai Yokohama-shi Nanbu Hospital
    • Contact: Tadao Fukushima
  • Yufu, Japan
    • Recruiting
    • Oita University Faculty of Medicine
    • Contact: Masafumi Inomata
  • Ōgaki, Japan
    • Recruiting
    • Ogaki Municipal Hospital
    • Contact: Yuichi Takayama
  • Ōta, Japan
    • Recruiting
    • Gunma Prefectural Cancer Center
    • Contact: Hitoshi Ojima

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 78 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Histopathologically proven adenocarcinoma or adenosquamous carcinoma on the resected specimen of the initial rectal cancer or endoscopic biopsy from the initial rectal cancer.
2. The main tumor location of the initial rectal cancer is upper, middle or lower rectum, or anal canal.

3. Either of the following treatments was performed for the initial rectal cancer, and classified as R0/1 or ER (Endoscopical R)0/1 on pathological diagnosis.

   i) Surgical resection (including local resection, with or without lymph node dissection).

   ii) Endoscopic resection.

4. Patients with distant metastasis during or after treatment for the initial rectal cancer, and radical surgical resection or radical radiotherapy performed more than 168 days before registration is eligible.

5. Recurrent rectal cancer diagnosed by any of the following modalities after treatment for the initial rectal cancer.

   i) The recurrent lesion is pathologically diagnosed. ii) Diagnosed as local recurrence by more than two modalities among contrast-enhanced CT, contrast-enhanced MRI, or positron emission computed tomography (PET).

   iii) Chronological progression of the lesion seen on more than one modality among contrast-enhanced CT, MRI, or PET.

6. The main tumor location is within pelvis as seen on contrast-enhanced CT and MRI if recurrent lesion is multiple, or recurrent lesions spread outside of pelvis continuously.
7. LRRC is diagnosed with no following condition. i) Judged as resectable endoscopically. ii) Depth of invasion within the muscularis propria as seen on contrast-enhanced CT, MRI, or PET in case of recurrence inside the intestine iii) Solitary ovarian metastasis. iv) Recurrence of the common iliac lymph node alone.

8. LRRC is diagnosed as resectable, and all the following conditions must be fulfilled:

   i) No distant metastasis on contrast-enhanced CT (cM0). ii) Estimated circumferential resection margin >0 mm. iii) Leg amputation not required. iv) Preservation of the first sacral nerve possible.

9. No prior surgery for recurrent rectal cancer.
10. No prior pelvic irradiation for any malignancies.
11. A patient who has received systemic chemotherapy for any malignancies and the final dose was administered more than 14 days ago.
12. Age at registration is 20 to 80 years old.
13. Eastern Cooperative Oncology Group (ECOG) performance status is 0 or 1.
14. Measurable lesion is not mandatory.
15. Adequate oral intake.
16. Sufficient organ function. i) Neutrophil count >= 1,500/mm3 ii) Hemoglobin >= 9.0 g/dL iii) Platelet count >= 100,000/mm3 iv) Total Bilirubin =< 2.0 mg/dL v) Aspartate aminotransferase (AST) =< 100 U/L vi) Alanine Aminotransferase (ALT) =< 100 U/L vii) Cr =< 1.5 mg/dL
17. Open surgery or laparoscopic surgery is planned.
18. Written informed consent is obtained.

Exclusion Criteria:

1. Synchronous or metachronous (within 5 years) malignancies except cancer with 5-year relative survival rate of 95% or more such as carcinoma in situ, intramucosal tumor, or early stage cancers.
2. Infections requiring systemic treatment.
3. Body temperature higher than 38 degrees Celsius at registration.
4. Pregnant female, female within 28 days post-parturition, or lactating mother. Men with partners planning conception in the near future.
5. Severe psychological disease.
6. Continuous systemic corticosteroid or immunosuppressant treatment.
7. Uncontrollable diabetes mellitus.
8. Uncontrollable hypertension.
9. Unstable angina pectoris, or history of myocardial infarction within 6 months.
10. Uncontrollable valvular disease, dilated cardiomyopathy, or hypertrophic cardiomyopathy.
11. Positive serum Hepatitis B (HB)s antigen or serum Hepatitis C Virus (HCV) antibody.
12. Positive serum HIV antibody.
13. Interstitial pneumonia, pulmonary fibrosis, or severe emphysema on chest CT.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A; Preoperative chemoradiotherapy (CRT) followed by Surgery plus Adjuvant chemotherapy Preoperative CRT: capecitabine (1650 mg/m2/day) and radiotherapy (50.4 Gy/28 Fr) Adjuvant chemotherapy: CAPOX (capecitabine+oxaliplatin) or mFOLFOX6 (5-fluorouracil+l-leucovorin+oxaliplatin) or capecitabine or 5-fluorouracil (FU) +l-leucovorin (LV) CAPOX: oxaliplatin (130 mg/m2/day, day 1) and oral capecitabine (2000 mg/m2/day, twice daily, days 1-14) mFOLFOX6: oxaliplatin 85 mg/m2 with l-LV 200 mg/m2 for over 2 hours followed by a fluorouracil 400 mg/m2 bolus and 2400 mg/m2 continuous infusion over 46 hours. Capecitabine: 2000 mg/m2/day, twice daily, days 1-14 5-FU+l-LV: leucovorin 200 mg/m2 for over 2 hours followed by a fluorouracil 400 mg/m2 bolus and 2400 mg/m2 continuous infusion for over 46 hours	Drug: Chemotherapy; Adjuvant chemotherapy: CAPOX or mFOLFOX6 or capecitabine or 5-FU+l-LV CAPOX: oxaliplatin (130 mg/m2/day, day 1) and oral capecitabine (2000 mg/m2/day, twice daily, days 1-14) mFOLOX6: oxaliplatin 85 mg/m2 with l-LV 200 mg/m2 for over 2 hours followed by a fluorouracil 400 mg/m2 bolus and 2400 mg/m2 continuous infusion over 46 hours. Capecitabine: 2000 mg/m2/day, twice daily, days 1-14 5-FU+l-LV: leucovorin 200 mg/m2 for over 2 hours followed by a fluorouracil 400 mg/m2 bolus and 2400 mg/m2 continuous infusion for over 46 hours; Other Names: CAPOX or mFOLFOX6 or capecitabine or 5-FU+l-LV; Radiation: Preoperative radiotherapy; Preoperative chemoradiotherapy (CRT) followed by Surgery plus Adjuvant chemotherapy Preoperative CRT: capecitabine (1650 mg/m2/day) and radiotherapy (50.4 Gy/28 Fr); Other Names: Capecitabine plus radiotherapy; Other: Procedure; Surgery for Locally Recurrent Rectal Cancer (LRRC) will be performed within 42 days from registration for the patients in arm A, and between days 56 and 98 from the completion of the preCRT for the patients in arm B. Appropriate surgical procedure will be performed to achieve R0 resection, such as low anterior resection, super low anterior resection, intersphincteric resection, Hartmann procedure, rectal amputation, pelvic exenteration, tumor resection, or lateral lymph node dissection; Other Names: Surgery
Active Comparator: Arm B; Surgery plus Adjuvant chemotherapy Adjuvant chemotherapy: CAPOX or mFOLFOX6 or capecitabine or 5-FU+l-LV CAPOX: oxaliplatin (130 mg/m2/day, day 1) and oral capecitabine (2000 mg/m2/day, twice daily, days 1-14) mFOLFOX6: oxaliplatin 85 mg/m2 with l-LV 200 mg/m2 for over 2 hours followed by a fluorouracil 400 mg/m2 bolus and 2400 mg/m2 continuous infusion over 46 hours. Capecitabine: 2000 mg/m2/day, twice daily, days 1-14 5-FU+l-LV: leucovorin 200 mg/m2 for over 2 hours followed by a fluorouracil 400 mg/m2 bolus and 2400 mg/m2 continuous infusion for over 46 hours	Drug: Chemotherapy; Adjuvant chemotherapy: CAPOX or mFOLFOX6 or capecitabine or 5-FU+l-LV CAPOX: oxaliplatin (130 mg/m2/day, day 1) and oral capecitabine (2000 mg/m2/day, twice daily, days 1-14) mFOLOX6: oxaliplatin 85 mg/m2 with l-LV 200 mg/m2 for over 2 hours followed by a fluorouracil 400 mg/m2 bolus and 2400 mg/m2 continuous infusion over 46 hours. Capecitabine: 2000 mg/m2/day, twice daily, days 1-14 5-FU+l-LV: leucovorin 200 mg/m2 for over 2 hours followed by a fluorouracil 400 mg/m2 bolus and 2400 mg/m2 continuous infusion for over 46 hours; Other Names: CAPOX or mFOLFOX6 or capecitabine or 5-FU+l-LV; Other: Procedure; Surgery for Locally Recurrent Rectal Cancer (LRRC) will be performed within 42 days from registration for the patients in arm A, and between days 56 and 98 from the completion of the preCRT for the patients in arm B. Appropriate surgical procedure will be performed to achieve R0 resection, such as low anterior resection, super low anterior resection, intersphincteric resection, Hartmann procedure, rectal amputation, pelvic exenteration, tumor resection, or lateral lymph node dissection; Other Names: Surgery

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Locally recurrent free survival	the period from registration in the trial to either the first event of local relapse or death from any cause and censored at the last date of contact for a living patient	3-years after registration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	s the time from registration to death from any cause and censored at the last date of contact for a living patient	3-years after registration
Recurrence free survival (RFS)	the time from registration to either the first incidence of relapse or death from any cause and censored at the last date of contact for a living patient	3-years after registration
Local relapse rate	Proportion of local relapse	3-years after registration
Distant relapse rate	Proportion of distant relapse	3-years after registration
R0 resection rate	Proportion of patients with pathological R0 resection	1 month after surgery
Response rate of preoperative chemoradiotherapy (preCRT)	Response rate of preCRT (arm B)	before surgery
Pathological complete response rate	Pathological complete response rate (arm B)	1 month after surgery
Completeness of the protocol treatment	Proportion of patients who completed the protocol treatment	8 months after surgery
Adverse event rate	Incidence of adverse events (adverse reactions)	3-years after surgery registration
QOL	QOL after surgery based on the Trial Outcome Index-Physical/Functional/Colorectal (TOI-PFC) [0(better)-84(worse)]	3-years after registration

Collaborators and Investigators

• Sponsor: National Cancer Center Hospital East
• Collaborators: Japan Agency for Medical Research and Development; Japan Clinical Oncology Group
• Investigators: Principal Investigator: Masaaki Ito, MD, PhD, National Cancer Center Hospital East

Publications and helpful links

General Publications

• Kadota T, Tsukada Y, Ito M, Katayama H, Mizusawa J, Nakamura N, Ito Y, Bando H, Ando M, Onaya H, Fukuda H, Kanemitsu Y. A phase III randomized controlled trial comparing surgery plus adjuvant chemotherapy with preoperative chemoradiotherapy followed by surgery plus adjuvant chemotherapy for locally recurrent rectal cancer: Japan Clinical Oncology Group study JCOG1801 (RC-SURVIVE study). Jpn J Clin Oncol. 2020 Aug 4;50(8):953-957. doi: 10.1093/jjco/hyaa058.

Helpful Links

• Japan Registry of Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2019
• Primary Completion (Anticipated): August 1, 2025
• Study Completion (Anticipated): October 1, 2028

Study Registration Dates

• First Submitted: February 26, 2020
• First Submitted That Met QC Criteria: February 26, 2020
• First Posted (Actual): February 28, 2020

Study Record Updates

• Last Update Posted (Actual): June 4, 2020
• Last Update Submitted That Met QC Criteria: June 2, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: Surgery; Rectal cancer; Chemotherapy; Chemoradiotherapy; Locally recurrent rectal cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms; Neoplasms by Site; Disease Attributes; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Recurrence; Rectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Capecitabine
• Other Study ID Numbers: JCOG1801

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No