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

Phase 3

Recruiting

• Conditions: Rectal Cancer Recurrent
• Interventions: Drug: Chemotherapy; Radiation: Preoperative radiotherapy; Other: Procedure

• Registration Number: NCT04288999
• Lead Sponsor: National Cancer Center Hospital East

Brief Summary

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.

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 Timeline

• Study Start: 2019-10-01
• Study First Submitted: 2020-02-26
• Study First Submitted QC: 2020-02-26
• Study First Posted: 2020-02-28
• Status Verified: 2020-06
• Last Update Submitted: 2020-06-02
• Last Update Posted: 2020-06-04
• Primary Completion: 2025-08
• Study Completion: 2028-10

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 110

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm A	Chemotherapy	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
Arm A	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) 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
Arm A	Procedure	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
Arm B	Chemotherapy	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
Arm B	Procedure	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

Primary Outcome Measures

Name	Time	Method
Locally recurrent free survival	3-years after registration	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

Secondary Outcome Measures

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

Trial Locations

Locations (45)

Gifu University School of Medicine; 🇯🇵 Gifu, Japan

Saitama Medical University International Medical Center; 🇯🇵 Hidaka, Japan

Kansai Medical University Hospital; 🇯🇵 Hirakata, Japan

Ishikawa Prefectural Central Hospital; 🇯🇵 Kanazawa, Japan

Shimane University Faculty of Medicine; 🇯🇵 Izumo, Japan

Hiroshima City Asa Citizens Hospital; 🇯🇵 Hiroshima, Japan

Kochi Health Sciences Center; 🇯🇵 Kochi, Japan

Kurashiki Central Hospital; 🇯🇵 Kurashiki, Japan

National Hospital Organization Shikoku Cancer Center; 🇯🇵 Matsuyama, Japan

Kyorin University Faculty of Medicine; 🇯🇵 Mitaka, Japan

Niigata Cancer Center Hospital; 🇯🇵 Niigata, Japan

Okayama Saiseikai General Hospital; 🇯🇵 Okayama, Japan

Saitama Cancer Center; 🇯🇵 Saitama, Japan

Nagoya University Graduate School of Medicine; 🇯🇵 Nagoya, Japan

National Hospital Organization Osaka National Hospital; 🇯🇵 Osaka, Japan

Osaka City General Hospital; 🇯🇵 Osaka, Japan

Shizuoka Cancer Center; 🇯🇵 Shizuoka, Japan

Sapporo-Kosei General Hospital; 🇯🇵 Sapporo, Japan

Miyagi Cancer Center; 🇯🇵 Sendai, Japan

Osaka University Graduate School of Medicine; 🇯🇵 Suita, Japan

Toho University Ohashi Medical Center; 🇯🇵 Tokyo, Japan

Osaka Medical College; 🇯🇵 Takatsuki, Japan

Suita Municipal Hospital; 🇯🇵 Suita, Japan

National Cancer Center Hospital; 🇯🇵 Tokyo, Japan

National Defense Medical College; 🇯🇵 Tokorozawa, Japan

Tokyo Medical and Dental University Hospital; 🇯🇵 Tokyo, Japan

Toho University Omori Medical Center; 🇯🇵 Tokyo, Japan

Tokyo Medical University Hospital; 🇯🇵 Tokyo, Japan

Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital; 🇯🇵 Tokyo, Japan

Oita University Faculty of Medicine; 🇯🇵 Yufu, Japan

Ogaki Municipal Hospital; 🇯🇵 Ōgaki, Japan

Kanagawa Cancer Center; 🇯🇵 Yokohama, Japan

Tochigi Cancer Center; 🇯🇵 Utsunomiya, Japan

National Cancer Center Hospital East; 🇯🇵 Kashiwa, Japan

Saiseikai Yokohama-shi Nanbu Hospital; 🇯🇵 Yokohama, Japan

Yokohama City University Medical Center; 🇯🇵 Yokohama, Japan

Yamagata Prefectural Central Hospital; 🇯🇵 Yamagata, Japan

Kurume University School of Medicine; 🇯🇵 Kurume, Japan

Chiba Cancer Center; 🇯🇵 Chiba, Japan

Saitama Medical Center, Saitama Medical University; 🇯🇵 Kawagoe, Japan

Kumamoto University Hospital; 🇯🇵 Kumamoto, Japan

Iwate Medical University; 🇯🇵 Morioka, Japan

Hyogo College of Medicine; 🇯🇵 Nishinomiya, Japan

Gunma Prefectural Cancer Center; 🇯🇵 Ōta, Japan

Hiroshima City Hospital; 🇯🇵 Hiroshima, Japan