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Rectal Cancer, Adjuvant Chemotherapy, FOLFOX(5-fluorouracil/Leucovorin/Oxaliplatin), Total Mesorectal Excision

Primary Purpose

Locally Advanced Rectal Cancer

Status

Unknown status

Phase

Phase 2

Locations

Korea, Republic of

Study Type

Interventional

Intervention

Arm A : standard neoadjuvant chemoradiotherapy group

Arm B : adjuvant FOLFOX group

About this trial

This is an interventional treatment trial for Locally Advanced Rectal Cancer

Eligibility Criteria

19 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Histologically confirmed adenocarcinoma of the rectum below 10 cm from the anal verge
Locally advanced rectal cancer (T3N0 or T1-3N+)
Age: 19-80 years old.
Without evidence of distant metastasis including paraortic lymph node, common & external iliac lymph node metastasis
MRI scan confirmed more than 2 mm circumferential margin
ECOG(Eastern Cooperative Oncology Group) performance status 0-2
preoperative ASA class I-III
No prior systemic treatment for rectal cancer (i.e. chemotherapy or immunotherapy)
No history of regional radiation treatment in the pelvic cavity
Adequate hematologic function: ANC(absolute neutrophil count) ≥ 1.5×109/L，Platelet ≥ 100×109/L, Adequate renal function: Cr ≤ 1.5×ULN or Glomerular filtration rate (Ccr calculated by Cockcroft formula) ≥ 50 ml/min, Adequate hepatic function: ALT(Alanine aminotransferase)/AST(aspartate aminotransferase) ≤ 2.5×ULN, Total bilirubin ≤ 1.5×ULN
Patients must be willing and able to comply with the protocol duration of the study
Signed informed consent

Exclusion Criteria:

Malignancy of the rectum other than adenocarcinoma or adenocarcinoma developed from inflammatory bowel disease
Suspicious distant metastasis
Patients with peripheral neuropathy ≥ NCI CTC(common terminology criteria) grade 1
Uncontrolled and significant cardiovascular disease (i.e. NYHA(New York Heart Association) class III or IV heart failure, myocardial infarction within the past 6 months, uncontrolled angina pectoris)
Uncontrolled active infection or serious concomitant systemic disorders incompatible with the study
Other co-existing malignancy or malignancy within the past 5 years, with the exception of adequately treated in situ carcinoma of the cervix or basal cell carcinoma of the skin
Patients requiring immunosuppressive treatment who received organ transplantation
Uncontrolled epilepsy and psychiatric disease
Pregnant or lactating patient
Females with a positive or no pregnancy test unless childbearing potential can be otherwise excluded (amenorrheic for at least 2 years,hysterectomy or oophorectomy)
Patients receiving a concomitant treatment with drugs interacting with 5-Fluorouracil or oxaliplatin such as flucytosine, phenytoin, or warfarin
Prior unanticipated severe reaction to fluoropyrimidine therapy, or known hypersensitivity to 5-Fluorouracil or known dihydropyrimidine dehydrogenase (DPD) deficiency.
Known hypersensitivity to platinum-based drugs, leucovorin or capecitabine
Patients taking sorivudine or brivudine
Patients taking tegafur, gimeracil, oteracil potassium complex or stopped the medication within 7days before.
Patients who have hereditary disease like as galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption, etc.
Participant in any clinical trial within 4 weeks before initiation of the study
Treatment with bevacizumab, cetuximab, oxaliplatin or irinotecan before screening

Sites / Locations

Severance Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Arm A

Arm B

Arm Description

Arm A; standard neoadjuvant chemoradiotherapy group fluoropyrimidine based concurrent chemoradiotherapy-> TME -> adjuvant chemotherapy (Low risk: fluoropyrimidine-based chemotherapy, High risk: FOLFOX)

Arm B : adjuvant FOLFOX group Total mesorectal excision (TME) --> 12 cycles of FOLFOX every 2 weeks (or Total mesorectal excision (TME) --> Concurrent chemoradiotherapy + 12 cycles of FOLFOX every 2 weeks)

Outcomes

Primary Outcome Measures

Disease free survival (DFS)

Secondary Outcome Measures

Disease free survival (DFS)

Overall survival (OS)

Local recurrence rate

Systemic recurrence rate

Total score for function of urination (IPSS) and defecation (Wexner's score)

Evaluation for rate of various events after surgery

Full Information

NCT ID

NCT02167321

First Posted

June 11, 2014

Last Updated

April 21, 2021

Sponsor

Yonsei University

1. Study Identification

Unique Protocol Identification Number

NCT02167321

Brief Title

Rectal Cancer, Adjuvant Chemotherapy, FOLFOX(5-fluorouracil/Leucovorin/Oxaliplatin), Total Mesorectal Excision

Official Title

Adjuvant Chemotherapy With FOLFOX After Total Mesorectal Excision for Locally Advanced Rectal Cancer; an Open-label, Multicenter, Prospective, Randomized Phase 3 Trial

Study Type

Interventional

2. Study Status

Record Verification Date

April 2021

Overall Recruitment Status

Unknown status

Study Start Date

December 2014 (undefined)

Primary Completion Date

May 2019 (Actual)

Study Completion Date

August 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Yonsei University

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

The introduction of total mesorectal excision (TME) and the progress of neoadjuvant chemoradiotherapy has significantly reduced the risk of local recurrence in locally advanced rectal cancer. However, systemic recurrence rate is not being improved and that is considered as the cause of unsatisfactory overall survival of patients with rectal cancer. Relatively higher systemic relapse rate than local recurrence rate is probably due to the insufficient control of systemic micrometastasis during adjuvant chemotherapy. The efficacy of adjuvant combination cytotoxic chemotherapy after surgery in treatment of rectal cancer remains controversial. In addition, preoperative radiotherapy increases surgical complication such as anastomosis site leakage and radiotherapy itself worsen sexual and urinary function and bowel habit which result in aggravation of the quality of life. Furthermore the preoperative chemoradiotherapy upto 3 months not only extends treatment period but increases cost of care. To reduce the possibility of overtreatment, it is needed to confirm that the preoperative chemoradiotherapy is absolutely necessary to locally advanced rectal cancer patients with safe circumferential margin (CRM) resected curatively by standardized TME operation. In this study, investigators aim to evaluate the efficacy of adjuvant FOLFOX chemotherapy after TME without preoperative chemoradiotherapy in patients with locally advanced rectal cancer having spared CRM are not inferior to that of current standard treatment.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Locally Advanced Rectal Cancer

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

90 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm A

Arm Type

Active Comparator

Arm Description

Arm Title

Arm B

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Arm A : standard neoadjuvant chemoradiotherapy group

Other Intervention Name(s)

fluoropyrimidine based CCRT -> TME -> adjuvant chemotherapy

Intervention Description

radiation : 45Gy±5.4Gy/28Fx/5.5weeks concurrent chemoradiotherapy : 5-FU (400 mg/m2, IV bolus on D1-3, D29-31), leucovorin (20 mg/m2, IV bolus on D1-3, D29-31), preoperative capecitabine : 825 mg/m² p.o. twice daily during XRT, postoperative FL : 5-FU (400 mg/m2, IV bolus)+leucovorin (20m g/m2, IV bolus) on days 1-5 of each 28 day postoperative capecitabine : 1250 mg/m² p.o. twice daily on days 1-14 of each 21 day cycle FOLFOX : oxaliplatin 85 mg/m2, IV over 2 hours on day 1 of each 14 day cycle, leucovorin 200 mg/m2, IV over 2 hours on day 1 of each 14 day cycle, 5-FU 400 mg/m2, IV bolus on day 1 followed by 1200mg/m2 IV over 24 hours on days 1 and 2 of each 14 day cycle

Intervention Type

Drug

Intervention Name(s)

Arm B : adjuvant FOLFOX group

Other Intervention Name(s)

Total mesorectal excision (TME) -> 12 cycles of FOLFOX every 2 weeks, or Total mesorectal excision (TME) -> CCRT + 12 cycles of FOLFOX every 2 weeks

Intervention Description

FOLFOX : oxaliplatin (85 mg/m2, IV over 2 hours on day 1 of each 14 day cycle), leucovorin (200 mg/m2, IV over 2 hours on day 1 of each 14 day cycle), 5-FU (400 mg/m2, IV bolus on day 1 followed by 1200mg/m2 IV over 24 hours on days 1 and 2 of each 14 day cycle) postoperative irradiation(if needed) : 54Gy/30Fx/6weeks

Primary Outcome Measure Information:

Title

Disease free survival (DFS)

Time Frame

3 years

Secondary Outcome Measure Information:

Title

Disease free survival (DFS)

Time Frame

5 years

Title

Overall survival (OS)

Time Frame

3 years and 5 years

Title

Local recurrence rate

Time Frame

3 years and 5 years

Title

Systemic recurrence rate

Time Frame

3 years and 5 years

Title

Total score for function of urination (IPSS) and defecation (Wexner's score)

Time Frame

1 month and 6 months after surgery

Title

Evaluation for rate of various events after surgery

Time Frame

14 days after surgery

10. Eligibility

Sex

All

Minimum Age & Unit of Time

19 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Histologically confirmed adenocarcinoma of the rectum below 10 cm from the anal verge Locally advanced rectal cancer (T3N0 or T1-3N+) Age: 19-80 years old. Without evidence of distant metastasis including paraortic lymph node, common & external iliac lymph node metastasis MRI scan confirmed more than 2 mm circumferential margin ECOG(Eastern Cooperative Oncology Group) performance status 0-2 preoperative ASA class I-III No prior systemic treatment for rectal cancer (i.e. chemotherapy or immunotherapy) No history of regional radiation treatment in the pelvic cavity Adequate hematologic function: ANC(absolute neutrophil count) ≥ 1.5×109/L，Platelet ≥ 100×109/L, Adequate renal function: Cr ≤ 1.5×ULN or Glomerular filtration rate (Ccr calculated by Cockcroft formula) ≥ 50 ml/min, Adequate hepatic function: ALT(Alanine aminotransferase)/AST(aspartate aminotransferase) ≤ 2.5×ULN, Total bilirubin ≤ 1.5×ULN Patients must be willing and able to comply with the protocol duration of the study Signed informed consent Exclusion Criteria: Malignancy of the rectum other than adenocarcinoma or adenocarcinoma developed from inflammatory bowel disease Suspicious distant metastasis Patients with peripheral neuropathy ≥ NCI CTC(common terminology criteria) grade 1 Uncontrolled and significant cardiovascular disease (i.e. NYHA(New York Heart Association) class III or IV heart failure, myocardial infarction within the past 6 months, uncontrolled angina pectoris) Uncontrolled active infection or serious concomitant systemic disorders incompatible with the study Other co-existing malignancy or malignancy within the past 5 years, with the exception of adequately treated in situ carcinoma of the cervix or basal cell carcinoma of the skin Patients requiring immunosuppressive treatment who received organ transplantation Uncontrolled epilepsy and psychiatric disease Pregnant or lactating patient Females with a positive or no pregnancy test unless childbearing potential can be otherwise excluded (amenorrheic for at least 2 years,hysterectomy or oophorectomy) Patients receiving a concomitant treatment with drugs interacting with 5-Fluorouracil or oxaliplatin such as flucytosine, phenytoin, or warfarin Prior unanticipated severe reaction to fluoropyrimidine therapy, or known hypersensitivity to 5-Fluorouracil or known dihydropyrimidine dehydrogenase (DPD) deficiency. Known hypersensitivity to platinum-based drugs, leucovorin or capecitabine Patients taking sorivudine or brivudine Patients taking tegafur, gimeracil, oteracil potassium complex or stopped the medication within 7days before. Patients who have hereditary disease like as galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption, etc. Participant in any clinical trial within 4 weeks before initiation of the study Treatment with bevacizumab, cetuximab, oxaliplatin or irinotecan before screening

Facility Information:

Facility Name

Severance Hospital

City

Seoul

Country

Korea, Republic of

12. IPD Sharing Statement

Citations:

PubMed Identifier

32264919

Citation

Lee JB, Kim HS, Jung I, Shin SJ, Beom SH, Chang JS, Koom WS, Kim TI, Hur H, Min BS, Kim NK, Park S, Jeong SY, Baek JH, Kim SH, Lim JS, Lee KY, Ahn JB. Upfront radical surgery with total mesorectal excision followed by adjuvant FOLFOX chemotherapy for locally advanced rectal cancer (TME-FOLFOX): an open-label, multicenter, phase II randomized controlled trial. Trials. 2020 Apr 7;21(1):320. doi: 10.1186/s13063-020-04266-6.

Results Reference

derived

Learn more about this trial

Rectal Cancer, Adjuvant Chemotherapy, FOLFOX(5-fluorouracil/Leucovorin/Oxaliplatin), Total Mesorectal Excision

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