Preoperative Chemoradiation Followed by Chemotherapy for Locally Advanced Rectal Cancer

Phase 2

• Conditions: Adenocarcinoma; Rectal Neoplasms
• Interventions: Drug: Capecitabine Oxaliplatin; Radiation: pelvic radiation capecitabine 5-fluorouracil

• Registration Number: NCT01952951
• Lead Sponsor: National Cancer Center, Korea

Brief Summary

The current standard treatment of locally advanced rectal cancer (clinical stage II or III) is preoperative radiation with chemotherapy (CRT) followed by surgery. But this approach can be suboptimal for patients with high risk features (more deeply-seated tumor or many regional lymph nodes involved)that are associated with recurrence. This study test a hypothesis that CRT followed by chemotherapy before surgery can improve efficacy of preoperative treatment.

Detailed Description

Downstaging rate with CRT using fluoropyrimidine monotherapy is usually 30-40%.In MRI-defined high-risk patients, downstaging rate with conventional fluoropyrimidine-based monotherapy with radiation has not been shown. We assume that the downstaging rate of chemoradiation arm (control arm) would be 30%, and that addition of CapOx after CRT (experimental arm) may increase downstaging rate 30% to 50%. A sample size of 52 patients per group is needed have 85% power to detect downstaging rate = 50% as compared to 30% with type I error rate of 15%. We will perform one interim futility analysis when half of the patients are recruited and evaluated for the primary endpoint. O'Brien-Fleming boundary will be considered. Therefore, when 26 patients per arm are evaluated, the interim futility analysis will be performed, and when the Z score at the interim is less than -0.09192 (one-sided p-value greater than 0.5366192), the study will be stopped for futility. Considering 5% follow-up loss, a sample size of 55 per arm (a total of 110 patients) will be studied.

Study Timeline

• Study First Submitted: 2013-09-11
• Study First Submitted QC: 2013-09-25
• Study First Posted: 2013-09-30
• Study Start: 2014-06
• Status Verified: 2017-09
• Primary Completion: 2017-09
• Last Update Submitted: 2017-09-12
• Last Update Posted: 2017-09-13
• Study Completion: 2019-12

Recruitment & Eligibility

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

Inclusion Criteria

• histologically confirmed adenocarcinoma of the rectum

• distal margin of tumor located from 0 to 12 cm from anal verge measured by digital rectal examination

• high risk clinical stage II or III in MRI (satisfying at least one of the followings)

  • circumferential resection margin < 1 mm involved
  • low-lying tumor below anal verge 3 cm
  • T3 > 5 mm extramural spread
  • T4 (involving surrounding structures or peritoneum)
  • cN2 (4 or more mixed signal intensity or irregularly bordered node or tumor deposit)

• age 20 years or more

• ECOG (Eastern Cooperative Oncology Group) performance status 0-2

• No prior chemotherapy, radiotherapy to pelvis

• Adequate bone marrow function

• Adequate renal function

• Adequate hepatic function

• patients must sign the informed consent indicating that they were aware of the investigational nature of the study in keeping with the policy of the hospital

Exclusion Criteria

• malignant disease of the rectum other than adenocarcinoma or arisen from chronic inflammatory bowel disease
• any unresected synchronous colon cancer
• any distant metastases
• intestinal obstruction or impending obstruction, but decompressing colostomy is permitted
• any previous or concurrent malignancy withih 5 years other than non-melanoma skin cancer / in situ cancer of uterine cervix / early gastric cancer / thyroid cancer of low risk
• any other morbidity or situation with relative contraindication for chemoradiotherapy
• patients with history of significant gastric or small bowel resection, or malabsorption syndrome, or other lack of integrity of the upper gastrointestinal tract that may compromise the absorption of capecitabine
• pregnant or lactating women or patients of childbearing potential not predicting adequate contraception

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
chemoradiation followed by CapOx	Capecitabine Oxaliplatin	preoperative chemoradiation 50.4Gy with capecitabine or 5-fluorouracil/leucovorin (pelvic radiation capecitabine 5-fluorouracil) followed by 2 cycles of chemotherapy (Capecitabine Oxaliplatin - CapOx) and surgery (total mesorectal excision)
chemoradiation followed by CapOx	pelvic radiation capecitabine 5-fluorouracil	preoperative chemoradiation 50.4Gy with capecitabine or 5-fluorouracil/leucovorin (pelvic radiation capecitabine 5-fluorouracil) followed by 2 cycles of chemotherapy (Capecitabine Oxaliplatin - CapOx) and surgery (total mesorectal excision)
chemoradiation	pelvic radiation capecitabine 5-fluorouracil	preoperative chemoradiation 50.4Gy with capecitabine or 5-fluorouracil/leucovorin (pelvic radiation capecitabine 5-fluorouracil) followed by rest for 8 weeks and surgery (total mesorectal excision)

Primary Outcome Measures

Name	Time	Method
downstaging rate	expected average of 15 weeks after start of study treatment	downstaging rate is defined as the proportion of patients with ypStage (pathologic stage after preoperative treatment) 0 or I (from pathologic findings after preoperative treatment and surgery) out of all patients who were assigned to each arm.

Secondary Outcome Measures

Name	Time	Method
pathologic response	expected average of 15 weeks after start of study treatment	pathologic response is assessed by Dworak's grading system from postoperative specimen.
radiologic response rate	expected average of 14 weeks after start of study treatment	radiologic response will be assessed according to RECIST (Response Evaluation Criteria in Solid Tumors) guideline 1.1
toxicity profile	expected average of 35 weeks after start of study treatment	Toxicities or any adverse events during study treatment, surgery and follow-up period will be assessed according to NCI CTCAE (Common Terminology Criteria for Adverse Events) version 4.0
relapse-free survival	3 years after surgery	Time from date of operation to date of recurrence of disease or deaths due to recurrence or progression of disease.
Disease-free survival	3 years after surgery	time from date of operation to date of recurrence of disease, a new occurrence of secondary colorectal cancer, a new occurrence of other malignancy, or deaths from any cause.
pattern of failure	3 years after surgery	if any recurrent lesion is noticed, anatomic sites of recurrent lesions and the date and the name of exam or imaging study (physical exam, CT or MRI...) will be recorded in case report form.
local control rate	3 years after surgery	Local recurrence is defined as tumor recurrence confined in radiation field (pelvic cavity). Cumulative incidence of local recurrence will be suggested.
overall survival	3 years after surgery	time from date of operation to date of death due to any cause.
quality of life	before study treatment, 7 weeks after completion of chemoradiation, and at 4 weeks after surgery	quality of life will be measured with FACT-C

Trial Locations

Locations (7)

Gangneung Asan Hospital; 🇰🇷 Gangneung, Korea, Republic of

Chung-Ang University Hospital; 🇰🇷 Seoul, Korea, Republic of

Severance Hospital; 🇰🇷 Seoul, Korea, Republic of

Seoul National University Bundang Hospital; 🇰🇷 Seongnam, Gyeonggi-do, Korea, Republic of

National Cancer Center; 🇰🇷 Goyang, Gyeonggi-do, Korea, Republic of

Hallym University Sacred Heart Hospital; 🇰🇷 Anyang, Korea, Republic of

Asan Medical Center; 🇰🇷 Seoul, Korea, Republic of