Preoperative CRT With or Without Induction Chemotherapy for Rectal Cancer With Liver Metastases

Phase 2

Completed

Conditions: Rectal Cancer
Liver Metastases

Interventions: Drug: Capecitabine, Oxaliplatin
Radiation: Radiotherapy

Registration Number: NCT01643070

Lead Sponsor: Asan Medical Center

Brief Summary: To investigate the feasibility of preoperative chemoradiation with oxaliplatin plus capecitabine, with or without prior induction chemotherapy in patients with locally advanced or marginally resectable rectal cancer with resectable synchronous liver metastases.

Detailed Description: Preoperative chemoradiation is now an initial treatment of choice for locally advanced resectable rectal cancer, and 5-fluorouracil is the standard agent during chemoradiation. Capecitabine is an oral fluoropyrimidine which has been thought to be a replacement for intravenous 5-fluorouracil, and several trials have proved that preoperative chemoradiation with capecitabine was also effective in this setting.

Oxaliplatin, a newer platinum agent, plus fluoropyrimidines (either 5-fluorouracil or capecitabine) is one of the standard cytotoxic chemotherapeutic regimen for metastatic colorectal cancer, and it is also proved to be effective as neoadjuvant chemotherapy for patients with liver only metastasis from colorectal cancer.

Approximately 25% of patients with colorectal cancer have liver metastases initially at the time of diagnosis and there have been quite well established evidences for clear survival benefits from hepatic metastasectomy in these patients. Treatment for colorectal liver metastases should be planned with consideration of both systemic chemotherapy and local treatment modality (surgery or radiofrequency ablation) because long term survival would be expected after curative liver metastasectomy. As mentioned previously, neoadjuvant oxaliplatin plus fluoropyrimidines before hepatic metastasectomy improved disease-free survival, thus it is thought to be that better systemic controls would be achieved with perioperative oxaliplatin based chemotherapy.

In patients with locally advanced rectal cancer, preoperative chemoradiation with fluoropyrimidines improves local control but not systemic control. Recent randomized trials of preoperative chemoradiation with oxaliplatin plus fluoropyrimidines failed to show better local control rates than those with fluoropyrimidines alone. But it is too early to determine the non-superiority of preoperative chemoradiation with oxaliplatin plus fluoropyrimidines in terms of systemic control; long-term duration of follow-up is needed to determine the efficacy in terms of disease-free or overall survival and it is evident that oxaliplatin based chemotherapy is effective for systemic control in patients who will be candidate for liver metastasectomy.

Thus, the investigators planned a randomized phase II trial of preoperative chemoradiation with oxaliplatin plus capecitabine, with or without prior induction chemotherapy in patients with locally advanced or borderlinely resectable rectal cancer with resectable synchronous liver metastases.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 38

Inclusion Criteria

Histologically confirmed adenocarcinoma of the rectum Tumor located within 12 cm from anal verge Clinical stage of T3-4 or N+ by rectal MRI ± endorectal ultrasound Age over 18 years No prior systemic treatment or radiation Adequate major organ functions Borderline resectability of primary rectal cancer Complete resectability of liver metastases (measurable by RECIST 1.1)

Exclusion Criteria

Unresectable liver metastases (6 or more metastatic lesions, major vessel invasion)
Extrahepatic metastasis

Study & Design

Study Type: INTERVENTIONAL

Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
XELOX RT	Capecitabine, Oxaliplatin	Concurrent XELOX-RT (Capecitabine, Oxaliplatin, radiotherapy)
XELOX RT	Radiotherapy	Concurrent XELOX-RT (Capecitabine, Oxaliplatin, radiotherapy)
Induction XELOX	Capecitabine, Oxaliplatin	Induction XELOX(Capecitabine, Oxaliplatin) followed by XELOX-RT (Capecitabine, Oxaliplatin, radiotherapy)
Induction XELOX	Radiotherapy	Induction XELOX(Capecitabine, Oxaliplatin) followed by XELOX-RT (Capecitabine, Oxaliplatin, radiotherapy)

Primary Outcome Measures

Name	Time	Method
Quality of Surgery for Primary Tumor	Arm A = Induction chemotherapy (XELOX, 6 weeks) followed by chemoradiotherapy (XELOX plus radiotherapy) to surgery (6 weeks); Arm B = Chemoradiotherapy (XELOX plus radiotherapy) to surgery (6 weeks)	R0 = complete resection with grossly and microscopically negative margins of resection; R1 =grossly negative but microscopically positive margins of resection; R2 = grossly and microscopically positive margins of resection
Quality of Surgery for Liver Metastases	Arm A = Induction chemotherapy (XELOX, 6 weeks) followed by chemoradiotherapy (XELOX plus radiotherapy) to surgery (6 weeks); Arm B = Chemoradiotherapy (XELOX plus radiotherapy) to surgery (6 weeks)	R0 = complete resection with grossly and microscopically negative margins of resection; R1 =grossly negative but microscopically positive margins of resection; R2 = grossly and microscopically positive margins of resection
R0 Resection Rate of Both the Primary Tumor and Livermetastases	Arm A = Induction chemotherapy (XELOX, 6 weeks) followed by chemoradiotherapy (XELOX plus radiotherapy) to surgery (6 weeks); Arm B = Chemoradiotherapy (XELOX plus radiotherapy) to surgery (6 weeks)	synchronous complete R0 resection rate, R0 = complete resection with grossly and microscopically negative margins of resection

Secondary Outcome Measures

Name	Time	Method
Pathologic Complete Response Rate of Primary Tumor	Arm A = Induction chemotherapy (XELOX, 6 weeks) followed by chemoradiotherapy (XELOX plus radiotherapy) to surgery (6 weeks); Arm B = Chemoradiotherapy (XELOX plus radiotherapy) to surgery (6 weeks)	The pathologic stage (ypT or N) was recorded according to the International Union Against Cancer TNM system. Pathologic complete response (ypCR) was defined as the absence of viable tumor cells in the surgical specimens, of the primary tumor (ypT0).
Tumor Regression Grade (Primary Tumor)	Arm A = Induction chemotherapy (XELOX, 6 weeks) followed by chemoradiotherapy (XELOX plus radiotherapy) to surgery (6 weeks); Arm B = Chemoradiotherapy (XELOX plus radiotherapy) to surgery (6 weeks)	The regression of the primary tumor was quantified according to the 5-point tumor regression grade proposed by Dworak. Complete regression = No tumor cells ; Near complete regression = Very few tumor cells; Moderate regression = Dominantly fibrotic changes with few tumor cells or groups; Minimal regression = Dominant tumor mass with obvious fibrosis