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

Randomized Phase II Trial of Preoperative Chemoradiation With or Without Induction Chemotherapy In Patients With Locally Advanced Or Borderlinely Resectable Rectal Cancer With Resectable Synchronous Liver Metastases

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.

Study Overview

• Status: Completed
• Conditions: Rectal Cancer; Liver Metastases
• Intervention / Treatment: Radiation: Radiotherapy; Drug: Capecitabine, Oxaliplatin

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.

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 2

Contacts and Locations

Study Locations

• Korea, Republic of
  • Songpa
    • Seoul, Songpa, Korea, Republic of, 138736
      • Asan Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: XELOX RT; Concurrent XELOX-RT (Capecitabine, Oxaliplatin, radiotherapy)	Radiation: Radiotherapy; Preoperative radiotherapy, 5040 cGy with 28 fractions; Drug: Capecitabine, Oxaliplatin; Induction chemotherapy - Induction XELOX (Capecitabine 1250 mg/m2 PO twice daily on D1-14 and oxaliplatin 130 mg/m2 on D1, every 3 weeks for 2 cycles) Preoperative chemoradiotherapy - XELOX RT (Capecitabine 825 mg/m2 PO twice daily during radiotherapy and oxaliplatin 50 mg/m2/day on weekly.)
Active Comparator: Induction XELOX; Induction XELOX(Capecitabine, Oxaliplatin) followed by XELOX-RT (Capecitabine, Oxaliplatin, radiotherapy)	Radiation: Radiotherapy; Preoperative radiotherapy, 5040 cGy with 28 fractions; Drug: Capecitabine, Oxaliplatin; Induction chemotherapy - Induction XELOX (Capecitabine 1250 mg/m2 PO twice daily on D1-14 and oxaliplatin 130 mg/m2 on D1, every 3 weeks for 2 cycles) Preoperative chemoradiotherapy - XELOX RT (Capecitabine 825 mg/m2 PO twice daily during radiotherapy and oxaliplatin 50 mg/m2/day on weekly.)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of Surgery for Primary Tumor	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	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)
Quality of Surgery for Liver Metastases	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	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 Resection Rate of Both the Primary Tumor and Livermetastases	synchronous complete R0 resection rate, R0 = complete resection with grossly and microscopically negative margins of resection	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)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathologic Complete Response Rate of Primary Tumor	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).	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)
Tumor Regression Grade (Primary Tumor)	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	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)

Collaborators and Investigators

• Sponsor: Asan Medical Center
• Investigators: Principal Investigator: Tae Won Kim, Professor, Asan Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2010
• Primary Completion (Actual): September 1, 2014
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: November 1, 2011
• First Submitted That Met QC Criteria: July 16, 2012
• First Posted (Estimated): July 17, 2012

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 4, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: Capecitabine; Rectal cancer; Oxaliplatin; Liver metastases
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colorectal Neoplasms; Intestinal Neoplasms; Rectal Diseases; Liver Diseases; Neoplastic Processes; Rectal Neoplasms; Neoplasm Metastasis; Liver Neoplasms; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Capecitabine; Oxaliplatin
• Other Study ID Numbers: XELOX-RT