At the time of diagnosis, 25% of patients with colorectal cancer present with liver metastasis (CRLM). Among patients with localized colorectal cancer (Stages I-III), 50% to 70% will develop liver metastases during the course of their disease. Surgery in combination with intravenous (IV) chemotherapy represents the only chance of cure for selected patients by removing all liver metastases and treat residual microscopic disease by postoperative chemotherapy for 3 months. However, up to two-thirds of patients will experience a relapse, with about two-thirds of recurrences occurring in the liver. Hepatic arterial infusion (HAI) chemotherapy has been proposed to improve the efficacy of chemotherapy by increasing the concentration of the drug in the liver. This treatment is currently administered by infusion through a specific catheter placed in the artery feeding the liver parenchyma, connected to a subcutaneous port-a-cath system. Several trials have shown that the administration of floxuridine or oxaliplatin via HAI combined with IV chemotherapy achieves a higher response rate compared to IV chemotherapy alone in patients with unresectable colorectal liver metastases. HAI chemotherapy has thus become an attractive therapeutic option for patients who underwent curative-intent surgery to reduce the risk of hepatic recurrence. The investigators recently demonstrated in the PACHA-01 phase II randomized study a 47% decrease of hepatic recurrence risk by HAI of oxaliplatin compared to IV chemotherapy alone, despite a higher but manageable toxicity among 99 patients who underwent curative surgery considered at high risk of recurrence. Moreover, this study showed promising results in terms of time to recurrence and survival. Moreover, feasibility has improved in recent years with the development of non-invasive techniques for HAI. The investigators propose to conduct the PACHA-02 trial to evaluate the efficacy in terms of disease-free survival of oxaliplatin administered via HAI in combination with IV chemotherapy after curative resection in patients with colorectal cancer at high risk of recurrence. A total of 272 patients who will undergo curative surgery for at least 4 CRLM with no residual disease on imaging performed within 4 weeks after surgery will be included. Patients will then be randomized to receive oxaliplatin-based chemotherapy either via HAI or IV combined with standard IV chemotherapy, every 2 weeks for at least 3 months. The primary objective of this study will be to determine if the administration of oxaliplatin via HAI increases the time between treatment and disease recurrence compared to IV administration. The secondary objectives include overall survival, hepatic recurrence-free survival, safety, pattern of recurrence, and quality of life.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
272
HAI administration of chemotherapy
IV administration of chemotherapy
Recurrence-free survival (RFS)
Comparison between the two arms of recurrence-free survival (RFS), defined by the time between randomization and the occurrence of the first oncological event observed according to RECIST v1.1 criteria, such as local or metastatic recurrence or death from any cause
Time frame: From date of randomization to the date of occurrence of the first oncological event, assessed up to 8.5 years
Overall survival (OS)
Overall survival (OS), defined as the time from randomization to death, irrespective of cause. Patients alive at the time of the analysis will be censored at last follow-up
Time frame: from randomization to death from any cause, up to 3.5 years minimum
Hepatic recurrence-free survival (h-RFS)
Hepatic recurrence-free survival (h-RFS), defined as the time from randomization to the occurrence of the first hepatic relapse according RECIST 1.1 criteria or death, irrespective of cause. Patients alive without hepatic recurrence at the time of the analysis will be censored at last follow-up
Time frame: From date of randomization to the date of occurrence of the first hepatic relapse, assessed up to 8.5 years
Patterns of recurrence
Patterns of recurrence, defined as hepatic recurrence rate and extra hepatic recurrence rate as first oncological event
Time frame: Date of the first oncological event documented assessed up to 8.5 years
Feasibillity
Feasibillity, defined as: * Proportion of patients receiving at least 4 cycles of oxaliplatin. * Proportion of patients treated within 8 weeks after surgery accordingly to the attributed arm. * Relative dose-intensity of oxaliplatin (calculated over the first three months of treatment).
Time frame: From date of randomization up to 3 months after treatment start
Incidence of the HAI in adverse events
Safety assessed according to Common Terminology Criteria for Adverse Events (CTCAE v5.0) system for treatment toxicity. In HAI arm catheter-related complications and treatment procedures will be analyzed. AE will be coded with the MedDRA dictionary
Time frame: From date of randomization up to 30 days after the last study treatment
Subsequent treatment description
Description of chemotherapy (IV, HAI, lines and cycles, curative intent) in case of recurrence
Time frame: From date of first subsequent treatment to the date of the end of study, assessed up to 8.5 years
Tumor response rate
Tumor response rate according to RECIST 1.1 criteria following reintroduction of chemotherapy in case of recurrence
Time frame: From the date of the first subsequent treatment to the date of the end of study, assessed up to 8.5 years
Quality of Life Questionnaire - Colorectal cancer associated with the Liver colorectal metastasis Module
This EORTC liver metastasis specific questionnaire QLQ-LMC21 (questions 31 to 51) is intended to supplement the QLQ-C30 (questions 1 to 30) to obtain a global score describing the quality of life of the patients
Time frame: At baseline, 3 months then every 3 months for 3 years and every 6 months for the following 2 years
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