Randomized Phase III Study Assessing the Interest of Primary Tumor Resection in Patients With Asymptomatic Colon Cancer and Unresectable Synchronous Liver Metastases.

At the time of diagnosis, 20-25% of patients with colorectal cancer (CRC) present synchronous liver metastases (SLM) and in the majority of patients (80-90%) liver metastases are unsuitable for curative surgical treatment. Whether either primary tumour (PT) resection followed by chemotherapy or immediate chemotherapy without PT resection is the best therapeutic option in patients with asymptomatic colon cancer and unresectable SLM is still controversial. No randomised trial has been conducted to answer this question.

Historically, surgeons have advocated resection of the PT to avoid potential complications of the intact PT (bleeding, obstruction, perforation). However, during the past decade, several highly active systemic agents have become available for treatment of patients with metastatic CRC. These agents have increased the median survival duration of patients with unresectable metastatic disease from 9 to 12 months with 5FU alone, to 30-35 months with the addition of modern cytotoxic and targeted agents. Modern agents have also demonstrated increased activity on the PT as well, and have been associated with low rates of PT-related complications during treatment in initially asymptomatic patients.

The impact of the strategy on survival has never been assessed properly. All published studies are of non-randomized design, single center, and retrospective in most of them. Moreover, few data on the use of systemic therapy are presented in these studies, which makes it difficult to assess the relative contribution of resection on outcome. In addition, patients with extensive disease or poor performance status were more likely to be offered chemotherapy rather than surgery thus introducing a bias at the ousted. Despite these limitations, PT resection at initial management of these metastatic CRC patients with unresectable SLM was related to prolonged survival on multivariate analysis in the majority of these series. The improvement in survival following PT resection may be attributed to the potential role of the PT to provide an angiogenic prosperous environment for metastatic tumour growth in the liver parenchyma adjacent to the SLM.

The present study is a multicenter randomized phase III trial designed to assess whether overall survival and quality of life are improved in patients with asymptomatic unresectable metastatic colon cancer treated with surgery followed by chemotherapy versus chemotherapy alone.

Patients (ECOG 0-1 performance status) with asymptomatic colon cancer (>15cm from the anal margin) and unresectable liver only metastatic disease on initial abdominal CT/MRI scan will be randomized to either colectomy followed by chemotherapy, or chemotherapy without resection of the PT. Systemic chemotherapy with or without targeted therapy will be let to the investigators' discretion according to standard local practices. The primary endpoint of the study is overall survival for >2 years. The secondary endpoints are: quality of life (EORTC QLQ-C30, QLQ-CR29), treatment safety (postoperative morbidity, complications related to the unresected PT, chemotherapy toxicity), progression-free survival and time to metastatic progression, radiological response to chemotherapy (RECIST v1.1 criteria), and the curative (R0) resection rate of metastases.