AIMS - The ATTACHE trial aimed to determine the differences in peri-operative morbidity between 2 groups of patients where chemotherapy is given prior to and post surgical resection versus chemotherapy given post surgical resection. This study also aimed to assess the tolerability of chemotherapy in these two groups, comparing surgical mortality between groups and determine treatment related toxicity, the response rate (RR) to pre-operative chemotherapy, the progression-free survival (PFS) for each treatment arm, the overall survival (OS) for each treatment arm and to determine the effects of treatment on the quality of life (QoL).

BACKGROUND - The liver is the most common site of colorectal cancer metastases, these patients have a poor prognosis, despite improvements in survival due to chemotherapy. Surgical resection of liver metastases remains the only curative treatment option for patients with metastatic disease confined to the liver. However, following hepatectomy, recurrences are observed in up to up to two-thirds patients, half of them occurring in the liver.

In an attempt to improve the outcomes for this group of potentially curable patients, the use of adjuvant chemotherapy after liver resection has been increasingly studied, with small randomised trials showing an improvement. Subsequent to the use of post-operative chemotherapy, the use of peri-operative chemotherapy has been reported in a randomised controlled trial and in three longitudinal cohort studies. Benefit from post operative or adjuvant chemotherapy compared to peri-operative treatment has been suggested in a recent retrospective study of 499 patients with resected colorectal liver metastases which showed an improved survival with post-operative rather than peri-operative chemotherapy.

To date, no randomised studies have directly compared the role of peri-operative chemotherapy to adjuvant chemotherapy for resectable liver metastases. Given this collective data, the role of post - operative chemotherapy alone as a means of improving outcomes while reducing the negative effects of pre-operative treatment needs to be examined.

STUDY DESIGN - This is a phase III, multi-centre, randomised comparison of chemotherapy given prior to and post surgical resection versus chemotherapy given post surgical resection.  Eligible patients will be randomised to receive 6 months of treatment post-operatively or 3 months of treatment pre-operatively and 3 months post-operatively. Site investigators must nominate which chemotherapy schedule they will use, mFOLFOX6, XELOX or FOLFIRI, prior to randomisation.

STUDY PROGRESS - The protocol was approved by the CINSW HREC in July 2010. In late 2010 bevacizumab was removed from the ATTACHE protocol following the preliminary results of the AVANT study which indicated no benefit to the use of bevacizumab in the adjuvant setting for early stage colon cancer.  Although the study population for the AVANT trial differed markedly from ATTACHE, which is a study involving patients with metastatic disease, an area for which bevacizumab remains an indication, the Trial Management Committee decided to take this precautionary measure to ensure patient safety.

The first site was opened in August 2011 and currently 20 Australian sites are open to recruitment.    To date only 8 patients have been recruited.   Active communication with study site investigators and surgeons in order to identify barriers to recruitment and a meeting with surgeons held in late July 2012 to discuss this matter have not identified particular issues and recruitment has continued to be very slow.   Despite the lack of recruitment, feedback from national and international meetings is that ATTACHE remains of interest to surgeons and oncologists.  

A prospective meta-analysis was planned with the UK based EPOC B Study and the US based NSABP C-11 study, however both of these trials closed early due to poor recruitment.

This schema was endorsed on three continents as worthy of study and one on which there was said to be clinical equipoise. Despite this, in all three trials recruitment has been unexpectedly low. The three trials groups concerned have agreed on a joint plan to explore the question of what degree of equipoise exists around the area of liver resection. They will explore if there are more compelling questions that would have more chance of success and what aspects of this study led to limited recruitment.