Original ResearchEfficacy of FOLFOXIRI plus bevacizumab in liver-limited metastatic colorectal cancer: A pooled analysis of clinical studies by Gruppo Oncologico del Nord Ovest
Introduction
The optimal integration of systemic treatments and locoregional approaches may lead to cure a subgroup of metastatic colorectal cancer (mCRC) patients [1]. The radical resection of liver metastases may be pursued also in patients initially deemed unresectable, and the rate of patients who may be converted to surgery is notably increasing, thanks to more active systemic regimens, innovative surgical techniques and a widespread multidisciplinary approach [2].
In these patients, the upfront systemic treatment has a dual goal: to shrink the tumour enough to make the surgical resection technically feasible, and to eradicate the micrometastatic disease, to reduce the risk of relapse and to impact on patients' long-term outcome.
To this purpose, the Gruppo Oncologico del Nord Ovest (GONO) studied a combination regimen including the three active cytotoxics, 5-fluorouracil, oxaliplatin and irinotecan (FOLFOXIRI), reporting notable percentages of conversion to resection and considerable results in terms of long-term survival [3], [4], [5].
More recently, a phase III trial by the GONO group demonstrated a significant advantage for FOLFOXIRI plus bevacizumab when compared with FOLFIRI plus bevacizumab in terms of response rate, early response, deepness of response, progression-free survival (PFS) and overall survival (OS) in a population of unresectable mCRC patients, not selected with a conversion intent [6], [7], [8]. The phase II OLIVIA study randomised patients with initially unresectable mCRC and liver-limited metastases to receive FOLFOXIRI plus bevacizumab or FOLFOX plus bevacizumab, showing a significant increase in R0 resection rate among patients receiving the triplet plus bevacizumab, with remarkable PFS and OS results [9].
In this pooled analysis, we aimed at describing the clinical outcome of mCRC patients with unresectable disease confined to the liver, who received FOLFOXIRI plus bevacizumab as first-line treatment in three prospective clinical trials conducted by the GONO group [8], [10], [11], and explored the association of baseline and ‘on treatment’ variables with radical resection following FOLFOXIRI plus bevacizumab. Finally, given that the triplet plus bevacizumab seems an efficacious option especially in poor prognosis patients (i.e. BRAF mutant), we asked whether the prognostic impact of negative clinical and molecular factors could be counterbalanced by such an intensive conversion treatment.
Section snippets
Patients' selection
From July 2007 to March 2015, 541 mCRC patients received first-line FOLFOXIRI plus bevacizumab in three multicenter clinical trials by GONO: the single-arm phase II FOIB study [10] (N = 57), the phase III randomised TRIBE study [8] (N = 508, 252 in the FOLFOXIRI plus bevacizumab arm) and the phase II randomised MOMA study [11] (N = 232). Forty Italian oncology units were involved in these studies.
Main inclusion criteria were homogeneous across the trials, and included histologically confirmed
Patients
Out of 541 patients treated with FOLFOXIRI plus bevacizumab in FOIB, TRIBE and MOMA studies, 205 (37.9%) patients with liver-limited disease were identified. Their baseline characteristics are summarised in Table 1. Briefly, most patients (90%) presented with synchronous metastases, at least four liver lesions (61%) and bilobar liver involvement (79%); the largest metastasis was >5 cm in the 42% of cases and more than six segments were involved in the 25% of patients. At baseline, primary
Discussion
The multidisciplinary management is an added value for mCRC patients, especially for those with liver-limited disease. The present series confirms the crucial role of the integration of a highly active upfront treatment with surgical procedures to improve mCRC patients' long-term outcome. In particular, a traditional paradigm is further strengthened in the contemporary era: maximising tumour shrinkage increases the chances of radical resection and this is the most important variable
Conflict of interest statement
Dr. Cremolini reports serving on advisory board for Roche and Merck Serono, and receiving grant support from Merck Serono; Dr. Loupakis reports serving on advisory board for Roche; Dr. Aprile reports serving on advisory board for Roche, Merck and Amgen; Dr. Tomasello reports serving on advisory board for Amgen, Merck Serono and Roche; Prof. Tonini reports serving on advisory board for Amgen and Roche; Prof. Falcone reports serving on advisory board for Amgen, Merck Serono and Roche, and
Acknowledgements
FOIB, TRIBE and MOMA studies were sponsored by GONO Group and ARCO Foundation, and partially supported by Roche.
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