Survival benefit of surgical resection after first-line triplet chemotherapy and bevacizumab in patients with initially unresectable metastatic colorectal cancer
Authors: Elshenawy Mahmoud A. , Badran Ahmed , Aljubran Ali , Alzahrani Ahmed , Rauf M. Shahzad , Eldali Abdelmonem , Bazarbashi Shouki 
Published: May 2020

Abstract
Background: Surgical resection of metastatic disease in patients with initially non-resectable colorectal cancer (CRC) has improved overall survival. Intensified chemotherapy regimens have increased the probability of converting unresectable metastasis to resectable. Here we report the result of combining intensive chemotherapy (triplet) and surgical resection of metastatic lesions in patients with metastatic CRC. Patients and methods: Patients with unresectable metastatic CRC were enrolled in phase I/II trial of triplet chemotherapy consisting of Capecitabine, oxaliplatin, Irinotecan, and Bevacizumab. Patients were given 5-8 cycles induction chemotherapy of the above regimen followed by maintenance capecitabine and bevacizumab until disease progression, unacceptable toxicity or patient request. All patients were assessed at a multidisciplinary conference for possible surgical resection of their metastatic disease at the time of inclusion in the trial and two-monthly intervals thereafter. Patients who underwent R0 resection of their metastatic disease received adjuvant oxaliplatin and capecitabine to complete a total of 6 months of chemotherapy. Results: Fifty-three patients were enrolled. The median age was 52 years (range 23-74), 29(55%) were males, ECOG PS 0-1 was 13(66%), 11 (42%) had a right-sided tumor, 29 (55%) had resection of their primary tumor, 22(42%) had a single metastatic site and 8 (15.1%) had a liver-limited disease. Thirteen patients (24.5%) underwent surgical resection of residual metastatic disease +/- the primary tumor with 10 (18.9%) of them were R0. The surgical group had higher incidence of males compared to non-surgical group ( 69.3% vs 47.2%,p = 0.2), equal performance status, lower median number of metastatic sites (1 vs 2, p=0.09), higher mutant Kras (53.8 % vs 34.2%, p=0.3) and higher response rate ( 84.6% vs 56.2%, p=0.3). With a median follow up duration of 89 months, the median PFS for the whole group was 16.1 months [95% confidence interval (CI); 9.1-20] and the median OS was 28.2 months (95% CI; 22.5-53.3). The median PFS for the surgery group was 18.9 months (95% CI; 12.6-not reached) compared to 9.6 months (95% CI; 7.0-18.3) for the non-surgical group, Log-rank p =0.0165. The median OS for both groups was not reached (95% CI; 53.3-not reached) and 23.2 months (95% CI; 17.0-28.4) respectively, Log-rank p=0.0006). Five-year PFS and OS for the surgery group were 46.2% and 67.6% respectively. Conclusions: Patients with unresectable metastatic CRC and fit for triplet chemotherapy should have the benefit of combining this intensified regimen and surgical resection of their metastatic disease if possible. Short title : Triplet chemotherapy regimens as conversion therapy for unresectable colorectal cancer Keywords: Colorectal cancer; Triplet chemotherapy; FOLFOXIRI-Bevacizumab; Surgery Trial registration: Clinicaltrials.gov, NCT01311050, registered March,06,2011, retrospectively registered. https://ClinicalTrials.gov/show/NCT01311050.