Survival outcomes for right- versus left-sided colon cancer and rectal cancer in patients receiving regorafenib and/or trifluridine/tipiracil for refractory metastatic colorectal cancer: Findings from the multicenter retrospective ReTrITa study.
Authors: Signorelli Carlo , Calegari Maria Alessandra , Passardi Alessandro , Lucchetti Jessica , Zurlo Ina Valeria , Morelli Cristina , Dell'Aquila Emanuela , Gemma Donatello , Emiliani Alessandra , Arrivi Giulia , Zoratto Federica , Chilelli Mario Giovanni , Morandi Maria Grazia , Santamaria Fiorenza , Dettori Manuela , Cosimati Antonella , Saltarelli Rosa , Minelli Alessandro , Lucci-Cordisco Emanuela , Basso Michele 
Published: January 2025

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Background:
Several studies show that patients (pts) with colon cancer, particularly pts with right colon cancer (RCC), have lower survival rates than those with rectal cancer. This argues that colorectal cancer should be divided into three clinical entities: RCC, left colon cancer (LCC) and rectal cancer (RC). In refractory metastatic colorectal cancer (mCRC), regorafenib (R) and trifluridine/piracil (T) were found to improve survival. This real-life subgroup survival analysis focused on treatment with R and T, sequential or not, according to the above three primary tumor sites.
Methods:
Clinical data of pts diagnosed with mCRC and treated with R and/or T between 2012 and 2023 were retrospectively collected at 17 Italian cancer centers. The purpose of this analysis was to compare the overall survival (OS) and progression-free survival (PFS) of pts who received R and/or T as third line and beyond, according to their primary tumor site.
Results:
The entire ReTrITA study enrolled 1156 patients. 261 (22.5%) of them received the T/R sequence (T/R), 155 (13.4%) the reverse sequence (R/T), 427 (37%) T, and 313 (27.1%) R. For the purpose of this subgroup analysis we identified 381 RCC pts (32.9%), 531 LCC pts (45.9%) and 244 RC pts (21.2%). When comparing the groups treated with the sequential treatment, we observed a statistically significant OS improvement for pts receiving R prior to T: 17,4 vs. 12,2 months (mos) in RCC pts (HR = 0,67; 95% CI = 0,46-0,99; P = 0,0461); 16,1 vs. 15,1 mos in LCC pts (HR = 0,71; 95% CI = 0,51-1,00; P = 0,0559) and 16,6 vs. 11,4 mos in RC pts (HR = 0,57; 95% CI = 0,36-0,89; P = 0,0153). R/T sequence was also found to provide a considerable PFS benefit: 11,8 vs. 7,8 mos in RCC pts (HR = 0,53; 95% CI = 0,37-0,76; P = 0,0006); 11,7 vs. 8,9 mos in LCC pts (HR = 0,64; 95% CI = 0,47-0,88; P = 0,0071) and 10,7 vs. 8,2 mos in RC pts (HR = 0,63; 95% CI = 0,42-0,96; P = 0,0342). The non-sequential administration of R and T had no statistically significant impact on survival outcomes in the three groups.
Conclusions:
Our real-world subanalysis suggests that the R/T sequence significantly increases survival for pts with primary colon and rectal cancer, even after third-line treatment. Examining the pts groups treated with R and T as monotherapy based on the primary tumour site, however, did not allow us to make any significant conclusions. Treatment decisions should, however, constantly include the patient's characteristics, such as sex, ECOG PS, and the extent of metastatic disease. However, in order to verify our findings, prospective studies are required.