A retrospective analysis of the phase III CALGB/SWOG 80405 trial revealed significant differences in survival and treatment response in patients with metastatic colorectal cancer (CRC) arising in the left vs right side of the colon.
First-line bevacizumab-based treatment was found to be more effective in patients with right-sided primary tumours, while first-line cetuximab-based treatment performed better in those with left-sided primary tumours. [ASCO 2016, abstract 3504]
“While previous studies suggested that tumour location may impact clinical outcomes in CRC, the effect we observed in this analysis appeared to be far greater than what we expected,” said lead investigator Professor Alan Venook of the University of California, San Francisco, CA, US.
The current analysis included 293 patients with KRAS wild-type right-sided primary tumours (caecum to hepatic flexure) and 732 patients with KRAS wild-type left-sided primary tumours (splenic flexure to rectum) from CALGB/SWOG 80405, a trial comparing the efficacy of bevacizumab- and cetuximab-based therapy as first-line treatment in metastatic CRC. [https://clinicaltrials.gov/ct2/show/NCT00265850]
Significantly longer median overall survival (OS) was observed in patients with left- vs right-sided primary tumours (33.3 vs 19.4 months; hazard ratio [HR], 1.55; p<0.0001).
Furthermore, patients with left-sided tumours who received bevacizumab-based treatment had longer OS than their counterparts with right-sided tumours (median, 31.4 vs 24.2 months; HR, 1.32; p=0.01).
“Surprisingly, a big difference in median OS of 19.3 months was observed in those with left- vs right-sided tumours who were randomized to receive cetuximab-based treatment [36.0 vs 16.7 months; HR, 1.87; p<0.0001],” pointed out Venook.
“Cetuximab was more effective than bevacizumab in improving OS in patients with left-sided tumours [HR, 0.82; p=0.01],” he reported. “In contrast, an OS trend favouring bevacizumab was noted in those with right-sided tumours [HR, 1.26; p=0.08].”
“The prognostic and predictive values of left vs right primary tumour location are not something magical. Possible explanations include differences in the distribution of mutations, transcriptional subtypes and hypermethylation,” he suggested. “Embryology may explain these differences – the midgut forms the right colon while the hindgut forms the left colon during embryonic development.”
Another interesting finding was noted in their extpolatory analysis of patients with KRAS mutant tumours. “Although cetuximab is not indicated in KRAS mutant CRC, those with right-sided KRAS mutant tumours who received cetuximab had longer OS than their KRAS wild-type counterparts [median, 23.3 vs 16.7 months],” noted Venook. “If this is eventually confirmed by other studies, we know less about RAS than we think we do.”
“First-line cetuximab and bevacizumab have different treatment effects in subgroups defined by left vs right sidedness of primary tumours,” he concluded. “The study results will influence decisions on treatment sequences, but will not preclude my use of either agent, at least for now.”