Primary tumor location is an important prognostic factor in previously untreated metastatic colorectal cancer, according to a pooled analysis reported online in Journal of the National Cancer Institute.

In the prospective PROVETTA study, patients with tumors originating in the left side of the colon, distal to the splenic flexure, lived nearly twice as long as those with right-sided tumors (median 42 months vs. 24.8 months; hazard ratio, 0.44; P value < .001).

Unadjusted progression-free survival (PFS) was also significantly longer with left-sided tumors in PROVETTA (median 12.1 months vs. 9.9 months; HR, 0.52; P < .001).

A multivariable model adjusted for baseline variables confirmed that left-sided primary tumors had a lower risk of progression (HR, 0.55; P = .01) and death (HR, 0.47; P = .01), independent of BRAF mutation status or mucinous histology, study author Dr. Fotios Loupakis , of the University of Southern California Norris Comprehensive Cancer Center in Los Angeles, reported.

Subsequent analyses using data from two large phase III studies of first-line chemotherapy with or without bevacizumab (Avastin) also showed favorable outcomes in patients with left-sided tumors.

Overall survival was significantly longer in patients with left-sided vs. right-sided tumors in the NO16966 (median 23 months vs. 18 months; HR, 0.71; P < .001) and AVF2107g (median 20.4 months vs. 14.6 months; HR, 0.55; P < .001) studies.

Unadjusted median PFS was significantly longer for left-sided tumors in AVF2017 (8.5 months vs. 7.1 months; HR, 0.68; P < .001), but failed to reach statistical significance in NO16966 (median 8.9 months vs. 7.6 months; HR, 0.90; P = .12).

Multivariable analyses confirmed the independent prognostic effect of tumor location, irrespective of exposure to bevacizumab, the authors noted.

A recent retrospective analysis using two independent and nonrandomized cohorts of patients treated with capecitabine (Xeloda) and oxaliplatin (Eloxatin) with or without bevacizumab suggested that the addition of bevacizumab may primarily benefit patients with left-sided primary tumors.

“Our data do not validate those findings and reject the hypothesis of an interaction of primary tumor location with the efficacy of bevacizumab,” Dr. Loupakis wrote (J. Natl. Cancer Inst. 2015;107:dju427 [doi:10.1093/jnci/dju427]).

Another important finding according to the authors was the association of right-sided tumors with chemoresistance.

In multivariable analyses, left-sided tumor location was associated with significantly higher response rates in both AVF2107g (odds ratio, 2.48; P < .001) and NO16966 (OR, 1.49; P = .01). There was a trend toward achieving response for left-sided tumors in PROVETTA, but it did not reach statistical significance (OR, 1.23; P = .59), likely due to the limited sample size.

“These data emphasize that right-sided and left-sided CRC [colorectal cancers] have potentially important biological differences,” Dr. Loupakis observed.

The authors called for validation of the results in adjuvant and additional metastatic studies of CRC.

“This easy-to-collect dichotomous information on side of origin could be of added value in clinical decision-making and should be considered an important stratification factor for future randomized trials,” they suggested.


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