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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.
The study involves patients with metastatic disease and thus may not apply to those with resected primary tumors and its results may have been influenced by the lack of controls and selection bias, Dr. Howard Hochster noted in an accompanying editorial (J. Natl. Cancer Inst. 2015;107:djv011 [doi:10.1093/jnci/djv011]).
That said, “This interesting analysis gives rise to some important and testable biological hypotheses,” he observed.
The analysis may also help resolve the long-standing debate over why the AVF2107 trial, which used irinotecan-based chemotherapy and led to the first approval of bevacizumab, was markedly positive for a survival effect of bevacizumab, while the larger NO16966 study failed to show a survival benefit with the addition of bevacizumab to an oxaliplatin-based backbone.
“The present report provides an apparent explanation, as the data demonstrate a greater benefit of oxaliplatin-based chemotherapy overall and a disproportionate effect on the right-sided colon lesions, reducing the relative bevacizumab benefit. We see here, that oxaliplatin may be more effective than irinotecan for right-sided metastatic colon cancer and that bevacizumab further narrows the gap by differential treatment effect for lesions originating in the right side of the colon,” he wrote.
Dr. Hochster is an international expert in cancer clinical trials and director of GI Oncology at the Yale Cancer Center in New Haven, Conn.
The study involves patients with metastatic disease and thus may not apply to those with resected primary tumors and its results may have been influenced by the lack of controls and selection bias, Dr. Howard Hochster noted in an accompanying editorial (J. Natl. Cancer Inst. 2015;107:djv011 [doi:10.1093/jnci/djv011]).
That said, “This interesting analysis gives rise to some important and testable biological hypotheses,” he observed.
The analysis may also help resolve the long-standing debate over why the AVF2107 trial, which used irinotecan-based chemotherapy and led to the first approval of bevacizumab, was markedly positive for a survival effect of bevacizumab, while the larger NO16966 study failed to show a survival benefit with the addition of bevacizumab to an oxaliplatin-based backbone.
“The present report provides an apparent explanation, as the data demonstrate a greater benefit of oxaliplatin-based chemotherapy overall and a disproportionate effect on the right-sided colon lesions, reducing the relative bevacizumab benefit. We see here, that oxaliplatin may be more effective than irinotecan for right-sided metastatic colon cancer and that bevacizumab further narrows the gap by differential treatment effect for lesions originating in the right side of the colon,” he wrote.
Dr. Hochster is an international expert in cancer clinical trials and director of GI Oncology at the Yale Cancer Center in New Haven, Conn.
The study involves patients with metastatic disease and thus may not apply to those with resected primary tumors and its results may have been influenced by the lack of controls and selection bias, Dr. Howard Hochster noted in an accompanying editorial (J. Natl. Cancer Inst. 2015;107:djv011 [doi:10.1093/jnci/djv011]).
That said, “This interesting analysis gives rise to some important and testable biological hypotheses,” he observed.
The analysis may also help resolve the long-standing debate over why the AVF2107 trial, which used irinotecan-based chemotherapy and led to the first approval of bevacizumab, was markedly positive for a survival effect of bevacizumab, while the larger NO16966 study failed to show a survival benefit with the addition of bevacizumab to an oxaliplatin-based backbone.
“The present report provides an apparent explanation, as the data demonstrate a greater benefit of oxaliplatin-based chemotherapy overall and a disproportionate effect on the right-sided colon lesions, reducing the relative bevacizumab benefit. We see here, that oxaliplatin may be more effective than irinotecan for right-sided metastatic colon cancer and that bevacizumab further narrows the gap by differential treatment effect for lesions originating in the right side of the colon,” he wrote.
Dr. Hochster is an international expert in cancer clinical trials and director of GI Oncology at the Yale Cancer Center in New Haven, Conn.
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.
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.
FROM JOURNAL OF THE NATIONAL CANCER INSTITUTE
Key clinical point: Metastatic colorectal cancer originating from the right side of the colon is associated with shorter progression-free survival and overall survival than left-sided colorectal cancers.
Major finding: Median overall survival was significantly shorter for patients with right-sided CRC tumors in the PROVETTA, AVF2107g, and NO16966 studies.
Data source: Pooled analysis from three studies in 2,027 patients with metastatic colorectal cancer.
Disclosures: The study was supported by a grant from the National Institutes of Health, the Daniel Butler Research Fund, the A.R.C.O. Foundation, Genentech, and F. Hoffmann-La Roche. Dr. Loupakis reported no conflicts of interest. Four coauthors are Roche/Genentech employees and two other coauthors have financial ties with Genentech.
