Left vs Right Difference in CRC: Now Practice Changing?

Kristin Jenkins

October 12, 2016

COPENHAGEN — Call it the "Left Side Story" or the saga of primary tumor "sidedness" in metastatic colorectal cancer (mCRC).

Either way, the evidence is growing that location of the primary tumor — on the right or the left side of the colon — is a valuable prognostic and predictive biomarker that could radically alter treatment for patients with mCRC.

The premise that left- and right-sided tumors are quite different was aired earlier this year, but now there is more evidence. The new findings were published October 10 in JAMA Oncology and presented here at the European Society for Medical Oncology (ESMO) Congress 2016.

Results from a retrospective analysis of two randomized clinical trials show that in patients with RAS wild-type mCRC, those with left-sided tumors treated with targeted chemotherapies had markedly better progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) than patients with right-sided primary tumors given the same treatments.

Analysis of the international trials indicates a "significant unmet clinical need for developing new treatment strategies for patients with right-sided mCRC," said lead author Sabine Tejpar, MD, PhD, from the University Hospital Gasthuisberg, in Leuven, Belgium.

Primary tumor location should be included in the stratification criteria for future trials in patients with mCRC, particularly those involving epidermal growth factor receptor (EGFR) inhibitors, she added. "The influence of tumor location on responsiveness to particular therapies remains incompletely understood."

For their analysis, Dr Tejpar and colleagues identified 142 patients with KRAS wild-type mCRC and left-sided tumors originating in the splenic flexure, descending colon, sigmoid colon, or rectum from the randomized phase 3 CRYSTAL (Cetuximab Combined With Irinotecan in First-line Therapy for Metastatic Colorectal Cancer) study.

When the anti-EGFR monoclonal antibody cetuximab (Erbitux, Merck Serono) was added to infusional FOLFIRI (fluorouracil, leucovorin, and irinotecan), all patients with left-sided KRAS wild-type mCRC "clearly benefited" with significantly improved PFS, OS, and ORR. More dramatic treatment results were observed with expanded RAS testing, said Dr Tejpar.

The investigators also identified 157 patients with KRAS wild-type mCRC and left-sided tumors in the randomized phase 3 FIRE-3 (FOLFIRI Plus Cetuximab Versus FOLFIRI Plus Bevacizumab as First-Line Treatment For Patients With Metastatic Colorectal Cancer) trial, which compared FOLFIRI plus cetuximab and FOLFIRI plus bevacizumab (Avastin, Roche).

ORR and PFS rates were similar between the two treatment groups in patients with left-sided tumors. However, OS significantly improved in patients with left-sided tumors treated with cetuximab.

"Preplanned evaluation of expanded RAS status suggested an increased treatment effect in terms of the cetuximab-conferred OS benefit," Dr Tejpar noted.

A total of 33 patients from the CRYSTAL trial and 38 patients from the FIRE-3 trial who were identified with right-sided tumors originating in the appendix, cecum, ascending colon, hepatic flexure, or transverse colon were not as responsive to treatment, Dr Tejpar said. These patients "derived limited benefit from standard treatments."

Allowing for variables such as sex, prior adjuvant therapy, and mutational status of the BRAF gene, analysis of both studies revealed a significant impact on OS between primary tumor location and treatment (CRYSTAL: hazard ratio [HR], 1.95; FIRE-3: HR, 0.40).

"These data further suggest a site and treatment interaction, with poor-prognosis right-sided tumors not significantly benefiting from the addition of cetuximab but with a profound benefit of cetuximab for left-sided tumors," said Dr Tejpar.

Analysis of the FIRE-3 trial by site indicated that "FOLFIRI and cetuximab would be the preferred option for RAS wild-type left-sided tumors in terms of OS, while right-sided tumors remain tumors of poor prognosis with any of the studied regimens."

These findings are "broadly consistent with other reports," she noted.

An EGFR inhibitor–sensitive phenotype appears to be more prevalent in left-sided tumors, and more research will determine whether patients with RAS wild-type right-sided mCRC might benefit from cetuximab, Dr Tejpar said.

Patients with right-sided tumors tended to be female and have multiple metastatic sites, while patients with left-sided tumors more often had liver-only metastases. These findings probably reflect the known biological and prognostic differences between left- and right-sided tumors, Dr Tejpar explained.

Potentially Practice Changing

This analysis provides "further validation" of a variable that could change the face of clinical practice, according to Kristen K. Ciombor, MD, MSCI, and Richard M. Goldberg, MD, from The Ohio State University Comprehensive Cancer Center in Columbus.

Primary tumor location "has the potential to be both prognostic and predictive, a circumstance that may change not only clinical trial design but also clinical practice in patients with metastatic colorectal cancer," they said in an accompanying editorial.

"Tejpar et al make a convincing argument that the prognostic and predictive effects of primary tumor sidedness in mCRC are real, particularly in the context of other recent data that corroborate these findings."

The "sidedness story," which began in 2001, is still relevant, Dr Ciombor and Dr Goldberg said, adding that whether primary tumor sidedness is predictive in patients treated with panitumumab (Vectibix, Amgen) as well "remains to be seen."

Current and future clinical trials should stratify for tumor location, they agreed.

More detailed molecular analysis of existing clinical trial specimens could provide "pivotal information" about the mechanisms underlying these prognostic and predictive effects. Whether these data might apply to earlier-stage colorectal cancer and RAS mutant disease or to other genetically defined diseases also needs to be determined.

Other investigators would appear to agree.

Earlier this year, results from a secondary analysis of data from the Cancer and Leukemia Group B/Southwest Oncology Group (Alliance) study could "change the way we approach colorectal cancer treatment and research, even as we seek to more deeply understand the biology," said Alan Venook, MD, professor of medicine at the University of California, San Francisco.

Dr Venook, who was the lead study author, presented findings from the Alliance study at the American Society of Clinical Oncology 2016 Annual Meeting, held in Chicago in May.

It showed that in 1137 patients with metastatic colorectal cancer, median OS was 33.3 months for patients with left-sided tumors and 19.4 months for patients with right-sided tumors (HR, 1.55; P < .001).

Previous studies had suggested that colorectal cancer outcomes could be affected by tumor location, Dr Venook noted, adding that, "The effect we observed in this analysis appears to be far greater than we expected."

Funding for the CRYSTAL study was provided by Merck KGaA, and funding for the FIRE-3 study was provided by Merck KGaA and Pfizer. Dr Tejpar reported relationships with Merck KGaA, Bayer, Sanofi, Boehringer, and Roche. Several coauthors also reported relationships with industry, including Amgen, Roche, Bayer, Merck KGaA, Sanofi, Lilly, AstraZeneca, Celgene, Chugia, Imclone, Millennium, Novartis, Symphogen, Tahio, Ipsen, Baxalta, Servier, and SIRTEX. Two coauthors reported being employees of Merck KGaA. Dr Venook reported relationships with Halozyme, Genentech, Roche, Bristol-Myers Squibb, Merck, Serono, Bayer, Onyx, Genentech/Roche, GlaxoSmithKline, and Lilly. The other authors have disclosed no relevant financial relationships.

JAMA Oncol. Published online October 10, 2016. Study full text, Editorial

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