Zosia Chustecka

May 19, 2016

UPDATED May 23, 2016 // There is a big difference in colorectal cancer when it occurs on the right side compared with the left side, according to a new analysis of data from a large, federally funded trial. There is also a suggestion that the position of the primary tumor could influence treatment choice.

Survival was significantly longer for patients with primary tumors that originated on the left side of the colon (in the descending colon, sigmoid colon, and rectum) than for patients with primary tumors that originated on the right side of the colon (in the cecum and ascending colon).

The median overall survival (OS) was 19.4 months for patients with right-sided tumors vs 33.3 months for patients with left-sided tumors.

"While previous studies had suggested that tumor location may impact clinical colorectal cancer outcomes, the effect we observed in this analysis appears to be far greater than we expected," said lead study author Alan Venook, MD, professor of medicine at the University of California, San Francisco.

 

"These findings will likely change the way we approach colorectal cancer treatment and research, even as we seek to more deeply understand the biology," he said in a statement.

Dr Venook will present the new data at the forthcoming American Society of Clinical Oncology (ASCO) 2016 Annual Meeting. He was discussing the findings at a premeeting presscast.

New Analysis of Data

The new findings derive from a further analysis of data from the CALGB/SWOG 80405 (Alliance) study, conducted in 1137 patients with metastatic colorectal cancer. The trial compared first-line treatment with two different chemotherapy regimens ― oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX), and irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) ― and two targeted agents, bevacizumab (Avastin, Genentech, Inc) and cetuximab (Erbitux, ImClone Systems Incorporated).

The main results from this trial, presented at ASCO 2014, showed no difference in either progression-free survival (PFS) or overall survival (OS) between any of the treatment arms, leading to the conclusion that either chemotherapy regimen and either targeted agent could be used as first-line therapy.

A follow-up to this, showing how a consideration of costs changes the conclusion, was reported at ASCO 2015.

This new analysis looks at patient outcomes with respect to where the original cancer was found.

Dr Venook reported that 293 patients had right-sided primary tumors, and 732 patients had left-sided primary tumors. An additional 66 patients had transverse tumors; these patients were excluded from the analysis, inasmuch as it made no difference to the results whether they were included among either the patients with right-sided tumors or those with left-sided tumors, Dr Venook explained. An additional 46 patients had tumors that were designated as uncertain; these patients were also excluded.

All the patients in this analysis had tumors without a mutated KRAS gene, which is a known biomarker of response to certain colorectal cancer therapies, including cetuximab (in fact, cetuximab is approved only for use in such patients).

The primary analysis showed that patients with colorectal cancer that originated on left side had better outcomes and longer survival than patients with cancer that originated on the right, regardless of the treatment they received.

However, a further exploratory analysis found differences that were related to treatment.

During the presscast, Dr Venook highlighted the finding that among patients who received cetuximab, those with left-sided tumors had a median OS of 36 months vs 16.7 months for patients with right-sided tumors.

The magnitude of this difference was "surprising to us," he said. He noted that this 16-month survival of patients with right-sided tumors who received cetuximab is "quite different" from what was seen in all the other subgroups. "It is clearly an outlier."

The exploratory analysis also showed that among patients who received bevacizumab, overall survival for those with left-sided tumors was 31.4 months vs 24.2 months for those with right-sided tumors.

"It appears that patients with right-sided colorectal cancer, broadly speaking, do not get benefit from cetuximab," Dr Venook said. He suggested that this finding will change clinical practice. "This could very well represent a shift," he said. Other factors need to be taken into consideration, but for now, these data argue strongly against using cetuximab and other EGFR antibodies in patients with colorectal cancer originating on the right side, he said.

He noted that further work is underway. Detailed, ongoing analysis is being conducted on 44,000 tumor samples taken from patients enrolled in this trial, and he hopes that this work will show that "sidedness" is a surrogate for biological markers. He said that for the time being, "The side can help us make decisions in the context of all the other information we gather."

A coauthor of the abstract was a little more cautious. "These are preliminary data and need confirmation," commented Richard Schilsky, MD, ASCO chief medical officer and former chief of the Section of Hematology-Oncology at the University of Chicago.

The new data suggest that left-sided and right-sided colorectal cancers are both biologically and anatomically different, he commented. "There have been some data trickling through that these differences may exists, but this was quite a large trial and is more definitive evidence to suggest that these are real differences that we should be paying attention to,” he told Medscape Medical News.

"The bottom-line conclusion is that in the future, clinical trials for colon cancer should stratify patients by 'sidedness,' so we can better understand this issue," Dr Schilsky commented.

"We're not ready yet to make treatment decisions on real-world practice based on this information, but it's pretty provocative...given that the overall results show that the choice of targeted therapy doesn't really matter. This new info suggests that it does matter, depending on sidedeness," he added.

Another expert also urged caution in acting upon the findings. Julien Taieb, MD, head of the gastroenterology and gastrointestinal oncology department of the Georges Pompidou European Hospital, Paris, pointed out that the new findings come from a post hoc analysis of subgroups of patients, which does not theoretically allow definitive conclusion. "From a scientific point of view, we now have to meet the standards for evidence-based medicine with a randomized controlled trial on that topic," he said.

"I think that these are very interesting findings on a huge clinical trial, but in my opinion, these results are not sufficient to change our practice," Dr Taieb told Medscape Medical News.

In addition, although talk of sidedness is interesting, it is not accurate enough in the current era of genetic and genomic medicine, he commented, adding: "We are now trying to move to international consensual molecular classifications to better define and treat the different types of colon cancer." He noted that it is already known that the two anatomic sites have different concentrations of some biological markers that may be involved in anti-EGFR resistance, including BRAF and RAS mutations.

"However, sidedness remains an easy factor to identify, either by colonoscopy or on a CT scan, and it is something that is 'doable' in every country in the world, where sophisticated genomic/genetic analyses may not be possible," he said.

He noted that the original trial found no difference between cetuximab and bevacizumab, whereas two smaller studies had found a significant difference, with improved OS on anti-EGFRs compared with bevacizumab in patients with wild-type disease who had undergone full RAS testing (which was not available for the whole population of the present trial).

This study received funding and support from BMS, Genentech, and ImClone in collaboration with the National Cancer Institute. Dr Venook has received expenses from Halozyme, Genentech, Roche, Bristol-Myers Squibb, Merck, and Serono and institutional research funding from Bayer, Onyx, Genentech/Roche, Bristol-Myers Squibb, GlaxoSmithKline, Lilly. Several coauthors also report relationships with industry. Dr Taieb has received honoraria from Roche, Merck, Celgene, AMGEN, Lilly, Sanofi, and Baxalta.

American Society of Clinical Oncology (ASCO) 2016 Annual Meeting: Abstract 3504, to be presented June 5, 2016.

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