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Colorectal Cancer: Capecitabine and Bevacizumab Found Safe and Effective in Older Patients

Tuma, Rabiya S. PhD

doi: 10.1097/01.COT.0000428319.60438.39


SAN FRANCISCO—Although the median age of patients diagnosed with colorectal cancer is 69, older patients remain under-represented in clinical trials and clinicians often assume that these patients will not to be able to tolerate standard chemotherapy regimens. Now, however, a Phase III trial reported here at the Gastrointestinal Cancers Symposium shows that older patients not only tolerate a combination of fluoropyrimidine plus bevacizumab, but also derive significant progression-free survival benefit from the combination.

“This is the first prospective Phase III trial in patients over the age of 70 with metastatic colorectal cancer,” said David Cunningham, MD, Consultant Medical Oncologist and Head of the Gastrointestinal Unit at the Royal Marsden, in presenting the results of the AVEX trial.

“This shows very convincingly and very clearly that progression-free survival was enhanced and significantly prolonged with the addition of bevacizumab to capecitabine. As a clinician treating these patients, I was certainly impressed at how well tolerated this approach was.”

In the study (Abstract 337), 280 patients with metastatic colorectal cancer were enrolled in a 10-country trial that compared capecitabine plus bevacizumab with capecitabine alone. To be eligible for the trial, patients had to be at least 70, have a performance status between 0 and 2, and be deemed an unsuitable candidate for doublet chemotherapy—“This was a fairly loose definition and up to the clinicians to decide what would be their preferred strategy for individual patients,” he explained.

Adjuvant chemotherapy was allowed if it was completed at least six months before enrollment. Patients were not eligible for the study if they had clinically significant cardiovascular disease or current or recent use of a non-steroidal anti-inflammatory drug or aspirin.

DAVID CUNNINGHAM, MD: “This shows very convincingly and very clearly that progression-free survival was enhanced and significantly prolonged from the addition of bevacizumab to capecitabine

DAVID CUNNINGHAM, MD: “This shows very convincingly and very clearly that progression-free survival was enhanced and significantly prolonged from the addition of bevacizumab to capecitabine

The median age for patients was 76 and 77 in the combination and monotherapy arms, respectively. The two groups were generally well balanced, although more patients in the combination arm had received adjuvant chemotherapy compared with those in the control arm (about 32% versus 19%).

Median progression-free survival, which was the primary endpoint of the trial, was 9.1 months in the patients receiving capecitabine plus bevacizumab compared with 5.1 months in the capecitabine-only group. This was a 47 percent decrease in the risk of progression with the combination regimen.

The trial was not powered to detect a difference in overall survival, but there was a non-significant trend for improvement with the combination over monotherapy (about 21 months vs. 17 months).

“I think most people looking at these curves would be impressed by the trend in favor of the combined arm,” he said. “And furthermore, when you look at the median survival for the combined arm of 20.7 months, which—given the set of patients we are recruiting to the trial—I think you would agree that is certainly a worthwhile endeavor for the patients receiving the treatment.”

The median treatment duration was 4.2 months of capecitabine in the monotherapy arm and 5.6 months in the combination arm, and 5.4 months of bevacizumab. During the question-and-answer period, several members of the audience noted that the median progression-free survival time was longer than the treatment duration. Cunningham explained that patients could be taken off treatment for reasons other than disease progression and then be rechallenged if they were still responding.

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No Unusual Safety Signals

“The safety profile was consistent with previously reported data for bevacizumab in metastatic colorectal cancer,” he said. “There were no unusual signals from this older patient population.” There were, however, significantly more adverse events leading to discontinuation in the combination arm than in the control arm (25% vs. 14%). There was no one type of adverse event driving the trend, he noted.

In terms of bevacizumab-related toxicities, any grade of bleeding or hemorrhage occurred in 25.4 percent of patients in the combination arm (no grade 3 or higher) and 6.6 percent of patients in the capecitabine arm (0.7% grade 3 or higher). Any grade hypertension occurred in 19.4 and 5.1 percent of patients in the two arms (grade 3 or higher: 2.2% vs. 1.5%), any grade venous thromboembolic events occurred in 11.9 and 5.1 percent (grade 3 or higher: 8.2% vs. 4.4%), and any grade proteinuria occurred in 7.5 and 0.7 percent (grade 3 or higher: 1.5% and 0%).

In terms of non-bevacizumab related adverse events, there was substantially more hand-foot syndrome in patients on the combination regimen compared with those on the monotherapy treatment (any grade: 48.5% and 39.7%; and grade 3 or higher 14.9% and 6.6%). Cunningham attributed that difference to the longer treatment duration in patients on capecitabine plus bevacizumab.

During the discussion following his presentation, an audience member asked Cunningham to elaborate on the grade 5 adverse events in the trial, which occurred in 8.2 percent of patients receiving capecitabine plus bevacizumab and 11.8 percent of patients in the capecitabine-monotherapy arm.

“This is higher than we would normally expect, but I think it reflects the population being treated,” he answered. For example, there were three myocardial infarctions in each arm, two cases of pneumonia in each arm, and two pulmonary emboli in each arm. “So I think it is something we will wish to look at further, but I do think it reflects the risks of chemotherapy in a group of patients with an average age of 76.”

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More Options

Meanwhile, Robert Wolff, MD, Professor of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center, asked about the magnitude of benefit seen with the addition of bevacizumab. The results, he said, are reminiscent of those of early trials that combined bevacizumab with fluorouracil-based chemotherapy, whereas the magnitude of benefit is “quite modest” when using more active cytotoxic agents.

Cunningham acknowledged that those early trials clearly demonstrated that bevacizumab enhances the effects of fluoropyrimidine-based therapy. But it begs another question, as to whether continuous capecitabine exposure is the best way to combine a drug with bevacizumab. “We know bevacizumab has a half-life of 21 days. It's in the body. So perhaps the fluoropyrimidine given orally continuously is a better way to add cytotoxic drugs to bevacizumab.”

On the other hand, he noted, even the control group did relatively well in this trial—“which suggests that the enrollment somehow selected a group of patients with relatively indolent colorectal cancer, which is reflected in the long median survival, despite the fact that they largely received only one line of treatment.”

“As Bob Wolff pointed out, the work by Cunningham does support prior data suggesting that fluoropyrimidine plus bevacizumab does have an interesting effect,” said Jordan Berlin, MD, Ingram Professor of Cancer Research and Clinical Director of the GI Oncology Program at Vanderbilt-Ingram Cancer Center, who was on the podium as Discussant for other abstracts.

“It also confirms work from the MRC FOCUS trial and other trials, showing that there may be a subset of patients for whom starting with the most aggressive therapy is not necessarily the best thing, for whom there is benefit for treating with monotherapy without necessarily going to doublets, etc., that are more toxic.”

Referring to this trial and a FOLFOXIRI trial presented in the same session, he said that the trials don't necessarily change the standard of care, but “they give us a little more option in our treatment and a little more leeway in how we treat our patients individually, based on their age, their performance status, and their ability to tolerate therapy, and what our goals of therapy are.”

Cunningham noted in his disclosure statement that he has received research funding from F. Hoffmann-La Roche Ltd., Merck KGaA, Novartis, Celgene, Amgen, and AstraZeneca.

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4 Co-sponsors

The multidisciplinary symposium is co-sponsored by the American Gastroenterological Association Institute, the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

© 2013 Lippincott Williams & Wilkins, Inc.
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