Bevacizumab with FOLFOX4 improved survival, but not response in colorectal cancer

Benefit was termed significant, but it was more modest than in prior studies.

Issue: March 1, 2007

ORLANDO, Fla. — Using bevacizumab as a first-line treatment with oxaliplatin-based chemotherapy improved progression-free survival in patients with metastatic colorectal cancer, according to results of the NO16966 trial, presented at the 2007 Gastrointestinal Cancers Symposium.

The phase-3 trial, one of the largest ever in patients with metastatic colorectal cancer, also established that the XELOX chemotherapy regimen is an acceptable alternative to the FOLFOX4 regimen.

First-line treatment

Leonard Saltz, MD, professor of medicine and member of the gastrointestinal oncology service at Memorial Sloan-Kettering Cancer Center, and colleagues evaluated the effect of bevacizumab (Avastin, Genentech) when used as first-line treatment, combined with either XELOX (capecitabine [Xeloda, Roche] plus oxaliplatin [Eloxatin, Sanofi Aventis]) or FOLFOX4 (5-fluorouracil and leucovorin plus oxaliplatin) chemotherapy regimens.

Leonard Saltz, MD
Leonard Saltz

“Although previous studies have not examined the addition of bevacizumab to oxaliplatin-based front-line chemotherapy as first-line treatment, this combination has become the most widely used front-line regimen in standard practice for metastatic colorectal cancer,” Saltz said.

“This was the first study to examine the regimen’s use as a first-line treatment, and the data do support its continued use in standard practice.”

Adding bevacizumab to standard irinotecan-based front-line chemotherapy, or to second-line FOLFOX4, has previously been shown to improve response rate, progression-free survival and overall survival in several randomized clinical trials. The NO16966 trial is the first to study the efficacy of bevacizumab when used with either FOLFOX4, a standard chemotherapy regimen for colorectal cancer, or XELOX, in first-line.

The researchers randomized 1,401 patients to receive FOLFOX4 or XELOX chemotherapy, plus bevacizumab or placebo. The initial trial design was a two-arm, open-label study to compare FOLFOX4 and XELOX. After bevacizumab phase-3 data became available, the design was amended.

“When bevacizumab came along, it became clear that we could not hope to continue the study without offering bevacizumab,” Jim Cassidy, MD, MSc, cancer research U.K. professor of oncology at Beatson Oncology Centre in Glasgow, Scotland, and European investigator for the trial, said in an interview. “So we amended the design to a 2x2 study of XELOX vs. Folfox, ± bevacizumab. This was more efficient than starting a completely new study to test bevacizumab.”

Median progression-free survival for the bevacizumab groups was 9.4 months vs. 8.0 months for the placebo group (P<.003). The study protocol included drug treatment until disease progression; however, only 56% were treated this way. More than half of patients who discontinued did so for reasons unrelated to disease progression.

“The contribution of bevacizumab to front-line oxaliplatin-based therapy in this trial was smaller than might have been expected based on previous colorectal trials,” Saltz said. “Furthermore, the response rates were no better with bevacizumab than without.”

2007 Gastrointestinal Cancers Symposium Adverse events for both groups were similar and primarily due to the cytotoxic chemotherapy. They included neuropathy, lowered resistance to infection, fatigue and diarrhea. The only adverse event clearly related to bevacizumab was elevated blood pressure, which was easily controlled with medication. No unexpected toxicity was reported.

FOLFOX4 vs. XELOX

This study initially started as a phase-3 trial to compare FOLFOX4 with XELOX. A phase-2 study of patients with metastatic colorectal cancer showed that XELOX had similar efficacy compared with historical reports of FOLFOX4. XELOX differs from FOLFOX4 in that oral capecitabine is used instead of a 48-hour IV infusion.

“XELOX disrupts patients lives less and has less overall hospital attendances,” Cassidy said. “We started off with the premise that if it was as good as Folfox, then it would be sensible to replace with the easier treatment.”

Previous research has shown that capecitabine alone is as effective as bolus 5-FU/leucovorin alone as first-line treatment for colorectal cancer. In the XELOX regimen, capecitabine is given orally, twice-daily, for two weeks on, one week off, with oxaliplatin administered intravenously on day one of each three-week cycle.

Conversely, the FOLFOX4 regimen uses an intravenous oxaliplatin infusion every two weeks, followed by a continuous two-day intravenous infusion, typically administered as an outpatient via ambulatory pump.

“For some selected patients who are motivated and reliable, oral capecitabine may be more convenient,” Saltz said. “This study showed that XELOX is an acceptable alternative to Folfox.”

Alan Venook, MD
Alan Venook

Alan Venook, MD, professor of hematology and oncology at the University of California, San Francisco, and Gastrointestinal Cancers section editor for Hem/Onc Today, cautioned that although this study indicates that XELOX is not inferior to FOLFOX4, the capecitabine dose may not be well tolerated in Americans.

“This study was mostly done in Europe, and there is a lot of evidence that the dose of capecitabine can be higher in European patients than in American patients,” Venook said. “We don’t really know why Europeans can tolerate higher doses, but there are speculations. Although the study suggested XELOX is not inferior to FOLFOX4, it used a dose of capecitabine that Americans don’t usually use.”