Maintenance Chemo Delays Progression in Metastatic CRC

Roxanne Nelson

January 27, 2014

SAN FRANCISCO — Maintenance treatment with capecitabine (Xeloda) and bevacizumab (Avastin) significantly delayed disease progression, compared with observation, in patients with metastatic colorectal cancer.

There was also a trend toward improved overall survival, although this did not reach statistical significance, according to final results from the CAIRO3 trial, which were presented here at the 2014 Gastrointestinal Cancers Symposium.

Specifically, the study demonstrated that providing maintenance treatment with capecitabine plus bevacizumab after induction therapy with bevacizumab, capecitabine, oxaliplatin, and bevacizumab (CAPOX-B) significantly prolonged time to disease progression.

It also prolonged the time from randomization to progression after the reintroduction of CAPOX-B.

"Maintenance treatment with capecitabine and bevacizumab after 6 cycles of CAPOX-B in mCRC is effective," explained study author Miriam Koopman, MD, PhD, from the University Medical Center Utrecht in the Netherlands, who presented the findings. The benefit in overall survival did not reach statistical significance, but there were some issues in the multivariable analysis, she explained.

Significant Improvement in Second Progression

The CAIRO3 trial involved 558 previously untreated patients with metastatic colorectal cancer that was at least stable after 6 cycles of CAPOX-B.

Dr. Koopman and colleagues randomized patients to observation or to maintenance treatment with capecitabine 625 mg/m² twice-daily continuously and intravenous bevacizumab 7.5 mg/kg every 3 weeks.

On first progression, patients in both groups received treatment with CAPOX-B until second progression, which was the primary end point.

The study's secondary end points were overall survival and time to second progression, which was defined as the time to progression or death on any treatment after first progression. All of the end points were calculated from the time of randomization.

At a median follow-up of 48 months, CAPOX-B was reintroduced to more patients in the observation group than in the maintenance group (61% vs 47%).

There was a significant improvement in median second progression that favored the maintenance group over the observation group (11.7 vs 8.5 months; stratified hazard ratio [HR], 0.67; P < .0001). Maintenance therapy also conferred a significant increase in median first progression, compared with observation (8.5 vs 4.1 months; stratified HR, 0.43; P < .0001).

There was also a significant improvement in the median time to second progression (13.9 vs 11.1 months; stratified HR, 0.68; P < .0001).

Dr. Koopman pointed out that the time to first and second progression was evaluated from randomization, and excluded the 4 to 5 month period of induction treatment.

Although there was a trend toward improvement in median overall survival in the maintenance group, it did not reach statistical significance (21.6 months vs 18.1; HR, 0.89; P = .22).

"Quality of life was maintained and not clinically inferior, compared with observation," said Dr. Koopman.

Survival Benefit in Subgroups

In the preplanned subgroup analysis, there was a benefit in all groups for the study's primary end point. However, multivariable analyses for survival, after adjustment for a series of prespecified potentially confounding factors at baseline, showed significant interactions for treatment (observation vs maintenance) with resection of the primary tumor (yes vs no) and metastases at baseline (synchronous vs metachronous) (P values for interaction < .0001).

In particular, in the subgroup of 180 patients with synchronous metastases and resected primary tumor, overall survival was better with maintenance treatment than with observation (25.0 vs 18.0 months; P < .0001). However, this finding requires confirmation in future studies, Dr. Koopman emphasized.

Median overall survival was also better in the maintenance group than in the observation group for patients who experienced a complete or partial response to induction therapy (24.1 vs 18.8 months; P < .0001).

More Work Needed

Study discussant Neal J. Meropol, MD, from the University Hospitals Seidman Cancer Center and Case Western Reserve University in Cleveland, noted that the CAIRO3 findings show that it is "feasible yet challenging to conduct a window-of-opportunity study after induction therapy."

"This study was completed, which is a heroic effort, but fewer than 2 patients per center per year were enrolled, showing the challenge of doing this type of study," said Dr. Meropol.

He added that although maintenance treatment will clearly delay progressive disease, "more work is needed to identify patients who may safely receive a treatment holiday."

The study was sponsored by the Dutch Colorectal Cancer Group, Koningin Wilhelmina Fonds, Sanofi, and Hoffmann-La Roche. Study coauthor Cornelis J.A. Punt, MD, PhD, reports receiving honoraria from Roche and serving as a consultant or in an advisory role for Roche.

2014 Gastrointestinal Cancers Symposium (GICS): Abstract LBA388. Presented January 18, 2014.

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