CHICAGO – Patients with metastatic colorectal cancer who had at least stable disease after induction chemotherapy fared better on maintenance therapy with capecitabine and bevacizumab than on observation alone.
That’s the conclusion reached by investigators in a phase III trial conducted in the Netherlands. They found that patients who were randomly assigned to maintenance therapy after six cycles of induction therapy with capecitabine (Xeloda), oxaliplatin (Eloxatin), and bevacizumab (Avastin) – the CAPOX-B regimen – had better progression-free survival (PFS) and time to progression (TTP) than did patients assigned to observation alone.
With maintenance therapy, "the quality of life is maintained and clinically not inferior to observation," said lead author Dr. Miriam Koopman of the University Medical Center Utrecht Cancer Center, the Netherlands. She presented the final results of the CAIRO3 (Maintenance Treatment With Capecitabine and Bevacizumab Versus Observation After Induction Treatment With Chemotherapy and Bevacizumab as First-line Treatment) trial at the annual meeting of the American Society of Clinical Oncology.
The investigators enrolled 588 patients with metastatic colorectal cancer who had a response of stable-disease or better following six cycles of CAPOX-B to either observation or maintenance with oral capecitabine 625 mg/m2 twice daily and intravenous bevacizumab 7.5 mg/kg on day 1 every 3 weeks. The patients were stratified by prior adjuvant therapy, serum lactate dehydrogenase, response to induction therapy, World Health Organization performance status, and institution.
In both arms, CAPOX-B reintroduction was planned at the time of first progression. The primary endpoint was progression-free survival following reintroduction of CAPOX-B (dubbed PFS2). For those patients who for any reason did not receive CAPOX-B after the first PFS, PFS2 was considered to be equal to PFS1, Dr. Koopman explained.
Of the 279 patients assigned to observation, 168 (60%) had CAPOX-B reintroduced. Of the remaining 111 (40%) of patients in this arm, seven had ongoing observation, 31 received no treatment, and 73 received treatment other than CAPOX-B.
Of the 279 assigned to maintenance, 132 (47%) had CAPOX-B reintroduced. Of the remaining 147 patients (53%) in this arm, 13 continued on maintenance, 45 had no further treatment, 88 had other treatments, and 1 withdrew.
The median PFS from the time of randomization (not including induction) to first progression was 4.1 months in the observation arm and 8.5 months in the maintenance arm (stratified hazard ratio 0.43, P less than .0001).
The benefits of maintenance were also seen with the primary endpoint of PFS2, with a median of 8.5 months for observation, compared with 11.7 months for maintenance (stratified HR 0.67, P less than .0001)
The median time to second progression was 11.1 months among patients randomized to observation, vs. 13. 9 months for those randomized to maintenance (stratified HR 0.68, P less than .0001).
There were no significant differences in median overall survival (OS), however, at 18.1 months for the observation arm and 21.6 months for the maintenance arm.
There was a small but significant difference in quality of life scores between the groups (3.9 point difference on a 100-point scale, P = .004), but this difference was too small to be considered clinically meaningful, Dr. Koopman said.
In preplanned subgroup analyses, the authors found evidence to suggest that patients with synchronous metastases who had resection of the primary tumor had a greater OS benefit from maintenance therapy than did patients with metachronous disease, and that those who had complete or partial response as best response to induction therapy seemed to do better than did patients with stable disease after induction.
"We do not have a clear-cut explanation for this subgroup analysis," Dr. Koopman said.
The investigators hypothesize that the differences between patients with synchronous and metachronous disease could be due to differences in sensitivity to systemic treatment, the prognostic role of resection of the primary tumor, dependence of the angiogenic environment in metastases on the resection status of the primary tumor, or co-option of the local vasculature by the tumor, leading to decreased sensitivity of metachronous metastases to bevacizumab.
The CAIRO3 results suggest that "treatment breaks for all patients at 4 months may be too many breaks, and too early," said Dr. Leonard Saltz, chief of the gastrointestinal oncology service at Memorial Sloan-Kettering Cancer Center, New York.
"Responding patients likely benefit from treatment at least until maximal response, and that’s an aspect to consider in terms of figuring out how to utilize a treatment strategy. And treatment-break strategies will need to be individualized, but should not be abandoned," said Dr. Saltz, who was the invited discussant.
He also cautioned that the quality of life results reported by Dr. Koopman and colleagues may not accurately reflect how patients feel.