Adding bevacizumab (Avastin, Roche) to capecitabine (Xeloda, Roche) significantly improves progression-free survival in elderly patients with metastatic colorectal cancer, with no unexpected safety concerns, according to results from the first phase 3 study of bevacizumab in an exclusively elderly population.
The findings, from the AVEX (Avastin in the Elderly With Xeloda) study, were published in the October issue of theLancet Oncology.
"Our data suggest that bevacizumab plus capecitabine is an effective and tolerable treatment regimen for patients with metastatic colorectal cancer aged 70 years and older who are deemed unsuitable for irinotecan-based or oxaliplatin-based treatments," say the researchers, headed by David Cunningham, MD, from the Royal Marsden Hospital, London, United Kingdom.
In an accompanying comment, Stefan Kubicka, MD, from the Cancer Center Reutlingen in Germany, wonders if this trial establishes the combination as a new standard of care in elderly patients with metastatic colorectal cancer. "Most oncologists would agree that it does," he writes.
"The AVEX study has shown a clinically meaningful benefit," he notes. For most elderly patients with advanced colorectal cancer, "the combination of bevacizumab with capecitabine seems to be a good option for the initiation of systemic treatment."
Dr. Kubicka emphasizes that this study is an "essential" addition to the evidence base because patients with colorectal cancer older than 70 years have been highly underrepresented in clinical trials, despite the fact that this age group accounts for about half of all patients with metastatic colorectal cancer.
Survival Advantage With Combination
The study was conducted in 280 patients 70 to 87 years of age. About two thirds of the patients were older than 75 years, and the majority had comorbidities and received concomitant medications.
These patients had previously untreated and unresectable metastatic colorectal cancer, and were not deemed to be candidates for oxaliplatin-based or irinotecan-based chemotherapy regimens.
They were randomized to 1 of 2 treatments: twice-daily oral capecitabine 1000 mg/m² on days 1 to 14, or the same regimen of capecitabine plus intravenous bevacizumab 7.5 mg/kg on day 1 every 3 weeks until disease progression, unacceptable toxic effects, or withdrawal of consent.
The daily dose of capecitabine used in the study is slightly lower than the standard dose used in clinical practice, which is 2500 mg/m².
The results show a significant improvement in median progression-free survival with the combination, compared with monotherapy (9.1 vs 5.1 months; hazard ratio [HR], 0.53; P < .0001).
Median overall survival did not differ significantly in the combination and monotherapy groups (20.7 vs 16.8 months; HR, 0.79; P = .18), but the study was not sufficiently powered to detect an overall survival difference, the researchers note. The proportion of patients who used any subsequent treatment was the same in the 2 groups.
The results were consistent across all age subgroups assessed, and the HR for progression-free survival benefit was the same in patients younger than 75 years and those 75 years and older, the researchers report.
Toxicity in Elderly With Comorbidities
Many oncologists are reluctant to treat elderly patients with combination chemotherapy or molecular drugs because they are concerned about the possibility of severe toxic effects, especially in patients with comorbidities, the researchers write. This is a common perception that contributed to the rationale underpinning the AVEX trial. All patients enrolled in the trial were older than 70 years so that the use of bevacizumab plus capecitabine in this specific population could be assessed.
Despite concerns about the safety of bevacizumab in elderly patient populations, the researchers identified no new safety signals. "The safety profile was consistent with that reported by other studies of bevacizumab plus capecitabine in metastatic colorectal cancer," Dr. Cunningham and his colleagues write.
The most common any-grade adverse event of special interest for bevacizumab was hemorrhage. It affected 25% of patients in the combination group and 7% in the monotherapy group.
Table. Treatment-related Outcomes
| Treatment-related Outcomes | Capecitabine Plus Bevacizumab, n (%), n = 140 | Capecitabine Monotherapy, n (%), n = 140 |
| Deaths | 5 | 4 |
| Serious adverse events | 19 (14) | 11 (8) |
| Grade 3 or higher adverse events | ||
| Total | 53 (40) | 30 (20) |
| Hand–foot syndrome | 21 (16) | 9 (7) |
| Venous thromboembolic events | 11 (8) | 6 (4) |
Overall rates of thromboembolic events were consistent with findings from previous trials of bevacizumab in patients with metastatic colorectal cancer. The researchers suggest that this provides "further evidence that bevacizumab is safe to give to elderly patients."
They add that although more patients experienced adverse events that led to death or discontinuation in this study than in other studies of bevacizumab plus fluoropyrimidine monotherapy, this was expected because the patients studied were elderly and many had comorbidities. "Importantly, the number of deaths from treatment-related adverse events was low in both groups, and much the same in each group," they note.
Dr. Cunningham and colleagues suggest that their findings might inform treatment options for younger patients who are not candidates for irinotecan-based or oxaliplatin-based chemotherapy. "Bevacizumab plus capecitabine might also be considered when patients choose to avoid the toxic effects of irinotecan and oxaliplatin," they write.
The study was sponsored by F. Hoffmann-La Roche. Dr. Cunningham reports receiving research funding from F. Hoffmann-La Roche, Merck KgaA, Novartis, Celgene, Amgen, and AstraZeneca. Dr. Kubicka reports being a scientific advisor to and receiving honoraria from Merck, Amgen, sanofi-aventis, and Roche.
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