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SAN FRANCISCO -- Twice as many patients with metastatic colorectal cancer remained alive after 5 years with a four-drug chemotherapy regimen plus bevacizumab (Avastin) versus three drugs and the angiogenesis inhibitor, investigators reported here.

The 5-year overall survival was 24.9% with leucovorin, fluorouracil (5-FU), irinotecan, oxaliplatin (FOLFOXIRI), and bevacizumab and 12.4% with leucovorin-fluorouracil-irinotecan (FOLFIRI)-bevacizumab. After a median follow-up of 4 years, overall survival was 29.8 months with FOLFOXIRI and 25.8 months with FOLFIRI.

Median progression-free survival (PFS) increased from 9.7 months with FOLFIRI to 12.3 months with the four-drug chemotherapy regimen, Chiara Cremolini, MD, of in Pisa, Italy, reported at the .

"FOLFOXIRI plus bevacizumab doubles the estimated 5-year overall survival rate as compared to FOLFIRI plus bevacizumab," Cremolini said during a press briefing that preceded the symposium. "FOLFOXIRI plus bevacizumab represents a valuable option for the upfront treatment of metastatic colorectal cancer."

The more intense regimen was associated with increased toxicity, which was manageable, she added. However, the regimen would not be suitable for patients older than 75 or those who are 70 to 75 and not in good health. The trial excluded patients who were 75 or older.

The results reflect the ongoing efforts to extend the survival gains achieved in metastatic colorectal cancer over the past decade. Though the disease still has a poor prognosis, survival has improved significantly with the advent of modern combination chemotherapy and the introduction of targeted therapy, such as bevacizumab.

The two most widely used first-line chemotherapy regimens for metastatic colorectal cancer are FOLFIRI and FOLFOX (leucovorin-fluorouracil-oxaliplatin). Giving bevacizumab in addition to the chemotherapy has been shown to improve survival compared with chemotherapy alone.

Whether increasing the intensity of chemotherapy would improve survival without undue toxicity remained unclear, Cremolini said. To examine the issue, investigators in the Italian Gruppo Oncologico Nord Ovest (GONO) conducted a randomized trial to compare FOLFIRI and FOLFOXIRI, each in combination with bevacizumab, in patients with previously untreated metastatic colorectal cancer.

Cremolini reported data for 508 patients who received a maximum of 12 cycles of induction treatment with randomized therapy, followed by bevacizumab plus 5-FU until disease progression. , the primary endpoint was PFS, and FOLFOXIRI demonstrated superiority over FOLFIRI.

The initial survival analysis after 2.5 years showed a trend toward improvement in the FOLFOXIRI arm but not a statistically significant advantage. The analysis also showed an increased incidence of grade 3/4 diarrhea, mucositis, neuropathy, and neutropenia with the four-drug regimen.

In the current study, after a median follow-up of 48.1 months, the PFS advantage conferred by FOLFOXIRI remained (12.3 versus 9.7 months, P=0.006). Additionally, the 4-month difference in overall survival achieved statistical significance (HR 0.80, 95% CI 0.65-0.98, P=0.030). The advantage held up in a subgroup analysis, and a multivariate analysis showed an even larger survival benefit in favor of FOLFOXIRI (HR 0.77, 95% CI 0.61-0.96, P=0.020).

"This study clearly demonstrates that FOLFOXIRI plus bevacizumab is a safe and effective option for patients with advanced colorectal cancer who can tolerate the regimen," said press briefing moderator , of University Hospitals-Case Medical Center in Cleveland. "We have to consider that 90% of the patients in this study were asymptomatic at the time of enrollment, and patients over the age of 75 were not eligible. The regimen is not for everyone, but for the right patients, this is one of the most active regimens, with an impressive almost 25% difference survival rate at 5 years."

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