by ecancer reporter Clare Sansom

The prognosis for patients with colorectal cancer depends greatly on the stage at which it is diagnosed, with more than 60% of patients with lymph node involvement (Stage III cancer) but only about 5% of those with metastatic disease (Stage IV cancer) living for at least five years after diagnosis.

Bevacizumab, a monoclonal antibody that inhibits the vascular endothelial growth factor A (VEGF-A) and suppresses angiogenesis, has been licensed for the treatment of Stage IV colorectal cancer since 2004.

The potential efficacy of combining bevacizumab with standard chemotherapy as adjuvant treatment for stage II/III colorectal cancer has now been tested in Phase III clinical trials.

The first of these to report was the National Surgical Adjuvant Breast and Bowel Project.

(NSABP) C-08 trial in the US, which found no survival benefit in these patients but suggested that bevacizumab might show a transient effect for up to three months.

The results of the large AVANT trial of bevacizumab in this setting have just been published by an international team led by Aimery de Gramont of the Hôpital Saint Antoine, Paris, France.

A total of 3451 patients with Stage III or high-risk Stage II colon cancer were recruited into the AVANT trial, with the large majority of these (2867) diagnosed with Stage III disease.

All patients received a combination of drugs as adjuvant treatment 4-8 weeks after potentially curative surgery.

Patients were randomized equally into three arms, to receive either the standard combination chemotherapy regimen FOLFOX4; FOLFOX4 with the addition of bevacizumab; or the alternative chemotherapy regimen XELOX plus bevacizumab.

FOLFOX4 consists of the platinum based drug oxaliplatin combined with fluorouracil and leucovorin, and XELOX consists of oxaliplatin combined with capecitabine.

Patients were followed up for at least five years after randomization.

The primary endpoint for the trial was disease free survival, defined as the time between randomization and recurrence of the original tumour; identification of a new colorectal tumour; or death from any cause.

Secondary endpoints were overall survival and adverse events, with patients monitored for these throughout the observation phase; patients diagnosed with Stage II cancer were included in the adverse events analysis only.

By the cutoff date 237 (25%) of 955 patients in the FOLFOX4 arm; 280 (29%) of 960 receiving FOLFOX4 and bevacizumab; and 253 (27%) of 952 receiving bevacizumab with XELOX had relapsed, been diagnosed with a new colorectal cancer, or died.

This data gave hazard ratios for bevacizumab–FOLFOX4 versus FOLFOX4 of 1·17 (95% confidence interval 0·98–1·39; p=0·07) and for bevacizumab–XELOX versus FOLFOX4 of 1·07 (95% CI 0·90–1·28; p=0·44).

Recurrences of the original tumour occurred significantly more often than new tumours or deaths.

This data shows that more patients randomized to either of the two arms including bevacizumab had recurrent disease than those who received FOLFOX4 alone, although only the comparison between FOLFOX4-bevacuzimab and FOLFOX4 approached statistical significance.

In contrast, there were significantly fewer recurrences in the first year after randomization in either of the arms that included bevacizumab than there were in the FOLFOX4 arm, with hazard ratios of 0.63 for bevacizumab–FOLFOX4 and 0.61 for bevacizumab–XELOX.

At the final cutoff date for overall survival, 17% of patients in the FOLFOX4 arm, 21% of those receiving bevacizumab–FOLFOX4 and 19% of those receiving bevacizumab–XELOX had died.

It was not possible to define any subgroups of patients with apparent better or worse prognoses on any of the treatments studied based on demographic or clinical factors.

All treatments were relatively well tolerated, with the most common severe adverse effects in all three arms being neutropenia, diarrhea, peripheral neuropathy and hypertension; neutropenia was more common in patients receiving FOLFOX4, and diarrhea and hypertension in those receiving bevacizumab.

Taken together, the results of this trial support those of the C-08 trial and suggest that, despite some short-term benefit, bevacizumab does not prolong disease-free or overall survival when added to standard chemotherapy regimens in adjuvant treatment for curable colon cancer.

Therefore, De Gremont and his co-workers do not recommend the use of bevacizumab in this indication.

Reference

De Gramont, A., Van Cutsem, E., Schmoll, H.J. and 17 others (2012). Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncology 13: 1225–33. doi: 10.1016/S1470-2045(12)70509-0