Expert comment on the National Surgical Adjuvant Breast and Bowel Project (NSABP) C-08 study at this year’s American Society of Clinical Oncology meeting in Orlando, USA, gave a thumbs-down to the possibility of Roche/Genentech's Avastin becoming a long-term adjuvant therapy given alongside and following chemotherapy to maintain patients with early colon cancer free of disease recurrence.

The C-08 study compared Avastin (bevacizumab) added to FOLFOX chemotherapy against FOLFOX alone for six months, with the combined arm also getting Avastin alone for a further six months in a randomised prospective trial of 2,672 patients with stage II or stage III colon cancer. Patients were then followed for three years. The objective of the trial was to prolong disease-free survival (DFS).

Presenting results, Professor Norman Wolmark of Allegheny General Hospital, Pittsburgh, PA, said the trial had failed but had failed “cum laude”. For the first year, while patients received Avastin there was a highly significant 40% difference in DFS compared to FOLFOX without Avastin or no therapy with wide separation of the curves. The trial initially favoured Avastin to such an extent it was almost halted. "But alas we had peaked at that stage and didn’t know it,” he said. Had the trial stopped at that point, the result would have been highly positive. However continuation for a further two years revealed the effects of Avastin were transient and lost significance completely by the end of three years.

The study did show that there was no harmful rebound effect of aggressive metastasis formation from stopping anti-vascular endothelial growth factor therapy as had been hypothesised might occur by some researchers. A further trial, AVANT, with 3,450 patients is still continuing comparing addition of Avastin to FOLFOX or XELOX compared to FOLFOX alone. “It is our sincere hope the AVANT trial will refute the results of C-08” he remarked. “Alas we think it will confirm them, showing a benefit for Avastin only as long as it is given.”

The implications of the C-08 findings were that Avastin use in the adjuvant setting should be considered for longer duration than one year, he suggested. “Clearly we have a great deal more to learn about how it is used.”

Commenting on the trial as discussant, Lee Ellis of MD Anderson Cancer Center said the early benefit of Avastin seen at one year was real and not “a statistical fluke” because it had a sound biological explanation. However the treatment had clearly not increased the cure rate by eradicating microscopic tumour deposits and there was no reason to believe it would do so with longer-term use, he said.

Even if Avastin was continued long-term, the incremental increase in benefit would be only 3% at three years. Benefits of longer duration of therapy had to be weighed against the substantially increased financial cost of treatment and inconvenience to patients of regular visits for intravenous infusions, he pointed out. Long-term use might have detrimental effects of pain and unwanted CNS and cardiovascular effects.

Dr Ellis added: “Cardiologists say it could worsen hypertension over time and although this can be managed it is changing the physiology of patients. In metastatic disease we are tolerant of inconvenience and side effects because patients’ backs are against the wall but in adjuvant settings patients and insurers are unlikely to put up with them for a relatively small benefit”.

In conclusion, he said no more trials of a potent drug like Avastin in the adjuvant setting should be conducted. Patients exposed to anti-VEGF therapy should be followed long term for cardiovascular events and tested for cognitive and CNS effects, he suggested. Alternative treatments such as targeting epidermal growth factor receptors were being investigated and should be considered.