Drug cocktail offers hope to metastatic melanoma patients

November 1, 2007

Patients with metastatic melanoma are treated palliatively, with the two most tic melanoma imperative goals of therapy being to extend their survival and improve quality of life. Breakthrough research has made this possible by a combination drug cocktail, giving much hope for terminally ill melanoma patients.

Key Points

Rochester, Minn. - A drug combination consisting of paclitaxel, carboplatin and bevacizumab can significantly increase life expectancy (progression-free survival) from six weeks to six months, a recent study shows.

Svetomir N. Markovic, M.D., Ph.D., associate professor of medicine and oncology of the departments of medicine and oncology at the Mayo Clinic and Foundation, Rochester, Minn., has done extensive research with drug therapies used in metastatic melanoma, achieving remarkable results.

"From our research with drug combinations, we saw that potentially targeting the blood vessel supply of the melanoma may be something worthwhile. Our strategy consisted of directly targeting the tumor with one drug (carboplatin) and targeting its vascular supply with another (low-dose paclitaxel and others). We found that the malignancies and malignant melanoma, in particular, tend to repair the damage induced by chemotherapy by promoting - in an autocrine fashion - a release of molecules that favor angiogenesis. It is herein where our strategic approach was born," Dr. Markovic tells Dermatology Times.

Dr. Markovic and his team conducted a single arm, phase 2 clinical trial in 53 patients with metastatic melanoma, in which each patient received a paclitaxel/carboplatin combination drug therapy. The carboplatin treated the melanoma and the paclitaxel inhibited the angiogenesis of the metastatic growths.

To this drug combination, Dr. Markovic added a third drug, bevacizumab, which would remove some of the VEGF (vascular endothelial growth factor) overproduction that was expected following PC chemotherapy.

Bevacizumab is an antibody to VEGF-A - one of the subspecies of vascular endothelial growth factor - that is massively overproduced when a malignant melanoma is exposed to chemotherapy, is highly expressed in patients with metastatic melanoma, and also surges in concentration after exposure to chemotherapy.

Dr. Markovic explains that the carboplatin produces a cytotoxic injury, which in turn, generates a massive overproduction of repair signals by the malignant melanocytes. The paclitaxel disrupts the growth of the neo-vasculature, blocking the responding arm of the angiogenesis and the consequence of the angiogenesis signals on the surrounding tissue around the tumor. The bevacizumab binds up the loose or free spillover of some of the VEGF that is produced. Only VEGF-A is removed, which is only one subset of all the molecules that promote angiogenesis and promote repair that get released in this fashion.

"I believe that it is the interplay of all three drugs here that produces the improved clinical results. We saw that patients that have had lower level VEGF-A in plasma as a result of the bevacizumab therapy seem to be the ones to have done better clinically, compared to those patients that have had higher spikes of VEGF-A following carboplatin chemotherapy. This suggests, of course, that perhaps the bevacizumab dose, which is very empiric, was sufficient to take care of part, but not all, of the released VEGF following chemotherapy," Dr. Markovic says.

Results

The median value in the progression-free survival of patients with advanced-stage melanoma went up from six weeks - which is what one sees and has historically seen for the last 40 years - to six months. Patients received paclitaxel at 80 mg/m2 on days one, eight and 15, carboplatin at six times the area under the curve - 6AUC on day one, and bevacizumab at 10 mg/m2 on days one and 15 of the same 28-day treatment cycle.

"This data is intriguing and exciting at the same time, because we have approached this from a standpoint of not studying melanoma in a petri dish in the absence of its surrounding environment. Instead, we took a clinical approach, trying to understand how the tumor interacts in vivo with its surrounding tissues, and trying to capitalize on the possible mechanisms that the tumor may use to protect itself from cytotoxic therapy. It may, in fact, be that melanoma is not resistant to chemotherapy, but it only repairs itself very efficiently from it," Dr. Markovic says.

The disruption of the VEGF pathway also effects anti-tumor immunity, as many of these mediators that favor tumor growth also dampen immune reactivity. Future research will likely concentrate on a chemotherapy-induced aggressive response, which is VEGF-mediated.