TNF-alpha use for metastatic melanoma

Vancouver, British Columbia - Multiple in-transit metastases develop in some 5 percent to 8 percent of melanoma patients. Although a small number of lesions can usually be removed by surgical excision, when there are multiple lesions, surgery is no longer an option.

In the past, isolated limb perfusion with chemotherapy alone has proven to be uniformly unsuccessful in dealing with large metastatic tumors.

Also, use of mild hyperthermia at 38 degrees to 39 degrees for isolated limb perfusion produces an 80 percent to 90 percent overall response rate, with a generally better response in distal lesions than in those above the knee. Further temperature elevation to about 41 degrees may somewhat improve response but also intensifies regional toxicity to a degree that this increased hyperthermia is not recommended.

As an alternative to standard treatment protocols, physicians should consider vaccine protocols. Speaking at the sixth World Congress on Melanoma, Alexander Eggermont, M.D., Ph.D., says the introduction of tumor necrosis factor alpha (TNF-alpha) has completely changed therapeutic possibilities.

Dr. Eggermont, professor of surgical oncology at Erasmus University Medical Center in Rotterdam, the Netherlands, says, "In combination with chemotherapy, very good responses can now be obtained in the treatment of soft tissue sarcomas or bulky melanoma lesions."

"The problem is," he concedes, "Response rates with vaccination protocols are very low."

A major problem with vaccine protocols is that response rates are below 5 percent and that patients usually end up with recurrences that require treatment with isolated limb perfusion. However, when vaccines are effective, the response is systemic.

Cases in point

Dr. Eggermont describes one female patient who underwent isolated limb perfusion with TNF-alpha and melphalan.

An iliac isolated limb perfusion was performed with a tourniquet positioned in the groin. The woman responded with 99 percent necrosis of the tumor bulk, which was then successfully resected.

Another woman - with some 50 in-transit metastases - who was given the vaccine protocol was "one of the few" who did experience a complete response that lasted for 18 months. Then she had recurrences in the leg and in the pelvis. Also, the woman previously had enlarged mediastinal lymph nodes. The lymph nodes were subsequently resected and she had a complete response to isolated limb perfusion treatment of the new lesions.

Administering TNF-alpha

Systemic administration of TNF-alpha can only be given at ineffective doses that mediate important systemic toxicity. But it can be used safely and effectively in the isolated limb perfusion setting at greater than 100-fold concentrations, without systemic toxicity.

Dr. Eggermont notes TNF-alpha's antivascular or vascular toxic effects selectively increase drug uptake in the tumor when administered in combination with a chemotherapeutic agent such as melphalan. This is followed by tumor-selective eradication of the tumor vasculature, which further contributes to the antitumor efficacy.

Dr. Eggermont describes his own study - undertaken cooperatively with colleagues in Rotterdam - of 100 consecutive TNF-alpha perfusions in melanoma patients. Overall complete response was about 70 percent, partial response occurred in 25 percent, and there was no change in 5 percent of the patients.

Complete response was obtained in 82 percent of the patients with in-transit metastatic stage III-A disease, in 63 percent of those with stage III-AB disease who also had lymph node disease and in 43 percent who had extremely bulky disease plus metastatic disease at distant sites. In this last category, treatment was offered more as palliation for the last six to nine months of life.

Local progression occurred in 55 percent of responders at a median of 16 months and in complete responders at a median of 22 months. Overall the median time to systemic disease progression was 14 months, with 71 percent going on to develop stage IV disease. The overall survival rate at five years was 32 percent.

Indications for vaccine treatment

Dr. Eggermont suggests that indications for using TNF-alpha in melanoma are those cases of bulky disease and in patients who have failed prior melphalan-only treatment perfusions.