Medical treatment for advanced melanoma

Clay M. Anderson, M.D.

Malignant melanoma is a significant clinical problem in the United States. In 1997, there were approximately 40,000 new cases of melanoma and nearly 8,000 deaths.¹ While 80 percent of those diagnosed will be cured by surgery, 20 percent will die from metastatic disease.

Medical therapy to treat resected regional disease or distant metastases has been disappointing. Now, however, more promising clinical results, described here, are being recorded for both adjuvant therapy and therapy for stage IV disease.

Adjuvant therapy
Patients who present with intermediate thickness or deep primary melanomas, or resectable nodal disease at the outset, risk recurrence after surgery from 20 percent to 80 percent. Once the disease recurs, these patients likely will die.

Various adjuvant strategies have been attempted after surgery in these at-risk populations. These randomized studies include chemotherapy, immunotherapy, chemotherapy/immunotherapy combinations and high-dose chemotherapy with bone marrow transplantation.² Until recently, no approach produced significant benefits compared to observation.

In 1995, results of several randomized studies were reported comparing interferon-a (IFN-aÑ a cytokine that is a potent immuno stimulant and can kill cancer cells directly) with observation only.^3-6 All four trials showed a trend toward improved disease-free and overall survival in the IFN-a arm. The most significant benefit was seen from the ECOG 1684 trial, which used high-dose IFN-a for one year in patients with nodal involvement or primaries greater than 4 mm thick.⁵ This trial formed the basis for FDA approval of IFN-a in 1996, showing a 10 percent absolute improvement in overall survival at five years with IFN-a compared to observation. Investigators now are pursuing newer vaccine strategies and shorter, more intense ÒbiochemotherapyÓ approaches.

Therapy for stage IV disease

Chemotherapy
Metastatic melanoma usually resists chemotherapy drugs. In the stage IV setting, the only FDA-approved therapy is single agent dacarbazine, or DTIC, which is an alkylator drug also active in sarcomas and Hodgkin's disease. DTIC has never proved to prolong survival compared to supportive care. Other chemotherapy drugs shown equally low clinical activity against melanoma. Response rates range from 10 percent to 20 percent, with few complete responses. Combinations of active drugs consistently produce higher responses in phase II studies but not in phase III studies.⁷

The two most popular combination regimens are CVD (cisplatin, vinblastine and dacarbazine) and the Dartmouth regimen (cisplatin, carmustine, dacarbazine and tamoxifen), both of which are fairly well-tolerated and show impressive response rates in phase II studies. Newer cytotoxic agents also are being investigated alone or in combination with older drugs.

Biologic therapy
Because of cytotoxic drugs' lack of activity against melanoma and the interesting early observations of a host antitumor response in some melanoma patients, biologic therapy, or immunotherapy, has been actively investigated for decades.

Two cytokines Ñ interleukin-2 (IL-2) and IFN-a have produced durable remissions in stage IV melanoma. Recently approved by the FDA for treatment of stage IV melanoma, IL-2 is a potent stimulator of lymphokine-activated killing activity in NK cells and T cells. While significantly toxic at higher doses, IL-2 can lead to durable remissions in almost 10 percent of stage IV patients.⁸ The addition of stimulated, expanded immune cells to IL-2 has not improved clinical results.

IFN-a produces responses in the range of 15 percent of stage IV melanoma patients, but only 2 percent to 5 percent are complete or durable.⁹ IFN-a potentiates the effects of IL-2 and certain chemotherapy drugs.

Biochemotherapy
During the 1980s, investigators began to combine IFN-a or IL-2 with select chemotherapy drugs to explore synergistic clinical activity against melanoma. Until recently, these approaches seemed to increase toxicity without significantly improving response rates or survival.

A combination of DTIC and IFN-a or IL-2 has been shown to be no better than DTIC alone.⁷ The Cisplatin and IL-2 combination seems to be more clinically active than moderate-dose IL-2 alone, but no randomized studies have been conducted.⁷

More recently, several centers have reported the combination of cisplatin-based chemotherapy with IL-2 and IFN-a. They report response rates of up to 70 percent and complete response (CR) rates of 10 percent to 20 percent, with most CRs being durable.⁷ Although encouraging, this form of therapy is more toxic than other regimens. Results of ongoing randomized studies are anticipated.

Other treatments

Vaccines
Much like cytokine therapy, vaccine therapy for stage IV melanoma has had a fairly long track record but with less documented success. Newer vaccines are replacing the older autologous or allogenic whole-cell vaccines of the 1970s and 1980s.

Gene therapy
With the identification of genes for important melaonma antigens and cytokines, the stage is set for applying gene therapy techniques against this disease. Researchers are transfecting immune cells and tumor cells with cytokine genes or melanoma antigen genes for therapeutic use. Results are pending.

Conclusion
While historical results for systemic therapy in advanced melanoma are disappointing, reason for optimisim exists.

First, new agents, which may have unique activity, are emerging rapidly. These drugs likely will play a role in combination with other proven agents. Second, newer cytokines just now are emerging from phase I and phase II trials and have yet to be tested in combination with chemotherapy drugs. Third, we anxiously await the results of randomized studies of biochemotherapy vs. combination chemotherapy as well as the findings of basic research into the determinants of melanoma cells' resistance to cytotoxic drugs and specific immunity.

IFN-a is a new standard for adjuvant therapy. No standard of care exists for the treatment of stage IV disease. Clinicians should refer patients for participation in clinical trials at centers with expertise in the medical management of melanoma.

References

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