Systemic Therapy Of Malignant Melanoma

Jaswant G. Jadeja, M.D.
Jaswant G. Jadeja, M.D. is a medical oncologist in private practice.

The incidence of malignant melanoma in the United States has been increasing steadily since the 1930s. The lifetime risk of an American developing invasive melanoma is estimated at one in eighty seven. While the majority (85%) of these patients present with localized disease (AJCC Stage I or II), approximately 2% have distant metastases. Patients with thick lesions and lymph node metastases are at a high risk of developing distant metastases. Surgical excision of an isolated metastatic lesion can result in a long-term survival.

Surgically unresectable metastatic melanoma presents a challenging problem. The prognosis for patients with distant metastases is poor. Although a small proportion of patients can attain long term survival with systemic therapy, the median survival ranges from 6 to 12 months. Metastatic melanoma in certain sites is associated with a more favorable prognosis. For example, patients with metastases to the skin, subcutaneous tissues, or the lungs have a median survival of 12 to 15 months. Whereas patients with liver, bone or brain metastases have a median survival of 3 to 4 months.^1,2

The treatment for a patient with metastatic melanoma depends on multiple factors including the patient's age and performance status, time interval between primary and metastatic disease, and the patient's wishes. Options include chemotherapy, biotherapy and the vaccines. The goal of these treatments is to palliate the symptoms. There is no clear evidence that treatment of metastatic melanoma has a significant impact on prolonging the survival.

Chemotherapy

Single Agents

Several chemotherapeutic agents have modest activity in melanoma as outlined in Table 1. However none of them have shown a response rate greater than 25% and most responses are of a short duration.

DTIC (dacarbazine) is the single most active agent in melanoma with a response rate of 15% to 20%. Complete remissions (CRs) are infrequent. The median duration of response approaches 1 year. Long term CRs are seen in 1% to 2% of the patients. Subcutaneous, lymph node and pulmonary lesions are most likely to respond to DTIC. This drug is frequently administered in 3, 5, or 10 day regimens. Like most chemotherapy agents, DTIC is given intravenously. It is generally well tolerated. Side effects include nausea, emesis, and bone marrow suppression. Rarely photosensitivity and hepatocellular dysfunction have been reported. 

Nitrosoureas (BCNU, CCNU) are also active with response rates of 10% to 20%. These agents are lipid soluble and can cross the blood brain barrier. The median duration of response is 3 to 6 months. BCNU is administered intravenously whereas CCNU is given orally. Since nitrosoureas can cause prolonged bone marrow suppression, they are administered every six weeks or so. Gastrointestinal toxicity is mild to moderate.

Vinca alkaloids (vindesine, vinblastine) produce a response rate of 10% to 15%.The toxicity includes peripheral neuropathy and bone marrow suppression. Gastrointestinal side effects are mild.

Cisplatin (DDP) is a heavy metal compound with a response rate of 15% to 20% in melanoma. The median duration of response is 4 to 6 months. Side effects include nephrotoxicity, neurotoxicity, and bone marrow suppression.

Taxanes (paclitaxel, docetaxel) are a new class of antitumor agents derived from the western yew shrub Taxus brevifolia. Their primary mode of action is to stabilize the polymerization of microtubules. Taxanes produce a response rate of 15% to 19%. The side effects include hypersensitivity reactions, mucositis, peripheral neuropathy, and bone marrow suppression.

Investigational Agents

Several new agents are being investigated in melanoma. Fotemustine and temozolamide have shown significant activity and betulinic acid also appears to be promising.

Fotemustine (2 chloroethyl nitrosourea) is a new nitrosourea which is now commercially available in Europe. Of 184 patients treated in phase II studies, 40 responded including 4 CRs.^3,4 Eleven of the responses were in brain metastasis. Preclinical trials have shown that fotemustine rapidly crosses the blood brain barrier.⁵

Temozolomide is an analog of DTIC. It is an oral prodrug of monomethyl 5 triazemoimidazole carboxamide (MTIC), which is the active form of DTIC. The absorption of temozolomide from the gastrointestinal tract is 100%. Preclinical trials have shown that temozolamide crosses into the central nervous system. Results from recent phase II studies showed overall response rate of 21% with 5% CRs. Most of the responses were in lung metastases. Responses in brain metastases have been reported.⁶

Betulinic acid is extracted from the stem bark of white birch trees. It has a cytotoxic effect on melanoma cell lines. The mechanism of cytotoxicity is the accumulation of cells in the G0/G1 interface of the cell cycle followed by the induction of apoptosis. Animal studies have confirmed the in vivo effectiveness of this agent with no toxicity.⁷

Biologic Agents

The recombinant cytokines, interferon alpha and interleukin-2, have been studied extensively in melanoma. CRs are seen in approximately 5% of the cases. In contrast to CRs achieved with chemotherapy, about half of the CRs achieved with biologic agents are durable and last for several years. Furthermore, durable CRs have been observed in visceral sites other than the lungs.

Interferon Alpha (IFN) is a glycoprotein that performs immunoregulatory, antiviral, and antineoplastic functions. In melanoma the response rate is approximately 10% to 15%.^8,9 Responses can be observed as late as 6 months after initiating the therapy. The effective dose is 10 MU/m2 to 20MU/m2 given intravenously or subcutaneously three times a week. The side effects are discussed elsewhere in this issue.

Interleukin-2 (IL-2) is a lymphokine which is involved in T-cell proliferation, induction of lymphokine activated killer (LAK) cells, and enhancement of natural killer (NK) cell cytotoxicity. Experimental studies in animal models showed that high-dose IL-2 can induce tumor regression. This led to human trials. The overall response rate of 10% to 20% has been observed in metastatic melanoma.¹⁰ About 10% of the responding patients live beyond 5 years. These encouraging results led to the FDA's approval of IL-2 for treatment of metastatic melanoma. The effective dose range is 9MU/m2 to 20 MU/m2 per day for 4 days. It is usually administered by intravenous or subcutaneous route. The use of IL-2 has been limited by toxicity which can mimic bacterial sepsis. Side effects include hypotension, fluid retention, capillary leak syndrome, and catheter-related sepsis. Patients often need to be monitered in the hospital while receiving this therapy. Treatment related mortality has been observed in 1% of the patients, usually secondary to myocardial infarction or catheter related sepsis.

Combination Chemotherapy

Several chemotherapy combinations have been reported to have higher response rates than single agent therapy (Table 2), but these regimens have not shown a significant survival advantage. Combinations such as BHD (BCNU, hydroxyurea, DTIC) and BOLD (bleomycin, vincristine, CCNU, DTIC) were initially reported to have high response rates but there was no survival advantage. The two most commonly used regimens are CBDT (cisplatin, BCNU, DTIC, tamoxifen) and CVD (cisplatin, vinblastine, DTIC).

Del Prete, et al reported their experience with CBDT in 1983.¹¹ Of the 20 patients, 4 achieved complete remission and 7 had partial remission with a total response rate of 55%. Since then several investigators have used this regimen with responses ranging from 19% to 55%. The median duration of response is 6 to 12 months. Legha et al¹² replaced BCNU with vinblastine in their CVD combination to avoid prolonged bone marrow suppression. Their response rate was 40%. There was no significant improvement in the median survival.

The role of tamoxifen (TAM) in the treatment of melanoma is unclear. Single agent TAM is of limited benefit. Several randomized clinical trials have been conducted to assess the therapeutic benefit of TAM in combination chemotherapy regimens. Of the 5 studies that have been reported, one showed an improvement in the response rate and survival with DTIC and TAM versus DTIC alone.¹³ The benefit was observed only in female patients. All other studies have failed to show any benefit of adding TAM to chemotherapy.

Combination Chemo-biotherapy

Several recent studies have examined the value of adding IFN and/or IL-2 to chemotherapy. In most studies, combining IFN and DTIC has not resulted in improved results. The Eastern Cooperative Oncology Group (ECOG) recently completed a four-arm phase-III trial in which patients were randomized to DTIC, DTIC+TAM, DTIC+IFN, or DTIC+TAM+IFN.¹⁴ IFN added significant toxicity (18% incidence of life-threatening toxicity) but failed to enhance the response rate or the survival in these patients. Similarly, combining IFN to CVD or CBDT has produced disappointing results.

The combination of chemotherapy with IL-2 and IFN has been evaluated by many investigators ( Table 3). Richards et al reported a response rate of 55% using CBDT, IFN, and IL-2.¹⁵ Another study by Khayat et al in France showed a response rate of 52% using DDP, IFN, and IL-2.¹⁶ At the University of Texas, M.D. Anderson Cancer Center, Legha et al combined CVD, IFN, and IL-2 in various schedules.¹⁷ Using a sequential schedule of chemotherapy preceding biotherapy, a response rate of 60% was reported. In a prospective randomized trial of DDP, DTIC, TAM with or without IL-2 and IFN, Rosenberg et al¹⁸ concluded that addition of immunotherapy to chemotherapy increased toxicity but did not improve survival.

Vaccines have been used successfully in the prevention and treatment of many infectious diseases. In the last two decades there has been a concerted effort to develop cancer vaccines. Unlike IFN and IL-2 which stimulate the immune system in a nonspecific fashion, the goal of cancer vaccine therapy is to stimulate the host immune system to destroy cancer cells by targeting specific antigens found in those cells (active specific immunotherapy). Melanoma is a suitable tumor for this novel approach for several reasons.

1. Melanoma is an immunogenic tumor. Laboratory studies have shown that blood from melanoma patients contain antibodies against tumor antigens^19,20 as well as cytotoxic T cells that can destroy tumor cells in vitro.^21,22
2. Melanoma commonly metastasizes to superficial sites, so the tumor can be easily removed surgically.
3. Melanoma cells are easy to extract from tumors to grow in vitro.
4. Melanoma is resistant to traditional therapies and investigational vaccines can be considered early in the course of the disease.

Melanoma vaccines range from complex antigen mixtures (polyvalent) to purified single antigens (univalent). Polyvalent vaccines, made from whole melanoma cells or cell lysates, are more immunogenic and produce a broad range of protective responses. They are also less vulnerable to antigen modulation. Many trials using melanoma vaccines have shown improvement in survival when compared to historical controls. However, these trials are subject to selection bias. Morton et al²³ used whole cell vaccine (CancerVax®) in the adjuvant setting and showed an improvement in disease-free and overall survival compared with the historical control group. Similarly, Mitchell et al²⁴ used melanoma cell lysates (Melacine®) in 80 stage III and IV patients in whom the tumors were completely resected. The overall survival at 2 years was 80%. Other trials using similar vaccines have not shown any benefit. Melanoma vaccines have been used in stage IV disease as well. Using CancerVax, Morton et al²⁵ achieved a 15% response rate. Vaccine induced regression occurred in patients with lesions less than 2 cm in diameter. They also reported decrease in the incidence of brain metastasis in patients receiving CancerVax (22% versus 49% in the historical control group). The median survival was 23 months (compared to 8 months in the historical controls), with 5 year survival rate of 25% (compared to less than 10% in the historical controls). The survival benefit was highest among patients who had undergone complete resection of the metastatic disease. In a randomized phase III trial,²⁶ 140 patients with stage IV melanoma received either CBDT chemotherapy or Melacine vaccine. The objective response rate was higher in the chemotherapy arm (28% versus 6%), but there was no significant difference in survival (12 months versus 11 months respectively).

Univalent vaccines are less immunogenic and more vulnerable to antigenic modulation. Such vaccines consist of gangliosides, proteins, anti-idiotypic antibodies or peptides. Livingston et al²⁷ conducted a double blind trial in stage III melanoma. Patients received either the GM2 ganglioside mixed with BCG or BCG alone. Of the 58 patients in the GM2/BCG arm, 50 developed GM2 IgM antibodies compared to 7 of 64 in BCG arm. The patients with anti-GM2 antibodies had a better disease-free (p=.04) and overall survival (p=.02) than the antibody-negative patients. The efficacy of the GM2/BCG vaccine in comparison to high-dose IFN is under evaluation in an ongoing ECOG trial.

Genetically modified cell line vaccines are in clinical trials. The role of vaccine therapy in melanoma will continue to evolve as we gain more knowledge of tumor immunology and molecular biology. Vaccines are particularly attractive because of their low toxicity profile.

The treatment options for metastatic melanoma include surgical resection, single agent chemotherapy, combination chemotherapy, biologic agents and vaccine therapy. Although a few long-term survivals have been reported with each of these options, most patients have a poor outcome. Hence patients should be encouraged to participate in clinical trials.

Surgical resection of isolated metastatic lesions can infrequently result in long term disease-free survival. The limitation of surgery is that most patients eventually develop metastasis at other sites. A careful selection of patients is therefore very important. The patients most likely to benefit from surgery are those with solitary lesions, good performance status and a long disease-free interval between the primary and secondary lesions. It has been suggested that prior to surgery patients should be observed for 3 to 4 months. This will provide relevant information about the rate of tumor growth. Additionally, if there are subclinical metastatic lesions, they may become evident in this time period and surgery can be avoided in these patients. An alternative approach is to treat a potential surgical candidate with systemic therapy first. If a CR is not obtained and the patient has no other metastatic lesions after 3 to 4 months, surgical resection can be performed at that time.

Patients with unresectable metastatic lesions and good performance status can be treated with chemotherapy, biotherapy or the combination of both. Selection of these options will depend on the experience and preference of the treating physician. Patients with poor performance status and those unwilling to undergo systemic treatment may be appropriate candidates for hospice care.

We have yet to identify a treatment that clearly improves the survival rate of patients with metastatic melanoma. Patients should be encouraged to participate in clinical trials which continue to explore different avenues to improve the outcome of these patients. If an investigational study is not available, a trial of systemic chemotherapy and/or biotherapy is reasonable since durable albeit infrequent remmissions have been reported.

REFERENCES

1. Balch CM, Soong J-J, Murad TM. A multifactorial analysis of melanoma: IV. Prognostic factors in 200 melanoma patients with distant metastasis (Stage III). J Clin Oncol. 1983; 1:126.
2. Barth A, Wanek LA, Morton DL. Prognostic factors in 1521 melanoma patients with distant metastasis. J Am Coll Surg. 1995; 181:193-201.
3. Jacquillat C, Khayat D, Banzet P, et al. Final report of the French multicenter Phase II study of the nitrosourea fotemustine in 153 evaluable patients with disseminated malignant melanoma including patients with cerebral metastasis. Cancer. 1990; 66:1873-1878.
4. Falkson CI, Falkson G, Falkson HC. Phase II trial of fotemustine in patients with metastatic malignant melanoma. Invest New Drugs. 1994; 12:251-254.
5. Khayat D, Avril M, Auclerc G, et al. Clinical value of the nitrosourea fotemustine in disseminated malignant melanoma: Overview of 1022 patients including 144 patients with cerebral metastasis. Proc Am Soc Clin Oncol. 1993; 12;1343.
6. Bleechen NM, Newlands SM, Thatcher LN, et al. Cancer research campaign Phase II trial of temozolomide in metastatic melanoma. J Clin Oncol.1995; 13:910-913.
7. Pisha E, Chai H,Lee IS, et al. Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction on apoptosis. Nature Med.1995; 1046-1051.
8. Hersey P, Hasic E, MacDonald M, et al. Effects of recombinant leucocyte interferon ( rIFN-alpha A ) on tumor growth and immune responses in patients with metastatic melanoma. Br J Cancer. 1985; 51:815-826.
9. Legha SS, Papadopoulas NE, Plager C, et al. Clinical evaluation of recombinant interferon alpha-2a (Roferon A) in metastatic melanoma using two different schedules [ published erratum appears in J Clin Oncol. 1987; 5:1868 ]. J Clin Oncol. 1987; 5:1240-1246.
10. Atkins MB, Lotze M, Wiernik P, et al: High-dose IL-2 therapy alone results in long-term durable complete responses in patients with metastatic melanoma ( abstract ). Proc Am Soc Clin Oncol. 1997; 16:494.
11. DelPrete SA, Maurer LH, O'Donnell J, et al. Combination chemotherapy with cisplatin, carmustine, dacarbazine and tamoxifen in metastatic melanoma. Cancer Treat Rep. 1983; 12:1343.
12. Legha SS, Ring S, Papadopoulas NE,et al. A prospective evaluation of a triple drug regimen containing cisplatin, vinblastine, and dacarbazine (CVD) in metastatic melanoma. Cancer. 1989; 64: 2024 _ 2029.
13. Cocconi G, Bella M, et al. Treatment of metastatic malignant melanoma with dacarbazine plus tamoxifen. N Eng J Med. 1992; 327:516-523.
14. Falkson CI, Ibrahim J, Kirkwood J, et al. A randomized phase III trial of dacarbazine (DTIC) versus DTIC + interferon alfa-2b (IFN ), versus DTIC + tamoxifen (TMX) versus DTIC + IFN + TMX in metastatic melanoma. An ECOG Trial. Proc Am Soc Clin Oncol. 1996; 15:A1350.
15. Richards JM, Gilewski TA, Ramming K, et al. Effective chemotherapy for melanoma after treatment with interleukin-2. Cancer. 1992; 69:427-429.
16. Khayat D, Borel C, Tourani JM, et al. Sequential chemoimmunotherapy with cisplatin, interleukin-2, and interferon alfa-2a for metastatic melanoma. J Clin Oncol. 1993; 11:2173-2180.
17. Legha S. Durable complete responses in metastatic melanoma treated with interleukin-2 in combination with interferon alfa and chemotherapy. Sem Oncol. 1997; 24(1): Suppl 4: S4-39- S4_43.
18. Rosenberg SA, Yang JC, Schwartzentruber DJ, et al. Prospective randomized trial of the treatment of patients with metastatic melanoma using chemotherapy with Cisplatin, dacarbazine, and tamoxifen alone or in combination with interleukin-2 and interferon alfa-2b. J Clin Oncol. 1999; 17:968-975.
19. Morton DL, Malmgren RA, et al. Demonstration of antibodies against malignant melanoma by immunoflorescence. Surgery. 1968; 64:233-240.
20. Morton DL, Eilber FR, Malmgren RA, et al. Immulogical factors which influence responses to immunotherapy in malignant melanoma. Surgery. 1970; 158-164.
21. Mukerji B, Chakroboity NG, Sivanadham M, et al. T-cell clones that react against autologous human tumors. Immunol Rev. 1990; 116:33-62.
22. Kan-Mitchell J, Huang XQ, Steinman L, et al. Clonal analysis of in vivo activated CD8 and cytotoxic T lymphocytes from a melanoma patient responsive to active specific immunotherapy. Cancer Immunol Immunother. 1993; 37:15-25.
23. Morton DL, Barth A. Vaccine therapy for malignant melanoma. Ca Cancer J Clin. 1996; 46:225-244.
24. Mitchell MS, Spear L, Dean G, et al. Effects of a melanoma lysate vaccine on survival in minimal residual melanoma [abstract 1331]. Proc Annu Meet Am Assoc Cancer Res. 1995; 36:223.
25. Morton DL, Nizze A, Hoon D, et al. Improved survival of advanced stage IV melanoma following active immunotherapy : Correlation with immune response to melanoma vaccine. Proc Annu Meet Am Soc Clin Oncol. 1993; 12:391.
26. Mitchell MS, Rechtman DJ, Von Eschen KB. A randomized phase III trial of Melacin versus combination chemotherapy in patients with disseminated melanoma. Can J Inf Dis. 1995; 6 (Suppl C):347c.
27. Livingston PO, Wong GYC, Adluris S, et al. Improved survival in stage III melanoma patients with GM2 antibodies: A randomized trial of adjuvant vaccination with GM2 ganglioside. J Clin Oncol. 1994; 12:1036-1044.