New Approaches in the Treatment of Metastatic Melanoma: Thalidomide and Temozolomide

Introduction

The survival of patients with metastatic melanoma varies widely, ranging from only a few months to more than 10 years. Survival is primarily dependent on the sites of the first metastases, the number of metastatic sites, and responsiveness to treatment.[1] Melanoma can metastasize to virtually any organ or tissue. However, the initial sites of metastases are most commonly the skin, soft tissue, lymph nodes, and lung. The liver, bone, and brain are also common, though less frequent, sites of initial relapse. Patients with nonvisceral disease (ie, skin, lymph nodes, and lung metastases) have a better median survival, ranging from 12 to 15 months, and are more likely to respond to systemic therapy.[1,2] Patients with visceral disease (ie, liver, bone, and brain metastases) have a median survival of only 3 to 4 months, and few respond to treatment. In general, cure is not a realistic goal of treatment at this stage of the disease. Therefore, treatment strategies must endeavor to preserve quality of life while attempting to prolong life.

Systemic Therapy

The primary treatment for patients with metastatic melanoma is systemic therapy, in which response is associated with prolonged survival. Systemic therapy includes single- and multiagent chemotherapy, immunotherapy, and biochemotherapy. Melanoma is a relatively chemoresistant disease. The few drugs that have antitumor activity in melanoma have not surpassed the 10% to 20% response rates of dacarbazine(Drug information on dacarbazine) (DTIC-Dome). Many combination chemotherapy regimens have been reported to have higher response rates and to be more effective for visceral metastases. However, most of the combination regimens are associated with increased toxicity, with little evidence of improved survival when compared to dacarbazine alone in phase III trials.[3] Even the addition of high-dose tamoxifen(Drug information on tamoxifen) (Nolvadex) to a combination regimen of cisplatin(Drug information on cisplatin) (Platinol)/carmustine (BCNU)/dacarbazine (the Dartmouth regimen) did not improve the response rate or survival in a phase III study.[4]

The administration of biological agents, such as interferon alfa and interleukin-2, has been shown to produce 10% to 15% responses in advanced melanoma with occasional durable complete response. Good-prognosis groups are similar to those for chemotherapy, and include patients with good performance status, and metastatic disease in soft tissue, skin, and lymph nodes. Biochemotherapy or chemoimmunotherapy—that is, the combination of chemotherapy and biological agents—is another treatment strategy intended to improve the antitumor effect of systemic therapy. The results of several phase II studies have demonstrated high response rates and durable responses.

Recently, a randomized phase III study comparing a chemotherapy regimen (composed of cisplatin, dacarbazine, and tamoxifen) with the same chemotherapy plus high-dose interleukin-2 and interferon alfa was reported by the surgery branch at the National Cancer Institute.[5] The response rate was 27% (4 out of 52 complete responses) for chemotherapy-treated patients and 44% (3 out of 50 complete responses) for biochemotherapy-treated patients. However, the tendency toward an increased response rate in patients who received biochemotherapy did not translate into an increase in overall survival, and there was, in fact, a trend for a survival advantage in patients receiving chemotherapy alone (median survival: 10.7 vs 15.8 months). Because of the severe toxicity associated with the biological agents, biochemotherapy is contraindicated in elderly patients, or patients with central nervous system (CNS) metastases, known cardiac disease, or symptomatic pulmonary disease.

Clearly, dacarbazine remains the most active drug and is the standard chemotherapy for metastatic melanoma. However, response is seen primarily in the skin, soft tissue, lymph nodes, and lung. It is estimated that up to 70% of patients who die of metastatic melanoma have either known or subclinical brain metastases. Like many other chemotherapy agents, dacarbazine does not penetrate the blood-brain barrier; thus it is inactive against CNS metastases. Furthermore, disease relapse in the CNS is often a major problem in patients responding to chemotherapy.

Improving Current Management

Efforts to improve management of metastatic melanoma should focus on the development of new antitumor agents and novel combination regimens. Desirable characteristics of new treatment strategies include improved response in visceral metastases, penetration of the blood-brain barrier with activity in brain metastases, improved survival, and preservation of quality of life in the form of reduced toxicity, improved tolerability, and ease of administration.

Temozolomide

Temozolomide, which was recently approved for the treatment of refractory anaplastic astrocytoma, is an oral alternative to dacarbazine. The agent exhibits approximately 100% oral bioavailability, penetrates the blood-brain barrier, and has activity against brain tumors. The clinical activity of temozolomide(Drug information on temozolomide) against melanoma was confirmed in a large randomized study, when patients were treated with a 5-day schedule of either dacarbazine or temozolomide.[6] More interestingly, patients who responded to temozolomide had a four times lower incidence of melanoma relapse in the brain than did patients who responded to dacarbazine.[7] As has been reported by Brock et al,[8] when temozolomide is administered at an extended continuous schedule over a 7-week period, it permits a 2.1-fold greater drug exposure over 4 weeks, in comparison with the 5-day schedule repeated every 28 days.

In this phase I study, responses were observed in two of four patients with metastatic melanoma: a partial response in a patient with pulmonary metastases and a mixed response in a patient with CNS metastases. The improved clinical activity is postulated to be related to the cumulative depletion of O⁶-alkylguanine-DNA-alkyl-transferase, a DNA repair protein involved in dacarbazine drug resistance of melanoma. It is anticipated that temozolomide will replace dacarbazine as first-line treatment for disseminated melanoma because of its ease of oral administration, improved clinical activity, and ability to achieve adequate CNS penetration.

Thalidomide

Thalidomide has been shown to exert antiangiogenic effects, including inhibition of angiogenesis induced by basic fibroblast growth factor in the rabbit corneal micropocket assay.[9,10] Thalidomide(Drug information on thalidomide) has a number of other biological activities that may contribute to its role as an effective agent in treating melanoma; these include alteration of adhesion molecule expression, suppression of tumor necrosis factor-alpha, increased production of interleukin-10, and enhancement of cell-mediated immunity via direct costimulation of T cells resulting in increased interferon gamma(Drug information on interferon gamma) and interleukin-12 production.[11-15]

Combined Antiangiogenic and Cytotoxic Chemotherapy

Prospects for new combination regimens have been heightened by the recent discovery of vasculogenic mimicry in aggressive human uveal and cutaneous melanomas.[16] In particular, it has been shown that both primary and metastatic melanomas can form tumor-cell-lined vascular channels, and that this activity is correlated with tumor aggressiveness and clinical outcomes. These findings suggest that the therapy directed against both endothelial- and tumor-cell compartments of a tumor is more effective than therapy against tumor cells only. Thus, combining standard chemotherapy with an antiangiogenic agent has the potential to improve its antitumor effect for this chemoresistant malignancy.

We initially used thalidomide on a compassionate-use basis in select patients with disease progression who had received standard chemotherapy or immunotherapy. One case was that of a 60-year-old woman who developed multiple in-transit metastases in the leg and metastases in the inguinal lymph nodes 37 years after a primary melanoma was removed from her ankle. She was treated initially with inguinal lymphadenectomy and isolated limb perfusion with carboplatin(Drug information on carboplatin) (Paraplatin).

Postoperatively, she received adjuvant high-dose interferon therapy, but her disease recurred in the leg shortly after completion of 1 year of adjuvant therapy; treatment included isolated limb perfusion with melphalan(Drug information on melphalan) (Alkeran) and tumor necrosis factor. Subsequently, her disease progressed in the pelvis and retroperitoneum and interleukin-2 systemic therapy was used. However, disease progression continued not only in the leg, pelvis, and retroperitoneum, but new metastases had also developed in the liver and mesentery with massive malignant ascites.

On initial presentation, the patient was cachectic with a distended abdomen and had a Karnofsky performance status of 40%. She was started on thalidomide at 100 mg/d and dacarbazine on an every-3-week schedule. After 3 months, not only did the ascites completely resolve, but significant shrinkage of metastases in the liver and mesentery was observed, the retroperitoneal adenopathy had completely resolved, and the pelvic adenopathy had markedly improved.

The patient elected to discontinue dacarbazine, but remained on thalidomide at a maximum dose of 200 mg/d. After an additional 3 months, resolution of the liver metastases continued and virtually no adenopathy was detected. The patient has now been on single-agent thalidomide at 200 mg/d for over 1 year since stopping dacarbazine and recently has exhibited recurrence only in the leg. These encouraging results prompted us to combine thalidomide with the Dartmouth regimen in two additional patients who had disease progression after treatment with this combination chemotherapy regimen; treatment resulted in stable disease in one patient and a minor response in the other.