Surgical removal is the treatment of choice for melanoma. If the melanoma has spread locally or to distant organs, chemotherapy needs to be considered. This edition of MelanomaNet discusses the rationale for chemotherapy, types of chemotherapy, and side effects of this form of treatment.

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Chemotherapy is the use of anti-cancer drugs in the treatment of melanoma (1) in conjunction with surgical removal of melanoma, and (2) in the treatment of metastatic melanoma that cannot be surgically removed.

Chemotherapy in conjunction with surgical removal of a melanoma is called adjuvant chemotherapy. It is administered after surgical removal of a melanoma in a patient in whom there is no clinical, radiologic or pathologic evidence of secondary or metastatic disease. The purpose of adjuvant chemotherapy is to eliminate any "undetectable" tumor cells that may have entered the circulation and settled at local and distant sites before the primary melanoma was removed. Adjuvant chemotherapy is considered only for melanomas at very high risk for metastasizing, based upon tumor thickness and/or presence in regional lymph nodes but no other sites.

Chemotherapy for metastatic melanoma is given with the purpose of either (1) achieving shrinkage or remission of metastases, or (2) easing the symptoms of cancer in a patient with advanced and probably incurable metastatic disease.

Chemotherapy of melanoma is given in three forms, depending on the stage and site(s) of the tumor(s), and the ability of the patient to tolerate side effects. The three forms are:

Single-agent chemotherapy—a single chemotherapeutic agent selected for its activity in treating the patient’s type and stage of metastatic melanoma;

Combination chemotherapy—using two or more chemotherapeutic agents in combination when it is deemed likely that this form of therapy will enhance the effectiveness of chemotherapy, or avoid the problem of cancer-cell resistance to a single agent; and,

Isolated limb perfusion chemotherapy—giving very high doses of chemotherapeutic agents to treat metastatic tumors at surgically isolated local sites in the lower limbs, a method that allows these powerful agents to be given at much higher doses than is possible when they are given systemically.

Chemotherapy may sometimes be given in combination with biotherapy if the tumor is believed likely to respond to this approach. Radiation therapy may be used in combination with chemotherapy to ease the symptoms of advanced metastatic melanoma.

A number of anti-cancer drugs are in use, but not all have been shown to be effective in treating metastatic melanoma. No chemotherapeutic agent has been shown to produce long-term (5-year) survival in significant numbers of patients with metastatic melanoma.

Dacarbazine (DTIC) belongs to the class of anti-cancer drugs called alkylating agents. It is given intravenously (IV) for 1 to 10 days at a time in a dosing schedule compatible with the patient’s condition and ability to tolerate side effects that may include nausea, vomiting, pain at the IV site, or bone marrow suppression. In studies reported as of August 2000, some positive response to DTIC occurs in 10% to 20% of patients, and remission is typically maintained for 3 to 6 months. While DTIC is an important agent in cancer chemotherapy, it has never been compared to placebo in controlled clinical trials.

Temozolamide, a drug chemically related to DTIC, has the advantage of being given in pill form rather than intravenously. Tumor responses to temozolamide have been similar to responses to DTIC.

Other anti-cancer drugs that have been tested in single-agent melanoma chemotherapy include nitrosourea agents, the spindle-agent drugs vincristine and vinblastine, and the platinum analogs cisplatin and carboplatin. None, to date, has shown a response rate better than that of DTIC.

It is important to remember that response rates reported in clinical trials and other studies of drugs do not necessarily predict the response to a drug in an individual patient.

Combinations of two or more chemotherapeutic agents have been investigated, and used, in the treatment of metastatic melanoma. DTIC is usually one of the anti-cancer agents in the combination; the others include the drugs discussed under single-agent chemotherapy. Among newer drugs tried in combination with DTIC is the anti-estrogen agent tamoxifen that is used in treatment of some breast cancers. As of August 2000, the DTIC-tamoxifen combination had not been shown to significantly improve the response rate or survival seen with use of DTIC alone or in combination with other agents.

Isolated limb perfusion (ILP) chemotherapy is most often used in patients with recurrent metastatic melanoma or multiple aggressive metastatic tumors of the lower limbs (legs) that cannot be surgically removed. ILP is typically used to treat metastatic tumors where the site to be perfused can be surgically isolated from the rest of the body. The chemotherapeutic agent used most often in ILP is melphalan, an alkylating agent. Melphalan may be used alone, or may be combined with anti-cancer agents such as nitrogen mustard, cisplatin or DTIC, or with a cytokine such as tumor necrosis factor or interferon-gamma.

The basic technique of ILP is to surgically create a temporary arterial-venous (AV) loop that disconnects the limb’s blood circulation from the rest of the body. Because the AV loop isolates the limb from the rest of the body’s circulation, anti-cancer drugs can be given in high doses that would cause severe side effects if they reached the general circulation. By means of a tube inserted into the AV loop, the high-dose chemotherapeutic agent is perfused through the area where the tumors are located. The high-dose therapy presumably achieves a higher cancer-cell "kill rate" than chemotherapy that is given systemically. A radioisotopic tracer may be used to monitor precise flow of the anti-cancer agent to the tumor site(s). A heating unit may be used to warm the drug before it in perfused into the AV loop, and a warming blanket may be placed to maintain the perfused tissue at a constant temperature. Some studies have shown that warming increases the anti-tumor activity of the drug, but other studies have indicated that warming of drug and tissues does not improve tumor response to the drug.

Studies have shown that ILP can achieve complete remission of tumors in the perfused leg in a substantial number of patients, and may eliminate the need for limb amputation. However, metastatic disease recurs in a substantial number of patients after ILP, and ILP has not been shown to increase overall survival of patients with metastatic melanoma.

Side Effects of Chemotherapy

All cancer chemotherapy produces side effects that may range from unpleasant to severe and intolerable. Side effects of chemotherapy given intravenously or orally (systemically) may include nausea, vomiting, stomatitis (inflammation or ulceration of tissues in and around the mouth), hair loss, and bone marrow suppression. Dose adjustments may alleviate some symptoms. ILP side effects may include local inflammation and pain at the perfusion site.

Chemotherapy side effects, the ability to tolerate them, and the likelihood of response to chemotherapy, should be discussed with a patient’s physician.

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