Melanoma

Description

Alternative Names

Treatment

Treatment depends on various factors, including the following:

• The site of the original lesion.
• The stage of the cancer.
• The patients age and general health.

Treatment options include the following:

• Surgery is performed at every stage to remove the melanoma cancer cells.
• Melanoma that has spread to lymph nodes or additional nearby sites usually requires additional forms of treatment including chemotherapy, immunotherapy, and radiation therapy.
• Advanced melanoma that has spread to distant sites often cannot be cured, although surgical removal of metastatic tumors may provide some benefit by easing pain, increasing the general quality of life, and lengthening survival. Patients should seek to enter clinical trials, studies that examine new immunotherapies (vaccines, cytokines), gene therapies, chemotherapy combinations, or other treatments.

Surgery

Surgery is the primary treatment for all stages of melanoma.

Removal of the Melanoma. Some or all of the melanoma is often been removed during the biopsy. If cancerous tissue still remains after a diagnosis of melanoma, a surgeon will cut away additional tissue from the surrounding area to remove any stray cancer cells.

Mohs micrographic surgery was developed to allow meticulous surgical removal of skin tissue. This procedure involves the following:

• Very thin layers are removed one at time, with each layer examined immediately under a microscope.
• When the layers are shown to be cancer free, the surgery is complete.

Because the physician needs to be certain that all cancer cells are removed, in some cases the surgical area required is very wide and requires plastic surgical techniques. The amount of tissue removed depends on the size, depth, and degree of invasion:

• Stage I lesions that are less than one millimeter deep require the smallest excisions, usually about one centimeter (2/5 inch) off each side and downward from the original lesion.
• For melanomas 2 mm or more in thickness, a margin of 3 cm is important for reducing the risk of recurrence.
• Thicker lesions require wider excisions.

It used to be customary to remove a large area, regardless of the stage of cancer. This potentially disfiguring approach has been abandoned because studies have shown that excising wider margins does not improve survival. Nevertheless, sometimes skin grafts may need to be taken from other body sites to help cover the wound.

Of note: recurrence rates are very high with lentigo maligna (LM) after conservative surgery. Although this is a very slowly progressive condition, LM can develop into melanoma. Most of these lesions appear on the face and neck, so extensive surgery can be disfiguring. Patients should discuss with their physician carefully staged surgery to remove all diseased tissue with as little cosmetic harm as possible.

Lymph Node Removal. If there is evidence that melanoma has spread to nearby lymph nodes but has not spread beyond, removing them may improve local disease control and might even improve survival in selected patients, although this is an ongoing area of investigation. At this time, Australian guidelines recommend lymph node removal only for patients younger than 60 years of age with 1 to 4 mm thick primary melanomas on the trunk.

Surgery for Metastatic Melanoma. In some cases, surgical removal of distant tumors may be possible and prolong survival, since often in melanoma the cancer spreads first only to a single site, such as the lung or the brain.

Cryosurgery. Cryosurgery freezes skin tissue and destroys it. This procedure is not useful for most melanomas, but it might have some value in specific situations. For example, it may be effective for smaller melanomas in the eye, a location that is difficult to treat with traditional surgery. It may be useful to eliminate residual cancer cells after standard surgery for lentigo maligna melanomas, an atypical form of melanoma that has a wide surface and is difficult to treat.

Chemotherapy

Chemotherapy is often used to treat recurrent or metastatic melanomas. The drugs are not intended as a cure but can prolong life and improve its quality.

Drugs Used. The following are some of the agents used to treat melanoma. They may be used alone or in combination under specific situations.

• Methylating agents, which impair the ability of cancer cells to divide, include dacarbazine (DTIC), temozolomide (TMZ), and procarbazine. To date, dacarbazine is the only drug approved for melanoma.
  • Temozolomide, an oral drug, may be comparable and improve quality of life. Because it can cross the blood-brain barrier (unlike dacarbazine), temozolomide is showing promise in preventing metastasis to the brain. It may also have some benefits in treating cancers that have already spread to the brain.
  • In a 2004 study, patients had a significantly higher response rate to fotemustine than to DTIC. Compared to DTIC, fortemustine was also associated with a slightly greater survival and longer time before brain metastases developed.
• Nitrosoureas, which include carmustine (BCNU) and lomustine (CCNU) are often used.
• Taxanes, such as docetaxel (Taxotere) and paclitaxel (Taxol), are showing some low-level activity against melanoma. Docetaxel is being studied in combination with other drugs.

Many other drugs and combinations used to boost drug effectiveness or minimize toxicity are under study. They include, vincristine, vinblastine, cisplatin, and tamoxifen.

Side Effects. Side effects occur with all chemotherapeutic drugs. They are more severe with higher doses and increase over the course of treatment.

Common side effects include the following:

• Nausea and vomiting. Drugs known as serotonin antagonists, especially ondansetron (Zofran), can relieve these side effects in nearly all patients given moderate drugs and most patients who take more powerful drugs. In one study, a combination of dexamethasone (a corticosteroid) with ondansetron taken within 24 hours of chemotherapy achieved either a major or complete reduction in nausea and vomiting.
• Diarrhea.
• Temporary hair loss.
• Weight loss.
• Fatigue.
• Anemia. Erythropoetin stimulates red blood cell production and can help reduce or prevent this side effect. It is available as epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp). Aranesp persists longer in the blood than epoetin alfa and so requires fewer injections.
• Depression.

Serious short- and long-term complications can also occur and may vary depending on the specific agents used. They include the following:

• Increased chance for infection from suppression of the immune system.
• Severe drops in white blood cells (neutropenia). Certain agents, such as taxanes, pose a higher risk for this than other chemotherapeutic drugs. White blood cell count may be improved with the addition of a drug called granulocyte colony-stimulating factor (either filgrastim or lenograstim).
• Liver and kidney damage.
• Abnormal blood clotting (thrombocytopenia).
• Allergic reaction.
• Menstrual abnormalities and infertility in women. A natural hormone medication called a gonadotropin-releasing hormone analogue that puts women in a temporary pre-pubescent state during chemotherapy may preserve fertility in some women.
• Rarely, secondary cancers such as leukemia.
• Problems in concentration, motor function, and memory, which may be long-term.

Benefits of Chemotherapy. About 20% of cancers shrink in response to one or more of these drugs, but the effects last only between three and six months. If the tumors completely disappear, the cancer may stay in remission much longer, but in virtually all cases it returns.

Immunotherapy

Immunotherapy uses drugs to boost the patient's own immune system. This treatment was developed after experts observed that in some melanoma patients, the tumor temporarily stopped growing and shrank, apparently in response to a very effective natural immune response. This phenomenon is very rare, though it appears more often in melanoma than in other cancers. Adjuvant immunotherapy (used after surgery) is proving to be helpful in melanoma patients at high risk of recurrence.

Cytokines. Specific powerful immune factors called cytokines, particularly those known as interferons, are being used to develop therapies for metastatic melanoma. These agents are typically administered with chemotherapy agents, with other immunotherapies, or both. (If cytokines are prescribed as single-agent therapy they are ineffective at lower doses while at higher, effective doses they become very toxic.) The results of one 2002 report, for example, reported that adding interferons and interleukins to chemotherapy doubled the five-year survival for advanced melanoma, from 5% to 10%. Side effects are greater with this approach but they are manageable. A number of other cytokines and combinations are being investigated.

• A 2004 study showed that long-term, low-dose interferon alpha-2a was not beneficial to patients who had undergone surgery to remove high-risk malignant melanoma.
• Interferon alpha-2b (Intron) is a genetically engineered agent (called a recombinant drug). It is given by injection and is the only FDA approved immunotherapy for late stage melanoma. A 2004 randomized clinical trial showed that neither interferon alpha-2b nor interferon gamma was beneficial in patients with high-risk melanoma. However, future trials of different interferon alpha-2b schedules, doses, or combinations with other agents may demonstrate some advantages. The most common side effects are fatigue, depression, and flu-like symptoms, which can be severe. (Starting an antidepressant, such as paroxetine (Paxil), several weeks before interferon therapy may help prevent depression.) Some patients have reported eye problems in the retina.
• Different forms of interferons, such a long-acting formulation called pegylated interferon and natural human interferon are under investigation. In one 2002 study of patients with Stage IIB or III melanoma who were first treated with two rounds of dacarbazine chemotherapy, low-dose natural interferon led to five-year relapse-free survival in 42%, compared to only 17% in those who did not receive any adjuvant interferon immunotherapy.
• Interleukin-2 (Proleukin) is a hormone-like substance that stimulates the growth of cancer-fighting white blood cells. High-dose interleukin-2 has obtained regression of metastatic melanoma in 15% to 17% of patients. In addition, a 2004 study showed a 35% response rate in patients with metastatic melanoma, including a complete response in 12% of patients. The drug, which is injected, can have significant side effects, including very low blood pressure, heart rhythm abnormalities, severe infections, and shortness of breath, but they are manageable and nearly always reversible.
• Another injectable cytokine under study is granulocyte-macrophage colony stimulating factor (GM-CSF, Leukine, Sargramostim), which boosts production of immune cells in the blood and bone marrow. An inhaled form of the drug is also being tested for melanoma that has spread to the lungs.

There is some concern that these treatments may actually produce substances called reactive oxygen species (ROS), which in turn inactivate immune cells that fight cancer. Histamine (Maxamine) is a powerful inhibitor of ROS, and researchers are testing it in combination with interleukin-2 cytokine therapy. In one study, the added benefits of histamine were modest except in patients with liver metastatic; in these patients, survival improved by 129 days, which was significant.

T-Cell Therapy. Some promising work uses T-cell therapy, which involves extracting white cells called tumor-infiltrating lymphocytes (TILs) from the patient's tumors. Specific TILs from this batch are then expanded. The selected TILs target specific molecules in the melanoma cells. In one study, patients were given chemotherapy that depleted their own lymphocytes, and the specially prepared TILs were then reinfused back into the patients. In the small study, 10 out of 13 patients had a substantial response with two patients experiencing over 95% tumor regression. There were significant adverse effects and not all patients benefited. Still, the study suggested a promising path for additional research.

Vaccine Immunotherapy. Vaccine immunotherapy uses melanoma-associated cells to serve as antigens (foreign proteins that antibodies in the immune system specifically seek out and attack). Part of the problem in developing a vaccine is that scientists are still unsure exactly which antigens are most likely to elicit an immune response that effectively kills cancer cells. Furthermore, antigens that are effective in one person may not be effective in another.

Many vaccines are now in advanced stages of development. Some are promising, but to date, none has yet emerged as an important weapon in treating advanced melanoma. In 2004, a long-term study of the bacillus Calmette-Guerin (BCG) vaccine reported the disappointing result that BCG provided no benefit in patients with stage I-III melanoma.

Some vaccines employ one or a few antigens (so-called monovalent vaccines); others consist of a cocktail of antigens (so-called polyvalent vaccines), which may be more likely to contain the right antigen targets.

Vaccines are often enhanced by substances or procedures called adjuvants (e.g., SAF-M, viruses, dendritic cells) to further boost effectiveness.

Most use one of two basic approaches, autologous and allogeneic, or a combination of the two (called a hybrid):

• Autologous vaccines are made from the patient's own cancer cells or parts of them. This produces a very specific immune response that can target the patient's cancer precisely. Some, such as Oncophage (HSPPC-96) and M-Vax, are showing promise in early trials and are undergoing additional testing. One problem with the autologous approach is that there is no way to scientifically assess outcome or even guarantee repeated success since each vaccine is unique to the individual patient. This approach is also appropriate only for select patients.
• Allogeneic vaccines purify and use antigens that may be derived from proteins from tumor cells, genetic material, or even bacteria. Such antigens are anchored on melanoma cells and stimulate an immune attack by powerful antibodies. A number of investigative vaccines (e.g., Melacine, Canvaxin) use multiple antigens (called allogeneic polyvalent vaccines) to reduce the risk for eventual tumor resistance to a single antigen. Studies are suggesting that the polyvalent vaccines may improve long-term survival rates in some patients. For example, Canvaxin achieved five year survival rates of 39% compared to 20% for unvaccinated patients. It is not yet clear if they are superior to high-dose interferon, but research continues.

Unlike chemotherapy, in which the drugs directly attack the tumor and shrinkage occurs quickly, the use of vaccines requires the body to build up its own defenses. It can take months before beneficial effects occur, but when they do, tumor reduction is much more lasting than with chemotherapy. Vaccines also seem to have fewer side effects than interleukin and interferon.

Antisense Compounds. Of interest is therapy that employs antisense compounds, which can prevent defective cancer genes from being translated into proteins that cause abnormal cell proliferation. Compounds are being investigated for use against mutations in bcl-xL and bcl-2 genes that block apoptosis, a natural process by which cells self-destruct and so do not become cancerous. A 2000 study using a combination of dacarbazine with oblimersen (G3139, Genasense), an antisense agent that turns off bcl-2 produced, achieved complete remission in one patient and partial responses in 43%. Late phase trials are in process.

Monoclonal Antibodies (MAb). Antibodies are natural substances produced by immune cells that home in and destroy cancer cells. Scientists are identifying specific antibodies that may attack melanoma cells and cloning them to create monoclonal antibodies. MAbs have shown promise for other cancers and are now being tested for melanoma, often in combination with vaccines and other forms of immunotherapy.

Other Experimental Therapies

Tetracyclines. Chemically modified tetracyclines, a common antibiotic, have been shown to modify metalloproteinase, an enzyme in the skin that promotes skin cancers, including melanoma.

Anti-Angiogenesis Agents. A number of trials are studying agents that block angiogenesis, which is the formation of new blood vessels. A tumor can fuel its own growth with angiogenesis. Thalidomide (Thalomid) is one of the most important anti-angiogenesis agents under investigation for melanoma. This agent had gained notoriety in the 1960s because of devastating birth defects in the children of women who took it during pregnancy. It not only has anti-angiogenic activity but also other anti-tumor effects when given concurrently with chemotherapy (e.g., temozolomide, dacarbazine). Several studies indicate that some cases of advanced melanoma may respond to thalidomide. A thalidomide derivative (Revimid) and Endostatin, another anti-angiogenesis drug, is also undergoing testing.

Herpes Virus. In a small study in five patients, injection of a modified version of the herpes virus (HSV1716) into metastatic melanomas caused cancerous cells, but not nearby healthy tissue, to die.

Radiation

In general, radiation is used to help relieve pain and discomfort caused by cancer that has spread or recurred. Radiation is not used as often for treating melanoma as it is for other forms of cancer because melanoma cells tend to be more resistant to its effects. It may be useful in some cases, however.

• In some patients with tumors less than 3 cm deep, however, radiation may help slow down metastasis when combined with a super-heating process using microwaves.
• Brachytherapy, in which radioactive seeds are implanted close to the tumor, has also been used with success for melanoma of the eye.
• Lentigo maligna may sometimes be treated successfully with specific radiation treatments called soft, or Grenz, x-rays.
• Radiotherapy using a so-called gamma knife (very focused gamma radiation) is also effective for cancer that has metastasized to the brain, in some cases halting the growth and, in rare situations, even eliminating it.