Treatment for Melanoma
Treatment depends on various factors, including the following:
- The site of the original lesion.
- The stage of the cancer.
- The patient's 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 doctor 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 1 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 doctor 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 reduce the chance of recurrence and help patients live longer.
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, fotemustine was also associated with a slightly greater survival and longer time before brain metastases developed.
- Melphalan plus temozolomide are being given in combination with hepatic perfusion in a clinical trial of patients with ocular melanoma metastases to the liver. Temporarily separating the liver from the blood supply enables higher concentrations of melphalan to be otherwise tolerated. Phase I and II trials produced a positive response in 62% of patients.
- 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.
- Lenalidomide (Revlimid), a novel drug that inhibits the growth of new blood vessels to tumors. This drug is being studied for melanoma that occurs in the eye (ocular melanoma, the most common form of eye cancer) and has spread to other organs. No effective treatment for metastatic ocular melanoma is currently available.
Many other drugs and combinations used to boost drug effectiveness or minimize toxicity are under study. They include vincristine, vinblastine, cisplatin, tamoxifen, carboplatin and sorafenib.
The combination of carboplatin, paclitaxel and sorafenib for patients with unresectable stage III or IV melanoma is being studied at the National Cancer Institute. Sorafenib is a new drug that works by blocking key proteins important for cell proliferation and for generating new blood vessels to tumors (angiogenesis). The researchers hope sorafenib will weaken melanoma tumors and enhance the lethal effects of chemotherapy.
*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. Erythropoietin 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 3 and 6 months. If the tumors completely disappear, the cancer may stay in remission much longer, but in virtually all cases it returns.
Chemotherapeutic Regional Perfusion
Chemotherapeutic regional perfusion (also called isolated limb perfusion) allows the administration of very high-dose chemotherapy. It is often used effectively for metastasized or recurrent melanoma that occurs on the arm or leg. (It does not appear to be useful for preventing metastasis after a first occurrence of melanoma in one of these locations.)
This technique involves the following:
- The blood supply to the limb with melanoma is temporarily interrupted using a tourniquet and then rechanneled through a heart-lung machine.
- Anticancer drugs (usually with the drug melphalan alone or in combination with other drugs) are added to the blood in doses up to 10 times the standard doses.
- The blood is then heated to enhance the drug's potency.
- The chemo-infused blood is then sent directly to the melanoma site, minimizing the likelihood of drug toxicity.
- Adverse effects occur in less than 1% of cases and include the following:
- Severe problems in the treated limb; in rare cases amputation is needed.
- Drug leakage into the general blood stream. This can severely reduce white blood cells and lead to serious infection.
Other treatments being explored include combinations of melphalan with immunotherapy drugs, notably interferon and tumor necrosis factor. Complete response rates as high as 90% have been reported in some patients, but more research is needed to verify the safety and effectiveness of this treatment.
In addition to arms and legs, perfusion techniques have been tested for the pelvis, head, neck, skin of the breast, and even the abdomen.
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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 5-year survival for advanced melanoma, from 5 - 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.
- A phase II trial in patients with Stage IV melanoma showed tumor disappearance in 50% of patients treated with their own tumor-infiltrating lymphocytes (TIL). These lymphocytes are harvested, boosted in number, and reinjected into the patient. One study is ongoing that combines TIL therapy with Interleukin-2 (IL-2), a highly toxic drug. Another study of TIL is being conducted without IL-2 in the hopes of achieving results with fewer side effects.
- 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. Response to alfa-2b appears to be tied to autoimmunity. The NCI recently reported that in clinical trials of alfa-2b, benefits were largely confined to patients who showed clinical signs of developing autoimmunity. These patients were 50% less likely to develop recurrent melanoma. 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 5-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 - 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. Immunotherapy that uses T cells is showing promising results, especially for patients with advanced melanoma who have failed to respond to other treatments. T-cell therapy extracts white blood cells, (tumor-infiltrating lymphocytes, or TILs), from the patient. The TILs are treated with a drug that improves their tumor-fighting capabilities, and then injected back into the patient. Patients also receive chemotherapy to help increase the tumor-fighting cells. In a 2005 study of 35 patients with advanced melanoma, half of patients who received T-cell therapy showed substantial improvement.
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 5-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. Antisense compounds can prevent defective cancer genes from being translated into proteins that cause abnormal cell proliferation.
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.
Curcumin. The yellow spice found in turmeric and curry powders may contain cancer-fighting properties. In a preliminary laboratory study, curcumin stopped the growth of melanoma cells. It is far too early, however, to recommend curcumin for clinical use
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.
