- 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.
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