For patients with Stages III and IV disease, surgery is usually followed with an additional adjuvant therapy. Ask your physician to explain the possibilities and grounds for selection of one treatment over the other.
Select a treatment to learn more about it.
A number of drugs active in fighting cancer cells are being used to treat melanoma, either one at a time or in combinations. Currently, Dacarbazine (DTIC), given by injection, is the only chemotherapy approved by the Food and Drug Administration (FDA). DTIC may be combined with carmustin (BCNU) and tamoxifen, or with cisplatin and vinblastine. Temozolomide, an oral drug closely resembling DTIC, is FDA-approved for brain cancers but also used off-label for melanomas that have spread to the brain or nervous system.
Another class of drugs, based on a different principle, has come into use more recently. They are anti-angiogenic, which means that they prevent new blood vessels from forming. The reason this is important is that they cut off the blood supply that would otherwise nourish the cancer cells and enable them to grow. These drugs are still experimental for melanoma, and a good deal of research into improving and combining them with others is going on. Studies are under way with the anti-angiogenic drug thalidomide, combined with the chemotherapeutic agent, temozolomide. Angiostatin and endostatin are two other drugs in this class that have shown some degree of activity against melanoma in preliminary studies.
Isolated Limb Perfusion Method: This palliative treatment, which relieves symptoms, is sometimes used when melanoma metastases have reached an arm or leg. “Isolated” means that the chemotherapy is “perfused” (shunted directly) to the blood flowing through the affected limb, but to no other part of the body, to limit toxic effects. The drug melphalan is the chemotherapy most frequently used, often combined with other agents.
This is one of the most exciting and changing fields in medicine, based on drugs that act on the body's immune system. A number of newly developed treatments are now being tested with some success. Among the immunotherapies, several types of experimental melanoma vaccines are now viewed as promising. Unlike the influenza vaccine, given when you are well to prevent disease, these are given to people who already have melanoma. Clinical trials of various types of vaccine are under way with patients whose disease is in Stages III and IV. The vaccines are intended to stimulate the immune system so that it reacts more strongly against a patient's melanoma cells, destroying the cancer or slowing the progression. These vaccines are not a part of routine treatment at this time, so patients with advanced melanomas may wish to discuss this possibility with their physicians.
Another type of immunotherapy (also known as biologic therapy) makes use of chemicals that occur naturally in the body. One therapy you are likely to hear about is injectable interferon (IFN) alpha-2b, the only drug with FDA approval to treat “high-risk” Stage II and Stage III melanomas. High-risk melanomas are tumors that have a high chance of recurring (such as those that are ulcerated or over 4 mm thick) or have spread to the nearby lymph nodes. At first, IFN alpha-2b appeared to increase overall 5-year survival. After further study, it proved to give patients a longer period without relapse, extending their disease-free interval to an average of 9 months, but did not lengthen overall survival. It has significant flu-like side effects.
Tumor necrosis factor (tumor-killing) factor is another of these naturally occurring substances. Both of these — especially interferon-alpha — are produced by white cells (lymphocytes) when they come in contact with tumor cells, viruses or other harmful substances, and have been shown to kill a number of tumors, including melanomas. They have some anti-angiogenic properties as well. However, both drugs have significant side effects that can limit their use. And while interferon-alpha is FDA-approved, tumor necrosis factor is not.
Lymphokines, immune chemicals naturally produced by the white blood cells in small quantities, are being used for Stage IV patients. They may also be produced by white blood cells that have been specially stimulated by antigens, a basic part of the immune system, to make them better “killers”of malignant cells. The best known of these therapies uses the injectable lymphokine interleukin-2 (IL-2), with or without the addition of interferon alpha or other biotherapies and chemotherapies. It enters melanoma cells and attacks them. High-dose IL-2 (“Proleukin”), in fact, is the only FDA-approved immunotherapy used to treat Stage IV metastatic melanoma. It is associated with very significant side effects when given in high doses, but has been found to increase disease-free and overall survival in some patients. About 10-16 percent of carefully selected patients on IL-2 regimens respond to the drug, and about 60 percent of those patients have significantly extended lives.
Tumor-infiltrating lymphocytes (TILs) also play a part in some new therapies for advanced melanoma. Of special note is a technique from the National Cancer Institute called adoptive cell transfer (ACT), which involves harvesting TILs from the patient’s blood, then isolating from them the cells expressing T cell receptors that can recognize melanoma-specific antigens; in other words, the most aggressive melanoma-killing lymphocytes are identified and isolated. These are then grown in large numbers in the lab and reinjected into the patient in the hope that they will massively attack the patient’s melanoma cells. High doses of IL-2 may be added to make these tumor-fighting cells mature and multiply, and certain drugs are used to eliminate immune factors that might inhibit the tumor-fighting cells; this is called lymphodepletion. In clinical trials with metastatic melanoma patients who had not responded to previous treatment, the patients’ response rates have been far higher than those seen with chemotherapy.
In the latest trials, total-body irradiation was added to enhance lymphodepletion, and response rates up to 72 percent were observed in 93 patients, with 11 achieving complete remissions lasting 18 to 75 months or more.
Anti-CTLA-4 therapy is another important new direction for melanoma immunotherapy. CTLA-4 is a kind of natural “brake” in the immune system that can inhibit activation of healing T-cells to keep them from overproducing. Anti-CTLA-4 therapies are designed to block CTLA-4 so that more T-cells can be produced when needed to fight a cancer. In fact, the therapy is also referred to as “checkpoint blockade” immunotherapy.
The most promising of these therapies to date is ipilimumab (also called MDX-010 or MDX-101), a monoclonal antibody (a purified class of antibodies cloned and mass-produced in the lab from one specific type of cell or cell line) that has been tested in clinical trials for advanced Stage III and IV melanoma. The therapy was at first deemed a failure, but then patients started to improve over time. It has yielded dramatic, sustained responses akin to “cures” in certain patients, with some surviving more than 5 years. In a study of 676 people with advanced, inoperable melanoma reported in June, 2010 at the American Society for Clinical Oncology annual meeting, 24 percent of patients given ipilimumab alone or combined with another immune-stimulating treatment were alive after two years, vs. only 14 percent of those given the other immune-stimulating treatment alone. The FDA has promised to review the study results promptly, and ipilimumab could be approved by the end of 2010.
Unfortunately, some recent avenues in immunotherapy that initially held great promise have been disappointments. For example, a major theory has held that a specific, rare number of tumor-making cancer cells (stem cells) are the springboard for all cancers, and that by finding certain markers revealing those cells, specific “targeted” therapies could be designed to attack them, thereby making all the cancer cells die. This has proven possible with some kinds of cancer, but a 2008 study showed it is not the case with melanoma. Tumor-making cells proved to be common in melanoma, and no markers could be found to identify stem cells, so targeting them proved to be impossible.
Indeed, in a much heralded study of targeted therapy in the New England Journal of Medicine (NEJM) published recently, researchers removed CD4+ T cells, a form of white blood cells, from a Stage IV melanoma patient, isolating the portion of those T cells specific to targeting the patient’s melanoma, then expanding them vastly in the lab. They injected some 5 billion of these cloned T cells (specific to the melanoma-associated antigen NY-ESO-1), and found that the patient’s entire tumor regressed following the infusion. However, just as the NEJM article was appearing, a larger study of this therapy proved to be a failure, when the patients failed to respond to it. Another targeted immunotherapy, imatinib (Gleevec), has produced encouraging but mixed early results in metastatic melanoma, and greater numbers of patients must be tested. Imatinib inhibits c-KIT, the receptor for an enzyme called tyrosine kinase, which has been associated with some cancers, including melanoma. Genetic aberrations or mutations in KIT have been frequently found in certain gastrointestinal tumors and leukemias, which have responded well to treatment with imatinib. Some types of melanoma also frequently have KIT mutations, so it has been hypothesized that these melanomas will similarly respond to imatinib treatment. Indeed, lab experiments have been promising, and some patients, especially those with acral lentiginous melanoma and mucosal melanoma, have initially responded well, but thus far, significant clinical improvements from the drug as a single therapy have been minimal. Imatinib is continuing to be tested in different dosage regimens and combined with other therapies.
To date, the most notable success in targeted melanoma therapy has been PLX-4032, which inhibits a gene called BRAF. BRAF produces a protein that normally regulates skin cells, causing them to multiply only when growth is needed. However, a specific mutated version of BRAF called v600E produces an abnormal version of the protein that stays switched on.
This leads to out-of-control growth, i.e., cancer. PLX-4032 can bind to the defective protein and deactivate it. In a preliminary trial of 21 metastatic melanoma patients receiving the highest doses of the drug, 16 had the specific v600E BRAF mutations linked to melanoma. In 14 of these patients, the treatment caused significant or complete tumor regression within a couple of weeks, and about 56 percent total at least had partial responses. It is too early to know long-term results, but preliminary estimates are an average six months without disease progression, a noteworthy improvement over available therapies. Many more patients are being studied in clinical trials now under way, the goal being improved overall survival, not just short-term regression. As with imatinib, the hope is that altering the dosing regimen and combining PLX-4032 with other therapies will significantly lengthen survival.
A gene is the basic unit of genetic material. It is the code or "blueprint" by which our body's proteins are made. Alterations in these codes can result in uncontrolled cell growth as in cancer.
On the other hand, selected genes can be altered so as to correct genetic defects or enhance the cancer-fighting potential of cells. There is hope that making changes in genes will lead to successes in treating a wide range of illnesses, so this kind of therapy frequently gets newspaper headlines. However, keep in mind that this treatment is in the very early stages of research, and its effectiveness is yet to be proven conclusively.
One form of gene therapy is based on creating alterations in the white blood cells or in the tumor-infiltrating lymphocytes (TILS) so that they will attack the melanoma. This is achieved by removing these cells from the patient, growing them outside the body and treating them so as to increase their number. The next step is the addition of genetic material that produces one of the many growth factors which make the lymphocytes more aggressive as cancer-fighters. These more aggressive lymphocytes are returned to the patient's body in an effort to stimulate the immune system to kill the melanoma and its metastases.
The focus of current research is the identification of genes for specific melanoma antigens. These are molecules found on the cell wall that stimulate the production of antibodies, which are a part of the body's immune defense system. An antibody attaches itself to only one type of antigen. By injecting the gene for the melanoma antigens, the hope is to increase their number and produce a broad attack by the patient's immune system.
Many patients, especially those with advanced disease, are participating in clinical trials to obtain new treatments that are still experimental and not generally available.
Patients who have Stage III and IV melanoma might consider enrolling in a clinical trial of a new or experimental treatment. There are risks involved in enrolling in a clinical trial, but there can be benefits as well. More treatment possibilities exist than ever before, giving new hope to people with melanoma.
This method makes use of trichloroacetic acid (TCA) or a similar agent applied directly to the skin. The top skin layers slough off, usually replaced within seven days by new epidermis (the skin's outermost layer). This technique requires local anesthesia and can cause temporary discoloration and irritation.
Laser light can be used on cancers and precanders. Carbon dioxide (CO2) and argon lasers are used most often. The laser can evaporate tissue from the skin surface, or to cut tissue away, which the beam is able to do bloodlessly. It can also cut bone without blood loss.Advantages and disadvantages
The lack of bleeding make this an option for people who are taking blood thinners, and it is good for patients in poor health. However, the treatment itself is time consuming, the equipment is expensive, and it is not readily available.
Photodynamic therapy (PDT) is based on the use of the light-sensitive (photosensitive) agent, 5- aminolevulinic acid (5-ALA). This is applied topically to the skin cancer or precancer or injected into the bloodstream. It is absorbed preferentially by the tumor cells. When exposed to a powerful light source, usually the laser, the following day, the chemical is activated to destroy the cancer.
It is currently used most often for numerous superficial BCCs, and has Food and Drug Administration approval as a treatment for actinic keratoses.
Two types of radiation are most often used to treat skin cancer: conventional x-rays and the electron beam.
Radiation therapy is usually reserved for elderly patients who are too ill to undergo surgery or who refuse to have it performed. It may also be used to treat very large cancers where reconstruction would be difficult. Short-term cosmetic results can be good, especially when the treated area is small. It should never be used on skin that has already suffered radiation damage.
The area to be irridiated is outlined. Then a radiation beam is directed at the outlined area. The healthy tissue is protected with a lead shield. The treatment usually requires several exposures a week for a few weeks.
Radiation is essentially painless and within the first two or three years, cosmetic results are usually better than those obtained by other techniques. The cure rate is high.
If the radiation is used in a hairy area, it will produce permanent hair loss. Also, the radiation itself can cause skin cancer. If the treatment requires many sessions, the cosmetic results are often worse than those after treatment by other methods.
Undesirable long term after-effects are common, so this procedure should only be used when other methods are ruled out, and rarely on patients under the age of 35.
Surgical excision is used to treat all types of skin cancer. At its best - given an experienced surgeon and a small, well-placed tumor - it offers results that are both medically and cosmetically excellent.
The physician begins by outlining the tumor with a marking pen. A "safety margin" of healthy-looking tissue will be included, because it is not possible to determine with the naked eye how far microscopic strands of tumor may have extended. The extended line of excision is drawn, so the skin may be sewn back together.
The physician will administer a local anesthetic, and then cut along the lines that were drawn. The entire procedure takes about thirty minutes for smaller lesions.
Wounds heal rapidly, usually in a week or two. Scarring depends on many factors, including the placement of the tumor and the patient's care of the wound after the procedure.
The tissue sample will be sent to a lab, to see if any of the "safety margin" has been invaded by skin cancer. If this is the case, it is assumed that the cancer is still present, and additional surgery is required. Usually, this is when Mohs micrographic surgery is used.
Cure rate is high, and in some cases, the scar is hardly noticeable. It provides an opportunity to examine the surrounding tissue to see if the entire tumor has been removed, which is a good safety precaution. Also, the entire procedure is done in one session, unlike chemotherapy and radiation.
The procedure does require the removal of healthy skin, which results in a larger wound. In certain places on the body, like the head and scalp, it can be difficult to put the wound edges back together. This treatment is best suited to tumors in locations where the wound can be easily stitched and closed. In some cases, the size of the tumor will necessitate skin grafts to close the wound.