The addition of immunotherapy to chemotherapy for malignant skin cancer that has spread does not improve survival rates, researchers have found, and patients have more serious side effects, such as anemia, when the two treatments are combined.

Malignant melanoma develops when cancer grows in the cells responsible for skin color, and is one of the most aggressive forms of skin cancer. Having unusual moles, exposure to sunlight and being fair-skinned are thought to place people at higher risk.

The use of oral or injected chemotherapy drugs to kill melanoma cancer cells can be effective if the cancer is diagnosed early, but once it has spread - metastasized - it is almost always fatal.

According to the National Cancer Institute, each year about 53,600 people in the United States are diagnosed with melanoma and 7,400 die from it. The incidence of melanoma has risen an alarming 3 percent a year since 1981, according to the Centers for Disease Control and Prevention.

Researchers have hoped that a combination of immunotherapy - treatment that bolsters or stimulates patients' immune systems - and chemotherapy might be an option for people with malignant melanoma.

Authors led by Andre Sasse, M.D., at the research center Onco-Evidencias in Sao Paolo, Brazil, reviewed 18 studies of 2,625 patients who were treated with either chemotherapy alone or a combination of chemo- and immunotherapy.

"No difference was seen in survival rate and toxic effects were increased" when immunotherapy was added to chemotherapy, the researchers write.

The review appears in the current issue of The Cochrane Library, a publication of The Cochrane Collaboration, an international organization that evaluates medical research. Systematic reviews draw evidence-based conclusions about medical practice after considering both the content and quality of existing medical trials on a topic.

The review examined two kinds of immunotherapy combined with chemotherapy, interferon and interleukin-2. Of the 11 studies that reported on side effects from chemoimmunotherapy, eight showed blood disorders and flu-like symptoms resulting from the combined treatment. In four studies that used interleukin-2 without interferon, patients had more blood side effects after treatment.

Jedd Wolchok, M.D., an oncologist at Memorial Sloan-Kettering Cancer Center, said that it is difficult to tease out which of the two immunotherapy agents might be responsible for the side effects to patients' blood.

"Both immunotherapies have considerable side effects," Wolchok said. "Interleukin-2 is likely more difficult since it can lower blood pressure and cause fluid to build up in the body. These side effects are a consequence of what these immune hormones were originally designed to do - for example, interferon is a natural antiviral agent, so the fact that it causes flu-like symptoms very commonly is not a surprise."

Sasse said, "The interleukin is more toxic and needs hospitalization for its administration. It is also known to promote more systemic reactions than interferon. But the adverse effects of either drug are dose dependent."

Wolchok said, "This area should definitely continue to be investigated. My hypothesis is that chemotherapy may be used to modulate and potentiate newer immunotherapy drugs."

Sasse, however, said, "There are some controversies about the use of chemotherapy in advanced melanoma - the chemotherapy does not save lives and additionally, there is doubt that it prolongs the survival of these patients."

"My opinion is that there are enough studies in this subject and therefore, no need of new trials," Sasse added. "At the moment, the focus should be given to the development of new therapeutic approaches to melanoma." He cited advances in molecular biology and the carcinogenesis of melanoma as possible avenues for new treatment in the future.