May 6, 1997
AIDS Patients Face Growing Threat From Cancer
GraphicA Mysterious Combination
By LAWRENCE K. ALTMAN, M.D.
ETHESDA, Md. -- As more people with AIDS survive longer, many are confronting yet another serious health problem: cancer.
Malignant tumors, particularly Kaposi's sarcoma and certain cancers of the lymph system, have been common among AIDS patients since the disease was first recognized in 1981. But now the array of cancers is broadening in mysterious ways. Once rare cancers are appearing more often. Some kinds of cancer that were expected to increase in frequency have not. And strange geographical patterns of certain cancers are emerging.
It is a baffling situation, yet scientists see hope in it. Researchers are looking at the puzzling trends with the aim of identifying and using biological clues to unlock the secrets of the myriad cancers that afflict people who are not infected with HIV, the virus that causes AIDS, and to devise new ways to treat them.
Like everyone else, people with AIDS can develop any kind of cancer. And to a doctor, a slide of a specific tumor looks the same under a microscope, regardless of whether it came from a person infected with HIV.
Now, though, the new patterns of disease have raised the possibility that further studies of subtle differences might eventually help researchers improve cancer therapy.
An emerging theory is that most AIDS-related cancers are somehow linked to viral infections. But doctors do not know if HIV enhances the ability of other viruses to produce certain cancers, scientists said here last week, at the first international meeting devoted to AIDS and cancer. The meeting was sponsored by the National Cancer Institute.
Dr. Richard Klausner, the director of the federal institute, said that at least 30 percent of people with AIDS also developed cancer. The frequency is estimated from a variety of studies and cancer registries using information collected from hospitals and death certificates.
Dr. Valerie Beral of the University of Oxford in England said that studies had definitely linked five cancers with HIV infection: Kaposi's sarcoma (skin and internal organs); non-Hodgkins lymphoma (lymph system); squamous cell cancer of the conjunctiva (eye); and in situ (early stage) carcinomas of the cervix and anus.
Three other cancers are probably related to HIV. Two affect the lymph and blood system (Hodgkins disease and plasmacytoma) and one affects muscle (leiomyosarcoma). Once rare, leiomyosarcoma has become the second most common cancer in HIV infected children but, for unknown reasons, not in adults.
Studies have also suggested an increase in lung, lip, testicular and other cancers. Although the overall incidence of breast cancer is not increased in AIDS patients, several cases of unusual types of aggressive breast cancers have been reported. But their link to AIDS remains uncertain.
Most perplexing is why HIV-infected people are not developing liver and certain other cancers. For example, many HIV-infected people are also infected with either the hepatitis B or C viruses, which increase the risk of liver cancer, yet they are not unusually prone to liver cancer.
The meeting took place at a time of optimism about AIDS. Combinations of newer anti-HIV drugs like protease inhibitors, and older ones like AZT, can suppress the virus to levels below the limits of detection by the latest laboratory techniques.
But whether the new therapies will reduce or increase cancer rates among people with HIV is not known.
If the cancers are somehow related to problems with the immune system, therapies that prevent HIV damage to the immune system may prevent these cancers as well.
If not, people may survive with HIV only to develop life-threatening malignancies. In the years ahead, doctors at the conference said, cancer may become a standard, accepted risk of HIV infection, just as it is for those who receive transplanted organs or who are successfully treated for childhood leukemia and other cancers.
But there was little formal discussion about the adequacy of the current techniques to track cancer among people infected with HIV and to detect what proportion, if any, might be caused by the new combination anti-HIV drugs themselves. In hindsight, members of the program committee said in interviews, they should have added this problem to their agenda.
The cancer institute's system to track cancers among AIDS cases relies heavily on studies and registries that link the two diseases. Two officials at the institute, Dr. Ellen Feigal and Dr. James J. Goedert said the existing system should be able to detect an increase in cancer rates among long-term survivors of HIV infection, though the information may be delayed.
The Centers for Disease Control and Prevention also tracks AIDS-related cancers through its own system. It includes information about certain cancers if they are detected at the time AIDS is diagnosed, said Dr. Harold W. Jaffe, an AIDS expert at the federal agency in Atlanta.
But if an AIDS patient develops a cancer after the initial report, he said, "we probably do not know that, and we need to do a better job of getting that information in a timely way."
If the frequency of AIDS-related cancers does increase or turns out to be linked to anti-HIV drugs, it would be important to get the word quickly to patients and their doctors, who are now being urged to begin combination therapy early in the course of HIV infection.
Dr. Alexandra M. Levine, an AIDS and cancer expert at the University of Southern California, said she was "extremely worried that we will see more and more cancer" among HIV-infected patients.
Treatment of HIV infection in its early stages might prevent major damage to the immune system, though it could still leave an individual with a slightly impaired immune system. "If therapies prolong lives, the immune system may be more effective at combating HIV than in controlling cancer cells" because different components of the immune system may be involved in fighting the two diseases, Levine said.
Earlier this year, a panel appointed by the National Institutes of Health urged careful long-term follow-up of all children whose mothers took AZT during pregnancy. The use of AZT in pregnancy has been one of the most striking successes in the AIDS story because it greatly reduces maternal transmission of HIV to a newborn. But a study has shown development of tumors among the offspring of mice that received very high daily doses of AZT during pregnancy.
It was the sudden appearance of the Kaposi's sarcoma cancer in large numbers of gay men in New York City that led doctors to recognize what is now called AIDS. Until then, Kaposi's sarcoma had been rare, and few experts suspected that it was related to a virus.
Then in late 1994, Dr. Patrick S. Moore and his wife, Dr. Yuan Chang, working at Columbia University without a federal grant, used a new technique to discover human herpes virus 8 (HHV-8). Further studies suggested that infection with HHV-8 was needed before Kaposi's sarcoma developed. Scientists have also linked HHV-8 to a rare type of lymphoma in people infected with HIV. But scientists do not know how HHV-8 virus causes normal cells to become cancerous or precisely how it is transmitted, and they continue to debate the possible ways.
Might other viruses help produce other cancers? Scientists are now looking hard. For example, virtually all lymphomas arising in transplant recipients are related to the Epstein-Barr virus. But only about 50 to 75 percent of the lymphomas arising in AIDS patients are linked to Epstein-Barr.
Dr. Robin Weiss of the Institute of Cancer Research in London said he was among those who had sought but failed to detect a new virus in the lymphomas linked to Epstein-Barr among people with AIDS.
One enigma is why HIV-infected women have about four times the risk of developing in situ carcinoma of the cervix yet do not go on to have an increased incidence of the more deadly invasive cervical cancer.
"It defies logic," Levine said.
Experts said they doubted the explanation that it was because Pap smears and other tests were preventing the progression of the cervical cancers. Invasive cervical cancers are not being detected in Africa and other areas where such health care is not available.
Another enigma concerns the Burkitt's type of lymphoma, which can produce grotesque tumors of the face and neck. Before the AIDS epidemic, Burkitt's was common in central Africa, but rare in developed countries. Now an estimated 2 percent of AIDS patients in developed countries get Burkitt's lymphoma, said Dr. Alan Rickinson of the University of Birmingham in England.
Rickinson said he had assumed that doctors in Africa, where there is an epidemic of HIV infection, "should see a flood of Burkitt's coming in." But Rickinson said he was astonished to learn last week from doctors at a cancer registry in Kampala, Uganda, that the incidence of Burkitt's had not increased among Africans infected with HIV.
"This is completely counterintuitive," Rickinson said. Yet, he added, "They tell me that the spectrum of AIDS-associated malignancies in Africa is different from that which we see in the West."
Burkitt's has historically occurred in regions of Africa where malaria commonly infects children. Rickinson speculated that HIV infection, by mimicking the chronic effect of malaria through an unknown mechanism on the immune system, might somehow protect against Burkitt's lymphoma.
If scientists can identify such protective mechanisms and other viruses that help produce HIV-related tumors, then they can target them in developing new strategies to prevent Burkitt's and other cancers. For example, several scientists reported using such an approach in treating Epstein-Barr-related lymphomas.
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