AIDS-Related Cancers: An Update
The "modern era" of antiretroviral therapy has resulted in a significant decrease in the number of people who develop AIDS-related cancers. Obviously, this is great news for people living with HIV. But it has presented a challenge to the conduct of clinical trials for the treatment of AIDS-related cancers since fewer people are available to participate in these trials.
The AIDS Malignancy Consortium (AMC) is a group of 15 major medical centers funded by the National Cancer Institute (NCI) that conducts research in the field of HIV-related cancer treatment. Along with Michael Marco and Jeff Taylor, I am one of three community representatives who serve on the AMC's Steering Committee. The AMC research effort focuses on the two most common cancers seen in people with HIV, Kaposi's sarcoma and lymphoma. Recently, the AMC has also begun developing trials for human papillomavirus (HPV)-associated precancerous lesions and anal cancers.
Kaposi's sarcoma (KS) is an abnormal cancerous growth of blood vessels associated with a herpes virus known as KSHV (KS-herpes virus) or HHV-8 (human herpes virus type 8). KS most commonly appears as flat or raised purple spots on the skin. For unknown reasons, HIV-associated KS is primarily seen in men who have sex with men, but very rarely in people with hemophilia or injection drug users. KS can occur in women, but it is much less common than in men. It is not known how KSHV is transmitted, but it is present in saliva as well as blood and genital secretions. KSHV infection in gay men has been associated in some studies with a higher than average number of sex partners, various sexually transmitted infections, and the use of poppers (amyl nitrate). It is not known how these associations are related to the development of KS, particularly in the case of amyl nitrate. The incidence of KSHV infection is twice as high in HIV-positive gay men, compared to HIV-negative gay men.
Cases of AIDS-related KS have decreased by 90% in HIV-positive gay men since the availability of combination antiretroviral therapy in 1996. In Mediterranean countries and Africa, a non HIV-associated form of KS has been present for many years, which usually presents as KS lesions on the feet and legs in elderly men and rarely causes death. This non HIV-related form of KS is also associated with KSHV infection. In Africa, KSHV infection appears to be acquired quite early in life, and it is not known how the infection is transmitted. It does not usually appear to be transmitted at birth.
KS involving the skin usually does not cause life-threatening problems. However, KS can also involve the internal organs, particularly the intestinal tract and the lungs, which can lead to death. Additionally, KS can invade and obstruct lymph node groups, causing blockage in the flow of lymph. Very serious leg swelling can result if the lymph nodes in the groin are blocked. Also, if the lymph nodes around the intestines have extensive KS, intestinal absorption can be greatly impaired. Although the incidence of KS has declined dramatically, it still remains a problem for many people.
Besides antiretroviral therapy for HIV, the most significant advance in the treatment of KS in the last few years has been the chemotherapy drugs DaunoXome (daunorubicin citrate liposome injection) and Doxil (doxorubicin HCl liposome injection). These drugs use encapsulated liposomal formulations -- small amounts of the drug are encased in fat bubbles called liposomes. The liposomal formulation increases the amount of time the drug stays in the blood and improves delivery of the drug to the tumor site. Based on the FDA approval, DaunoXome is indicated as a first line chemotherapy for advanced HIV-associated KS and is not recommended for patients with less than advanced HIV-related KS. Doxil is indicated for the treatment of AIDS-related KS in patients with disease that has progressed on prior combination chemotherapy or in patients who are intolerant to such therapy.
People with KS who begin antiretroviral therapy have up to a 50% chance that suppressing HIV alone, with the subsequent strengthened immune system, will result in good control of the KS. One recent study has shown that treating HIV with antiretroviral therapy results in significant decreases in KSHV viral load in the blood, probably due to the strengthened immune system. The response rates to Doxil or DaunoXome, which are administered intravenously once every three weeks, range from 50-75% in clinical trials. Another chemotherapy drug that can suppress KS is Taxol, which is also administered intravenously every couple of weeks. In general, DaunoXome and Doxil are used as first line treatment since they have fewer side effects than Taxol. But the dose of Taxol used to treat KS is much lower than when it is used to treat other cancers, such as breast cancer, and it is pretty well tolerated. Additionally, Taxol may have an added advantage to DaunoXome and Doxil in that tumors seem to have a better and longer response to Taxol. It is no longer necessary to treat KS with combinations of three chemotherapy drugs, as was the case only 5-10 years ago. The chemotherapy combinations resulted in no greater control rates, but much higher rates of serious side effects.
There are also topical, locally applied treatments for KS lesions. The FDA approved a topical compound, Panretin Gel (alitretinoin), in 1999 for the treatment of KS. Local treatments may be useful if there are only a few lesions needing treatment. KS also responds well to low doses of radiation therapy, which is sometimes used to control localized disease. Other local treatments include freezing the lesions or injecting chemotherapy drugs directly into the KS lesions. The only role of surgery is to perform a biopsy to establish a diagnosis. Removing lesions surgically is not usually helpful due to the number of lesions and the high likelihood of developing new ones after surgical removal. Usually, if someone has a significant amount of KS requiring treatment, chemotherapy is more effective than local, topical applications.
A major reason for ongoing interest in KS research is the association between a viral infection, KSHV, and a cancer, KS. Learning more about how a virus causes cancer could provide very important insights into the causes and treatment of other cancers. The most exciting new agents being tested for the treatment of KS and some other solid organ cancers are agents that inhibit the growth of new blood vessels, known as "angiogenesis inhibitors." Since the actual KS tumor is compromised mostly of new blood vessels, hence the purplish color, inhibition of blood vessel growth might be a good way to reduce and control KS. The AIDS Malignancy Consortium has conducted several KS trials evaluating these agents. However, to date, the results, evidenced by reductions in KS lesions, have been rather disappointing.
One very significant challenge to the use of angiogenesis inhibitors is determining the best dose to use. Normally, early in drug development, the highest tolerated doses are identified in small trials. The dose is determined by the rate of side effects observed as higher doses are administered. Despite conventional testing of various doses, the best dose still has not been found. Many of the angiogenesis inhibitors can be given at very high dosages without significant side effects. One possible explanation for the low response rates seen with angiogenesis inhibitors is that a large enough dose was not given. Since they work by inhibiting blood vessel growth, we need an accurate biologic assay to determine the dose needed to inhibit blood vessel growth. This is a new concept for determining drug dosing, and there are no standardized methods to accomplish this task.
Another significant challenge today in conducting research on the treatment of KS is that the number of people requiring treatment has dropped dramatically since 1996. KS is now pretty well controlled with antiretroviral therapy and DaunoXome or Doxil. Thus, these excellent clinical improvements have made it difficult to conduct studies of the newer agents to treat KS.
Lymphoma is a cancerous growth of lymphocytes, a type of white blood cell that is part of the immune system. Lymphoma usually starts in the lymph glands. The major collections of lymph glands in the body are in the neck, under the arms, in the groin, and inside the belly. The most common symptom of lymphoma is rapid growth in one or more lymph gland. Because they filter out foreign substances from the body, normal temporary swelling of the lymph glands is not uncommon. An example of this is swollen lymph glands in the neck when you have a sore throat or a cold. However, when there has been significant swelling in a localized lymph gland of greater than one inch, for more than 4-6 weeks, with no obvious cause such as a localized skin infection, consideration should be given to having a biopsy performed to see if the swelling could be due to lymphoma. Generalized symptoms such as fever, night sweats, and weight loss can also be caused by lymphoma. Because many of the lymph glands are just beneath the skin, a lymph gland biopsy may be a relatively minor surgical procedure.
With current antiretroviral therapy, the overall incidence of lymphoma in HIV-positive people is declining, but not as much as the decline seen in KS. Lymphoma occurs more often in Caucasian men and people with blood clotting disorders, such as hemophilia. People born in the Caribbean and Africa have much lower rates of lymphoma. It is not known why this is. The most common type of lymphoma seen in people with HIV is non-Hodgkin's lymphoma (NHL). Hodgkin's lymphoma (HL), which generally has a higher cure rate than NHL, was not seen frequently in HIV-positive people in the past. However, there appears to be an increase in the percent of lymphoma cases of the Hodgkin's type recently in HIV-positive people, even though the total number of people with lymphoma appears to be declining.
Fortunately, the use of antiretroviral therapy has resulted in a dramatic decline in cases of one of the most aggressive and deadly lymphomas, that of the brain -- central nervous system (CNS) lymphoma. In fact, the AMC has been unable to enroll enough people in its most recent CNS lymphoma trial and has closed the trial due to the rapidly declining incidence of CNS lymphoma.
There has also been a decline, though not as significant, in some of the other more aggressive cell types of lymphomas. However, there still remains an ongoing need for clinical research into the treatment of HIV-associated lymphomas.
Prior to 1996, people with HIV-associated lymphoma had an average survival of only six months due to much weakened immune systems. In a trial conducted before the use of combination antiretroviral therapy, the AIDS Clinical Trials Group (ACTG) compared the use of standard-dose to low-dose m-BACOD chemotherapy in people with AIDS-associated NHL. m-BACOD is a combination of six chemotherapy agents: methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone. The study found that the standard dose of m-BACOD had a greater rate of serious side effects but no better outcome measured by either response rates or survival. While low-dose m-BACOD is a treatment option for lymphoma, other chemotherapy drugs that have less toxicity are more commonly used now.
With the use of antiretroviral therapy, both treatment and recovery from lymphoma seem to have improved. Over 50% of people treated with chemotherapy have a good chance of being cured. Generally, if there is a recurrence after treatment for lymphoma, it occurs within the first couple of years. So the longer someone remains free of disease after treatment, the less likely the chance of recurrence. Antiretroviral therapy has allowed standard doses of chemotherapy to be used with fewer complications, and strengthened immune systems have resulted in much higher remission rates.
The current standard chemotherapy regimen for non-Hodgkin's lymphoma is called CHOP, which consists of cyclophosphamide, doxorubicin, vincristine, and prednisone. The first three drugs are given intravenously on the first day of treatment, and the prednisone is taken orally for five days. The "cycle" is repeated every three weeks, four to six times. The AIDS Malignancy Consortium has just completed a large non-Hodgkin's lymphoma trial, number 010, which enrolled over 150 people. The trial data are being analyzed, and results should be presented late this spring. The 010 trial compared CHOP to CHOP plus rituximab, a monoclonal antibody that attacks lymphoma cells. (Monoclonal antibodies are drugs, administered intravenously, which contain one specific antibody that attacks a specific target.) Rituximab attacks a site on the surface of the lymphocyte known as CD20. Most HIV-associated lymphomas have CD20 present on the lymphoma cell surfaces. Rituximab plus CHOP has already been shown to be better than CHOP alone in people with lymphoma not associated with HIV infection.
The next AMC non-Hodgkin's lymphoma trial to begin, number 034, will study a chemotherapy regimen that is probably more potent than CHOP. The regimen is called EPOCH. It requires a four-day continuous intravenous infusion of etoposide, vincristine, and doxorubicin, with cyclophosphamide added on day five, and prednisone given orally on days one through five. The "cycle" is repeated every three weeks, for two to six cycles, depending on response. The 034 study will determine if treatment results are better if rituximab is given with the EPOCH or afterwards. A total of 70 people will be enrolled in this trial. Trial participants and their healthcare providers will be able to decide whether or not to continue antiretroviral therapy during the chemotherapy treatment period.
A trial conducted by the National Cancer Institute (NCI) using a similar four-day infusion regimen, CDE (cyclophosphamide, doxorubicin, and etoposide), showed very high response rates, with few relapses in HIV-associated NHL. In the NCI study, all anti-HIV treatment was stopped during the chemotherapy treatment period because of concerns over possible drug interactions. For people who have recurrent lymphoma, or fail to get a good response to the initial treatment regimen, there are some trials investigating bone marrow transplantation and other chemotherapy agents.
Human papillomavirus (HPV) is associated with cancer of the cervix in women and anal cancer in men and women. Precancerous changes caused by HPV are called "intraepithelial neoplasia" (IN) or dysplasia -- CIN for the cervix and AIN for the anal region. There is a great deal of controversy around the topic of screening for AIN with anal Pap smears in men and women, with no uniform standard of care.
There are several issues about routine screening for precancerous anal changes. First, the technique requires specific training in the performance of anal colposcopy. This is an examination of the anal canal with a magnifying anoscope. Second, there is no proven treatment for precancerous changes. Unlike in the cervix, abnormal tissue cannot be readily removed from the anal canal. Approaches have included surgical excision or removal using electricity or laser. Lastly, and perhaps most importantly, there are no data to show that any currently available treatment will lower the long term chances of developing anal cancer. Men who have sex with men are at increased risk for anal cancer, as is anyone who has anal intercourse. What is surprising, and reassuring, is that the "precancerous" changes in the anal canal observed in many HIV-positive gay men have not resulted in a much higher rate of cancer compared to HIV-negative gay men -- at least not yet. [See Tim Horn's discussion of HPV.]
Dr. Joel Palefsky of the University of California in San Francisco is evaluating a type of treatment, an instrument called an infrared coagulator, to destroy precancerous anal lesions. There are a couple of AMC trials studying AIN and anal cancer and one in development to minimize damage to the rectal lining, the mucosa, during radiation treatment for anal cancer.
The increasing focus on the international AIDS epidemic and, hopefully, more widespread affordable treatment should present new research opportunities to study KS in Africa where both KSHV and HIV infection rates are very high. Because of the high rate of acquisition of KSHV early in life in Africa, understanding how KS is transmitted may be best learned there.
The greatest challenge currently facing AIDS-related cancer research is securing adequate funding to maintain a multi-center clinical trials network. This is particularly critical to the research effort. With fewer people to enroll into trials, the importance of a network of sites cannot be overstated. Although the National Cancer Institute now funds the AIDS Malignancy Consortium, the current grant expires next year. The NCI has indicated that it may not refund the AMC after next year, has already begun to close some trials, and is not allowing any new trials to be developed. This field cannot move forward without an adequately funded multi-center trials network. If you think that funding to support AIDS-related cancer treatment is important, share your concerns with the NCI. As with so many advances in AIDS-related research, community pressure can have an enormous impact.
Jeffrey T. Schouten, M.D. is a Community Representative to the AIDS Malignancy Consortium.
This article was provided by AIDS Community Research Initiative of America. It is a part of the publication ACRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.