Epidemic, AIDS-associated Kaposi's sarcoma (KS) is an unusual malignancy first noted in 1981 at the start of the global HIV pandemic. The epidemiology of KS is unusual in that it is mainly confined to a subset of the HIV-infected population, gay and bisexual men, suggesting that KS may be linked to an as-yet undiscovered infectious agent or cofactor other than HIV. While the etiology of AIDS-KS remains to be determined, its pathogenesis has recently been partially explained as the result of inflammatory processes in endothelial cells leading to spindle-cell formation, neoangiogenesis, edema, and ultimately, a multifocal, apparently non-clonal neoplastic disease. KS sometimes appears relatively early during HIV-associated immune dysregulation, and may be indolent in course. Later in disease, KS is more often found in visceral organs, and when found in the lungs may be fatal. Whether cutaneous or visceral, cosmetic or life-threatening, KS imposes a major burden on the quality of life of people with HIV, and may become life-threatening. Currently we lack reliable evidence about the incidence and severity of KS in all HIV-infected populations, but it appears to be becoming more common and more severe as people with HIV survive or avoid multiple opportunistic complications. Current standard-of-care treatments for KS remain incompletely validated and disappointing. While interferon alpha has shown limited anti-KS activity in people with relatively intact immune systems and CD4 counts over 200/mm3, progressive disease in persons with more advanced immunodeficiency is only imperfectly controlled with combination cytotoxic chemotherapies such as adriamycin, bleomycin and vincristine (ABV). Against the limited clinical utility of these approved agents must be set their toxicities, expense and inconvenience. Novel experimental approaches to the treatment of KS are now in preliminary studies, including liposomally-encapsulated anthracyclines, cytokines and their inhibitors, and several kinds of angiogenesis inhibitors. The safety, efficacy and optimal uses of these agents remain to be defined in well-controlled clinical studies. Current opinion among AIDS oncologists, infectious disease specialists, and primary care AIDS clinicians remains divided about when to initiate anti-KS therapy, what are the optimal regimens, and how best to integrate KS management into the spectrum of HIV primary care. Currently, research on the etiology, pathogenesis, epidemiology and treatment of KS remains inadequately supported by the National Institutes of Health (NIH). KS clinical trial programs remain ill-coordinated between multiple networks separately funded by the National Cancer Institute (NCI) and the National Institute of Allergy and Infectious Disease (NIAID). We recommend a series of new scientific initiatives and programs to resolve these problems and improve our understanding of and clinical management of AIDS-associated Kaposi's sarcoma, a disease which eventually afflicts over 30% of people with AIDS living in the United States.
KS Project Recommendations
- The National Institutes of Health (NIH) must add an AIDS-related malignancies study section under its Division of Research Grants (DRG), or the National Cancer Institute (NCI) should charter an ongoing ad hoc AIDS-oncology study section.
- NCI should provide more extramural funding for AIDS-related malignancies.
- The NCI should provide funding in the form of supplemental awards to AIDS clinical trial units (ACTUs) to conduct AIDS oncology trials, by supporting on-site oncology expertise and necessary ancillary services.
- The AIDS Clinical Trials Group oncology committee should remain an autonomous, separate committee within the ACTG.
- All NCI cooperative clinical oncology groups should set up AIDS committees; they should form a joint umbrella AIDS oncology working group to liaison with the ACTG and conduct cross-network studies.
- NIH's Office of AIDS Research (OAR) should work to foster collaboration and cooperation between NCI's cooperative groups and NIAID's ACTG in conducting large-scale clinical efficacy studies to further define the standard of care and develop new agents for the treatment of AIDS-related malignancies.
- NCI should support an initiative to train more AIDS oncologists.
- OAR should support the NCI's bypass budget request to provide funds (through the p20 mechanism) to their cancer centers for the development of new research programs focusing on AIDS-related malignancies.
- OAR should support the NCI's 1996 bypass budget request for the provision of funds for pilot projects and feasibility clinical AIDS oncology studies to be run through the NCI's cancer centers and ACTUs.
- NCI and NIAID should establish, among existing cohorts (e.g., MACS or ACTG, CPCRA), and/or among new populations, a prospective epidemiological survey of the incidence and natural history of AIDS-related malignancies, with central tissue and serum banking, to provide better information on who develops these complications and how they progress and respond to treatment.
- OAR, in collaboration with NCI, NIAID, and the Agency for Health Care Policy and Research (AHCPR), should establish a state-of-the-art panel to review current treatment options for AIDS-related malignancies (especially KS) and recommend standard-of-care guidelines, as well as identify gaps in knowledge which could be filled by well-designed and executed randomized controlled studies. A standard of care must be established so that we finally know what is the optimal therapy for KS patients at various stages of disease.
- The new treatment guidelines should make it clear that KS and lymphoma patients should be referred to an AIDS oncologist for evaluation and a discussion of possible treatments. "The [mere] observation of patients with progressive KS is unacceptable."
- A mechanism needs to be established to teach oncologists about AIDS and how to become more involved in basic and clinical research.
- Primary care physicians and patients must also learn more about the current pathogenesis of AIDS malignancies.
- Serious thought needs to go into how we get physicians to refer KS patients into current (and the next generation of) anti-angiogenesis/cytokine modulation trials, and other novel approaches to treating AIDS-related malignancies.
- We need to study whether angiogenesis inhibitors and cytokine modulators (maybe in combination) are appropriate for patients with early stage KS or may prevent the formation of new lesions. In time, after we have learned more about these agents, will we be at the point where we can say that these compounds might be effective as prophylaxis for KS?
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