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HIV-Related Cancers in the Age of HAART

Winter 1998/1999

Over the past ten years, an incredible amount of progress has been made in the management of cancers associated with HIV. Not surprisingly, highly active antiretroviral therapy (HAART) has had the most significant impact, not only in bringing down their rates of occurrence, but also in helping patients recover more fully. Unfortunately, HIV-infected patients are not out of the red just yet. HAART does not appear to have much of an effect on the incidence of non-Hodgkin's lymphoma (NHL), a potentially fatal form of cancer. And, while many patients are seeing improvements in their Kaposi's sarcoma (KS) lesions -- along with fewer new lesions -- these benefits are by no means universal and are often slow to develop. Needless to say, more effective treatments for both types of cancer are still very much needed.

In recent months, results from several studies looking at the number of new cases of HIV-associated cancers in the age of HAART were unveiled at conferences in the U.S. and elsewhere. For example, Dr. Susan Buchbinder of the San Francisco Department of Health presented data last April from a study suggesting that rates of KS have gone down in the age of HAART while the number of NHL cases have remained the same.

To reach this conclusion, Dr. Buchbinder and her colleagues reviewed the medical records of 6,704 gay or bisexual men (both living and dead) in the San Francisco area. According to Dr. Buchbinder, 3 of every 100 men were diagnosed with KS between the years 1993 and 1995, the years preceding HAART. After HAART was introduced in 1996, the rate of new KS reports fell to zero. In terms of NHL, approximately 2.2 of every 100 men were diagnosed with the cancer from 1993 to 1995. In 1996, the number of new cases only fell slightly, to 1.8 of every 100 men.

According to these data, Dr. Buchbinder concluded that, while the risk of KS has been significantly reduced in recent years, HAART appears to have little impact on the risk of developing NHL.


Kaposi's Sarcoma

Concepts of Prevention

One of the hottest concepts being talked about with greater frequency these days is the possibility of preventing KS using pharmaceutical compounds. This concept arrived on the heels of a discovery made a few years ago by a team of researchers at Columbia University: that a herpes virus -- dubbed HHV-8 (or KSHV) -- was thought to play a major role in the development and growth of KS lesions. While the role of HHV-8 is not yet entirely understood, numerous researchers have been relentlessly pursuing the idea that KS may become the PCP of the future: a completely preventable disease.

According to Dr. Steven Miles of UCLA, KS may become preventable if the following three criteria are met as research progresses:

1) That HHV-8, or another microorganism, is identified as the true cause of KS. Now some researchers are not entirely convinced that HHV-8 is the true cause, as it may be a "passenger" virus that plays very little role in the development of KS lesions.

2) The development of a test that can predict if or when disease might occur, such as a blood test that can measure the amount of HHV-8 in the blood.

3) The discovery of drugs that are effective against the microorganism and safe for use in humans. Candidates include lobucavir, adefovir dipivoxil (Preveon®), ganciclovir (Cytovene®), and foscarnet (Foscavir®), all of which have been shown to be active against HHV-8 in test tube studies and relatively safe for human use.

"Treatment options for KS have expanded over the last few years, such as that there are now four FDA-approved drugs for the treatment of KS and several novel compounds in development."

Past, Present...

Treatment options for KS have expanded over the last few years, such that there are now four FDA-approved drugs for the treatment of KS and several novel compounds in development.

Prior to 1995, the major modalities of treatment for KS included local treatments, such as radiation therapy, vinca alkaloids, and alfa interferon. Also used were standard chemotherapeutic drugs taken orally or intravenously, such as adriamycin, bleomycin and vincristine (ABV), and bleomycin and vincristine (BV). Unfortunately, these therapies were rarely associated with a complete remission of KS lesions and, at least with the latter group, often carried a number of serious side effects.

In 1996, two liposomal chemotherapeutics -- liposomal daunorubicin (Daunoxome®) and liposomal doxorubicin (Doxil®) -- were approved by the FDA, representing the first two drugs approved specifically for treatment of KS. The theory goes that, because the active compound is encapsulated in microscopic spheres of fat (liposomes), more of the drug would be available to attack the lesions without causing irreparable harm to healthy tissues and organs. In clinical trials and in practice, these drugs proved to be slightly more effective and caused fewer side effects than their chemical ancestors. Also approved over the past year were the drugs paclitaxel (Taxol®), a powerful intravenous chemotherapy, and altretinoin, a topical gel that seems to work best for patients with a small number of lesions.

...and Future

All the above mentioned local and systemic chemotherapies are effective treatments, but none is a cure. Luckily, much has been learned about the pathogenesis of KS and, as a result, a number of new treatment concepts are currently being developed.

In a nutshell, researchers tend to view KS as a disease of immune activation, beginning with HIV-infected lymphocytes and monocytes (two kinds of white blood cells) and their production of hormone-like proteins called cytokines. These cytokines include interleukins 1 and 6 (IL-1; IL-6), tumor necrosis factor (TNF), oncostatin M and gamma interferon. These cytokines have been shown to aid in the proliferation of vascular endothelial cells, a group of cells responsible for the protection and growth of blood vessels (called angiogenesis); it has also been suggested that HHV-8 plays a large role in the activity of these particular cells. To promote angiogenesis, vascular endothelial cells produce two of their own proteins, dubbed basic fibroplast growth factor (bFGF) and vascular endothelial growth factor (VEGF). For the most part, KS lesions are characterized by overgrowth of blood vessels, which ultimately lead to the appearance of KS lesions.

As confusing as this process sounds, it represents a golden opportunity for researchers attempting to develop better treatments for KS. For example, interferons, particularly alfa intereferon, have been shown to inhibit the cytokines responsible for angiogenesis (e.g., basic fibroblast growth factor). In hepatitis studies, interferon has been found to stimulate the production of IL-1. Interferon also inhibits herpesvirus activity, making it a suitable candidate to combat the effects of HHV-8.

Other compounds being developed that appear to inhibit angiogenesis, at least in test tube studies, include IL-2, TNP-470; IM-862, col-3, SU-5416, and thalidomide. Another drug in development is human chorionic gonadotropin (hCG). In the test tube, hCG causes KS cells to die. In humans, when the drug was injected directly into lesions or administered through an IV, KS lesions often shrank or became less noticeable; only the systemic formulation, however, has been shown to delay the development of new lesions.

Also in development for the treatment of KS are some of the drugs listed in the above discussion of prophylaxis. One antiviral in particular, cidofovir, has been shown to inhibit IL-6 production by HHV-8-infected cells and to prevent the development of KS tumors in mice.

Non-Hodgkin's Lymphoma (NHL)

Without a doubt, the most significant change in the treatment landscape for NHL has been the effects of HAART. In the years before HAART, NHL in the setting of HIV was associated with a 4 to 6 month survival rate. Now, when patients are treated with both HAART and chemotherapy, the survival rate often exceeds two years. While this is certainly good news, it is also true that HIV-infected patients do not seem to be any less likely to develop NHL while on HAART; just as many patients are developing this life-threatening form of cancer now as they were in the years before HAART.

"In the years before HAART, NHL in the setting of HIV was associated with a 4 to 6 month survival rate. Now, when patients are treated with both HAART and chemo, the survival rate often exceeds two years."

Today's NHL patients are often treated with the same chemotherapeutic drugs that have been in use for years. While this may not seem like progress, researchers have learned a great deal in the past few years about how best to use these drugs more effectively and safely. After all, NHL can kill the patients. But so can the chemotherapy. For example, researchers have learned that two standard chemotherapeutic combinations for NHL -- CHOP (cyclophosphamide, adriamycin, vincristine (Oncovin®), and prednisone) and mBACOD (methotrexate, bleomycin, adriamycin, cyclophosphamide, vincristine, and dexamethasone) -- can be administered at lower doses to achieve response rates that are similar to those associated with standard doses, often with fewer side effects. Moreover, researchers have learned that by starting G-CSF (Neupogen®) early on in the course of chemo, neutropenia (a decrease in bacteria-fighting white blood cells) can be delayed.

But these successes are clearly not enough. New cases of NHL do not appear to be going away in the era of HAART. Moreover, only 50% of people diagnosed with HIV-related NHL are successfully treated with these two chemotherapeutic combinations. And of those who do experience a complete remission, 50% will see their NHL return. Clearly, new treatments are desperately needed to aggressively fight this horrible HIV-related manifestation.

New chemotherapeutic regimens in development include CDE, a combination of cyclophosphamide, doxorubicin, and etoposide. In clinical trials, complete remission was reported in 62% of patients who took CDE; a percentage that appears higher than both CHOP and mBACOD. Patients enrolled in the CDE study also seemed to have fewer side effects than those enrolled in similar studies of CHOP and mBACOD. Only head-to-head comparisons will enable us to tell whether or not this combination is superior to today's standard ones.

Like KS research, much has been learned about the pathogenesis of NHL. In turn, a crop of potential compounds has entered the research arena. For starters, there are immunotoxin therapies, including anti-CD22 and anti-CD19 (anti-B4-blocked ricin). Simply put, both compounds are antibodies from mice that attack and kill B-cells. Because the hyperactivity of B cells has been found to play a role in the development of HIV-related NHL, therapies that directly target B-cells without damaging other immune system cells are of particular interest to researchers.

Also in development are compounds known as topoisomerase-1 inhibitors (also known as camptothecins). One compound in particular is topotecan, a drug also being developed for the treatment of HIV-related progressive multifocal leukeoncephalopathy (PML). Because topotecan and other camptothecins inhibit DNA function, cancer cells -- particularly those involved in NHL -- cannot replicate. SmithKline Beecham, who makes toptecan, is currently studying the safety and efficacy of the drug in clinical trials.

Tim Horn is the Executive Editor of The PRN Notebook, published by Physicians' Research Network in New York

Back to the CRIA Update Winter 98/99 Contents Page.

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This article was provided by AIDS Community Research Initiative of America. It is a part of the publication CRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.
See Also
Fact Sheet on HIV/AIDS Malignancies
The Basics on Cancers & HIV