Special Issue: Kaposi's Sarcoma
Treatment OverviewWith the increasing use of pneumocystis prophylaxis, anti- retroviral treatment, and subtle improvements in the management of opportunistic infections, people with AIDS are living longer today than several years ago. Unfortunately, as people live longer, increasing numbers are having to cope with complications of Kaposi's sarcoma (KS) and lymphoma, and more people are dying from these conditions. For this reason, we are presenting a comprehensive article covering standard and experimental treatments for KS. We hope this article will provide a clear picture of both current and future potential treatment options.
We will briefly discuss standard approaches for treating isolated cutaneous (skin) lesions, including intralesional chemotherapy, radiation, and liquid nitrogen. In addition, experimental approaches for cutaneous lesions will be reviewed. Some of these, like intralesional interferon and topical tretinoin (retin-A), are available by prescription for other uses. Others, like 5-FU collagen matrix, are still in clinical trials or earlier stages of development.
For disseminated KS (involving either internal organs and/or many skin lesions), we will discuss the use of interferon, standard chemotherapy, and chemotherapy drugs which are available for other indications, such as oral and intravenous etoposide (also called VP-16). Some newer chemotherapy agents, including liposomal daunorubicin, liposomal doxorubicin, and piritrexim, are still in clinical trials or earlier stages of development. Growth factors (also called colony stimulating factors) like GM- CSF and G-CSF appear to be effective in limiting the bone marrow damage associated with chemotherapy and interferon; we will describe their FDA (U. S. Food and Drug Administration) approval status and informal expanded access programs.
A discussion of an exciting new class of compounds called anti-angiogenesis agents will follow. These drugs work by an entirely different mechanism than do the chemotherapy drugs. They include experimental compounds like the Japanese drug brought to widespread attention by Robert Gallo, M. D., from the National Cancer Institute, fumagillin analogues, and PF4. Pentosan is an anti-angiogenesis compound currently in clinical trials sponsored by the National Institutes of Health. Finally, we will discuss the experimental use of agents such as Vitamin D derivatives and synthetic heparin/steroid combinations as anti- angiogenesis compounds.
A discussion of the broad area of biological response modifiers, a growing area of interest in the treatment of HIV infection and cancer, will include descriptions of the experimental compound IL-2 and the prescription drug levamisole. We will also describe the immunomodulatory and anti-angiogenic properties of cimetidine, an ulcer medication, and its potential utility in KS. In addition, we will outline the current status of the Prosorba column, an approach we first discussed in 1989 (issue #75, March 10, 1989), and briefly mention the application of hyperthermia in KS.
Standard Treatment Options
The choice of standard treatment approaches for KS today depends on the location and extent of the lesions, the individual's overall immune status (usually determined by T- helper cell counts and other laboratory markers), and the bone marrow production capacity, especially the neutrophil count. (Neutrophils are a type of white blood cell important in fighting bacterial infections.)
Limited Skin Lesions
A small number of skin lesions causing cosmetic problems can be treated with injections of small doses of a cancer chemotherapy drug called Velban (vinblastine) and/or with radiation therapy. Some clinicians freeze the lesions with liquid nitrogen, causing the cells to die and the lesions to fade.
Disseminated (Widespread) KS
Alpha interferon (INF-alpha, INTRON A, Roferon) is an FDA- approved treatment for people with KS and a T- helper cell count greater than 200. It has been shown to have an anti-HIV effect as well as an anti-KS effect and is being studied, alone and in combination with AZT, for both indications. Preliminary results suggest that lower doses of each drug used together (3-5 million units interferon plus 600 mg AZT per day) may be more useful than either drug alone with respect to both antitumor and antiviral effects; a larger proportion of people are responding to the combination than would be expected to respond to interferon alone1. Alpha interferon is usually used in people who have disseminated internal or skin lesions but may also be used if there are only a few lesions.
Interferon has been shown to be much more effective in people with higher T-helper cell counts (over 400) who have not had a previous opportunistic infection. It is also more effective in people who do not have fever, night sweats, or weight loss.2 Studies combining chemotherapy agents (either vinblastine or VP-16/etoposide) with interferon have been disappointing, showing increased toxicity and a lower response rate than expected with either agent used alone. A recent study looked at the ability of patients to tolerate increasing doses of interferon after completing chemotherapy (adriamycin, bleomycin, and vincristine). It was hoped that the interferon would maintain the regression of the lesions, reducing the need for ongoing chemotherapy. Again, the results were disappointing overall, although two patients with higher T-helper counts (350- 400) were able to tolerate the interferon and responded well to the therapy during this short study.
While there has been a great deal of interest in interferon in both KS and HIV, the side effects are significant. Although rarely life-threatening, the flu-like symptoms, including chills, headaches, fatigue, muscle aches, and low grade fevers, can be debilitating and affect quality of life.
New types of interferon are also being studied. These include beta interferon and variations of alpha interferon. One such variation, consensus interferon, is a single molecule made of the seventeen different alpha interferon molecules which have been identified. As far as we can tell, no distinct advantages of any specific product have yet been demonstrated.
The other standard approach to the treatment of widespread KS is cancer chemotherapy. The specific choice of which drugs to use depends on the individual's blood counts and medical history, including a history of peripheral neuropathy since some of the drugs might aggravate this condition. The most commonly used regimens today are a combination of bleomycin and vincristine, with or without adriamycin (doxorubicin), or alternating vincristine and vinblastine. Some clinicians include etoposide (VP-16) or use variations of the combinations described above. A complete review of a series of single agent and combination chemotherapy clinical trials by Donald Northfelt, M. D., can be found in the September 1990 issue of AIDS Medical Report,3 published by American Health Consultants. A copy of volume 3, number 9 can be purchased for $13.25 by calling 800/688-2421. (Also see AIDS TREATMENT NEWS issue #73 for a discussion of the specific toxicities of the different chemotherapeutic drugs.)
It is unfortunate but important to note that although significant lesion improvement has been seen with several chemotherapeutic regimens, survival time has often not been prolonged. There appears to be a high rate of bacterial and other infections occurring in patients receiving chemotherapy for KS. Two obvious but important suggestions were made in a recent paper reporting on a trial of chemotherapy plus aerosolized pentamidine for pneumocystis prophylaxis: 1) it is essential to use pneumocystis prophylaxis drugs, and to consider prophylaxis for toxoplasmosis and other opportunistic infections, and 2) use of growth factors which stimulate the bone marrow to produce specific types of blood cells, like G-CSF (granulocyte colony stimulating factor) or GM-CSF (granulocyte-macrophage colony stimulating factor), should be considered in an attempt to reduce the bone marrow suppressive effects of chemotherapy.
How to Obtain G-CSF and GM-CSF
The difference between G-CSF and GM-CSF is that G-CSF only stimulates the production of cells called granulocytes (especially neutrophils, a type of granulocyte), whereas GM-CSF also stimulates the production of cells called macrophages. Some clinicians, researchers, and activists believe that G-CSF would be a better choice for use in people with HIV infection because macrophages serve as a reservoir of HIV and some other infectious agents.
G-CSF, manufactured by Amgen Inc., (trade name: Neupogen) was approved by the FDA for marketing on February 21, 1991. This product was approved for patients with cancer who are using chemotherapy which suppresses white blood cell production. The approval does not include HIV- or KS-specific indications. Although any doctor can prescribe a drug for any use once it has been FDA-approved, securing reimbursement from insurance companies and Medicaid/Medicare may prove to be difficult for off-label use of the drug.
Amgen has established a "Safety Net" program for uninsured and medically needy patients. This program requires that both the patient and physician qualify. Physicians must complete an application form and purchase the G-CSF directly from Amgen. Patients will be eligible if they are uninsured and earn a combined family income of less than $25,000 per year or if they are insured, earn a combined family income of less than $25,000 per year, and have significant out-of-pocket expense for the product. Physicians only can call 800/272-9376 for more information on this program.
Preliminary studies suggest that GM-CSF is helpful in reducing neutropenia (low neutrophil counts) and the incidence of infections in people being treated for KS. See AIDS TREATMENT NEWS #110 for background on GM-CSF in lymphoma treatment and AIDS TREATMENT NEWS #108 for information on its use with ganciclovir for CMV infections). Clinical trials are testing GM-CSF's ability to reduce bone marrow damage caused by the chemotherapy, interferon/AZT combinations, and a variety of other treatments in people with HIV infection. For information on ACTG-sponsored trials which include GM-CSF, call 800/TRIALS-A.
Two variations of GM-CSF are being developed by four different pharmaceutical companies. We spoke with Carol Colvin, Pharm. D., the professional services manager at Immunex Corporation in Seattle. She explained that Immunex, in collaboration with Hoechst-Roussel Pharmaceuticals, is developing one product while Schering-Plough and Sandoz are jointly developing a slightly different product. According to Dr. Colvin, Immunex's product has been recommended for approval by the FDA Biological Response Modifiers Advisory Committee and the company is awaiting general FDA approval. She said that such approval has historically come a couple of months after Advisory Panel recommendation. An application for approval has also been filed with the FDA for the Schering/Sandoz product. This application has not yet been recommended by the Advisory Committee.
Immunex's initial application seeks approval only for patients with cancer receiving bone marrow transplants followed by high-dose chemotherapy. Again, reimbursement for off-label use of this product may be difficult. Immunex has established a reimbursement hotline to assist physicians in getting insurance companies to pay for the product and a patient assistance program for those patients who have exhausted all other avenues of paying for the drug. According to Dr. Colvin, both of these lines will be open, and the price of thecase-by-case basis, but would give no further details. Physicians can call the company at 800/526- 4099 for information about enrolling specific patients
Immunex does not have an expanded access program for HIV- positive patientsc injections. He told us that he is able to get high concentrations of the interferon in the lesions and that the approach is "worth pursuing." He recommended its use for people with high T-helper cell counts.
A small study (sevof topically applied 1% All Trans Retinoic Acid (tretinoin) gel for cutaneous KS. Although only eight people were studied, all treated lesions showed a reduction in color and size of the nodules as compared to lesions which were untreated or treated
response after two weeks; five experienced a 50% reduction in size and firmness of their lesion(s) after three months. Retin-A is used in the United States for the treatment of severe cases of acne.
A note on retinoids: Tretinoin is a vitamin A derivative known as a retinoid. Other retinoids available in the United States include isotretinoin (Accutane) and etretinate. [The use of accutane and etretinate has been limited in women because they both cause severe birth defects. Etretinate should not be used for an undetermined period of time even before becoming pregnant because it takes an unknown amount of time to be eliminated from the body.] Topical and systemic retinoids have been found to be useful, by themselves and in combination with alpha interferon, in various benign (non-cancerous) and cancerous growths of the skin and mucous membranes. Each of the retinoids tested has different efficacies in different conditions, including hairy leukoplakia (accutane) and molluscum contagiosum (retin-A). Unfortunately, it has not been possible to achieve therapeutic doses of natural Vitamin A to treat the human cancers which have been studied.
Given the growing interest in retinoids for the prevention and treatment of a wide range of cancers and non- cancerous growths, we believe that research in the possible application of retinoids for the management of KS, by themselves or in combination with other treatments, should be designed and conducted promptly. In the meantime, it is important to remember that there are serious toxicities associated with some of the retinoids; any use of these drugs should be undertaken with medical advice and careful monitoring by a physician. It is also important to realize that the only data available on the use of a retinoid in KS is the small study mentioned above. In addition, the conditions for which the retinoids have been shown to be useful may involve different mechanisms than those which cause KS.
* 5-FU Collagen Matrix. This experimental treatment is currently being tested for use in HIV-negative people with anal or genital warts. We mention it here because an intralesional implant trial for the treatment of KS had been listed in the Community Consortium's Directory of HIV Clinical Research in the (San Francisco) Bay Area since the Summer 1990 issue. The KS trial was supposed to take place in the offices of a doctor in San Francisco with a large HIV practice. When we contacted his office we were told that the company had pulled out of the study for unknown reasons. A worker at the HIV- negative anogenital wart study site in San Francisco told us that the FDA had put a hold on testing the drug in HIV-positive people. When we contacted the drug company, Matrix, to discuss the status of their product, all we were told was that the trials were on hold and would not be starting soon. Further messages have not been returned.
5-FU is a cancer chemotherapy drug. Collagen is a structural component of the skin and connective tissue. The collagen matrix was developed to help keep the chemotherapy agent in the lesion longer. We do not know if this treatment would have any advantages over currently existing KS therapies. All we do know is that there is a bit of a mystery around why the planned trial has been discontinued before it even started.
Experimental Chemotherapy Treatments
Non-standard cancer chemotherapy drugs which have been studied in KS include oral and IV formulations of etoposide (VP- 16), liposomal daunorubicin, doxorubicin (also being developed in a liposomal form), piritrexim, epirubicin, idarubicin, and mitoxantrone. As far as we can tell, the most useful drugs from this list at this time are etoposide, liposomal daunorubicin, and piritrexim.
* Etoposide (VP-16). An oral formulation of etoposide is currently being evaluated for safety and dosage at five hospitals associated with the government-sponsored AIDS Clinical Trial Group (ACTG). The drug is being administered weekly for 52 weeks. The advantage of an effective low-dose oral chemotherapy drug would be in itnd vincristine, with or without adriamycin, have often been used as first line treatment in KS. However, she said thatVP-16 might be used earlier more routinely if the results from the ACTG study are positive. Some clinicians currently use either IV on his studies yet due to problems with drug supply. At this stage, the drug company has promised him only a small supply and he plans to enroll patients on a first-come- first-served basis when the drug is available. He will consider pbe studies. Dr. Chew said he felt that there is not yet sufficient data to support that conclusion.
Dr. Chew told us that liposomal daunorubicin has been under study for 2 years at the University of Southern California in Los Angserved, but it is unclear whether they are due to the liposomal daunorubicin, AZT, or some other factor. The drug appears to arrest the further development of KS in many patients and, in some cases, reduces lesion size. However, the disease does prog another drug company using a different technology. Dr. Chew expects it to be available for clinical trials within six months.
* Piritrexim is an experimental compound similar to the chemotherapy drug methotrexate. It is not yet approved by the FDA for any indication. Two studies have been conducted in people with KS at the University of Miami. The first used two courses of piritrexim alone, followed by a combination of piritrexim with interferon. This study has been completed. A second study using only piritrexim was initiated to look at the safety and efficacy of using the drug in low doses on a daily schedule. This study will be completed within weeks.
We spoke with the principal investigator of these two studies, Margaret Fischl, M. D., from the University of Miami School of Medicine. She explained that piritrexim had been shown to have some success in solid tumors, suggesting that it may be useful for KS. So far, the drug has been relatively well tolerated, with skin rashes and depressed white blood cell counts among the common side effects. The two most important findings so far, according to Dr. Fischl, are: 1) as with alpha interferon, piritrexim appears to be most useful in early KS, where tumor regressions have been seen, and 2) there is both test-tube and human evidence to suggest that piritrexim may also be useful in preventing pneumocystis pneumonia. Dr. Fischl explained that daily dosing with a low dose seems to be superior to the cyclic schedule used in the first study.
Dr. Fischl plans to present the data from these two studies to the ACTG for consideration of future studies. She told us that the main question that needs to be considered in deciding where to go next with this drug is whether or not piritrexim will have any significant advantage over alpha interferon. She pointed out that interferon does show activity against HIV in addition to early KS, whereas piritrexim does not have any anti-HIV activity.
* A number of small studies have also been conducted with the chemotherapy drugs doxorubicin (adriamycin), epirubicin, idarubicin, and mitoxantrone. In general, results have been inconsistent or not dramatic. Test-tube studies have suggested that mitoxantrone should be pursued, whereas previous clinical studies have been disappointing. Dr. Chew told us that data which is awaiting publication suggests that idarubicin, recently approved for acute leukemia, acts more quickly than daunorubicin in leukemia and thus might be more effective in KS. We will continue to follow developments in new chemotherapy drugs for KS.
Anti-Angiogenesis Compounds
With the exception of a single trial (of pentosan, described below), the U. S. government-sponsored clinical trials in KS have focused on the use of chemotherapy and interferon by themselves and in combination with anti- retrovirals and the white blood cell growth factors (GM- CSF and G-CSF) discussed earlier in this article. However, a growing number of scientists working in the areas of cancer and basic research are focusing their attention on an entirely different class of compounds, those which interfere with angiogenesis (the growth of new or abnormal blood vessels).
Most solid tumors rely on an abundant blood supply, provided by in KS because KS appears to be a proliferation of abnormal blood vessels. It is believed that many of the growth factors involved in the development of blood vessels in solid tumors are the same as those involved in the development of KS lesions. [mThese compounds and/or others in the same class may prove to be more specific and thus less toxic than the cancer chemotherapy drugs which are currently in widespread use for KS. Although many of the most promising compounds are still in very early pre experiments and in clinical trials with humans now. Some physicians and researchers in the AIDS community, including Joseph Sonnabend, M. D., from New York, have been discussing, writing about, and urging further research in this area for several years.
Hundreds of compounds are being studied in laboratories around the world for their anti-angiogenic properties. A computer search revealed over 1,000 articles in the scientific literature in this area. The retinoids mentioned earlier in this article are believed to have anti-angiogenic properties. We will describe briefly only a few additional compounds, including pentosan, PF4 (platelet factor 4), fumagillin analogues, vitamin D3 analogues, and a synthetic heparin/steroid combination. These are not necessarily the most promising compounds, nor the most available; they are simply the ones which have received the most attention so far in the AIDS research, treatment, and activist communities.
It is our strong belief that the experts in the field of angiogenesis and cell differentiation, whether or not they are involved in HIV, should be actively recruited by the government- sponsored research agencies to share their knowledge, theories, data and expertise in the effort to find safe and effective treatments for KS.
* Pentosan is a sulfated polysaccharide being studied for safety and dosage at the National Cancer Institute (NCI). Pentosan is an anti-coagulant which is believed to have both anti-HIV and anti-KS properties. We spoke with James Pluda, M. D., who is directing this study. So far, three doses have been studied in groups of three to six patients. Patients in the lowest dose group have been receiving the drug for several months. Some patients using the second dose showed some anti- coagulant effects; therefore, it was decided to test an intermediate dose rather than trying to increase the dose any further. Other side effects seen so far have included reversible liver function test abnormalities, and thrombocytopenia (decreased platelet count).
Dr. Pluda explained that this drug does not kill the KS cells; it just stops their growth, so it takes some time to see an effect. He emphasized that he does not know how to use this drug safely yet, and that people who have obtained it should only use it with the careful monitoring of a physician experienced with the drug. All slots for the NCI study have been filled.
* rPF4 is a recombinant (genetically engineered) version of a protein which is found in platelets, a type of blood cell. It has been found by researchers at Repligen Corporation to inhibit angiogenesis in test tube studies and in animals with of a variety of different tumors. It does not cure the tumors, but prevents further growth.
According to Theodore Maione, Ph.D., principle investigator of the animal studies, the activity of the compound has been specifically targeted to the cell type found in blood vessels (endothelial cells). KS lesions include a large number of fast growing endothelial cells. Therefore, it is hoped that PF4 will specifically target the cells which comprise the KS lesions. While no formal toxicity tests have been conducted yet, no toxicities have been observed in animals.
rPF4 is not yet ready to enter human trials. After animal testing is completed, Dr. Maione told us that Repligen will file an application with the FDA to do testing in people with KS. The initial studies will use intralesional injections to determine if there is a local tumor response. The FDA application will not be filed until the end of 1991. In the meantime, Repligen is scaling up production of the compound.
* Fumagillin analogues are synthetic variations of a naturally occurring antibiotic. We asked Donald Ingber, M. D., Ph.D., the author of a recent article in Nature, about these compounds. He told us that fumagillin itself is too toxic to be used in humans but that the synthetic analogues have shown tumor response in every solid tumor tested in animals to far. As with PF4, the tumors generally do not regress, but their growth stops. Dr. Ingber described these compounds as very specific to growing tumors and non-toxic. He anticipates that therapy with this type of compound would be life-long, as with diabetes.
No tests have yet been conducted in humans. The drug company, Takeda Chemical Industries, Ltd., is attempting to increase production of the compounds in order to begin clinical trials, hopefully, within the next two years. These trials may not, however, be in people with KS. The company is also involved in an active search for other anti-angiogenesis compounds.
* "Gallo's Japanese KS Drug." For background on the scientific and political issues involved in this area, refer to Project Inform's PI Perspectives, issue number 9, October, 1990 (National 800/822-7422; California 800/334-7422) and AIDS TREATMENT NEWS issue #99, March 16, 1990.
* Vitamin D3 analogues also appear to have anti- angiogenesis properties in test-tube studies. Vitamin D3 itself was not found to be effective in these studies. The authors suggest that these vitamin D3 analogues may work by a similar mechanism as the retinoids discussed earlier in this article.
* Synthetic heparin substitutes in combination with specific steroids have been found to inhibit angiogenesis in two experimental models. Heparin is a potent anti- coagulant; however, fragments of the compound which have lost their anti- coagulant properties retain anti- angiogenic activity when combined with certain steroids. The most potent heparin substitute reported on in this paper was beta-cyclodextrin tetradecasulfate. This compound actually stimulated angiogenesis when used alone, but was inhibitory in combination with a steroid.
The heparin substitutes were combined with the steroid hydrocortisone or with a hydrocortisone derivative which has lost most of its steroid properties. We have spoken with many physicians and researchers about this particular combination. Without exception, two concerns were raised. The first was the need to use heparin substitutes rather than heparin in order to avoid the anti-coagulant effects. The second was that steroids have been shown to stimulate the growth of KS when they have been given to patients for other purposes. Therefore, while heparin substitutes and steroid derivatives which lack the usual steroid properties appear to be a potentially useful anti-angiogenic combination, a standard heparin/steroid combination could be more harmful than helpful.
Biological Response Modifiers in KS
Another area of intense scientific interest is in the use of immune modulators, or biological response modifiers, in the treatment of a wide variety of illnesses, including cancer and HIV infection. Many of the biological response modifiers being studied now are compounds which the body's cells produce naturally as a part of the immune response or in normal blood cell production (IL-2, the interferons, G-CSF, GM-CSF). Some others are drugs which have been used for completely different indications, but are suspected to have biological response modifier properties as well (cimetidine, levamisole), and somefically for this purpose (Prosorba column).
Many people believe that one of the keys to managing HIV infection will be combining one or more biological response modifier(s) with various antivirals and prophylactic agents. It is hoped that the e of four patients using a combination of IL-2 and beta interferon. It was suggested by the authors of that study that investigators who use IL-2 should avoid intermediate to high dose bolus (injection over a very short period of time) therapy. In ad outcome of people with KS who are using IL-2.
* Cimetidine (Tagamet) is an ulcer medication which has been found to have both anti-angiogenic and immunomodulatory effects. We first reported on the use of cimetidine in patients with KS in 1989 (see AIDS TREATMENT NEWS #80). Interest in studying this drug for use in HIV and cancer has been nearly nonexistent since that time. We have heard speculation that there might be little interest in further studies because the patent is running out in the next year, significantly decreasing the drug's profitability.
A small study performed by Thomas Smith, M. D., from the Massey Cancer Center in Richmond, Virginia, was recently published as a letter in the Journal of the National Cancer Institute. Of the eight patients treated for skin, oral, and/or gastrointestinal KS lesions, one experienced a complete response, one a partial response, and one a mixed response. There were no subjective or objective toxicities reported.
We spoke with Dr. Smith who told us that his impression is that cimetidine is most effective in people with relatively high T-helper cell counts. He explained that it seems to be useful in skin and oral lesions, not just in gastrointestinal lesions. Cimetidine appears to enable Natural Killer (NK) cells, the immune system's main defense against cancer, to fight the KS.
Dr. Smith believes that cimetidine will ultimately be most useful in combination with cancer chemotherapy and/or other biological response modifiers. He also told us that patients who cannot tolerate low doses of alpha interferon, his first choice treatment in combination with AZT, may benefit from cimetidine.
Dr. Smith did not know of anyone else studying cimetidine. Because of the small patient population where he practices, he is not planning future studies of this drug in people with KS. If he gets funding, he will be studying the drug in patients with cancer.
* Levamisole is also a prescription drug which may have some immunomodulatory function. Originally approved for the treatment of worms, its approval was recently expanded to include the treatment of advanced colon cancer (stage C) when it
source: AIDS Treatment News
