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The KS Project Report

Current Issues in Research & Treatment of Kaposi's Sarcoma

25 oncologists, dermatologists, radiation oncologists, primary care physicians and laboratory researchers who have worked on AIDS-related KS for over 10 years were interviewed by telephone or in person. They were all asked about their work to get an idea about the current state of KS research. Many were asked about articles they have published over the years concerning various studies which provide the basis for current treatments used on patients with KS. They were all asked three questions about several of the myths and truths surrounding KS treatments as well as three basic questions: 1) "How has the course of KS changed from the beginning of the AIDS epidemic to 1994?"; 2) "What do you feel the standard of care treatment should be for patients with KS?"; and 3) "What are some of the problems you have with the current state of KS research?"

Specific comments from those interviewed are unattributed. The assurance of anonymity allowed individuals to relate sensitive issues that they will not discus publicly.


I. The Myths and Truths About Chemotherapy

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A majority interviewed talked about the use of cytotoxic agents for KS. Many blamed treating physicians for spreading myths about various cytotoxic agents, telling their patients that their immune system was "too shot" to handle cytotoxic agents even though some have such wide-spread symptomatic cutaneous KS with horrible edema that prevented their mobility.

A. "Is there any proof that cytotoxic agents deplete your immune system?"

Most could not come up with clear-cut proof or cite studies in which cytotoxic agents actually depleted patients' CD4 cells. Many cited studies that showed that various cytotoxic agents caused severe neutropenia, anemia, and even peripheral neuropathy.

One oncologist noted that a patient's CD4+ cells can and do drop when receiving cytotoxic agents, but this usually correlates with a falling white blood cell count. He said, however, that cytotoxic agents do not have an effect on a patient's CD4 percentage.

Some even hark back to an early ABV pilot study conducted by Gill and colleagues at USC (Gill 1990) in which 23 of the 33 patients developed OIs, 17 of which were PCP. PCP prophylaxis was not required in this study. This caused many to demand PCP prophylaxis on all subsequent chemotherapy trials.

B."Where did these ideas about the risk outweighing the benefits of Chemotherapy come from?"

One primary care physician noted that patients are afraid of chemotherapy because of horrible anecdotes about cancer patients losing all their hair, looking like ghosts and throwing their guts up. He has had to tell patients that these myths/anecdotes were from cancer patients in their 50s, 60s and 70s who had prostate or breast cancer. He often says, "Yes, we have seen horrible side effects in women with breast cancer and men with prostate cancer in their 60s and 70s, and if you feel like an elderly man or women, then chemo is not for you."

One oncologist mentioned that the patients who come to see him say that they "want to try everything in the book" before using any chemotherapy. In accordance with their wishes, this oncologist uses various other standard treatments and or immune modulators. When they don't work and patients finally go on to use single or combination cytotoxic agents, they often see results and don't feel as bad as they thought they would. He says, "They yell at me for wasting their time and not initially being more persuasive."

One primary care physician also went as far as to say that oncologists are "trigger happy" when it comes to giving chemotherapy. He will not recommend chemotherapy unless his patient has symptomatic pulmonary KS.

Another physician explained that cytotoxic agents now used to treat KS have been around for a number of years and oncologists learned how to use them when treating various cancers in the 1970s. However, when KS started to surface in New York, oncologists used the doses they were "familiar with" which were way too much and proved to be extremely toxic if not deadly. (For example, Adriamycin was often administered at 40 to 60 mg/m2 on cancer patients, but studies have now proven that the maximum tolerated dose of Adriamycin on young men with AIDS-KS is probably 10 to 20 mg/m2.) He recalls an event in the early 1980s, in which he was observing an AIDS patient who had just died. The oncologist turned to him and said "Look, there are no more lesions." He said, "Yes, but he is also dead."

Some oncologists mentioned that fellow oncologist also follow truisms that were handed down from early cancer days, such as "The maximum cumulative dose of bleomycin that should be given to a patient is 300 mg/m2," and "The maximum cumulative dose of Adriamycin given to a patient ranges from 450 to 550 mg/m2." Many believe this is not the case for young men with KS -- nor has it been clinically proven for KS -- and this information came from cancer studies in the 1970s (Pascual 1973; De Lana 1972).

C. In 1994, how can cytotoxic agents be used in KS patients so that they might not cause so many toxicities?

A majority of those interviewed, especially the oncologists, felt that the use of GM-CSF and G-CSF will help in preventing neutropenia which is caused by Adriamycin and other cytotoxic agents. While GM-CSF has been studied in many ACTG trials (and others) in combination with single agent and combination cytotoxic agents, its toxicities appear to be greater than those of G-CSF, although both appear relatively equivalent when it comes to ameliorating neutropenia. The tendency is to use G-CSF, rather than GM-CSF, because it does not cause the "flu-like" toxicities that have been seen with GM-CSF.

In fact, anecdotal information from ACTG 094 (ABV + AZT + GM-CSF) is that 20 mg/m2 of Adriamycin was the maximum tolerated dose. The objective of the study was to see if patients could tolerate up to 40 mg/m2 of Adriamycin and BV when administered 10 mcg/kg of GM-CSF. This never happened because the dose of GM-CSF had to be dropped from 10 mcg/kg to 5 mcg/kg to 2.5 mcg/kg because of the continual flu-like toxicity noticed with GM-CSF. Thus, neutropenia was never ameliorated because a 2.5 mcg/kg dose of GM-CSF was not potent enough.

Others noted that Epogen, which wasn't around in the 1970s or 1980s, is now extremely helpful for preventing severe anemia. And even though extreme nausea is not often seen with low doses of cytotoxic agents used on KS patients, Zofran is a new drug that works for ameliorating nausea.

Various agents that have been approved recently for prophylaxis against OIs (PCP and MAI) are now mandated in most protocols. Most believe this should be standard practice for any HIV positive patient with a CD4+ cell count of under 200, but note that a patient with raging KS might either have an underlying, undetected OI or become more susceptible.

Another oncologist mentioned the fact that patients receiving cytotoxic agents in the late 1980s were also taking 1,200 mg of AZT a day, which might have contributed to the neutropenia and anemia. Now, the AZT dose is usually less than a half, and some patients eschew nucleosides for various reasons.

This fact was echoed by another oncologist who is involved in the ACTG 163 trial (ABV + ddI or ABV + ddC). While he mentioned that results have been impressive, there is still some toxicity seen with ddI and ddC. He believes that if a patient is truly late stage with pulmonary KS, they might be better off sticking just with ABV and holding off for a while on their nucleosides.

One oncologist, however, related that if a patient comes to see him with extreme, uncontrolled KS, the first thing he likes to do is put them on an antiretroviral. This uncontrolled KS, he says, is probably due to a flurry of HIV activity with rapidly declining CD4+ cells. He feels that usually the antiretroviral will calm things down. It will, of course, not take away existing lesions, but might stop the explosion.


II. How Has the Patient Population With KS Changed Over the Past 10 Years?

Most all who were interviewed believed that the patient population with KS has changed over the past 10 years. They seemed to all agree that patients with KS in the early 1980s often had CD4+ cells between 200 and 400 and even higher. Now days most patients seen by many of the various physicians have a CD4+ cell count below 200 and often under 100.

A. What are some of the reasons patients now appear to develop KS at lower CD4+ counts than earlier in the epidemic?

A good many believe that KS is not only a function of HIV immune dysregulation, but that co-factors and some type of infectious agent is responsible for certain individuals -- most notably homosexuals -- getting KS. Most contend that this co-factors or infectious agent was usually sexually transmitted through oral-fecal transmission, and some hold to the poppers myth. The patients with HIV who got KS were probably very sexually active gay who were either getting the "KS agent" or chronic immune stimulation from rimming or unprotected anal sex with a man who had this infectious agent. Thus, when HIV was being transmitted through sex, sometimes this infectious agent was also being transmitted.

This hypothesis was based on the presumption that this group of men infected each other in the late 1970s and early 1980s. Hence, this cohort had HIV, their KS sprouted early on because of the infectious agent -- with or without an intact immune system -- and now most all of them are dead.

Now, however, this different population of men may not be engaging in rimming or exposing themselves to a population who had this infectious agent.

There are also those who don't believe the oral-fecal/infectious agent analysis. Many just believe that the course of HIV has evolved over the past ten years, and didn't know, or care to guess, why patients now seem to develop KS as a late-stage disease.

One oncologist does not believe in the infectious agent analysis. He says that if it were true, and all the people with this infectious agent have died, then why is the prevalence of KS still the same? He pointed to current MACS cohort epidemiological data which shows an high ongoing incidence of KS in the HIV-infected population.

Some felt that the reason was simple: 1) There are drugs patients have been taking to cure other OIs and prophylaxis for OIs. Since they are not getting PCP or dying from PCP, as were many in the 1980s, and because patients can prophylax for and treat MAI, then there is more time in which to develop KS. 2) Since patients are not getting these other OIs, whose inflammatory complications may have triggered KS, patients may not be as susceptible to early KS. 3) Early AIDS patients died quickly from PCP or another OI, so, of course, they never had KS, early on or later. 4) Anti-retroviral therapy now keep patients CD4+ cell count up. Patients with high CD4+ cells are not as likely to develop KS. Patients were not taking these drugs in the 1980s and their CD4+ dropped rapidly and they, in turn, developed KS.

One oncologist didn't really have an answer, but related that unlike all other OIs, "KS is a totally unpredictable disease." He said that a patients may have a few lesions early in the course of their disease and they have gone away. After a few months and maybe even sometimes years, the same patient will suddenly get 16 new lesions.

There were also those that were not sure if patients who now develop KS have a lower CD4+ cell count. These doubts came from a few oncologists and radiation oncologists. They believe that there are probably KS patients out there with CD4+ cells of 200 to 400, but primary care physicians are "hiding them" and don't refer patients to them, as they did in the 1980s.

A few oncologists reported that it is too often the case that they only see KS patients with advanced disease who have low CD4+ cells. This angered those oncologists who would have liked to have established some sort of a relationship with the patients and start treatment, instead of getting a patient with 17 CD4+ cells and horrible edema that prevents their mobility. One oncologist proclaimed that up to a third of the patient who come for treatment are self-referred because their primary care physicians have chosen to ignore their KS or tell them they are too weak for chemotherapy.

Some primary care physicians balked at the assertion that they are "hiding" patients with KS. They noted that they don't always feel the need to refer patients to an oncologist. A few noted that since they are the patient's primary care physician, and they know the treatments available for the various stages of KS, they can administer injections of Velban (vinblastine), liquid nitrogen and even IFN-alpha. One admitted to administering cytotoxic agents (without a chemotherapy certified nurse) to patients who need it.

Another mentioned that some patients are reluctant to go to an oncologist because they only trust their primary care physician and having to go to an oncologist makes them think they have cancer. Having HIV and admitting they have a malignancy -- a "cancer" -- is often more than a patient is ready to deal with.


III. Standards of Care

It was expected that most of those interviewed felt that the treatments they were providing were safe, effective and part of the standard of care regimen for KS at various stages of the disease. It is also important to note that those interviewed have been treating patients for a number of years, have published widely and are considered the experts in their respective fields. Those interviewed also practice in major cites (New York, San Francisco, Los Angeles, Chicago) where there is a much higher incidence of KS. Oncologists, radiation oncologists, dermatologists, and primary care physicians from small cities or rural areas, who have not seem much KS and might not know exactly how to treat KS, were not interviewed or consulted. Thus, no one gave "crack-pot" or "scary" answers on how to treat a patient with KS.

The use of liquid nitrogen for freezing small, indolent lesions was often recommended and rarely contested. Most said that it should be done when the lesion is in its early stage and relatively small. Some mentioned that hypopigmentation results after therapy so this might not be acceptable for darker skinned patients. Primary care physicians felt that they can administer therapy and there is no need to refer patients to a dermatologist for liquid nitrogen.

The use of Velban (intralesional vinblastine) was problematic for many who were interviewed. Some mentioned the price of Velban as being an issue. One said, "Velban is dirt cheap." Another said, "Velban is expensive. Doctors make a lot of money off Velban because you can charge for Velban as a chemo drug and you also get to charge for each injection. Every time you inject Velban, that's more money."

Some oncologists had trouble with Velban being used so widely and on patients who have 20 to 50 lesions. One had trouble with dermatologists who choose to inject Velban into a patients with numerous lesions. This oncologist chided, "Just because you inject one lesion, doesn't mean that the other 20 on the leg are going to go away. Doesn't the patient or doctor notice the scarring from the [intralesional] Velban? A dose or two of intravenous bleomycin might be able to clear them all away."

One primary care physician, however, said, "Some patients demand numerous injections of Velban. They will deal with the pain over taking chemotherapy. I have to try real hard to tell them that we probably aren't getting anywhere, and chemotherapy might be the answer."

There was often some disagreement about how and when to treat oral KS lesions. Most thought that oral lesions should not be treated unless they are highly symptomatic, causing a loosening of the teeth or interfering with eating. When they are, some recommended injections of bleomycin, Velban, liquid nitrogen or surgical incision.

One thought that the oral lesions should be treated right away, because if you stop that lesion, you might prevent other lesions by interfering with cytokine proliferation.

Most physicians, but not the radiologists, believe that radiation therapy can be harmful for oral lesions because of severe confluent mucositis and salivary gland dysfunction.

Radiologists said that radiation therapy is effective on highly symptomatic and hard to reach oral lesions, but that the patient should be on an anti-fungal drug and probably Acyclovir before and during treatment. One noted that a single field dose of 8 Gy is effective, followed by smaller, fractionated doses. Another mentioned her pre-treatment of the lesions with topical Oratect gel that allows her now to treat lesions without the usual side effects.

Many believe that IFN-alpha is useful for patients who don't want or are not ready for systemic cytotoxic agents. IFN-alpha as a single agent was not recommended mostly because treating physicians aren't seeing patients with over 200 CD4+ cells. Some even said that single agent IFN-alpha was "obsolete." There are those who feel comfortable, and claim to see results, using IFN-alpha in combination with nucleosides.

One oncologist mentioned that although IFN-alpha might not be for all patients, he has not seen "anything as useful as IFN for totally making lesions disappear. When it works it really works."

Most everybody agreed that cytotoxic therapy (as a single agent or in combination) must be used for symptomatic visceral KS. While many are not happy with certain toxicities, they noted that there are many agents to choose from. Some thought that administering a few doses of single agent cytotoxic therapy was warranted for problematic cutaneous KS.

Most oncologists are thankful for having G-CSF for dealing with myelotoxicity that accompanies cytotoxic therapy. "Now, with the use of G-CSF," mentioned one oncologist, "neutropenia might no longer be an issue." One oncologist, however, thought that G-CSF was being overused in some cases, and that he has heard about patients going on to G-CSF with an ANC above 2,000.

Almost all agreed on two issues surrounding cytotoxic agents: 1) even though response rates are high, the duration to relapse is often short; and 2) there needs to be something that can be used after cytotoxic therapy for maintenance therapy.

There are those that hope that some of the new angiogenesis inhibitors (Tecogalan, TNP-470, rPF4) will be that maintenance therapy. Some believe that this class of agents now in clinical trials, or others that may come along, will be the "answer" for treating KS instead of chemotherapy. And, even if these angiogenesis inhibitors don't take away existing lesions, many feel that they will help in preventing new lesions from occurring. One physician doesn't feel that any "one" will do it, but that it may have to be a combination of these or one of the angiogenesis inhibitors with an immune modulator.

There are also those who are excited about DOX-SL and Daunoxome. Some believe that they will be more effective than ABV. Many believe that these liposomal anthracyclines will be effective in combination with B and V. Others are not sure if they will be more effective than ABV, but they bet that they will probably be less toxic. A few oncologists giving DOX-SL to patients who have been on other cytotoxic regimens say that their patients are "grateful" and "feel much better" after taking DOX-SL than when they were on other cytotoxic regimens. Others report a mixed bag of results, some partial responses and some progressive disease.

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This article was provided by Treatment Action Group.
 

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