ddodell@stjhmc.fidonet.org (David Dodell) (03/04/91)
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AIDS TREATMENT NEWS Issue #122, March 1, 1991
phone 800/TREAT12, or 415/255-0588
copyright 1991 by John S. James;
permission grantedfor non-commercial use.
Special Issue: Kaposi's Sarcoma
Treatment Overview
by Michelle Roland
With 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 the drug will be announced, on the day
FDA approval is received. How well these programs actually
function remains to be seen.
Until GM-CSF is approved, physicians may try to get the drug
through expanded access for patients with low neutrophil counts.
A representative of Schering-Plough said that the drug may be
supplied to individuals on a case-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 patients, purportedly because of limited experience with
the use of GM-CSF in people with AIDS. In spite of a growing
sense of the utility of GM-CSF in a wide variety of HIV-
associated conditions, and an increasing collection of data in
these situations, Immunex has no plans to include HIV-positive
patients in its compassionate-use program.
Experimental Approaches to Treat Individual Lesions
* Intralesional interferon. Terrance Chew, M. D., a
hematologist-oncologist studying this approach at St. Francis
Hospital in San Francisco, explained that the interferon might
have an immune stimulating and anti-HIV effect in the lesion
itself and that injecting it locally would reduce the toxic side
effects experienced with systemic 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 (seven patients) published in the abstract
book of the Sixth International Conference on AIDS in San
Francisco suggested that all lesions treated with intralesional
interferon responded in thickness, size, and color, but that
patients with higher T-helper cell counts and without any prior
opportunistic infection experienced a larger response. Dr.
Chew's study calls for three injections per week; the study from
the Conference used daily injections for four weeks, followed by
three injections per week. Intralesional Velban, liquid
nitrogen, and radiation therapy usually require significantly
fewer treatments.
* Topical tretinoin gel (Retin-A). Another abstract from
the Sixth International Conference on AIDS described the use of
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
only with the oil used in the gel. One patient had a complete
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 its ease of administration and milder side
effects. We spoke with Susan Krown, M. D., Chair of the ACTG
Oncology Committee, who told us that the study is accruing
rapidly and proceeding without any problems. The oral
formulation of VP-16 is approved for the treatment of a specific
type of lung cancer.
Dr. Krown told us that until now other drugs, such as
bleomycin and vincristine, with or without adriamycin, have often
been used as first line treatment in KS. However, she said that
VP-16 might be used earlier more routinely if the results from
the ACTG study are positive. Some clinicians currently use either
IV or oral VP-16 (weekly or monthly) in combination with other
chemotherapy drugs. Others are trying the oral form daily in
very low doses for several weeks.
* Liposomal daunorubicin. Liposomes are small spheres of
fat into which drugs can be placed. The hope with liposomal
technology is that toxic drugs can be targeted more specifically,
and at higher concentration, to the areas where they are needed.
It is thought that the liposomal drugs will leak in those areas
in which there are abnormal blood vessels and will target the
abnormal cells that comprise the KS lesions. Daunorubicin is a
cancer chemotherapy drug.
We spoke to Dr. Chew about his plans for two studies with
this drug. No patients have been enrolled in 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 patients with widespread KS which
has not responded to treatment or has never been treated. He
will try to include patients with the greatest need first, when
the drug supply is limited. For more information about this
trial, please call Drew Catapano at (415) 775- 4321, extension
2512.
The original trial has been written to include 16 patients.
Dr. Chew agreed that if this initial trial is promising, future
trials should be designed to look at the efficacy of the
liposomal daunorubicin in combination with other chemotherapy
agents and/or biological response modifiers (immunomodulators)
like interferon. An abstract presented at a recent scientific
meeting claims that daunorubicin has an anti-HIV effect in test-
tube 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
Angeles and that it has shown promise. We spoke with Sue
Cabriales, R. N., the research nurse who administers the drug to
patients in that trial. There are currently 15 people enrolled
in the trial, and the drug company is just beginning to analyze
the data. The drug is administered every two weeks over a 40-
minute period. Ms. Cabriales told us that it is a very easy drug
to deliver because it does not cause local tissue damage, unlike
many cancer chemotherapy drugs.
Although the data have not yet been analyzed, Ms. Cabriales
gave us her unofficial impression of the drug. Toxicities appear
to be minimal, with some fatigue, mild nausea, and increased
cholesterol and triglyceride levels. Depressed blood counts have
been observed, 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 progress if the treatment is stopped. The longest a patient
has been on the trial is over one year.
* Liposomal doxorubicin (adriamycin) is being developed by
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
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