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Radiation Therapy for Malignancies in the Setting of HIV Disease

Radiation Therapy for Malignancies in the Setting of HIV Disease

ABSTRACT: With the introduction of increasingly effective antiretroviral agents for the management of AIDS, the life expectancy of appropriately treated patients will continue to lengthen, as will the length of time during which infected patients may develop malignancies, both HIV-related and non-HIV-related. The management of such patients will require careful consideration of the impact of all oncologic therapy on the immune system's ability to hold the virus at bay. Radiation therapy, with its recognized immunosuppressive effects, plays an important role in the management of the major AIDS-defining neoplasms, Kaposi's sarcoma, primary central nervous system lymphoma, and cervical carcinoma, and is used in approximately 50% of patients with non-HIV-related malignancies at some point in the disease course. The judicious use of radiation therapy and proper integration of aggressive antiretroviral therapy can result in control of malignancies without contributing to the rapid progression of HIV disease. [ONCOLOGY 11(5):683-694, 1997]

Introduction

By December 31, 1995, in the United States, a cumulative total of 513,846
AIDS cases and 310,849 deaths due to AIDS had been reported to the Centers
for Disease Control (CDC).[1] It is estimated that over 4.4 million cases
of AIDS have occurred worldwide[2] and over 20 million people have been
infected with the virus since the beginning of the epidemic. Up to 65%
of HIV-positive patients currently develop one of two main neoplasms identified
as AIDS-related tumors: Kaposi's sarcoma (KS) and non-Hodgkin's lymphoma
(NHL).[3]

The incidence of the established HIV-related malignancies will continue
to rise as the number of infected patients increases.[4] As life expectancies
of HIV-infected patients lengthen, they will also go on to develop common
non-HIV-related malignancies, such as colon, prostate, and lung cancer.[3,5]
Thus, issues related to the appropriate management of these illnesses will
increase in importance. Other virally initiated malignancies with longer
latency periods between oncogenic transformation and clinical appearance
may also emerge in this population.[6] Increased frequencies of such diseases
as cervical and anal dysplasia, anal carcinoma, and Hodgkin's disease have
already been reported in the setting of HIV disease.[6,7]

As details of the life cycle of the HIV virus are better understood,[8]
it has become clear that the so-called latent period between initial infection
and the development of clinical symptoms is a time of continuous viral
replication and gradual destruction of critical aspects of the immune system
in the large majority of infected patients. Little information has been
gathered or released on the impact of current oncologic therapies on the
course of HIV replication and progression in patients with cancer and AIDS.[9,10]

Radiation therapy has a well-known immunosuppressive effect that has
been utilized therapeutically to prevent graft rejection in organ transplantation.[11,12]
Total lymphoid irradiation, in conjunction with the use of antiretroviral
therapies, has been suggested as a potential method for reducing the total
body load of HIV-infected cells.[12,13] It is not yet clear, however, whether
or not the clinical use of radiation results in an increase in HIV replication
in vivo.

Elegant studies of HIV replication in vitro revealed that both ultraviolet
and ionizing radiation increased binding of the transcription factor nuclear
factor-kappa-B to the promotor element of the integrated HIV genome of
HIVcat/HeLa cells.[14] Unlike ultraviolet radiation, ionizing radiation
alone did not cause an immediate increase in HIV gene transcription. After
a period of several days from the time of exposure, however, rising levels
of HIV-cat gene expression were observed, as compared with unirradiated
controls. A separate study of the impact of 50 cGy of ionizing radiation
on HIV-infected mononuclear cells showed a substantial rise in p24 antigen
levels at 7 days after exposure,[15] supporting the idea that ionizing
radiation may trigger enhanced HIV replication.

The development of a rational strategy for the optimal integration of
radiation therapy into the management of malignancies in HIV-infected patients
is critical. By analyzing the patient's past infectious history, known
duration of disease (time since seroconversion), immune status (indicators
such as CD4 count, trend of CD4 decline), history of antiretroviral use
(monotherapy vs combination therapy, specific nucleoside and nonnucleoside
reverse transcriptase inhibitors, protease inhibitors), and viral burden,[16,17]
the treating physician can get an idea of the rapidity of decline of the
overall immune system and a rough estimate of the patient's expected life
duration.[5,18]

Prior to the introduction of the protease inhibitors, the average life
expectancy of an HIV-infected person in the United States was 7 to 11 years
after seroconversion[19] and approximately 1.5 years after the diagnosis
of AIDS. During these periods, the quality of the patient's life can degenerate
considerably due to undertreated or overtreated malignancies. With the
proliferation of new antiviral agents, such as the protease inhibitors
and nonnucleoside analog reverse transcriptase inhibitors, the life expectancy
of these patients should increase, leaving the clinician with the dilemma
of recommending the best oncologic intervention for patients who develop
any malignancy. For example, a 50-year old HIV-positive patient with stage
B2 prostate cancer, a CD4 count of 550 cells/mm³, and no prior infections
should not be managed in the same way as a similar man with a CD4 count
of less than 10 cells/mm³ and a history of two bouts of Pneumocystis
and cryptococcal meningitis. But what about a man with a CD4 count of 150
cells/mm³, no prior antiretroviral therapy, and one episode of Pneumocystis
pneumonia? Therapeutic nihilism is not justifiable in this last case,[16,17]
as there is a reasonable chance that this patient would live long enough
to succumb from progressive prostate cancer rather than from AIDS.

Also, treatment intent (palliative vs curative) must be clear from the
onset of treatment. If palliative, a reasonable estimation must be made
of the expected length of time that symptom control may be required to
ensure maximal quality of life. If curative, the aggressiveness of the
approach must be weighed against the risk of further damaging the immune
system in the presence of HIV.

Antiretroviral Intervention

The use of systemic chemotherapy or extensive radiation is a major stress
that may redirect critical immune resources from maintaining a balance
with the prime offender, HIV, allowing a rapid increase in overall viral
burden. Initiation of antiretroviral therapy (preferably in combination
form) and appropriate infection prophylaxis should be strongly considered
for patients who have not been previously treated with such agents or have
received minimal therapy.[9,10,16]

In a case-control review of patients with HIV disease, patients with
systemic lymphoma were matched with patients without lymphoma (with similar
CD4 levels and no prior opportunistic infections).[10] Exposure of the
first group to systemic chemotherapy resulted in a twofold increase in
the incidence of AIDS-defining events during and after the chemotherapy
period. CD4 and CD8 counts fell and viral loads increased during chemotherapy,
and CD4 counts remained at a depressed level for up to a year after the
end of chemotherapy.

Caveats

The most appropriate antiretroviral program for patients with malignancies
and HIV disease has not been established.[10,16] Although combination programs,
including protease inhibitors and reverse transcriptase inhibitors, seem
to show the most benefit for previously untreated patients, certain constraints
must be kept in mind relative to the oncologic regimen. First, drugs should
be selected that do not have additive toxicities to those expected with
the anticancer agents used. Given the myelosuppression expected with radiation
fields encompassing large amounts of bone marrow or with systemic agents,
such as cisplatin (Platinol) and the alkylators, antiretroviral agents
with a significant risk of myelosuppression, such as zidovudine (Retrovir),
should be bypassed in favor of others with less myelosuppression, such
as didanosine (Videx).[10]

Also, drugs associated with a risk of neuropathy (didanosine, stavudine
[Zerit], or zalcitabine [Hivid]) should be avoided if extensive nerve or
central nervous system (CNS) radiation is planned. Also, the radiation
oncologist should be aware that the protease inhibitors alter the P450
enzyme system, and thus, can affect the metabolism of chemotherapeutic
agents (taxanes, vinca alkaloids, anthracyclines, etoposide [VePesid])
and adjuvant medications routinely prescribed during radiation therapy
(meperidine, benzodiazepines, terfenadine [Seldane], and a host of others).
Whether or not any of the antiretroviral medications currently in use or
under development has radiation-sensitizing properties remains to be seen.

Anti-infectious Prophylaxis

Anti-infectious prophylaxis regimens are well-described for patients
with HIV disease, and improve the life expectancy of such patients.[10]
In general, prophylactic measures are not initiated until a patient's CD4
count drops below 200 cells/mm³. However, due to the fact that radiotherapy
or chemotherapy may result in a sudden decline in the CD4 count, such prophylaxis
should be considered at an earlier level. Prevention of Pneumocystis
carinii
and toxoplasmosis with trimethoprim- sulfamethoxazole, Mycobacterium
avium-intracellulare
with rifabutin (Mycobutin), and streptococcal
pneumonia with the pneumococcal vaccine should be seriously considered.

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