Radiation Therapy for Malignancies in the Setting of HIV Disease

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(Drug information on cisplatin) (Platinol) and the alkylators, antiretroviral agents with a significant risk of myelosuppression, such as zidovudine(Drug information on zidovudine) (Retrovir), should be bypassed in favor of others with less myelosuppression, such as didanosine(Drug information on didanosine) (Videx).[10]

Also, drugs associated with a risk of neuropathy (didanosine, stavudine(Drug information on stavudine) [Zerit], or zalcitabine(Drug information on 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(Drug information on etoposide) [VePesid]) and adjuvant medications routinely prescribed during radiation therapy (meperidine, benzodiazepines, terfenadine(Drug information on 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(Drug information on trimethoprim)- sulfamethoxazole(Drug information on sulfamethoxazole), Mycobacterium avium-intracellulare with rifabutin(Drug information on rifabutin) (Mycobutin), and streptococcal pneumonia with the pneumococcal vaccine should be seriously considered.