Gay Men's Health Crisis Treatment Issues, Vol. 5, No. 7 - October, 1991
Mary Beth Caschetta

In HIV-related NHL, tumors also commonly occur outside of the lymph system. Common sites for lymphomas in HIV-infected patients include the stomach, bone marrow, liver, and lungs. Tumors can also occur in the brain, where serious neurological damage can take place and symptoms are sometimes mistaken for AIDS dementia complex (ADC) or toxoplasmosis. Other unusual, but not altogether uncommon sites for lymphoma have been reported, including the heart, the gums, the urethra, earlobes, and rectum. It is important to carefully assess HIV-positive patients with signs or symptoms of lymphoma, in order to diagnose and treat the disease when tumors occur in unusual sites.

BACKGROUND

The clustering of high-grade non-Hodgkin's B-cell lymphomas, as NHL is formally called, was found to occur with frequency in HIV-infected people several years after the discover of AIDS. NHL was a relatively late manifestation of HIV disease, according to researchers, instead of one that was merely overlooked. In any case, NHL was not added to the Centers for Disease Control (CDC) definition of AIDS-defining illnesses until 1985.[1] Most recently, an increased incidence of cancers, especially lymphomas, has been observed in people at all stages of HIV infection. In 1990, the media ran a blitz of stories regarding a rise in HIV-related lymphomas, and at the international conference in Florence this year, there were several reports confirming the increased incidence.

It is interesting to note that NHL has increased in the total U.S. population and not just in people with AIDS. In the past 17 years, in fact, NHL has increased in the general population by more than 50%.[2] The cause of this increase is unknown, but the National Cancer Institute projects that as many as 10% of AIDS patients will develop cancer, and that in 1992, approximately 5,000 patients will develop non-Hodgkin's lymphoma in the United States.[3]

Not much is known in general about non-Hodgkin's lymphoma. Researchers believe that both congenital and acquired immunosuppression substantially increase the risk for developing NHL.[4] The condition is about 60 times more common in AIDS patients than in the general U.S. population. [5]

This article will overview different aspects of non- Hodgkin's lymphoma and some of the treatments available.

CLINICAL FINDINGS

Widely disseminated lymphoma sometimes occurs at the time of initial diagnosis of AIDS, with tumors found outside of the lymph system in 65%-98% of patients. It is thought to be unusual to find lymphoma only in the lymph nodes in patients with HIV. Lymphoma involving the bone marrow occurs in approximately 20%- 30% of all HIV-related cases: gastrointestinal tumors in 15%-45%; and approximately 1/3 of patients with HIV-related lymphoma have brain involvement. Patients with brain involvement are usually the most ill of all patients with HIV-related lymphoma.[8] Many patients with HIV-related lymphoma have fever as an initial symptom, which may mimic other infections, such as PCP.

Only a few patients with HIV infection have developed low- grade lymphoma, which is known to be fairly responsive to treatment.[9] These are not considered to be AIDS-defining events, but they are thought to occur by chance or simply to co- exist with HIV. Six patients at the University of Southern California (USC) have done very well, using minimal therapies, as is the usual prognosis for patients without HIV.[10] Single-agent chemotherapy, such as chlorambucil, or multi-agent regimens such as CVP (cyclophosphamide, vincristine, prednisone), may be well tolerated. It cannot be ruled out, however, that these lymphomas may be related in some way to HIV-induced immunosuppression.

The symptoms of brain lymphoma (sometimes called lymphoma of the central nervous system, CNS) are headaches, seizures, abnormal gait or speech, or change in personality and behavior.[11] In an observation of eleven patients with brain lymphoma treated at USC, the median survival time was 2.5 months.[12] These patients had very advanced disease and T cell counts below 30. Often times, brain lymphoma is diagnosed at the time of autopsy, and seems to have occurred more frequently in patients with disseminated or widespread lymphoma. Lymphomas usually appear as single lesions on the brain, always larger than 3 cm.[13] Since NHL lesions are sometimes mistaken for toxoplasmosis, a brain biopsy may be warranted for definitive diagnosis. However, since brain biopsy is difficult, it is common practice to treat an HIV-infected patient with CNS mass lesions for toxoplasmosis for a period of one week. After a repeat CT scan is performed, if the lesion is not significantly improved, a brain biopsy is conducted.[14] Thought many people fear brain biopsies, they can be performed safely by experienced neurosurgeons without major complications.

CO-FACTORS

The Epstein-Barr virus (EBV) has been implicated in a majority of lymphomas associated with immunodeficiency and in transplant patients with induced immunosuppression.[15] EBV is the virus which causes mononucleosis. There has been little concrete information concerning the role of EBV in HIV-related lymphoma. The theoretical connection is that EBV can create an environment suitable for gene rearrangement that may lead to a cancerous event.[16]

Cytomegalovirus infection, low T4/T8 ratios, and Kaposi's sarcoma (KS) may also be potential risk factors for the development of lymphoma in AIDS.[17] Oral hairy leukoplakia (OHL), which is thought to be caused by EBV, may also be associated with the development of NHL.[18] Additionally some studies indicate that many HIV-positive patients with lymphoma have a history of injecting drugs. However, it is not possible to predict definitively who will develop NHL based on HIV transmission factors.

LYMPHOMA AND AZT

A 1990 study, published in the Annals of Internal Medicine, reported an increase in HIV-related NHL in long-term survivors and raised much concern about the role of AZT in the development of NHL.[19] Specifically, the authors found that increases in NHL were found most commonly in people with AIDS who were long- term survivors taking AZT. From this study, some have concluded that long-term use of AZT actually causes NHL. Many professionals, however, have questioned that theory, since the occurrence of cancers, including NHL, in immunosuppressed patients has long been recognized.[20] Still others suggest that the increased frequency of lymphoma is most likely due to the fact that AIDS patients today live longer and, therefore, prolonged immunosuppression may contribute to the development of lymphoma.

A more recent study by Richard Moore of Burroughs Wellcome, maker of AZT, was reported in the Journal of the American Medical Association.[21] To further investigate the incidence of NHL and risk factors associated with the development of lymphomas, the authors of this study analyzed data from a group of 1,030 persons with AIDS or ARC who received AZT in 1987 and early in 1988. Patients were observed two years after the initiation of AZT therapy. NHL developed after initiating therapy in 24 (2.3%) of the 1,030 patients. Development of NHL was determined to be possibly associated with a prior diagnosis of other conditions, but the direct role of AZT therapy was found to be difficult to evaluate. The incidence of NHL found in this study was consistent with the incidence found in earlier studies of persons with HIV infection who did not receive antiretroviral therapy.[22] No association between NHL and the average daily dose of AZT or the length of time on AZT was found. However, it should be noted that all patients in the study received AZT, therefore, there was no control group of patients who did not receive [the] drug.

TREATMENT FOR LYMPHOMA

Optimal therapy for AIDS lymphoma has not yet been found. Data in print is conflicting, and participants in studies are not all known toe HIV-positive. Deciding how aggressively to treat a patient with NHL is difficult, and may depend on clinical judgement and patient preference. Toxicities from treatment can be extensive, and dose modification is often called for.

For the most part chemotherapy, which consists of an intravenous (IV) administration of several different drugs, is the treatment of choice. Although it should be noted that lymphoma involving the whole brain (or other specific sites of disease) often calls for radiotherapy, as well as intrathecal chemotherapy. Some of the chemotherapeutic regimens for lymphoma include the following:

1. Cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP). [23]

2. Cyclophosphamide, methyl-GAG, bleomycin, prednisone, doxorubicin, vincristine (NHL-7).[24]

3. Cyclophosphamide, vincristine intrathecal methotrexate, doxorubicin and prednisone induction (L-17).[25]

4. Methotrexate, bleomycin, doxorubicin, cyclophosphamide, dexamethasone (m-BACOD).[26] This particular regimen is considered standard therapy, and has been shown to demonstrate a complete remission rate in approximately 50% of patients.[27]

MANAGING TOXICITY

Innovations in dose scheduling, such as split-course or short and long-term continuous infusions, have alleviated the toxic side-effects of several chemotherapeutic agents.[28] Additionally, new trends seem to indicate that less may be better. In fact, a recent study reported that low-dose multi- agent chemotherapy along with CNS prophylaxis and antiretroviral therapy achieved remission in 18 (51%) of 42 patients.[29] Toxicities were also reduced.

A study at the National Cancer Institute reported on the efficacy of combining chemotherapy with AZT and granulocyte- macrophage colony-stimulating factor (GM-CSF), a drug used to combat neutropenia and bone marrow damage from chemotherapy.[30] Pluda et al studied 11 patients with high grade systemic NHL. Treatment consisted of 21 day cycles of cyclophosphamide, VP-16, doxorubicin, vincristine, methotrexate and leucovorin. AZT was given at 500 mg/day and GM-CSF in doses of 10 microg/kg/day. Patients were given radiation and received aerosolized pentamidine to prevent PCP. Of the patients enrolled, five had ARC, three AIDS and three were asymptomatic. No patients experienced OIs [Opportunistic Infections], and three patients (43%) of the seven who were evaluable achieved a complete response. The authors conclude that although blood toxicity was observed, AZT and GM-CSF can safely be administered with chemotherapy. However, a modified protocol is in the works, which may cut back on toxicity.

It should also be noted that the recently FDA approved GM- CSF, manufactured by Immunex Corporation, is expensive and may stimulate HIV (as opposed to G-CSF, which does not act on macrophages, HIV reservoirs). Additionally, reimbursement for the drug may be complicated when used for HIV-related conditions, since licensing of the drug is specifically for cancer patients.

CONCLUSION

NHL remains an illness to be reckoned with, especially as people with HIV live longer and receive better medical care for OIs. It is clear that better antiretroviral and/or immunorestorative therapy, as well as more optimal chemotherapy, will be required in order to impact upon the expected survival of patients with HIV-related lymphoma. However, early diagnosis and modified treatment regimens, especially those which use lower doses of chemotherapy drugs, may be promising options for the future.

REFERENCES

[Note: the source material for the following references contains a number of cosmetic errors, implying that numeric citations may also be inaccurate. Therefore, readers searching the literature may wish to be prepared for secondary or cross-referenced searches.]

1. Centers for Disease Control. Revision of the case definition of acquired immunodeficiency syndrome for national reporting -- United States. MMWR 34:373-5, 1985.

2. The Surveillance Program, Division of Cancer Prevention and Control, National Cancer Institute. Summary of 15 year trends. In: Ries LA et al. eds. Cancer Statistics Review, II:4, Bethesda, Md., 1973-1987.

3. Foreman J. Cancer risk in AIDS patients is said to rise as they live longer, Boston Globe, Wednesday, June 19, 1991.

4. Kinlen LJ. Immunosuppressive therapy and cancer. Cancer Surv 1:567-83, 1982.

5. Beral V et al. AIDS-associated non-Hodgkin [sic] lymphoma. Lancet 337(8745); 805-9, 1991.

6. Penn I. Lymphomas complicating organ transplantation. Transplant proc 15:2790-97, 1983.

7. Editorial. Lymphoma in organ transplant recipients. Lancet i:601-603, 1984.

8. Levine AM: Reactive and neoplastic lymphoproliferative disorders and other miscellaneous cancers associated with HIV infection, in DeVita VT et al (eds): AIDS: Etiology, Diagnosis, Treatment and prevention. Philadelphia, PA, Lippincott, pp. 263-276, 1988.

9. Ziegler JL et al. Non-Hodgkin's lymphomas in 90 homosexual men: Relation to generalized lymphadenopathy and the acquired immunodeficiency syndrome. N Engl J Med 311:565-570, 1984; and Oksenhendler E et al. Reversal of polyclonal hypoimmunoglobulinemia after HIV infection in a patient with myeloma. N Engl J Med 318:1540, 1988; and Levine AM: Reactive and neoplastic lymphoproliferative disorders and other miscellaneous cancers associated with HIV infection, in DeVita VT et al (eds): AIDS: Etiology, Diagnosis, Treatment and prevention. Philadelphia, PA, Lippincott, pp. 263-276, 1988.

10. Levine AM: Reactive and neoplastic lymphoproliferative disorders and other miscellaneous cancers associated with HIV infection, in DeVita VT et al (eds): AIDS: Etiology, Diagnosis, Treatment and Prevention. Philadelphia, PA, Lippincott, pp. 263-276, 1988.

11. Levine AM. Therapeutic approaches to neoplasms in AIDS. Review of Infect Dis 12(5);938-943, 1990.

12. ibid.

13. ibid.

14. ibid.

15. Hanto DW et al. Clinical spectrum of lymphproliferative disorders in renal transplant recipients and evidence for the role of Epstein-Barr virus. Cancer Res 41:4253-4261; HO M et al. Epstein-Barr virus infections and DNA hybridization studies in post-transplantation lymphoma and lymphoproliferative lesions: The role of primary infection. J Infect Dis 152:876-886, 1985; Purtilo DT et al. Documentation of Epstein-Barr virus infection in immunodeficient patients with life-threatening lymphproliferative diseases by clinical, virological, and immunopathological studies. Cancer Res 41:4226-4236, 1981.

16. Frizzera G et al. Lymphoreticural disorders in primary immunodeficiency. Cancer 48:692-699, 1980; and Ziegler JL et al. High-grade non-Hodgkin's lymphoma in patients with AIDS. Ann NY Acad Sci 437:412-419, 1984.

17. Beckhardt R et al. Increased incidence of malignant lymphoma in AIDS: A comparison of risk groups and possible etiologic factors. The Mount Sinai Journ of Med 55(5):383-389, 1988.

18. Moore RD et al. Non-hodgkin's lymphoma in patients with advanced HIV infection treated with zidovudine. JAMA 265(17);2208-2211.

19. Pluda et al. Development of non-hodgkins lymphoma in a cohort of patients with severe HIV infection on long-term antiretroviral therapy. Annals of Intern med 113:276-282, 1990.

20. Beral V et al. AIDS-associated non-Hokgkin lymphoma. Lancet 337(8745); 805-9, 1991.

21. Moore RD et al. Non-hodgkin's lymphoma in patients with advanced HIV infection treated with zidovudine. JAMA 265(17);2208-2211.

22. Harnly ME et al. Temporal trends in the incidence of non- Hodgkin's lymphoma and selected malignancies in a population with a high incidence of acquired immunodeficiency syndrome. Am J Epidemiol 128:261-267, 1988; Bernstein L et al. AIDS-related secular trends in cancer in Los Angeles county men: a comparison by marital status. Cancer Res 49:466-470, 1989; and Centers for Disease Control. Revision of the case definition of acquired immunodeficiency syndrome for national reporting -- United States. MMWR 34:373-5, 1985.

23. Elias L et al. Combination chemotherapy of diffuse histiocytic lymphoma with cyclophosphamide, adriamycin vincristine, and prednisone (CHOP). Cancer 42:1705-1710, 1978.

24. Lowenthal DA et al. The NHL-7: Alternating non-cross resistant, combination chemotherapy (CT) containing methyl-GAG (MG for diffuse (D) non-Hodgkin's lymphoma (NHL) (Abst). Proc Am Soc Clin Oncol 6:197, 1987.

25. Slater DE et al. Lymphoblastic lymphoma in adults. J Clin Oncol 4:57-67, 1986.

26. Skarin A et al. Moderate dose methotrexate (M) combined with bleomycin (B), andriamycin (A), cyclophosphamide (C), oncovin (O), and dexamethasone (D), mBACOD in advanced diffuse histiocytic lymphoma (DHL) (abst). Proc Am Soc clin Oncol 2:220, 1983.

27. Levine AM. Therapeutic approaches to neoplasms in AIDS. Reviews of Infect dis 12(5):938-943, 1990.

28. Braverman AS. Medical oncology in the 1990s. Lancet 337:901, 1991.

29. Levine AM et al. Low-dose chemotherapy with central nervous system prophylaxis and zidovudine maintenance in AIDS-related lymphoma. JAMA 266(1):84-88, 1991.

30. VIIth Internat Conf on AIDS, abstract #2368, Florence, 1991.

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