Acquired Immunodeficiency Syndrome and Cancer



Acquired Immunodeficiency Syndrome and Cancer


Ariela Noy, Mark Dickson, Roy M. Gulick, Joel Palefsky, Paul G. Rubinstein and Elizabeth Stier



Summary of Key Points


Incidence


• Non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), Kaposi sarcoma (KS), cervical cancer, and anal cancer all occur with increased incidence in patients infected with the human immunodeficiency virus (HIV). NHL, KS, and cervical cancer are acquired immunodeficiency syndrome (AIDS) defining.


• KS occurs in HIV-infected patients who also are infected with KS-associated herpesvirus. Outside of Africa and in some Mediterranean populations, KS occurs mainly in men who have sex with men.


• Lymphoma (non-Hodgkin and Hodgkin) occurs in all HIV risk groups. These neoplasms tend to be aggressive and extranodal and manifest at an advanced stage. Burkitt lymphoma and HL tend to occur in patients with higher CD4 counts (typically greater than 200 cells/µL), whereas primary central nervous system lymphoma tends to occur in patients with very low CD4 counts (typically less than 50/mm3).


Overarching Principle


• The CD4 T-cell count and HIV load should be determined for all malignancies. Use of highly active antiretroviral therapy (HAART) should be optimized, possibly during but certainly after cancer therapy.


Etiology and Pathogenesis


• KS is always associated with KS-associated herpesvirus; immunocompromise, inflammatory cytokines, and perhaps the HIV TaT protein contribute to pathogenesis.


• Lymphoma in HIV-infected patients is associated with Epstein-Barr virus (EBV) in approximately half of the cases; immunocompromise, chronic antigen stimulation, and perhaps inflammatory cytokines and chemokines contribute to pathogenesis.


• Cervical and anal cancer require the oncogenic strains of human papilloma virus. The pathogenesis of these two cancers is remarkably similar.


Kaposi Sarcoma


• A biopsy is indicated to confirm diagnosis.


• A computed tomography (CT) scan of the chest and abdomen is also indicated.


• Gastrointestinal endoscopy is performed if clinically indicated.


• Highly active antiretroviral therapy (HAART) and treatment of opportunistic infections sometimes are associated with regression of KS.


• If disease is symptomatic or rapidly progressive, or with visceral involvement, systemic therapy with liposomal anthracycline or paclitaxel is instituted; all patients should receive pneumocystis prophylaxis. Hematopoietic growth factors, antifungal treatment, and antiherpesvirus prophylaxis or treatment also are appropriate for most patients receiving cytotoxic chemotherapy.


• If disease is indolent and antiretroviral therapy has just been initiated or major changes have been made, observation may be appropriate.


• For a few lesions, topical therapy, injection of lesions, or radiation therapy may be adequate treatment.


• For persons with systemic disease, consider interferon, thalidomide, or experimental therapy.


Non-Hodgkin Lymphoma


• Signs and symptoms of tumor lysis.


• Extent of disease can be determined with use of CT and bone marrow biopsy in most cases.


• Extranodal and atypical presentations of lymphoma are common, as are constitutional symptoms (especially with HL).


• Positron emission tomography scans with fluorodeoxyglucose labeling should be interpreted with extreme caution because HIV infection, inflammation associated with opportunistic infection, and immune reconstitution syndrome all are associated with fluorodeoxyglucose activity.


• Chemotherapy (with cyclophosphamide, hydroxydaunomycin [doxorubicin], vincristine [Oncovin], and prednisone [CHOP] plus rituximab or etoposide, Oncovin, doxorubicin, cyclophosphamide, and prednisone [EPOCH] plus rituximab) is used to treat NHL.


• Intrathecal prophylaxis is appropriate for patients with Burkitt lymphoma or Burkitt-like lymphoma, for patients with bone marrow involvement of NHL, and for patients with EBV-associated NHL. Either cytarabine or methotrexate can be used for this purpose.


• Patients with relapsed lymphoma may be appropriate candidates for high-dose therapy with stem cell rescue.


Hodgkin Lymphoma


• HIV-associated classic HL occurs in patients with higher CD4 counts. It is 80% to 100% associated with EBV. Patients are seen with more advanced disease and more aggressive histologies (mixed cellularity and lymphocyte-depleted HL).


• Staging and evaluation are similar to that for NHL.


• Treatment with doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD) results in an overall survival rate at 5 years of 75% (15% below that of the non-HIV population).


Cervical Cancer


• Prevention of invasive disease by screening for and treatment of preinvasive disease is the mainstay in the developed world.


• Staging requires both visualization of the cervical area and CT scanning.


• Treatment depends heavily on the extent of disease because it varies from colposcopic therapies to surgery alone or in combination with radiation and chemotherapy.


• Early stages are treated with curative intent.


• Distantly metastatic disease is largely treated for palliation.


Anal Cancer


• Prevention of invasive disease by screening for and treatment of preinvasive disease is an active area of research because the progression rates are under investigation.


• Staging requires both visualization of the anal area and CT scanning.


• Treatment of preinvasive lesions varies among practitioners and is an active area of investigation.


• Treatment depends heavily on the extent of disease because it varies from local therapies to surgery alone or in combination with radiation and chemotherapy.


• Early stages are treated with curative intent.


• Distantly metastatic disease is largely treated for palliation, although some patients with only local nodal metastases may be cured.


Hepatocellular Carcinoma


• Hepatitis B and C virus promote hepatocellular cancer. HIV infection dramatically accelerates this process, although hepatocellular cancer is not an AIDS-defining cancer.


• Early-stage disease is amenable to curative resection or possibly liver transplantation. For larger tumors, multiple tumors, or extrahepatic metastases, systemic chemotherapy is required. Specific approaches in the setting of HIV have not been studied.


Cytotoxic Therapy for Cancer


• Pneumocystis prophylaxis is given regardless of the CD4 count.


• Other prophylaxis for bacteria, fungi, herpes viruses, and mycobacterium depend on the regimen and level of preexisting immunosuppression.


• In HAART-naive patients, antiretroviral therapy should typically be initiated shortly after cytotoxic chemotherapy begins and when associated nausea is controlled.



Human Immunodeficiency Virus Infection and Acquired Immunodeficiency Syndrome


Human immunodeficiency virus (HIV) infection is a true pandemic, that is, an infection that affects persons in every country of the world.1 HIV is transmitted most commonly worldwide by sexual contact and also by intravenous drug use, transfusion of infected blood or blood products, and perinatally from an infected mother to her child. HIV may be transmitted by infected blood, blood products, bloody fluids, or genital secretions, but not by saliva, sweat, urine, other nonbloody fluids, or feces. Acquired immunodeficiency syndrome (AIDS) is diagnosed when severe immunodeficiency develops in a person with HIV infection as demonstrated by a CD4 lymphocyte count of less than 200/µL or the development of one or more of 25 specific AIDS-associated diseases, including opportunistic infections and malignancies.2 In the absence of HIV treatment, the time from initial HIV infection to the development of severe immunodeficiency and AIDS is approximately 10 years.3 Effective antiretroviral therapy has changed the natural history of the disease, prevents HIV disease progression, and prolongs survival.


The first cases of AIDS were described in 1981 in five young gay men in Los Angeles.4 Since the beginning of the HIV pandemic, an estimated 70 million people worldwide have acquired HIV infection and more than half of them died.1 Currently, an estimated 34 million people are living with HIV infection, with more than two thirds of them living in sub-Saharan Africa. An estimated 1.2 million people are currently living with HIV infection in the United States.5 The U.S. Centers for Disease Control and Prevention currently recommends routine HIV testing for all persons aged 13 to 64 years, not based on risk.6


Acute HIV infection can present as a nonspecific illness characterized by fever, oral ulcers, and maculopapular rash7; however, at least 50% of newly infected persons may be completely asymptomatic. The clinical illness will subside over several weeks and then the patient enters an asymptomatic phase, often with nonspecific generalized lymphadenopathy, that may last years as the CD4 lymphocyte count gradually declines over time. HIV-associated diseases that occur at higher CD4 counts (>300 cells/µL) include those caused by more aggressive pathogens (e.g., tuberculosis, herpes zoster, and pneumococcal pneumonia), as well as Kaposi sarcoma (KS). As the CD4 cell count declines below 300, other HIV-associated illnesses also occur, including oral hairy leukoplakia, oral thrush, and seborrheic dermatitis. When the CD4 cell count declines below 200, the case definition of AIDS is met, and AIDS-defining illnesses may also occur, including Pneumocystis jiroveci (formerly P. carinii) pneumonia, central nervous system (CNS) toxoplasmosis, and cryptococcal meningitis. Multiple opportunistic illnesses can occur simultaneously in a single patient.


With the development of effective antiretroviral therapy, HIV-associated malignancies have decreased markedly8; however, the risks remain high for both AIDS-defining and non–AIDS-defining cancers in comparison with the remainder of the population. AIDS-defining cancers include various aggressive B-cell non-Hodgkin lymphomas (NHLs), KS, and cervical cancer. The non-AIDS defining cancers include those disproportionately found in the setting of HIV such as Hodgkin lymphoma (HL), anal cancer, and hepatitis B and C virus (HBV and HCV)-related liver cancer, as well as cancers that are increased because of associated habits such as a high smoking prevalence in people living with HIV.


A recent study9 detailed the cancer burden in the U.S. AIDS population, which quadrupled from 1991 to 2005 (from 96,179 to 413,080), largely because of an increase in the number of people aged 40 years or older. Nearly 80,000 cancers occurred during this time frame. When comparing 1991-1995 to 2001-2005, AIDS-defining cancers decreased by more than a factor of three (34,587 to 10,325 cancers; P (trend) < .001), whereas non–AIDS-defining cancers increased by about a factor of three (3193 to 10,059 cancers; P (trend) < .001). From 1991-1995 to 2001-2005, estimated counts increased for anal cancer (206 to 1564 cases), liver cancer (116 to 583 cases), prostate cancer (87 to 759 cases), lung cancer (875 to 1882 cases), and HL (426 to 897 cases).


In the 1980s and early 1990s, the average life expectancy of a patient with AIDS was less than 1 year. Today, it is estimated that a person diagnosed with HIV infection and appropriately managed with antiretroviral treatment will live close to the average life expectancy of the general population.10 This outcome is attributable to the 27 unique drugs for the treatment of HIV infection approved by the U.S. Food and Drug Administration, which typically are used in combination regimens of three or more drugs. This life expectancy makes treatment of the various malignancies more of an imperative than in the pre-highly active antiretroviral therapy (HAART) era. In addition, the aging HIV-infected population will experience cancers commensurate with the aging process. Cancer is now the leading cause of death for HIV-1–infected persons treated with HAART. A malignancy will develop in 25% to 40% of HIV-positive patients.1120 Recently, studies of HAART interruption have shown a sixfold increase in both AIDS-related and non-AIDS-related cancers and an increased risk of cancer-associated death.21


The development of malignancies is related to a number of factors, including immunosuppression and concurrent infections with other viruses such as human herpesvirus 8 (HHV-8) and Epstein-Barr virus (EBV) or the human papillomavirus (HPV), which foster malignant transformation. These viruses carry oncogenic proteins and cytokines that contribute to malignant pathogenesis. Additionally, HIV infection reduces the ability to clear the viral infection.



AIDS-Related Lymphoma


Epidemiology


NHL and HL occur with increased frequency in patients infected with HIV.9 NHL will develop in approximately 10% of HIV-positive people, and although the incidence has greatly reduced during treatment with HAART, it is still increased 25-fold to 150-fold compared with the general population.2225 These recent studies also demonstrate that the duration and depth of the CD4 nadir and the duration of viremia increase the incidence of NHL. NHL remains the AIDS-defining condition in approximately 3% of HIV-infected persons.



Etiology and Biological Characteristics


As in the general population, lymphogenesis is a multistep process, with a panoply of acquired gene mutations contributing to the malignant phenotype. Each subtype of lymphoma has its own set of acquired genetic mutations that can also vary within a subtype. Particular to HIV, decreased immune surveillance, B-cell dysregulation,26 and, in certain subtypes, the oncogenic viruses HHV-8 and EBV are involved in the pathophysiology of the disorder.27 For example, CNS lymphomas are virtually always associated with EBV, whereas primary effusion lymphoma is associated with HHV-8 infection. AIDS-Burkitt lymphoma is variably associated with EBV but also contains activating mutations in the c-myc proto-oncogene, frequent inactivation of p53, and point mutations in BCL6. One study showed that loss of EBV-specific CD8+ T cells in subjects progressing to EBV-related NHL correlated with loss of CD4+ T cells and that these cells were better preserved in equally immunocompromised patients in whom lymphoma did not develop.28 Early studies suggest that HIV-associated NHL will have a unique set of mutations,29 but research in this area is ongoing. Inherited factors may also play a role. One study demonstrated that lymphoma is less likely to develop in HIV-infected patients who are heterozygous for the CCR5-D32 deletion, whereas lymphoma is more likely to develop in persons with stromal cell–derived factor-1 mutations.30


Three types of lymphoma are now recognized as AIDS defining by the Centers for Disease Control and Prevention: Burkitt lymphoma; immunoblastic lymphoma, which is a subtype of diffuse large B-cell lymphoma; and primary CNS lymphoma. Primary effusion lymphomas are also highly associated with HIV. The World Health Organization more recently provided a classification system for the HIV-associated lymphomas (Box 65-1 and Figure 65-1). The frequency of NHL increases with the degree of immunosuppression, particularly for CNS lymphoma, which is only seen when the CD4 count is less than 50/µL. T-cell and other lymphomas are rare.






Clinical Manifestations and Patient Evaluation


Patients with HIV-NHL frequently present with advanced stage III or IV disease. The majority will present with a rapidly growing mass or the development of systemic B symptoms (e.g., fever, night sweats, and unexplained weight loss). The clinical presentation is dependent on the site of involvement. Extranodal involvement including the bone marrow (25% to 40%), gastrointestinal tract (26%), and CNS (17% to 32%) is common. Leptomeningeal disease detected by flow cytometry may be present alone at a higher frequency than in the immunocompetent population.31 Involvement of the small bowel and rectum is also prevalent, particularly in persons with large cell histology. Several prognostic factors affect survival, including CD4 count, Karnofsky performance, age, and lactate dehydrogenase level predict response to therapy.32




Diffuse Large B-cell Lymphoma


The two most commonly used regimens are cyclophosphamide, hydroxydaunorubicin (doxorubicin), Oncovin (vincristine), and prednisone (CHOP) or the dose-adjusted infusional regimen adding etoposide to the same drugs (EPOCH). The latter is modified for CD4 count at chemotherapy initiation. Both are currently given with the anti–B-cell antibody rituximab.


A randomized phase 3 study of CHOP with or without rituximab failed to demonstrate any added benefit of rituximab and suggested increased toxicity in persons with a CD4 count less than 50.33 In contrast, in another study, the addition of rituximab to CHOP produced a complete response rate of 77% and a 2-year survival rate of 75% in patients with AIDS-related NHL, with no increase in the risk of life-threatening infections.34 The current standard of care is to use rituximab with attention to infection, including hematopoietic growth factors and antibiotic prophylaxis in persons at highest risk.


Treatment with etoposide, prednisone, Oncovin (vincristine), cyclophosphamide, and hydroxydaunorubicin (doxorubicin) (EPOCH) has produced responses of 79% in a preliminary study.35 Antiviral therapy was suspended during treatment in this protocol for fear of concurrent toxicities, leading to transient increases in viral load and decreases in CD4 counts. A multicenter trial by the AIDS Malignancy Consortium investigated EPOCH with concurrent versus sequential rituximab and found the complete response (CR) rate to be higher in the concurrent arm and similar to the National Cancer Institute pilot study.36 The vast majority of patients continued to undergo HAART during treatment, challenging the earlier assertion that HAART must be suspended.





Burkitt Lymphoma


Before HAART, treatments were too toxic and the prognosis was dismal. One small retrospective study40 and one small prospective study41 initially challenged the prevailing dogma, reporting intensive therapies such as cyclophosphamide, Oncovin (vincristine), doxorubicin, high-dose methotrexate/ifosfamide, VePesid (etoposide), and Ara-C (cytarabine) (CODOX-M/IVAC) or hyper–cyclophosphamide, vincristine, Adriamycin (doxorubicin), and dexamethasone (CVAD). CVAD with methotrexate and high-dose cytarabine could be safely given with HAART with success rates of 80% to 90%. More recent publications have also suggested the same.42,43 Another retrospective study has supported the use of EPOCH-rituximab as more efficacious and less toxic.44 A recently completed clinical trial by the AIDS Malignancy Consortium was designed to reduce toxicity while maintaining efficacy and may confirm these results prospectively in a multicenter setting.45 The National Cancer Institute has also reported early results with EPOCH-rituximab in a prospective study, citing nearly 100% efficacy.46 A confirmatory multiinstitutional study is ongoing.



Plasmablastic Lymphoma


Plasmablastic lymphoma is a very rare CD20-negative variant of HIV-associated NHL. It was originally described as almost exclusively associated with HIV and nearly always fatal in the pre-HAART era.47 The sine qua non of stage I disease is a mass in the jaw, but disseminated disease, including numerous bone lesions, is common. A retrospective study suggested curability in the HAART era in both HIV-positive and HIV-negative patients.48 Optimal management will be difficult to define because of the rarity of the disease.



The Controversial Timing of HAART


The optimal timing of HAART with combination chemotherapy is controversial.49 Many oncologists continue to administer antiretroviral drugs during chemotherapy, but some oncologists temporarily discontinue them, citing fears of drug-drug interactions and increased toxicities. However, early immune reconstitution could be important, and six randomized studies in persons with infections have shown a decrease in infection mortality when HAART is started immediately.50 A retrospective Italian study reported decreased infection but great neurotoxicity and anemia when CHOP was combined with HAART, but this early study was performed in the 1990s.51 The panoply of currently available HAART medications allows minimization of drug-drug interaction. It is unlikely that a controlled clinical trial will be conducted.



Hodgkin Lymphoma


As a population, patients infected with HIV have a ten- to twenty-fivefold increased risk of developing HL compared with the general population. Patients diagnosed with HIV-associated HL present with many high-risk characteristics that distinguish it from non–HIV-related classic HL.52 The differences, described in the following sections, are seen in the epidemiology, patients’ advanced presentation, more aggressive histologies, immunohistochemistry, and poorer overall outcome.52



Epidemiology


Multiple large database studies of linked cancer and HIV/AIDS registries from 1992-2005 in the United States showed that HIV-associated classic HL represents the second to third most common non-AIDS defining cancer.9,53 In 2001 the World Health Organization categorized it as an HIV-associated lymphoma.54,55 However, unlike HIV-associated NHL, the risk for developing HIV-associated classic HL was 68% higher in 1996-2002, the post-HAART era (standardized incidence ratio [SIR] 13.6), than in 1990-1995 (SIR 8.1)56 and is increasing with time despite stable rates of HL in the general population.57 Patients who have HL and HIV are more commonly male (85% vs. 54% in the general population), and in contrast to HIV-associated KS and NHL, HIV-associated HL develops mostly in patients with higher CD4 counts (>200 cells/µL).52,58



Etiology and Biological Characteristics


The transformed cell that defines classic Hodgkin lymphoma is the Reed-Sternberg cell, a large multinuclear cell that expresses surface antigens CD15 and CD30 without B- or T-cell surface antigens55 and originates from germinal B cell lymphocytes, as demonstrated by the expression of PAX 5, B-cell specific activator protein, and B-cell clonality based on single-cell polymerase chain reaction of the IgH gene.5963 However, in persons with HIV, the Reed-Sternberg cell has been linked to postgerminal lymphocytes.64 It is interesting to note that diffuse large B-cell lymphoma derived from a nongerminal center has a worse prognosis than germinal cell–derived large cell lymphoma in most studies.


Reed-Sternberg cells are surrounded by B cells and CD4 cells, eosinophils, macrophages, and fibroblasts, all of which affect its survival and disease course.65,66 This trophic effect, which is attributed in part to CD4 cells, may explain the increase in incidence of HIV-related classic HL in the post-HAART era.58,62,63 The tumor microenvironment may also explain why patients with HIV-associated HL present with higher CD4 counts compared with other HIV-associated lymphoproliferative disorders, with the exception of Burkitt lymphoma.58,62,63 Mixed cellularity and lymphocytic depletion predominate in HIV-associated classic HL compared with the non-HIV population (discussed later).66 In addition, histologically, the Reed-Sternberg cell is found in much higher concentrations in HIV-associated classic HL than in non–HIV-associated classic HL.52 HIV-associated classic HL is associated in 80% to 100% of cases with EBV co-infection of the Reed-Sternberg cell, compared with 30% to 40% in patients with non–HIV-associated classic HL52,67,68 (see Figure 65-2).




Pathology


The pathology of HIV-associated classic HL changes as the immunosuppression progresses.58 In patients with CD4 counts greater than 200 cells/µL, the incidence of mixed cellularity (MC) classic HL is slightly higher than nodal sclerosing classic HL.58 At CD4 counts below 100 cells/µL, the incidence of HIV-associated classic HL decreases as a whole, but the incidence of nodal sclerosing classic HL decreases much more dramatically, falling almost to 0, compared with MC HIV-associated classic HL, explaining the increase of MC histology compared with all other histologic subtypes.58



Clinical Manifestations, Patient Evaluation, and Staging


As defined by the international prognostic score for advanced HL for non–HIV-associated HL, the following factors predict poorer outcome: >45 years of age, male gender, stage IV disease, a low albumin level, anemia, lymphopenia, and leukocytosis.69 In a single-institution retrospective study, half of the 51% of the patients who were seen with advanced disease had an international prognostic score of more than 5.70 Depending on the study, patients with HIV-associated HL are seen with advanced disease in 50% to 80% of cases.


Extranodal disease is common in HIV-associated HL. Accurate staging includes a computed tomography (CT) scan of the chest, abdomen, and pelvis, as well as a bone marrow biopsy. Baseline evaluations should include pulmonary function tests before administration of bleomycin (particularly because patients with HIV are more prone to smoking) and a cardiac function test to avoid toxicities with doxorubicin. It is important to understand that CD4 counts can drop during the course of therapy and prophylaxis for pneumocystis and/or mycobacterium avium complex should be initiated until it is clear that the CD4 counts are greater than 200 or 50 cells/µL, respectively.



Therapy


Currently, no standard of care exists for the upfront treatment of HIV-associated classic HL. Outcomes of prospective clinical trials for HIV-associated classic HL in the pre- and post-HAART era are summarized in Table 65-1. In the pre-HAART era, the AIDS Clinical Trials Group performed a prospective trial using Adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) with supportive granulocyte-colony stimulating factor (G-CSF).71 CR was attained in only nine patients (43%) and a partial remission was attained in 4 subjects (19%), resulting in a 2-year overall survival (OS) rate of 48%.71 Even with routine G-CSF use, severe neutropenia developed in 10 patients and opportunistic infections occurred in 6 patients (29%) during the study. A similar study with epirubicin, bleomycin, vinblastine, and prednisone (EBVP) in which only azidothymidine or dideoxyinosine was used as HIV therapy showed an equivalent 2-year OS of 40%.72



Table 65-1


Summary of Prospective Trials of Human Immunodeficiency Virus Classic Hodgkin Lymphoma in the Pre- and Post-Highly Active Antiretroviral Therapy Era

























































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Jun 13, 2016 | Posted by in ONCOLOGY | Comments Off on Acquired Immunodeficiency Syndrome and Cancer

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Regimen/Reference No. Trial Type HAART No. Patients Year Stage III/IV (%) OS % (mo)
EBV31 Prospective No HAART 17 1994  88 11
ABVD28 Prospective No HAART 21 1992-6  67 48 (24)
EBVP29 Prospective AZT or DDI 35 1993-7  66 40 (24)
ABVD32 Prospective HAART  8 2002  75 43
Stanford V33 Prospective HAART 56 2005  71 59 (60)
BEACOPP34 Prospective HAART