Handbook of Cancer Chemotherapy (Lippincott Williams & Wilkins Handbook Series), 8th Ed.

25. HIV-Associated Malignancies

Thomas S. Uldrick, Mark N. Polizzotto, and Robert Yarchoan

Patients with HIV infection have an increased susceptibility to several cancers. Three malignancies confer a diagnosis of AIDS when they arise in an HIV-infected patient: Kaposi sarcoma (KS), aggressive B-cell non-Hodgkin lymphoma (NHL), and cervical cancer. The incidence of some non-ATDS–defining malignancies (NADM) is also increased in people with HTV/AIDS.

With the availability of potent combination antiretroviral therapy (cART), the epidemiology of cancer in patients with HIV has changed. While AIDS-defining tumors are still the most common cancers in people with HIV, the incidence of KS and some NHL subtypes has decreased. However, as HIV-infected patients are living longer, as the number of people living with HIV/AIDS is increasing, and as the HIV-infected population is aging in the developed world, NADM are becoming an increasing public health concern. Cancers with increased incidence in HIV-infected patients include lung cancer, anal cancer, Hodgkin lymphoma (HL), certain head and neck cancers, and Merkel cell carcinoma. Liver cancer is also increased in people with HIV due to frequent coinfection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) and alcohol use. Many of these tumors have established viral associations. While certain common cancers such as breast or colon cancer are not more common in HIV-infected individuals, the burden of these NADM is also increasing as the population infected with HIV ages. Information on optimal treatment approaches to these cancers in the setting of HIV infection is needed.

The outlook for patients with AIDS-defining tumors has improved markedly in the last 15 years as a result of both the introduction of cART and improved specific therapy for several of these malignancies. However, given the recent epidemiologic trends in HIV-associated malignancies and the dramatic decline in infectious complications of AIDS, malignancies are now a leading, if not the foremost, cause of mortality in the HIV-infected population where cART is available, with about half the deaths from AIDS-defining malignancies and half from NADM. This is a rapidly evolving field, and several lines of research are contributing to improved therapies. Patients should therefore be considered for clinical trials when possible.

I. KAPOSI SARCOMA (KS)-ASSOCIATED HERPESVIRUS AND ASSOCIATED TUMORS

A. KS-associated herpesvirus (KSHV), also called human herpesvirus-8, is a gammaherpesvirus related to Epstein-Barr virus (EBV). KSHV is the causal agent of three tumors: KS, multicentric Castleman disease (MCD), and primary effusion lymphoma (PEL). KS derives from endothelial cells, and MCD and PEL from B-lymphocytes. KSHV infection occurs endemically in certain regions, such as sub-Saharan Africa and parts of the Mediterranean basin, and at lower levels worldwide. In the United States, KSHV seroprevalence is generally low, but the rate is more than 15% in men who have sex with men (MSM). In the immunocompetent host, clinical manifestations of KSHV infection are uncommon. However, HIV infection and other forms of immunodeficiency substantially increase the risk of KSHV-associated malignancies.

B. KS

1. Epidemiology. KS is a multifocal angioproliferative tumor. The tumor is comprised of spindle cells and infiltrating mononuclear cells around leaky vascular slits; blood in these slits gives KS its characteristic coloration. Clonality studies in KS are conflicting. Generally, it is thought to be oligoclonal or polyclonal, but it may have a monoclonal component, especially in advanced disease. Four epidemiologic categories of KS are described, each caused by KSHV. Classical KS is an uncommon, generally indolent tumor predominantly seen in older men in the Mediterranean basin. Endemic KS occurs in Africa and more often develops in women and younger patients. Iatrogenic KS occurs in solid organ transplant patients and other patients on chronic immunosuppressive agents. AIDS-associated KS is also called epidemic KS. After peaking in the early-1990s, epidemic KS incidence declined rapidly in developed countries, likely due to the use of nucleoside anti-HIV therapy and then cART. It is the second most common tumor in people with HIV/AIDS in the United States. In sub-Saharan Africa, where prevalence of both HIV and KSHV is high and access to cART remains limited, KS remains one of the most common tumors.

2. Presentation and patient evaluation. Early KS usually manifests as red, purple, or brown papules or plaques on the skin or mucous membranes. Lesions may occur at any site but there is a predilection for the extremities, ears, nose, and palate. Advanced lesions are often nodular and may become confluent or ulcerate. Involvement of lymph nodes and dermal lymphatics leading to edema is seen in advanced cases and may result in permanent impairment. KS involvement of visceral organs such as the lungs or gastrointestinal tract and effusions in serous body cavities are other manifestations of advanced disease. Gastrointestinal KS may present as occult blood loss or with other gastrointestinal symptoms. Pulmonary disease may manifest with cough, dyspnea, or hemoptysis, and may be life threatening. Radiographic findings in the chest include reticulonodular or nodular infiltrates, with or without effusions, and may be difficult to differentiate from infection. Endoscopy and bronchoscopy are useful in visually demonstrating luminal lesions. Given the risk of bleeding, endobronchial biopsy is rarely performed. The natural history of KS is variable, and even in the absence of treatment, KS commonly waxes and wanes.

Evaluation of a patient with KS should focus on the extent of disease, KS-associated symptoms (pain, edema, disfigurement, secondary infections), rate of progression, association with cART, and the use of immunosuppressive agents including glucocorticoids. Other important factors include the history of HIV treatment, opportunistic infections, nadir and current cluster of differentiation 4 (CD4) lymphocyte counts, and HIV viral load. Physical exam should include documentation of the extent of cutaneous and mucosal involvement, evaluation of lymph nodes and spleen, fecal occult blood test for occult gastrointestinal blood loss, and baseline chest radiography for asymptomatic pulmonary involvement. A biopsy should be performed when possible to exclude other cutaneous processes. Computed tomography (CT) scans and endoscopy are not indicated unless the initial evaluation suggests visceral disease. Pathologic evaluation of pleural effusions or lymphadenopathy should be performed when feasible, if present. Patients with KS are at elevated risk of PEL and MCD, and physicians should be alert for these tumors (see subsequent discussion).

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3. Staging. KS is a multicentric tumor that does not fit TNM categorization. Prior to the availability of cART, the AIDS Clinical Trials Group developed and validated a staging system that reflects various prognostic factors (Table 25.1). Patients are defined as good (designated with subscript 0) or poor (designated with subscript 1) risk on the basis of tumor burden (T), immune function assessed by CD4 count (I), and systemic illness (S) assessed by history of opportunistic infections, systemic symptoms, and performance status. Before the availability of cART, patients who were poor risk in any category were considered as being at poor risk overall. In the post-cART era, CD4 count is a less important prognosticator, and two overall risk categories are utilized: patients with a heavy burden of disease and systemic illness (T1S1) are poor risk compared to all other patients (T1S0, T0S1, or T0S0). Patients with pulmonary involvement have the highest risk of death and may require urgent evaluation and therapy.

4. Treatment All patients with HIV-associated KS should receive cART. The Department of Health and Human Services (DHHS) guidelines for treatment of HTV provide current information on topics including optimal drug therapy and interactions at http://www.aidsinfo.nih.gov/guidelines/. Effective HIV suppression and immune re-constitution can lead to sufficient tumor regression, especially in patients with limited (T0) disease, and it can improve response durability and overall survival in patients with any stage disease. However, some patients have initial worsening of KS on starting cART, believed to be due to immune reactivation syndrome.

A number of other therapies are effective in KS and should be considered in light of the risks, potential benefits, and needs of each individual patient. KS is not curable, and the goal of therapy is to induce durable responses or minimize the extent of disease while minimizing toxicity. Some patients, especially those with severe KS and low CD4 counts, may require intermittent therapy for years. Most patients with HIV-associated KS will either respond to cART or require systemic therapy, and local therapy is now rarely used. Systemic therapy is generally indicated for bulky, rapidly progressing, symptomatic, or life-threatening disease. In addition, it is worth considering for patients with disfiguring or other psychological distressing disease manifestations. Except for diagnostic biopsy, surgery is rarely indicated in settings where cytotoxic chemotherapeutic drugs are available.

a. Local therapy. Radiotherapy including electron beam therapy, topical therapy, cryotherapy, or intralesional injection of vinblastine or other cytotoxics can be used for localized KS. Topical alitretinoin 0.1% gel is specifically approved for this indication. The overall response rate with 12 weeks of therapy is 35% to 37%. Radiation therapy is also highly effective for local control; it is generally reserved for disease that is limited but causing severe pain or distress. Short-term local toxicities are usually manageable, but radiation can lead to “woody” skin and other long-term ill effects. Doses range from an 8 Gy single dose to fractionated therapy to a total of 16 to 30 Gy and are individualized for a given patient.

b. Systemic therapy

(1) Chemotherapy. Several cytotoxic chemotherapy agents are effective, providing rapid improvement in KS-related symptoms in the majority of patients (Table 25.2). Liposomal doxorubicin (20 mg/m2every 3 weeks) is generally the agent of choice. It is equivalent or superior in activity to older regimens containing bleomycin and vincristine, with or without doxorubicin, and less toxic. An absolute neutrophil count of 750 cells/μL is adequate to deliver therapy, although granulocyte colony-stimulating factor (G-CSF) support between cycles may be necessary. Treatment should generally be continued until maximal response is obtained. Treatment duration is variable. If possible, patients should not receive a cumulative lifetime anthracycline dose of over 550 mg/m2 because of the risk of severe, irreversible cardiotoxicity. The sense of some practitioners is that the risk is less with a liposomal formulation; however, this dose should not be exceeded without careful cardiac monitoring and an awareness of the risks involved.

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For second-line therapy, paclitaxel 100 mg/m2 every 2 weeks or 135 mg/m2 every 3 weeks has produced response rates of 50% to 70% when used without cART. Paclitaxel is substantially more toxic than liposomal doxorubicin, especially in patients with HIV-associated immunosuppression, and careful monitoring of blood counts is required. Caution should be used with medications that inhibit CYP3A4, such as protease inhibitors, or CYP2C8 (including trimethoprim), as these may increase the toxicity, and paclitaxel dose reduction may be necessary.

Lastly, oral etoposide 50 mg/day for days 1 to 7 of a 14-day cycle is active, with an overall response rate of 36% in previously treated patients, the majority of whom were not receiving cART. This may be particularly useful in resource-limited settings. Monitoring of complete blood counts is required.

(2) Immune modulators. Interferon-α (IFN-α) is the best-studied immunotherapy in KS. Responses have been reported with doses ranging from 1 × 106 IU/day to 36 × 106 IU three times per week (see Table 25.2). Common side effects include cytopenias and elevated transaminases. Fatigue, fevers, and flulike symptoms are common but decline with continued therapy and can be managed with acetaminophen or non-steroidal anti-inflammatory drugs. Patients should be monitored for depression and hypothyroidism. Most practitioners begin with low-dose IFN-α, 1 to 5 × 106 IU subcutaneous injection daily, and gradually increase the dose as tolerated.

C. KSHV-associated MCD (KSHV-MCD)

1. Epidemiology. There are several forms of Castleman disease, including a unicentric hyaline-vascular form, a multicentric plasma cell form, and a multicentric form associated with KSHV. Nearly all Castleman disease arising in the setting of HIV infection is KSHV-MCD. This polyclonal hyperproliferative B-cell disorder is considered to be rare, although its incidence is not well defined. In contrast with KS, there is evidence that MCD has become more common since the advent of cART. While most commonly seen in the setting of HIV, KSHV-MCD may occur in elderly or immunocompromised patients.

2. Presentation. KSHV-MCD is characterized by intermittent flares of inflammatory symptoms, including fevers, fatigue, cachexia, and edema, together with lymphadenopathy and/or splenomegaly. Gastrointestinal symptoms and cough are also common. Flares are often severe and can be fatal. Many symptoms are attributable to a KSHV-encoded viral interleukin-6. There is no validated staging or prognostic system. KSHV-MCD should be considered in the differential diagnosis of patients with HIV and unexplained inflammatory symptoms or autoimmune phenomena, particularly anemia or thrombocytopenia. The clinical course waxes and wanes, but untreated, it is frequently fatal within 2 years of diagnosis, with patients succumbing to the severe inflammatory syndrome or progressing to lymphoma.

3. Evaluation. Diagnosis of KSHV-MCD generally involves an excisional lymph node biopsy, including demonstration of characteristic pathologic changes and KSHV-infected cells by immunohistochemistry. Physical exam should focus on adenopathy, splenomegaly, edema, and evaluation for concurrent KS. Common laboratory abnormalities include anemia, thrombocytopenia, hypoalbuminemia, hyponatremia, and elevated inflammatory markers such as C-reactive protein. Lactate dehydrogenase (LDH) is generally not elevated. Patients with MCD should undergo CT of neck, chest, abdomen and pelvis.

4. Treatment. There is no standard therapy for KSHV-MCD. HIV-infected patients should receive cART. Several agents have reported activity in case series or small studies. Perhaps best studied is the anti-CD20 monoclonal antibody rituximab. Most patients respond initially to rituximab-containing regimens, although relapses are common. Rituximab monotherapy may be insuficient in advanced disease, and it has been associated with exacerbation of intercurrent KS. Other potentially active agents include ganciclovir, IFN-α, and NHL chemotherapy regimens. Survival of over 2 years is now relatively common. However, given the many uncertainties in managing patients with KSHV-MCD, consideration should be given to referral to a clinical trial.

D. Primary effusion lymphoma (PEL)

1. Epidemiology. PEL is a rare variant of B-cell NHL notable for its unusual presentation and aggressive clinical course. The great majority of reported cases occur in people with HIV, where it represents less than 4% of all lymphomas.

2. Presentation. PEL usually presents as a lymphomatous effusions in serous body cavities, frequently in patients with other KSHV-associated malignancies. Many cases are pleural, but peritoneal, pericardial, and leptomeningeal presentations are seen. Extracavitary PEL may rarely present in other locations, including lymph nodes and the gastrointestinal tract.

3. Evaluation. Diagnosis of PEL depends on the demonstration of KSHV infection of tumor cells. In more than 70% of cases, tumor cells are coinfected with EBV. Common B-cell surface markers (CD19, CD20, CD79a) are absent, while activation markers (CD30, CD38, CD71, CD138) are often present; presence of immunoglobulin gene rearrangements confirms B-cell monoclonality. Evaluation of disease extent should be performed as for NHL (see Section II).

4. Treatment. There are few data to guide the choice of therapy in PEL. Case series using doxorubicin-based regimens report initial complete response (CR) rates as high as 40%, but rapid relapse is common. Median survival is less than 6 months, although a few long-term remissions have been described. The potential role of novel therapies is being explored, and patients should be treated within clinical studies if possible.

II. NON-HODGKIN LYMPHOMA (NHL)

A. Background

NHL is now the most common cancer in HIV-infected patients in the United States. Histologies associated with HIV include both germinal center (GC) and non-GC subtypes of diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), plasmablastic lymphoma, primary central nervous system lymphoma (PCNSL), and PEL.

B. Presentation and patient evaluation

HIV-associated NHL often presents with constitutional symptoms (fevers, night sweats, and weight loss) and enlarging lymph nodes. Extranodal presentations occur more commonly than in HIV-uninfected patients, at sites including the gastrointestinal tract, bone marrow, liver, and central nervous system (CNS). Diagnosis depends on excisional lymph node biopsy or biopsy of an involved extranodal site, and review by pathologists with expertise in lymphoma is advised.

C. Staging

Staging should include CT of the head, neck, chest, abdomen and pelvis, 18fluorodeoxyglucose (FDG)-positron emission tomography (PET), LDH, complete blood count with differential, bone marrow biopsy, and lumbar puncture with evaluation of cerebral spinal fluid by cytology and flow cytometry. Evaluation of cardiac function using echocardiography or multigated acquisition scan is recommended. Magnetic resonance imaging (MRI) of the brain with gadolinium should be strongly considered to evaluate for CNS involvement, or other CNS complications of AIDS in patients with low CD4 counts. HIV viral load, CD4 count, and HBV core antibody and surface antigen, as well as HCV serology, should be evaluated. Patients with detectable HBV core antibody or surface antigen should be screened for a quantitative HBV viral load.

Ann Arbor staging classification is used in HIV-related NHL; however, assessment of prognosis in HIV-associated lymphoma also depends largely on tumor biology. The International Prognostic Index, when applied to patients with DLBCL receiving rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP), is valid in patients with HIV. For patients with DLBCL, immunohistochemical analysis to determine GC versus non-GC subtypes using Hans criteria provides prognostic information. When treated with short-course dose-adjusted etoposide, prednisone, doxorubicin, cyclophosphamide, vincristine, and rituximab (SC-EPOCH-RR), patients with non-GC have a worse outcome than patients with GC (5-year progression-free survival 44% for non-GC versus 95% for GC). Patients with low CD4 counts have a worse prognosis, reflecting both a propensity to develop more aggressive NHL subtypes and increased risk for death from AIDS-related infections during and after chemotherapy.

D. Treatment

1. General approach. Patients with HIV-associated NHL should be treated with curative intent whenever possible. Prior to cART, modified regimens using lower doses of drugs to reduce toxicity were often used, and the median survival was approximately 2 years. However, studies in the cART era have shown that prognosis improves with therapies that mirror those used in HIV-negative patients, albeit with particular attention to the prevention of infection. CR and prolonged progression-free survival are now achievable in a high percentage of patients.

Decisions regarding use of cART during lymphoma therapy are based on expert opinion. Its use is not essential; studies of dose-adjusted EPOCH (DA-EPOCH) in HIV-associated lymphoma have achieved excellent results withholding cART during lymphoma treatment. However, other studies have maintained patients on cART during therapy, and most specialists will continue well-tolerated cART regimens. In patients who have not yet started on cART, opinions vary. Optimized cART should not interfere with delivery of full-dose chemotherapy. Caution regarding possible drug–drug interactions is required. Ritonavir should generally be avoided due to strong inhibition of CYP3A4. Other protease inhibitors also inhibit CYP3A4 to varying degrees; nonprotease inhibitor cART regimens are preferred. Zidovudine should be avoided due to its additive hematotoxicity. If withheld, cART should be introduced immediately after completion of therapy.

Patients should receive prophylaxis against Pneumocystis pneumonia regardless of the CD4 count, preferably with trimethoprim/sulfamethoxazole (one double-strength tablet three times weekly throughout therapy, continued thereafter until CD4 >200 cells/μL). Patients with fewer than 50 to 100 CD4 cells/μL require azithromycin 1200 mg weekly as prophylaxis against Mycobacterium avium complex infection. Those with detectable hepatitis B viremia require HBV antiviral therapy. Care is required to ensure therapy of intercurrent HBV is tailored to avoid compromising HIV control. Single-agent therapy for HBV will increase the likelihood of a specific HV-mutation, M184V which renders patients resistant to several important antiretroviral agents. Patients with mucosal candidal infections should not receive azoles concurrently with chemotherapy.

2. Systemic therapy. The tolerability and efficacy of several rituximab-containing combination chemotherapy regimens have been evaluated in HIV-associated lymphoma. DA-EPOCH-R, SC-EPOCH-RR, R-CHOP, and rituximab plus cyclophosphamide, doxorubicin, and etoposide (R-CDE) have all been evaluated prospectively, although they have not been directly compared (Table 25.3).

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Rituximab improves CR rates and overall survival in a range of lymphomas in HIV-negative patients, and there is an emerging consensus that it should also be incorporated in the setting of HIV, although in patients with poor immune function (50 CD4 cells/μL), rituximab may confer enhanced risk of infection.

Three studies have used EPOCH as a platform for the treatment of HIV-associated NHL. Infusional DA-EPOCH, which used a stratified dose of cyclophosphamide based on initial CD4 count and withheld cART until completion of chemotherapy, led to a 77% CR rate with 30 months median follow-up; overall survival was 74%. Subsequently, four to six cycles of DA-EPOCH with concurrent or sequential rituximab was evaluated. Patients with BL and Burkitt-like lymphoma were included. This protocol maintained a dose stratification of cyclophosphamide based on CD4 count (see Table 25.3), and 76% of patients received concurrent cART. In patients receiving concurrent rituximab, the CR rate was 73%, with a 2-year overall survival of 63%. DA-EPOCH followed by rituximab yielded inferior CR rates with no decrease in infective toxicity. A further development of DA-EPOCH incorporated standard doses of cyclophosphamide and dose-dense rituximab. The number of courses administered was based on assessment of response by interim FDG-PET and CT, delivering a minimum of three (80% of patients) and maximum of six cycles with one cycle beyond stable imaging (SC-EPOCH-RR). The observed CR rate was 91% in DLBCL. With 48 months median follow-up, progression-free survival and overall survival were 84% and 64%, respectively. Notably, the estimated 5-year progression-free survival was 95% for those with GC DLBCL. However, validation of the approach—particularly the generalizability of the use of interim FDG-PET—is required before its adoption outside of clinical trials.

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Another infusional regimen, R-CDE, has been evaluated in three separate phase II studies, presented together in a pooled analysis. These studies included patients with BL. R-CDE was administered with G-CSF support every 4 weeks, with a planned six cycles. In these studies, 76% of patients received concurrent cART. The CR rate was 70%, and the estimated 2-year overall survival rate was 64%. This regimen was associated with a high rate of both opportunistic and neutropenia-related infections.

Although the survival of patients with HIV-associated NHL has improved considerably, additional studies are needed to optimize treatment, and patients with HIV-associated NHL should continue to be enrolled in clinical studies when possible. For patients not referred for clinical studies, one of the three discussed regimens (DA-EPOCH-R, R-CHOP, or R-CDE; see Table 25.3) is recommended. The consensus now is that patients, even those with poor immune function, should be offered established regimens at standard doses whenever possible, as delivery of less intensive therapy may compromise outcomes.

3. CNS prophylaxis and treatment. CNS involvement at presentation occurs in less than 10% of patients with HIV-associated lymphoma and is particularly common in patients with EBV-associated disease, BL, or extranodal involvement. In those patients where staging, including lumbar puncture, shows no evidence of CNS disease at presentation, CNS prophylaxis should be instituted. The prophylaxis utilized varies between studies, but most investigators employ intrathecal methotrexate (12 mg) or cytosine arabinoside (50 mg) for a total of four to eight doses. A single dose of leucovorin 25 mg, given orally 24 hours after methotrexate, is advisable. Patients with documented leptomeningeal disease generally have a poor prognosis. Several intensive intraventricular and intrathecal methotrexate schedules have shown activity. Most commonly, therapy is administered using an Ommaya reservoir twice weekly until 2 weeks after negative flow cytometry is documented (for a minimum of eight doses), and then continued weekly for 6 to 8 weeks, then monthly for 6 months.

4. Burkitt lymphoma (BL) is characterized by a very high rate of cell cycling (the proliferative index may approach 100%), an aggressive clinical course, and propensity to acquire chemotherapy resistance rapidly if treated improperly. Until recently, clinical trials of AIDS-related NHL included both DLBCL and BL. However, it is now appreciated that there are substantial differences in response of these diseases to therapy, and they must be considered separately. Combination dose intensive and infusional regimens are the standard of care for HIV-negative BL, and similar approaches are now being employed for AIDS-related BL.

DA-EPOCH-R with a risk-adapted approach (employing cyclophosphamide 750 mg/m2), and cyclophosphamide, vincristine, doxorubicin, and methotrexate plus ifosfamide, etoposide, and cytarabine (CODOX-M/IVAC) with rituximab each deliver high CR rates and are being evaluated in studies that include patients with HIV. There is evidence that patients with BL have a relatively poorer outcome with R-CDE or R-CHOP, and there is an expert consensus that these regimens should not be used. Particular attention to the risk of tumor lysis with induction is needed in BL. Intravenous hydration; monitoring of uric acid, calcium, potassium, and phosphate; and allopurinol prophylaxis should be employed during the first cycle of chemotherapy.

5. Plasmablastic lymphoma (PBL) is a rare EBV-associated B-cell NHL. While most commonly reported in the setting of HIV, PBL also occurs in organ transplantation patients and elderly individuals. It most commonly presents with extranodal disease within the oral cavity but may occur at other extranodal or nodal sites. Ann Arbor staging is not prognostic, and patients with stage I disease should be treated the same as those with systemic disease. PBL is characterized by a high proliferative index and aggressive clinical course. Historically, the prognosis has been poor, with median survival less than 2 years. CHOP has often been used with poor outcomes. Nonetheless, intensive regimens such as DA-EPOCH and CODOX-M/IVAC are recommended.

6. Use of high-dose therapy (HDT) and stem cell transplantation. Increasingly, data support the feasibility and effectiveness of HDT with autologous peripheral blood stem cell transplantation (PBSCT) in patients with relapsed HIV-NHL and HIV-associated HL. In the largest study of HDT-PBSCT, the Italian Cooperative Group on AIDS and Tumors evaluated 50 patients: 31 with NHL and 19 with HL; 27 patients actually received transplantation. By intent-to-treat analysis with median follow-up of 44 months, overall and progression-free survival were each approximately 50%. Limiting analysis to those who received transplant, overall and progression-free survival were 75%. These results are comparable to results in HIV-negative patients. The role of this approach is still unclear. Nonetheless, if an HIV-infected patient requires second-line therapy for NHL or HL, early consideration of the role of transplantation is critical, as disease progression and consequent compromised performance status impact transplant feasibility.

III. PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA (PCNSL)

A. Background

PCNSL typically occurs in patients with fewer than 50 CD4 cells/μL. Most are high-grade DLBCLs. The EBV genome is identified in nearly all investigated cases of HIV-associated PCNSL, and patients with AIDS-associated PCNSL have defects in EBV-specific CD4 activity, supporting the role of dysregulated lymphoproliferation of EBV-infected B-cells in its pathogenesis. The incidence of PCNSL has declined sharply since the introduction of cART, largely because the number of patients with under 50 CD4 cells/μL has decreased.

B. Presentation and diagnosis

Patients with AIDS-PCNSL may present with a headache, focal neurologic deficits, ataxia, or altered mental status. CT or MRI of the head typically shows single or multiple, periventricular, contrast-enhancing masses with surrounding edema. Lesions may be difficult to distinguish from those of toxoplasmosis. Given the changing epidemiology of HIV and HIV-associated malignancies, the differential diagnosis should also include other infections, such as tuberculosis. EBV-negative PCNSL, other CNS tumors, or meta-static cancer should also be considered, especially in patients with a CD4 count of more than 50 cells/μL. PCNSL is a curable malignancy with an extremely poor outcome if not treated. Expedited evaluation of patients with intracranial masses is therefore required.

Historically, AIDS patients with intracranial masses were often given an empiric trial of antitoxoplasmosis therapy. However, this approach is no longer considered acceptable except under unusual circumstances. Imaging should include MRI with gadolinium. Evaluation of CSF should include cytology, flow cytometry, and EBV polymerase chain reaction (PCR) in addition to evaluation of infectious etiologies. The presence of EBV by PCR in the cerebrospinal fluid is a sensitive marker for PCNSL, but EBV may be detectable in the cerebrospinal fluid in other settings. Patients with HIV-PCNSL should undergo ophthalmologic evaluation for ocular involvement. In the context of a patient with 50 CD4 cells/μL or less, the combination of a high titer EBV viral load in the cerebro-spinal fluid, a ring-enhancing brain mass on MRI, and a positive thallium scan or CNS FDG-PET may be considered highly suggestive of PCNSL, even without a tissue diagnosis. Whenever possible, patients in whom PCNSL is suspected should undergo stereotactic biopsy of the brain lesion. In patients who meet the criteria above, and who are too unstable for brain biopsy, empiric treatment for PCNSL may be warranted after careful consideration of the diagnostic possibilities, risks, and benefits. As 95% of HIV-positive patients with toxoplasmosis have serologic evidence of Toxoplasma sp. infection, the Toxoplasma titer can be a useful adjunct to determine a course of action. However, concurrent PCNSL and toxoplasmosis has been described.

C. Treatment

There is no standard therapy for HIV-associated PCNSL, and patients should be considered for referral to a clinical trial when possible. Therapy should include cART, which has been shown in retrospective studies to improve overall survival. After a pathologic diagnosis is made, a short course of dexamethasone may help control the mass effect of the tumor. Prior to cART, whole-brain radiation therapy (WBRT) was considered the standard of care. WBRT can be associated with severe late toxicity, but this was not a major concern in an era when the median survival in AIDS-associated PCNSL was 2 to 5 months. With the availability of cART, radiation-sparing approaches with curative intent that reduce the likelihood of late CNS toxicities are warranted. High dose methotrexate, 8 mg/m2 every 2 weeks with leucovorin rescue, crosses the blood-brain barrier, is minimally hematotoxic, and is the backbone of PCNSL regimens in non-immunosuppressed patients. PCNSL is strongly CD20 positive, and inclusion of rituximab may also be beneficial. HIV-infected patients with EBV-negative PCNSL should be considered for radiation-sparing combination regimens used in HIV-uninfected patients, especially if they have CD4 greater than 100 cells/μL. If chemotherapeutic approaches fail, WBRT salvage therapy can be considered.

IV. HUMAN PAPILLOMAVIRUS (HPV)–ASSOCIATED CANCERS

A. Background

HIV-infected patients have an increased incidence of several cancers caused by HPV, including cancer of the cervix, anus, penis, vulva, oral pharynx, and tonsil. This increase is related to an increased exposure to oncogenic strains of HPV and an impaired ability to clear these strains because of HIV-associated immunodeficiency.

HIV-infected women have about a fivefold increased incidence of cervical cancer as compared to HIV-uninfected women, and cervical cancer became an AIDS-defining cancer in 1993. Virtually all cervical cancer is caused by oncogenic strains of HPV. HIV-infected women also have a four- to fivefold increased risk of cervical intraepithelial neoplasia (CIN), and cervical cancer screening is an integral component of health care for HIV-infected women. HIV-infected individuals, and especially MSM, have a high incidence of anal intraepithelial neoplasia (AIN) and persistence of HPV infection in the anus. People with HIV are at a 100-fold increased risk of anal cancer, and its incidence is increasing. In addition, there is evidence that other HPV-associated cancers, especially cancers of the oral pharynx and tonsil, are increasing in the last decade.

B. Cervical cancer

1. Screening and treatment of premalignant lesions. The U.S. Preventative Services Task Force guidelines recommend that women with HIV should have evaluation of cervical cytology twice in the first year after diagnosis and then annually if the results are normal. Additional evaluation of HPV DNA during the first year, with a subsequent screening frequency of 6 months in women with detectable high-risk subtypes of HPV and yearly in those without high-risk HPV, has also been proposed as a more individualized screening algorithm. The management of premalignant cervical lesions in women with HIV is more complicated than that in HIV-negative women due to higher rates of positive margins and recurrent CIN, especially in women with low CD4 counts. Low-grade lesions (CIN1) are generally observed closely, while higher grade lesions (CIN2 or higher) are generally treated. Initiation of cART and associated immune reconstitution has been associated with regression of lesions over time in certain cases, and may decrease the risk of recurrence. Treatment options for CIN include ablative therapy, loop excision of the transformation zone, or conization procedures, and should be individualized based on the size and location of the lesion.

2. Staging and treatment. The International Federation of Gynecology and Obstetrics staging system, used for non–HIV-infected patients, is used in this population as well. More recently, FDG-PET has been incorporated in the initial assessment of women with cervical cancer, largely due to the prognostic value of FDG-avid para-aortic lymph nodes. However, this modality has not been evaluated in women with HIV and cervical cancer, and results should be interpreted with the understanding that uncontrolled HIV viremia alone is associated with lymph node FDG-avidity. Treatment is based on clinical stage. There are no clinical trials specific to HIV-infected women with cervical cancer. In the absence of information to the contrary, HIV-positive women with invasive cervical cancer should be treated in the same manner as those without HIV infection.

C. Anal cancer

1. Screening and treatment of premalignant lesions. The annual incidence of anal cancer in patients with HIV in the United States, estimated at 80 per 100,000 individuals, is much higher than that of the general population. Given the biologic similarities to cervical cancer and the effectiveness of cervical cancer screening, programs to screen HIV-infected men and women for AIN and treat high-grade lesions are being developed. This approach has the potential to prevent anal cancer by detecting and treating premalignant lesions. However, it has not yet been tested in prospective studies. A major difference between anal and cervical cancer is the greater difficulty in doing preventive surgery on precancerous lesions of the anus. The primary tool to screen for anal cancer is cytology of the anal epithelium. Abnormal cytology should be followed up with anoscopy if possible. Treatment decisions are based on the grade of the lesion. Current options for high-grade AIN include local treatment with topical immune modulator or antiviral agents, electrocautery, laser or infrared coagulation, and surgery.

2. Treatment. The standard of care for stages I to III anal cancer is concurrent chemoradiation, and patients with HIV should receive standard regimens. Given the concern of hematologic toxicity associated with mitomycin-C–based chemoradiation in patients with HIV, cisplatin-based regimens have been advocated by some. However, with the availability of cART, outcomes in patients with HIV receiving concurrent chemoradiation, including mitomycin-C–based therapy, appear to be comparable to that of the general population. The alternative to chemoradiation is surgical abdominoperineal resection (APR), which leaves patients with a permanent colostomy. APR is an option for patients with poor performance status or who do not wish to undergo concurrent chemoradiation, but should generally be employed only for the management of locoregional recurrence. Patients with HIV and anal cancer should be treated within clinical studies where possible.

V. NON-AIDS–DEFINING MALIGNANCIES (NADMs)

NADMs are an increasing public health concern, yet much remains to be learned about their epidemiology, pathogenesis, and optimal treatment. For some cancers, there are known biologic differences between those that arise in HIV-infected and uninfected patients (i.e., HIV-infected patients are more likely than the general population to present with mixed cellularity and lymphocyte-depleted HL subtypes). For other cancers, such biologic differences have not been established. Until recently, HIV-infected patients have generally been excluded from most cancer clinical trials of NADM, leading to a lack of specific data to guide therapy. A recent National Cancer Institute initiative encourages enrollment of HIV-infected patients in clinical trials where possible. In the absence of specific evidence, standard therapeutic approaches should generally be considered, especially in patients with good performance status.

Special considerations in the setting of HIV include the role of cART and of prophylaxis for opportunistic infections. For surgically managed tumors, cART should be prescribed based on DHHS guidelines. In patients for whom chemotherapy or radiation is required, most specialists recommend the use of cART in the absence of a clear contraindication. Potential drug–drug interactions between antiretroviral agents and chemotherapeutic agents should be considered, as outlined previously. Protease inhibitors, especially nelfinavir, may also have radiosensitizing effects. Generally, trimethoprim/sulfamethoxazole is recommended for patients with under 200 CD4 cells/μL, but more liberal use may be warranted in this setting, especially in patients receiving lymphotoxic regimens.

Selected Readings

Background

Biggar RJ, Engels EA, Ly S, et al. Survival after cancer diagnosis in persons with AIDS. J Acquir Immune Defic Syndr. 2005;39:293–299.

Bonnet F, Burty C, Lewden C, et al. Changes in cancer mortality among HIV-infected patients: the Mortalite 2005 Survey. Clin Infect Dis. 2009;48:633–639.

Engels EA, Biggar RJ, Hall HI, et al. Cancer risk in people infected with human immunodeficiency virus in the United States. Int J Cancer. 2008;123:187–194.

Yarchoan R, Tosato G, Little RF. Therapy insight: AIDS-related malignancies—the influence of antiviral therapy on pathogenesis and management. Nature Clin Prac Oncology. 2005;2:406–415.

Kaposi Sarcoma

Bower M, Weir J, Francis N, et al. The effect of HAART in 254 consecutive patients with AIDS related Kaposi’s sarcoma. AIDS. 2009;23:1701–1706.

Krown SE, Testa MA, Huang J. AIDS-related Kaposi’s sarcoma: prospective validation of the AIDS Clinical Trials Group staging classification. AIDS Clinical Trials Group Oncology Committee. J Clin Oncol. 1997;15:3085–3092.

Krown SE, Lee KY, Lin L, Fischl MA, Ambinder R, Von Roenn JH. Interferon-alpha 2b with protease inhibitor-based antiretroviral therapy in patients with AIDS-associated Kaposi sarcoma—An AIDS malignancy consortium phase I trial. J Acquir Immune Defic Syndr. 2006;41:149–153.

Martin-Carbonero L, Palacios R, Valencia E, et al. Long-term prognosis of HIV-infected patients with Kaposi sarcoma treated with pegylated liposomal doxorubicin. Clin Infect Dis. 2008;47:410–417.

Nasti G, Talamini R, Antinori A, et al. AIDS-related Kaposi’s sarcoma: evaluation of potential new prognostic factors and assessment of the AIDS Clinical Trial Group Staging System in the Haart Era—the Italian Cooperative Group on AIDS and Tumors and the Italian Cohort of Patients Naive From Antiretrovirals. J Clin Oncol. 2003;21:2876–2882.

Northfelt DW, Dezube BJ, Thommes JA, et al. Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine in the treatment of AIDS-related Kaposi’s sarcoma: results of a randomized phase III clinical trial. J Clin Oncol. 1998;16: 2445–2451.

Saville MW, Lietzau J, Pluda JM, et al. Treatment of HIV-associated Kaposi’s sarcoma with paclitaxel. Lancet. 1995;346:26–28.

Multicentric Castleman Disease

Bower M, Powles T, Williams S, et al. Brief communication: rituximab in HIV-associated multicentric Castleman disease. Ann Intern Med. 2007;147:836–839.

Casper C, Nichols WG, Huang ML, Corey L, Wald A. Remission of HHV-8 and HIV-associated multicentric Castleman disease with ganciclovir treatment. Blood. 2004;103:1632–1634.

Oksenhendler E, Duarte M, Soulier J, et al. Multicentric Castleman’s disease in HIV infection: a clinical and pathological study of 20 patients. AIDS. 1996;10:61–67.

Primary Effusion Lymphoma

Boulanger E, Gérard L, Gabarre J, et al. Prognostic factors and outcome of human herpesvirus 8-associated primary effusion lymphoma in patients with AIDS. J Clin Oncol. 2005;23:4372–4380.

Zelenetz AD, the NCCN Non-Hodgkin’s Lymphoma Panel. Non-Hodgkin’s lymphoma. In: NCCN Practice Guidelines in Oncology. 1st ed. Fort Washington, PA: National Comprehensive Cancer Network; 2010.

Non-Hodgkin Lymphoma

Dunleavy K, Little RF, Pittaluga S, et al. The role of tumor histogenesis, FDG-PET, and short course EPOCH with dose-dense rituximab (SC-EPOCH-RR) in HIV-associated diffuse large B-cell lymphoma. Blood. 2010;114:3017–3024.

Kaplan LD, Lee JY, Ambinder RF, et al. Rituximab does not improve clinical outcome in a randomized phase 3 trial of CHOP with or without rituximab in patients with HIV-associated non-Hodgkin’s lymphoma: AIDS-malignancies consortium trial 010. Blood. 2005;106:1538–1543.

Lim ST, Karim R, Nathwani BN, Tulpule A, Espina B, Levine AM. AIDS-related Burkitt’s lymphoma versus diffuse large-cell lymphoma in the pre-highly active antiretroviral therapy (HAART) and HAART eras: significant differences in survival with standard chemotherapy. J Clin Oncol. 2005;23:4430–4438.

Little RF, Pittaluga S, Grant N, et al. Highly effective treatment of acquired immunodeficiency syndrome-related lymphoma with dose-adjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology. Blood.2003;101:4653–4659.

Miralles P, Berenguer J, Ribera JM, et al. Prognosis of AIDS-related systemic non-Hodgkin lymphoma treated with chemotherapy and highly active antiretroviral therapy depends exclusively on tumor-related factors. J Acquir Immune Defic Syndr. 2007;44:167–173.

Re A, Michieli M, Casari S et al. High-dose therapy and autologous peripheral blood stem cell transplantation as salvage treatment for AIDS-related lymphoma: long-term results of the Italian Cooperative Group on AIDS and Tumors (GICAT) study with analysis of prognostic factors. Blood. 2009;114:1306–1313.

Ribera JM, Oriol A, Morgades M, et al. Safety and efficacy of cyclophosphamide, adri-amycin, vincristine, prednisone and rituximab in patients with human immunodeficiency virus-associated diffuse large B-cell lymphoma: results of a phase II trial. Br J Haematol. 2008;140:411–419.

Sparano JA, Lee JY, Kaplan LD, et al. Rituximab plus concurrent infusional EPOCH chemotherapy is highly effective in HIV-associated, B-cell non-Hodgkin’s lymphoma. Blood 2010;115:3008–3016.

Spina M, Jaeger U, Sparano JA, et al. Rituximab plus infusional cyclophosphamide, doxorubicin, and etoposide in HIV-associated non-Hodgkin lymphoma: pooled results from 3 phase 2 trials. Blood.2005;105:1891–1897.

Wang ES, Straus DJ, Teruya-Feldstein J, et al. Intensive chemotherapy with cyclophos-phamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide and high-dose cytarabine (CODOX-M/IVAC) for human immunodeficiency virus-associated Burkitt lymphoma. Cancer. 2003;6:1196–1205.

Primary Central Nervous System Lymphoma

Antinori A, De Rossi G, Ammassari A, et al. Value of combined approach with thallium-201 single-photon emission computed tomography and Epstein-Barr virus DNA polymerase chain reaction in CSF for the diagnosis of AIDS-related primary CNS lymphoma. J Clin Oncol. 1999;17:554–560.

Corcoran C, Rebe K, van der Plas H, Myer L, Hardie DR. The predictive value of cerebrospinal fluid Epstein-Barr viral load as a marker of primary central nervous system lymphoma in HIV-infected persons. J Clin Virol.2008;42:433–436.

Hoffmann C, Tabrizian S, WolfE, et al. Survival ofAIDS patients with primary central nervous system lymphoma is dramatically improved by HAART-induced immune recovery. AIDS. 2001;15:2119–2127.

Human Papillomavirus–Associated Cancers

Abramowitz L, Mathieu N, Roudot-Thoraval F, et al. Epidermoid anal cancer prognosis comparison among HIV+ and HIV- patients. Aliment Pharmacol Ther. 2009;30:414–421.

Frisch M, Biggar RJ, Goedert JJ. Human papillomavirus-associated cancers in patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. J Natl Cancer Inst.2000;92:1500–1510.

Minkoff H, Zhong Y, Burk RD, et al. Influence of adherent and effective antiretro-viral therapy use on human papillomavirus infection and squamous intraepithelial lesions in human immunodeficiency virus-positive women. J Infect Dis. 2010;201:681–690.

Palefsky JM. Anal cancer prevention in HIV-positive men and women. Curr Opin Oncol. 2009;21:433–438.

Wexler A, Berson AM, Goldstone SE, et al. Invasive anal squamous-cell carcinoma in the HIV-positive patient outcome in the era of highly active antiretroviral therapy. Dis Colon Rectum. 2008;51:73–81.

Wright TC Jr, Ellerbrock TV Chiasson MA, Van Devanter N, Sun XW Cervical intraepithelial neoplasia in women infected with human immunodeficiency virus: prevalence, risk factors, and validity of Papanicolaou smears. New York Cervical Disease Study. Obstet Gynecol. 1994;84:591–597.

Non-AIDS–Defining Malignancies

Deeken JF, Pantanowitz L, Dezube BJ. Targeted therapies to treat non-AIDS-defining cancers in patients with HIV on HAART therapy: treatment considerations and research outlook. Curr Opin Oncol.2009;21:445–454.

Persad GC, Little RF, Grady C. Including persons with HIV infection in cancer clinical trials. J Clin Oncol. 2008;26:1027–1032.