Bethesda Handbook of Clinical Oncology, 2nd Edition

Other Malignancies

31

Acquired Immunodeficiency Syndrome–Related Malignancies

Pallavi P. Kumar

Richard F. Little

HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Individuals with human immunodeficiency virus (HIV) infection are at increased risk for developing neoplastic disease. The clinical behavior of specific malignancies is often markedly altered in the setting of HIV infection as compared to the HIV-negative counterpart.

  • Three neoplasms are considered as acquired immunodeficiency syndrome (AIDS)–defining conditions when they occur in HIV-infected patients:
  1. Kaposi sarcoma (KS)
  2. Aggressive B-cell non-Hodgkin lymphoma, both peripheral and primary central nervous system (CNS) lymphomas
  3. Cervical cancer.
  • A number of other cancers that are not considered AIDS-defining occur with increasing frequency in HIV-infected patients, including Hodgkin disease (HD), multicentric Castleman disease, angiosarcoma, multiple myeloma, brain cancer, lung cancer, and seminoma.
  • Highly active antiretroviral therapy (HAART) for HIV infection has resulted in fewer AIDS complications, including malignancies.
  1. There is no cure for AIDS, but HAART increases longevity, thereby increasing the prevalence of people living with HIV and AIDS.
  2. Cancer prevalence in the HIV-infected population may be expected to increase over time.

KAPOSI SARCOMA

Epidemiology

  • KS was first described in 1872 by Moritz Kaposi.
  • KS is the most common HIV-associated tumor.
  • There are four epidemiologic forms of KS:
  1. Classic KS
  2. This is found predominately in elderly men of the Mediterranean and Eastern Europe.
  3. Epidemic KS
  4. In Africa, especially in the Nile–Congo watershed, KS is the most commonly diagnosed tumor.
  5. KS can be aggressive in children, involving the lymph nodes, internal organs, and skin.
  6. The seroprevalence of Kaposi sarcoma–associated herpesvirus (KSHV) exceeds 60% in some parts of sub-Saharan Africa (see subsequent text).

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  1. AIDS-related KS
  2. AIDS-related KS heralded the emerging AIDS epidemic in 1981.
  3. This previously rare tumor was suddenly seen with an unexpectedly high prevalence in young gay men, a population previously unaffected by this disease.
  4. Coinfection with HIV increases the risk of KS by more than 100,000 times, and the clinical course can be more aggressive than that of classical KS.
  5. In the developed world, the incidence of KS is highest among men who have sex with other men (MSM) and with their female sex partners. In the early stages of the epidemic, KS was the AIDS-defining diagnosis in nearly 50% of HIV-infected MSM.
  6. Currently, KS is the AIDS-defining diagnosis in less than 11% of HIV-infected MSM; the reasons for this include
  7. a change in the case definition of AIDS in 1992 that included less than 200 CD4 cells per mm3
  8. safer sex practices possibly leading to a decrease in KSHV transmission

iii.      induction of immune reconstitution by HAART, which can lower the risk of developing AIDS-related KS.

  1. Immune suppression from other causes (e.g., iatrogenic immune suppression in solid organ transplantation) can also increase the risk of KS in individuals infected with KSHV.

Pathophysiology of Kaposi Sarcoma

  • Kaposi sarcoma is an angioproliferative lesion caused by KSHV, also known as human herpesvirus 8 (HHV-8).
  • This novel gammaherpes virus was discovered in 1994.
  • It encodes for a number of viral mimics of human cytokines and other factors involved in KS pathogenesis.
  • Interleukin 6 (IL-6), macrophage inhibitory protein, and interferon regulatory factor upregulates vascular endothelial growth factor (VEGF) and its receptors.
  • KSHV-infected spindle-shaped cells are most likely of vascular endothelial origin.
  • KSHV-driven proangiogenic factors promote endothelial cell hyperproliferation and spindle-like morphogenesis.
  • KS endothelial/spindle cells respond to
  1. basic fibroblast growth factor (bFGF)
  2. VEGF
  • Most cells are latently infected and express latency-associated nuclear antigen (LANA). LANA promotes cell survival by interacting with the tumor suppressor protein p53. LANA interacts with p53 and inhibits its ability to promote apoptosis, thereby contributing to viral persistence and oncogenesis in KS. Some cells show lytic infection.
  • Transmission routes have not been established.
  • The possibilities include mother to infant, child to child, and sexual transmission.
  • Saliva contains high concentrations of KSHV.
  • KSHV appears to be transmitted inefficiently by transfusion of blood products.
  • It is an angioproliferative neoplastic disease.
  • The vascularity of the lesion gives it a purplish appearance.
  • The lesions can be flat or nodular.
  • Lymphadenopathy and edema may be present in the absence of cutaneous involvement.
  • KS arises simultaneously in multiple nonmetastatic sites.
  • Skin involvement is typical, but virtually any internal organ except the brain can be affected.

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Diagnosis

KS is diagnosed using the following techniques:

  • A 4- to 6-mm skin punch biopsy: Extensive surgical excision is not required and may not be clinically useful.
  • Differential diagnosis: Bacillary angiomatosis, melanoma, granulomatous conditions, or prominent vascularity in the lymph nodes.
  • HIV serology should be obtained whenever KS is suspected.

Clinical Presentation

  • Variable clinical course
  • Indolent waxing and waning of cutaneous involvement.
  • Relentless progression with ulceration, severe tumor-associated edema, pain, and disfigurement.
  • Patients with minimal KS may require no treatment unless the psychological impact, which can be severe, warrants therapy.
  • Extensive pulmonary involvement may be associated with a particularly poor prognosis (median survival less than 7 months in the pre-HAART era).
  • Substantial morbidity and death can ensue from involvement of other viscera (e.g., gastrointestinal tract).

Kaposi Sarcoma Staging

  • The TIS staging system (see Table 31.1), devised by the AIDS Clinical Trials Group Oncology Committee, is commonly used.
  1. T refers to tumor extent
  2. I refers to immune status
  3. S refers to other AIDS-related systemic illness.
  • The TIS system stages patients, overall, as being either at good risk, designated by the subscript 0, or at poor risk, designated by the subscript 1, the summary taking the form T0 or 1I0 or 1 S0 or 1.
  • In the HAART era, two different risk categories have been identified
  1. Good risk (T0S0, T1S0, T0S1)
  2. Poor risk (T1S1).

The immune status of the two risk categories appears not to be predictive. This most likely depends on the effectiveness of HAART; the original TIS may be more applicable for patients with multidrug-resistant HIV infection.

  • The staging of KS includes (a) enumeration and bidirectional measurement of cutaneous and oral lesions; (b) baseline chest x-ray: if this is abnormal, computerized tomography (CT) scan of the chest should be performed; (c) CD4 cell count; (d) endoscopy if symptoms referable to the gastrointestinal (GI) tract are present.
  1. Lesions should be characterized as
  2. flat or nodular
  3. lesions with or without tumor-associated edema.
  4. If there are more than 50 cutaneous lesions, representative areas containing at least 20 lesions are designated for individual lesion assessment for response to therapy.
  5. Abnormalities on chest CT may indicate pulmonary involvement by KS. Bronchoscopic evaluation can establish the diagnosis of pulmonary KS if lesions are visualized

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in the airways. Endobronchial or open lung biopsy should be avoided, because of risk of hemorrhage.

TABLE 31.1. Revised Acquired Immunodeficiency Syndrome Clinical Trial Group (ACTG) staging classification for Kaposi sarcomaa

 

Good risk (0) (all of the following)

Poor risk (1) (any of the following)

KS, Kaposi sarcoma; HAART, highly active antiretroviral therapy; HIV, human immunodeficiency virus.
The revised CD4 cutoff of 150 cells/mm3 is lower than the original proposal of 200 cells/mm3. Example of staging: A patient with only nodular oral KS, CD4 count of 175 cells/mm3, and a history of PCP would be T1 S0 I1. In the HAART era, two prognostic categories are considered good risk (T0 S0, T1 S0, T0 S1) and one category is considered poor risk (T1 S1).

aAdapted from Krown SE, Testa MA, et al., AIDS Clinical Trials Group Oncology Committee. AIDS-related Kaposi's sarcoma: prospective validation of the AIDS Clinical Trials Group staging classification. J Clin Oncol 1997;15(9):3085–3092.
Adapted from Nasti G, Talamini R, 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(15):2876–2882.

Tumor (T)

Confined to skin and/or lymph nodes and/or nonnodular oral disease confined to the palate

Tumor-associated edema or ulceration Extensive oral KS Nonnodal viscera

Immune system (I) (May not be predictive in those responding to HAARTb)

CD4 count ≥150/mm3

CD4 count <150/mm3

Systemic illness (S)

No history of opportunistic infection or thrush. No “B” symptoms (unexplained fever, night sweats, >10% involuntary weight loss, or diarrhea) persisting for more than 2 wk. Performance status <70 (Karnofsky)

History of opportunistic infections and/or thrush; “B” symptoms present. Performance status <70. Other HIV-related opportunistic illness

Prognostic Factors

  • Response to KS therapy may be related to a variety of factors:
  • Tumor extent
  • Performance status
  • Presence of a HAART-sensitive HIV (this may predict a better prognosis)
  • Extent of HIV replication: A better control of HIV may result in a more indolent course of KS. In addition, the HIV viral load predicts the rate of progressive immunosuppression.

Management of Kaposi Sarcoma

  • The goal of treatment is palliation.
  • KS is not yet curable.
  • It frequently reappears or progresses when therapy is suspended.
  • Complete response does not imply cure.
  • Well-controlled HIV infection (e.g., low HIV viral loads and high CD4 cell counts) may decrease the need for chronic KS-specific therapy.

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  • HAART is fundamental to the oncologic therapy of AIDS-KS.
  • For patients with minimal, slowly progressing KS, HAART alone may be the only therapeutic maneuver required.
  • Successful therapeutic effect is most likely if the increase in the CD4 cell count above the pretreatment baseline value is 150 cells per mm3or more and if HIV level is suppressed to undetectable levels.
  • Improvements are often noticeable within 3 to 4 weeks.
  • Responses may not be noticeable for several months or even longer.
  • Additional antitumor therapy will most likely be required if
  • HAART does not result in immunologic and virologic response
  • patients have been previously treated for HIV or KS
  • aggressive or widely disseminated tumor is present.

Additional Therapeutic Considerations

Local Therapy

Local therapy is reserved for minimal disease that is restricted to the skin or the oral cavity. It is limited by inadequate cosmetic outcome in some cases.

  • Surgical excision
  1. Acceptable cosmetic results are seen in very limited circumstances.
  2. It is not to be used as definitive therapy in any case.
  3. Its use is not appropriate in many cases.
  • Cryotherapy
  1. It is useful for small lesions.
  2. Permanent destruction of melanocytes may yield unacceptable cosmetic outcome, particularly in dark-skinned individuals.
  • Photodynamic therapy
  1. Many lesions can be treated during a single session.
  2. Moderate pain and photosensitivity is experienced for a number of weeks following the treatment.
  • Intralesional injection
  1. Vinblastine (0.1 mL of 0.1 mg per mL) or 3% sodium tetradodecyl sulfate injection (0.1 to 0.3 mL).
  2. This injection causes nonspecific necrosis or sclerosis of mucocutaneous tissue.
  3. Reasonable cosmetic outcome is exhibited for small lesions.
  • Topical 9-cis-retinoic acid (Panretin gel)
  1. Topical 9-cis-retinoic acid is approved by the U.S. Food and Drug Administration (FDA).
  2. Approximately 45% of lesions show responses.
  3. Inflammation and lightening of the skin yields inadequate cosmesis in some cases.
  • Radiotherapy

Radiotherapy may be useful as adjunctive therapy in severe disease.

  1. The painful areas involved may respond rapidly; therefore, radiation therapy is useful when the potentially slower responses to systemic therapy may compromise the therapeutic outcome. For example, oral lesions causing poor nutritional intake may best be treated with radiotherapy in some patients. Severe mucositis and xerostomia may result from radiotherapy. Tolerance to radiation may be decreased among AIDS-KS patients, particularly on the mucosal surfaces.
  2. Radiotherapy is also useful for cosmetic purposes. For example, when the eyelid or conjunctiva is involved, other local therapies are not practical.
  3. Reappearance of KS in the area of previous irradiation is common.
  4. Residual or late-occurring radiation-induced hyperpigmentation or telangiectasias can be severe and may compromise the cosmetic outcome.

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  1. Palliation of visceral disease, including pulmonary involvement, may be reasonably well tolerated in some circumstances, when chemotherapy is not an option.
  • Carbon dioxide laser therapy
  1. Carbon dioxide laser therapy may result in immediate improvement; for example, treatment of tumor involving the oropharynx and larynx can result in improved oral intake, with less toxicity than is sometimes seen with radiation to the oral cavity.

Systemic Therapy

  • Immunotherapy:Interferon-α
  1. Immune therapy with interferon-α is most successful if the CD4 cell count is more than 200 per mm3in conjunction with antiretroviral therapy.
  2. Toxicity includes flu-like symptoms, depression, and decreased white cell count.
  3. Dose escalation to 5 × 106to 10 × 106U per day or intramuscular or subcutaneous therapy three times weekly is the schedule that is given. Other dosing schedules may also be effective.
  • Cytotoxic Chemotherapy
  1. Monotherapy has replaced combination therapy as the standard of care.
  2. Liposomal anthracyclines or paclitaxel (see Table 31.2)
  3. Advantages of monotherapy over combination therapy include
  4. Better palliation
  5. Reduced toxicity

iii.      Simplicity of administration with concurrent complicated antiretroviral regimens.

  1. Liposomal daunorubicin (DaunoXome): The FDA has approved liposomal daunorubicin as first-line therapy for KS.
  2. The FDA approved second-line therapy for KS.
  3. Liposomal doxorubicin (Doxil)
  4. Paclitaxel (Taxol): Often reserved for particularly severe disease on the basis of high response rates seen in phase II trials, but is perhaps more toxic than liposomal anthracyclines.

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  1. Combination chemotherapy was the previous standard of care. Regimens include doxorubicin, bleomycin, and vinca alkaloid (either vincristine or vinblastine) (ABV).
  2. Response rates range from 28% to 84%, depending on the dose of doxorubicin.
  3. The higher doses tend to be associated with unacceptable toxicity, with pronounced myelosuppression.
  4. Toxic regimens are unsuited for the chronic dosing needed for many patients with this disease.

TABLE 31.2. Commonly Used Standard Therapies in Kaposi Sarcoma

 

Doses

Response rates

From Yarchoan R. Therapy for Kaposi's sarcoma: recent advances and experimental approaches. J Acquir Immune Defic Syndr 1999;21(Suppl 1):S66-73, with permission.

Standard KS therapy

Liposomal anthracyclines

   Doxorubicin

20 mg/m2 intravenously over 30 min q2–3wk

59%

   Daunorubicin

40–60 mg/m2 intravenously over 60 min q2wk

25%

Paclitaxel

135 mg/m2 intravenously over 3 h every 3 wk or 100 mg/m2intravenously over 3 h every 2 wk

59%–71%

Alternative therapies

Doxorubicin/bleomycin/vinca alkaloids (ABV)

ABV q2–4wk Doxorubicin 10–40 mg/m2Bleomycin 15 U Vincristine 1 mg (or vinblastine 6 mg/m2)

24%–88% (higher response rates with higher doxorubicin doses, but greater toxicity)

Vincristine/vinblastine

Vincristine 1 mg alternating with vinblastine 2–4 mg q wk

45%

Bleomycin/vinca alkaloids

Bleomycin 10 U and vincristine 1 mg or vinblastine 2–4 mg weekly

23%

Experimental Therapies

  • Because KS requires long-term treatment, there is strong interest in pathogenesis-based therapies, which may have less associated toxicity.
  • The use of antiangiogenic therapies and antiviral therapies are being investigated.
  1. Thalidomide: Two phase II trials suggest activity in a subset of KS patients.
  2. Interleukin 12: Interleukin 12 has antiangiogenic and immunomodulatory properties.
  3. COL-3: COL-3 exhibits antiangiogenic and antimetastasic effects.
  4. Bevacizumab: Bevacizumab is a monoclonal antibody that blocks VEGF binding to its receptors.

ACQUIRED IMMUNODEFICIENCY SYNDROME–RELATED LYMPHOMAS

Epidemiology

  • In 1985, the Centers for Disease Control and Prevention (CDC) included the aggressive and high-grade B-cell type of non-Hodgkin lymphoma (NHL) as an AIDS-defining condition.
  • AIDS-related lymphoma (ARL) is the second most frequently occurring AIDS-associated malignancy.
  • It is the AIDS-defining diagnosis in approximately 3% of HIV-infected patients.
  • Estimated incidence of up to 10% per year, with a prevalence of 4.5% to 25%, has been documented in certain patient populations.
  • The risk of developing NHL in the HIV-infected population increases by nearly 100 times the risk in the non–HIV-infected population.
  • The true incidence is not known because lymphoma is not a reportable condition among patients already defined as having a prior AIDS-indicating condition, such as less than 200 CD4 cells per mm3.
  • Risk of ARL is independent of the HIV-risk group.
  • HAART has affected the incidence of ARL.
  • The incidence of ARL decreased by up to 50% compared to the pre-HAART period.
  • The greatest decrease in incidence is in the immunoblastic diffuse large B-cell lymphomas (DLBCL): AIDS-related primary CNS lymphoma (AIDS-PCNSL).
  • The incident cases of Burkitt lymphoma have not changed. These tend to occur when the CD4 cell count remains relatively well preserved.
  • Median overall ARL survival has increased in the HAART era.
  • It is approximately 21 months compared to 4 to 18 months in the pre-HAART era.
  • This increase in survival is most likely related to a relative shift to tumor types with better prognosis.

Classification of Acquired Immunodeficiency Syndrome–Related Lymphomas

  • The World Health Organization (WHO) recognizes the predominant ARLs as
  • Burkitt lymphoma
  • DLBCL: includes AIDS-PCNSLs, which, in almost all cases, are of immunoblastic histology and are associated with Epstein–Barr virus (EBV).

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  • Primary effusion lymphoma (PEL); also termed body-cavity lymphoma.
  • Plasmablastic lymphoma of the oral cavity.
  • The non–AIDS-defining conditions (seen in the setting of HIV but not AIDS-defining) include
  • Hodgkin disease
  • Multicentric Castleman disease (MCD)

Acquired Immunodeficiency Syndrome–Related Lymphoma Pathology

  • Distinct clinical, histogenetic, and pathobiologic features correlate with the different ARL subtypes (Table 31.3).
  • Tumor histogenesis correlates with immunologic status (e.g., CD4 cell count).
  • The relative upward shift in CD4 cell count among patients with access to HAART has changed the epidemiology and biology of ARL. This change in bioepidemiology may be the most biologically plausible explanation for the increased survival in patients with ARL in the HAART era.

TABLE 31.3. Genetic and Clinical Features of Peripheral AIDS-related Lymphomas

Histogenetic origin

Histology

Viral associations

Immunophenotype and pathobiologic markers

CD4 cells

Relative proportionate incidence in HAART COMPARED TO pre-HAART era

Prospects for chemosensitivity

EBV (%)

KSHV (%)

CD20 (%)

BCL-2 (%)

BCL-6 (%)

p53 (%)

c-MYC (%)

HAART, highly active antiretroviral therapy; EBV, Epstein–Barr virus; KSHV, Kaposi sarcoma-associated herpes virus; DLBCL, diffuse large B-cell lymphomas.
Adapted from Yarchoan R, Little R. Cancer: AIDS-related malignancies. In: Devita VT, Hellman S, Rosenberg A, eds. Cancer principles and practice of Oncology. Philadelphia, PA: Lippincott Williams & Wilkins, 2005:2247–2263, with permission.

Germinal center

Burkitt

<50

0

~100

0

100

60

100

May be relatively well preserved

Increased

Favorable

DLBCL centroblastic

<30

0

~100

0

>75

rare

0–50

Primary brain DLBCL (immunoblastic)

100

0

variable

90

<50

0

0

<50/mm3

Markedly decreased

Responds to radiation

Postgerminal center

DlBCL immunoblastic

>80

0

variable

30

0

0

0–20

Usually low

Decreased

Poor

Primary effusion lymphoma

>90

100

<20

0

0

0

0

Plasmablastic

>70

0

Rare

0

0

Rare

0

Peripheral Acquired Immunodeficiency Syndrome–Related Lymphoma

Presentation

  • Peripheral ARL frequently presents as advanced stage 3 or 4 disease.
  • The lymphoma frequently behaves aggressively, with unusual patterns of organ involvement.
  • Most patients will present with
  • rapidly growing mass lesion
  • systemic “B” symptoms (i.e., unexplained fever, drenching night sweats, or unexplained weight loss in excess of 10% of the normal body weight).
  • Extranodal involvement is common.
  • bone marrow; 25% to 40%
  • gastrointestinal tract; 26%
  • CNS; 17% to 32%.
  • PEL
  • shows 100% association with KSHV.
  • presents as lymphomatous effusions of the pleural spaces but can occasionally present initially as nodal disease.
  • Plasmablastic lymphomas of the oral cavity
  • is localized in the oral cavity or jaw
  • is often associated with EBV.

Staging

  • Standard staging—using the Ann Arbor Staging Classification for NHL (as is done in non–HIV-infected patients)
  • History and physical examination
  • Clinical laboratory assessment of organ function
  • CD4 cell count
  • Bilateral bone marrow biopsies
  • CT scan of the chest, abdomen, and pelvis
  • CNS assessment for all patients
  • Radiologic imaging
  • CT scan of the brain with contrast is adequate to assess for larger parenchymal brain lesions.
  • Magnetic resonance imaging (MRI) with gadolinium has the potential advantage of revealing smaller lesions and providing evidence of leptomeningeal involvement by the lymphoma.

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  • CNS evaluation is not indicated for patients with human immunodeficiency virus–Hodgkin disease (HIV-HD) because the CNS is not commonly involved.
  • Cytologic evaluation of the cerebrospinal fluid to assess for potential CNS involvement.

Prognosis

  • The CD4 cell count is the primary prognostic indicator.
  • The international prognostic index is not widely validated in ARL.
  • Other factors associated with poor outcome are
  • patients older than 35 to 40 years
  • high concentration of lactate dehydrogenase (LDH)
  • presence of extranodal sites
  • intravenous drug use
  • preexisting AIDS diagnosis.
  • HAART era
  • Median overall survival is nearly 2 years; it may be less in cases of resistant HIV and lower CD4 cell counts (e.g., may behave as pre-HAART).
  • Pre-HAART era
  • If CD4 cell count is less than 100 cells per mm3, a median survival of about 4 months was observed.
  • If CD4 cell count is 100 or cells per mm3or greater, a median survival of 11 to 18 months was observed.

Treatment

  • Optimal therapy has not been defined (see Table 31.4).
  • Comparison of ARL clinical trial results should consider the effect of
  • CD4 cells
  • the different times the trials were conducted (HAART versus pre-HAART).
  • Many experts advocate routine CNS prophylaxis in ARL.
  • There is a predilection for leptomeningeal involvement (15% to 20% of cases).
  • Prophylaxis with intrathecal methotrexate or Ara-C should be considered standard practice for treatment of ARL.
  • Prophylaxis for opportunistic infections
  • All patients should receive prophylaxis for Pneumocystis cariniipneumonia (PCP) regardless of the CD4 count.
  • Prophylaxis should be considered for patients at risk for Mycobacterium aviumcomplex (MAC) (CD4 cell count <50 to 100 per mm3).
  • The CD4 cell count should be periodically monitored during chemotherapy because cytotoxic chemotherapy in itself can cause a profound drop in CD4 cell count.
  • Standard-dose chemotherapy has supplanted low-dose approaches in the HAART era.
  • For patients with advanced AIDS and drug-resistant HIV, less aggressive therapy may be useful.
  • Randomized study of standard versus low-dose m-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone) was completed in 1997 (pre-HAART).
  • Equivalent results were observed in both groups.
  • Complete responses ranging from 41% to 52% were obtained.
  • There was lower incidence of febrile neutropenia in the low-dose group; this finding formed the basis for its recommended use in ARL.

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  • Recent trials are generally phase II trials.
  • Low-dose cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (COHOT 1) and standard-dose CHOP (COHOT 2)
  • All patients received HAART (i.e., stavudine, lamivudine, and indinavir).
  • The trials showed a trend for superior results with standard-dose CHOP.
  • The follow-up time has been too short for assessment of long-term disease-free survival (see list on considerations for role of HAART during chemotherapy in ARL).
  • A large phase II trial of infusional cyclophosphamide, doxorubicin, and etoposide (CDE)
  • 182 patients
  • complete response rate of 46%
  • median overall survival of 8.2 months.
  • Dose-adjusted EPOCH (etoposide, vincristine, doxorubicin, prednisone, cyclophosphamide) (see Table 31.5)
  • The study had a long follow-up time of 53 months.
  • There were 39 patients in the study.
  • ARL outcomes were the same as those of similar tumors in non-AIDS NHL.
  • Complete remission was seen in 74% of patients (87% for those with CD4 counts >100 per mm3).
  • The disease-free and overall survivals were 92% and 60%.
  • Rituximab in ARL
  • On the basis of current available data, rituximab should not, at present, be considered as the standard of care in ARL.
  • Rituximab has been of considerable interest in ARL because it confers substantial therapeutic benefit in certain HIV-unrelated NHL types.
  • Preliminary results of a phase II study of CDE with HAART and rituximab are as follows:
  • Complete response rate of 85% has been observed.
  • Follow-up time is too brief to fully assess this approach.

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  • A randomized trial conducted by investigators of the National Cancer Institute (NCI)–sponsored AIDS Malignancies Consortium assessed the role of rituximab in ARL, with CHOP combined with HAART.
  • The differences in complete responses were not statistically significant—the complete response with rituximab was 58% and that without rituximab was 50%.
  • There were more treatment-related deaths in the rituximab group (p= 0.02)—15% in the group randomized to receive rituximab and 2% in the group with no rituximab.
  • In HIV-unrelated aggressive DLBCL, rituximab may confer the greatest additional benefit when added to standard chemotherapy for the subset of tumors expressing BCL2. Most ARL do not express BCL-2. Further research is needed in this regard.
  • Considerations for the role of HAART during chemotherapy in ARL:
  • Most studies have demonstrated the feasibility of administering HAART along with the chemotherapy regimens. This is a complicated issue, and no study has shown a benefit specifically attributable to such an approach.
  • Complicated pharmacokinetic interactions have been documented in pharmacokinetic studies that assess condition HAART and chemotherapy:
  • CHOP given with stavudine, lamivudine, and indinavir decreases cyclophosphamide clearance by approximately 50% as compared to historic control patients treated with CHOP alone. No obvious excess toxicity ensues.
  • A study of infusional CDE showed that cycles administered with didanosine tended to be associated with lower plasma etoposide levels than the cycles administered with CDE alone.
  • No controlled trials that assess toxicity have been performed.
  • Some retrospective studies have suggested that increased toxicity may be a concern when chemotherapy and HAART are coadministered.
  • Other retrospective studies suggest that HAART leads to improved tolerance to chemotherapy:
  • A higher response rate and better tolerance to more dose-intensive chemotherapy have been observed in patients with long-term HIV suppression on HAART than in those patients who fail HAART or are HAART naïve.
  • These results suggest that HAART does not undermine the efficacy of combination chemotherapy and is consistent with other prospective feasibility studies.
  • The dose-adjusted EPOCH (DA-EPOCH) study indicates that such a combination therapy is not needed for superior results.
  • Considerations for omission of HAART during chemotherapy include the following:
  • Actually chemotherapy causes substantially more lymphocyte depletion than HIV does.
  • HAART is unlikely to protect against chemotherapy-induced lymphocyte depletion.
  • In HIV not-infected individuals lymphocyte depletion occurs during chemotherapy, with recovery over 12 to 18 months after completion of therapy.
  • Similar dynamics in HIV sensitive to HAART.
  • Temporary suspension of HAART until completion of ARL therapy is consistent with Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents as developed by the Panel on Clinical Practices for Treatment of HIV Infection convened by the Department of Health and Human Services (DHHS) and the Henry J. Kaiser Family Foundation and published inhttp://www.aidsinfo.nih.gov/guidelines.
  • Because of potential interactions and toxicity, if HAART is to be combined with chemotherapy, care should always be taken to refer to appropriate drug information manuals when considering the therapeutic plan.

TABLE 31.4. Selected Regimens and Outcomes for Peripheral AIDS-related non-Hodgkin Lymphoma

Course of therapy

Number of evaluable patients

Median CD4 cells/mm3at baseline

Complete response rate (%)

Median overall/disease-free survival (mo)

Author

m-BACOD, methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; HAART, highly active antiretroviral therapy; CDE, cyclophosphamide, doxorubicin, and etoposide; EPOCH, etoposide, vincristine, doxorubicin, prednisone, and cyclophosphamide.

m-BACOD low dose

175

100

41

8 mo/8 mo

Kaplan et al. (randomized)

Standard dose

 

122

52

CHOP HAART Low dose

40

138

30

Not reached; follow-up time not of sufficient duration to assess long-term disease-free survival

Ratner et al.

Standard dose

23

122

48

 

 

Infusional CDE + rituximab + HAART

29

132

86

Not reached; follow-up time not of sufficient duration to assess long-term disease-free survival

Tirelli et al.

CHOP-rituximab

95

133

58

Median complete response duration has not been reached

Kaplan et al. (randomized)

CHOP

47

 

50

 

 

Dose-adjusted EPOCH

39

198

74

60%/92% at 53 mo

Little et al.

TABLE 31.5. Dose-adjusted EPOCH for Acquired Immunodeficiency Syndrome–related Lymphoma

Drug

Dose

Route

Time

CIV, continuous intravenous; ANC, absolute neutrophil count.
HAART is suspended until completion of all EPOCH cycles.
PCP Prophylaxis for all patients and continues until CD4 >200 cells/mm3.
Mycobacterium avium complex (MAC) prophylaxis for all patients with CD4 <100 cells/mm3.

Etoposide

50 mg/m2/d

CIV

d 1–4 (total dose/cycle = 250 mg/m2)

Doxorubicin

10 mg/m2/d

CIV

d 1–4 (total dose/cycle = 40 mg/m2)

Vincristine

0.4 mg/m2/d

CIV

d 1–4 (total dose/cycle = 1.6 mg/m2 (no cap)

Prednisone

60 mg/m2

PO

daily, d 1–5

Cyclophosphamide

Cycle one dependent on CD4 cell count

CD4/mm3

<100

187 mg/m2

i.v.

On d 5

≥100

375 mg/m2

i.v.

On d 5

Cycles two and beyond dependent on ANC nadir

ANC nadir

<500

Decrease dose by 187 mg/m2

≥500

Increase dose by 187 mg/m2 (maximum dose is 750 mg/m2)

Filgrastim

300 µg/d s.c., starting d 6; continues until ANC >5,000 cells/mm3

Treatment is repeated every 21 d

Acquired Immunodeficiency Syndrome–Primary Central Nervous System Lymphoma

Presentation

  • AIDS-PCNSL accounts for 19% of ARL in pre-HAART era.
  • In patients with non–AIDS-NHL, PCNSL accounts for approximately 1% of NHL.

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  • Since the introduction of HAART, there has been a three-fold decrease in the incidence of PCNSL.
  • PCNSL is the second most common mass lesion found in patients with AIDS and the most common brain tumor in this population.
  • AIDS-PCNSL occurs almost exclusively when the CD4 cell count is <50 per mm3.
  • The presenting signs and symptoms include:
  • may be asymptomatic
  • altered mental status
  • lateralizing signs
  • subtle personality changes, decreased alertness, or headache
  • seizures, seen in approximately 10% of cases.

Diagnosis

  • A definitive histopathologic diagnosis requires biopsy.
  • There is often some reluctance to do this procedure.
  • There have been major advances in the diagnosis of AIDS-PCNSL:
  • EBV is nearly ubiquitous in AIDS-PCNSL
  • Nuclear medicine studies can distinguish malignant lesions from infectious lesions.
  • Thallium-201 single–photon emission computerized tomography (SPECT)
  • Fluorodeoxyglucose positron emission tomography (FDG-PET)
  • Combined assessment of EBV in the cerebrospinal fluid by polymerase chain reaction (PCR) and imaging with either SPECT or positron emission tomography (PET) is diagnostic of PCNSL
  • If both EBV PCR and nuclear imaging are positive, the positive predictive value for PCNSL is 100% in this setting. In this case,
  1. initiation of antitumor therapy is justified
  2. biopsy confirmation may be omitted.
  • If both tests are negative, the lesion is highly unlikely to be lymphoma.
  • Discordance of the test results requires biopsy to establish the diagnosis.
  • In many medical centers, it has become standard practice to treat AIDS patients presenting with focal brain lesions and antitoxoplasma antibodies empirically with antitoxoplasmosis therapy, reserving biopsy for those patients who are seronegative for antitoxoplasma antibodies or who fail to respond to treatment. However, delay in diagnosis can adversely affect survival in AIDS-PCNSL.
  • If biopsy is to be performed, corticosteroids should be withheld until a diagnosis is made, unless the patient is in immediate danger of herniation, because corticosteroids can obscure the pathologic diagnosis owing to brisk tumor response.

Staging

  • The staging of PCNSL includes evaluation for potential peripheral lymphoma because its occurrence, by definition, indicates the central lesions to be of metastatic origin.
  • Because ocular involvement is frequent, ophthalmologic examination with a slit lamp should be included in the evaluation, and its finding should be interpreted as part of the CNS involvement.

Prognosis and Treatment

  • Median overall survivals are reported to be from 2 to 5 months.
  • Prognosis may be improved with adequate immune reconstitution. HAART initiation/optimization on diagnosis of AIDS-PCNSL may help decrease the risk of recurrence and opportunistic infection if adequate immune reconstitution can be achieved. The outcome may be favorably affected in this setting.

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  • The treatment modalities (with the exception of high-dose chemotherapy) used for immunocompetent patients are also applied to patients with AIDS-PCNL, but with greater toxicity and poorer results.
  • PCNSL is highly responsive to whole-brain irradiation. The generally recommended dose of whole-brain radiotherapy is 40 Gy. There is a high rate of recurrent lymphoma and opportunistic infection, leading to poor outcome.
  • Relapse can not only occur at a site remote from the primary site but can also occur within the radiation port.
  • Combining chemotherapy with radiotherapy has not benefited most patients, and the negative effects of this combination on immune reconstitution should be considered while assessing its role in a given patient.
  • Surgery has no therapeutic role in PCNSL because microscopic tumor infiltration into brain parenchyma extends from the site of primary involvement.

Human Immunodeficiency Virus–Associated Hodgkin Disease

  • HIV-HD is not an AIDS-defining condition.
  • The most common histologic subtypes are
  • mixed cellularity
  • lymphocyte depleted
  • nodular sclerosing Hodgkin disease, the most common histologic subtype in HIV-negative (primary-HD) patients.
  • EBV accounts for
  • 78% to 100% of cases in patients with HIV-HD
  • 15% to 48% of patients with non–HIV-related HD.
  • Compared to patients with non–HIV-related HD, those with HIV-HD have the following characteristics:
  • younger age
  • higher stage disease
  • less frequent mediastinal involvement
  • more frequent involvement of extranodal sites of disease
  • more frequent occurrence of “B” symptoms.
  • Prognosis is generally poorer for patients with HIV-HD than for those with primary HD, although patients often present with relatively well-preserved CD4 cell counts (median CD4 cell count is more than 275 per mm3in some series).

Treatment of Human Immunodeficiency Virus–Hodgkin Disease

  • Many physicians advocate the use of systemic chemotherapy for all stages.
  • The commonly presented disease features are associated with a poor prognosis
  • male gender
  • a large number of sites being involved
  • mixed cellularity or lymphocyte-depleted histology.
  • Treatment includes
  • radiotherapy and/or chemotherapy
  • doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD)
  • epirubicin, bleomycin, vinblastine, and prednisone (EBVP).
  • Complete response rates range from 50% to more than 80%.
  • Relapse of HD and progression of AIDS are common, contributing to poor overall survival.
  • Survival improvements may be seen in the HAART era.
  • Most patients are not diagnosed with AIDS when they develop HIV-HD.
  • Because the CNS is rarely involved, CNS prophylaxis is not commonly utilized.

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Kaposi Sarcoma–Associated Herpesvirus–Associated Multicentric Castleman Disease

  • KSHV-MCD is a rare lymphoproliferative disorder.
  • KSHV is associated with MCD in approximately 50% of non–HIV-infected patients.
  • It has a short median survival:
  • Approximately 2 years
  • In many cases, delay in diagnosis may lead to bias in the statistical calculations.
  • The syndrome is possibly related to the high levels of IL-6 produced by the tumors. Other factors include:
  • fevers
  • cytopenias
  • multiorgan dysfunction.
  • Treatment—there is no defined standard of care. Most of the information has been obtained from case reports.
  • Single agent and combination chemotherapy
  • Interferon-α
  • Splenectomy
  • Rituximab
  • Antiviral therapy
  • Published reports of monoclonal antibody to IL-6 being useful in KSHV-MCD support the role of IL-6 in the pathogenesis of the disease.

ANOGENITAL CANCERS IN HUMAN IMMUNODEFICIENCY VIRUS INFECTION

Overview

  • Cervical cancer is an AIDS-defining condition.
  • Anal cancer is not an AIDS-defining condition.
  • It is relatively prevalent in
  • HIV-infected women
  • homosexual and bisexual men with HIV infection.
  • Anogenital cancers in HIV infections are associated with human papilloma virus (HPV).

Screening

  • The CDC recommends cytologic screening as part of initial evaluation when HIV-seropositivity is diagnosed.
  • If the initial PAP smear is normal, at least one additional evaluation should be repeated within 6 months. If the results of the repeat test are normal, then reevaluation should be done at least annually.
  • If the initial or follow-up Papanicolaou smear shows severe inflammation with reactive squamous cellular changes, another Papanicolaou smear should be collected within 3 months.
  • If the initial or follow-up Papanicolaou smear shows squamous intraepithelial lesions (SILs) or atypical squamous cells of undetermined significance, the patient should be referred for a colposcopic examination of the lower genital tract and, if indicated, should undergo colposcopically directed biopsies.
  • HIV infection is not an indication for colposcopy among women with normal Papanicolaou smears.
  • HPV-associated cytologic abnormalities are common in the anal mucosa of both HIV-infected women and homosexual men. Some experts have suggested that routine periodic cytologic examination of the anal mucosa should also be considered in high-risk individuals.

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Cervical Cancer

Epidemiology

  • SIL, vulvovaginal condyloma acumináta, and anal intraepithelial neoplasia are seen approximately five times more in HIV-infected women than in women who are not infected with HIV.
  • The prevalence of cervical intraepithelial neoplasia has been reported to range from 11% to 29% overall for HIV-infected women.
  • Among sexually active women, HIV-infected women have a substantially higher rate of persistent HPV infections of the types most strongly associated with intraepithelial lesions and invasive cervical cancer, for example, HPV-16 or HPV-18–associated viral types.
  • HPV infection is associated with the development of SIL, and increased prevalence of HPV infection among HIV-infected women may explain the increased incidence of SIL in this population.
  • Women with a CD4 cell count <500 per mm3appear to be at greater risk for poor outcome.
  • The incidence of invasive cervical cancer appears unchanged since the advent of HAART.
  • It is unclear whether this is due to the reduced usage of these medications among the women at highest risk for both HIV and HPV or whether this is related to some other factor.

Therapy

  • Standard therapy for preinvasive cervical neoplasia includes
  • cryotherapy
  • laser therapy
  • cone biopsy
  • loop excision.
  • Recurrence of preinvasive cervical neoplasia among HIV-infected women (even among those with high CD4 cell count) is twice that found in HIV-seronegative women.
  • The lower the CD4 count, the higher the risk for recurrence.
  • Preliminary data suggest that early preinvasive lesions can regress with effective antiretroviral therapy.
  • HAART may reduce recurrence and progression following standard excisional therapy.
  • Invasive cervical cancer should be approached with the same principles of oncologic management that guide the treatment of cervical cancer in HIV-negative patients.
  • Patients with well-controlled HIV infection and relative immune preservation can be expected to have outcomes similar to that of HIV-negative women.
  • Patients with advanced HIV disease may be less tolerant of the myelosuppressive effects of radiation therapy and combination chemotherapy.
  • Following surgery, recurrence is common.
  • When antineoplastic therapy is administered concomitantly with antiretroviral therapy, the potential for overlapping toxicity of the various agents should be considered in the therapeutic plan.

Anal Cancer

  • HPV infection of the anal canal, and anal cancer and the immediate precursor lesions, high-grade anal intraepithelial neoplasia, are common among HIV-infected women and among MSM, especially those with HIV or immunosuppression.
  • The prevalence of cytologically abnormal anal epithelium has been reported to be as high as 39% and the incidence of high-grade anal intraepithelial lesions has been reported to be as high as 15% among HIV-seropositive men.
  • Anal SILs do not appear to regress in patients receiving HAART, except perhaps in some patients with high CD4 cell count.

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  • In invasive anal cancer, the standard combined chemotherapy and radiation appears to effectively control disease in most patients.
  • Patients with CD4 cell counts of 200 per mm3or greater appear to have better disease control, with acceptable morbidity.
  • Patients with CD4 cell counts of <200 per mm3appear more likely to experience treatment-related toxicity including cytopenias, intractable diarrhea, moist desquamation requiring hospitalization, or a colostomy either for a therapy-related complication or for salvage.
  • In the non–HIV-infected population, the considerations for using therapies that may be associated with less toxicity include the use of infusional cisplatin and 5-flourouracil with concomitant radiotherapy, although this has not been formally assessed in the HIV-infected population.

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