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Clinical Trials and NCI Resources for Cancer in HIV-Positive Patients

Clinical Trials and NCI Resources for Cancer in HIV-Positive Patients

The association between HIV infection and the development of
cancer was noted early in the acquired immunodeficiency syndrome (AIDS)
epidemic. The AIDS-defining malignancies are Kaposi’s sarcoma, intermediate-
or high-grade B-cell non-Hodgkin’s lymphoma (NHL), and cervical cancer. All of
these cancers feature specific infectious agents in their etiology. These agents
are human herpesvirus 8/Kaposi’s sarcoma-associated herpesvirus, or HHV-8/KSHV
(implicated in Kaposi’s sarcoma), Epstein-Barr virus, or EBV (in primary
central nervous system lymphoma and a subset of systemic B-cell NHL) and
human papillomavirus, or HPV (in cervical cancer).[1]

The Effect of HAART

Although the types of related cancers have not substantially changed since
the beginning of the AIDS epidemic, the incidence of certain cancers has
markedly changed with the use of highly active antiretroviral therapy (HAART).
Populations with access to HAART have shown a substantially reduced incidence of
Kaposi’s sarcoma and primary central nervous system lymphoma and a much
smaller decrease in other types of NHL.[2] However, long-term cancer risks are
as yet unknown. Kaposi’s sarcoma remains the most commonly diagnosed
AIDS-related cancer.[3] NHL, a late and frequently systemic complication of
AIDS, occurs in approximately 5% of cases.[4]

The non-AIDS-defining tumors with particular relevance for the human
immunodeficiency virus (HIV) population include invasive anal cancer and the
preneoplastic lesions in the anus and cervix. These tumors and lesions are also
etiologically associated with HPV. The relative risk of invasive anal cancer in
HIV-positive men and women is 37.9 and 6.8, respectively.[5] The incidence of
high-grade squamous intraepithelial (anogenital or cervical) lesions and
invasive cancer is higher in HIV-positive/HPV-positive individuals than in the
HIV-negative/HPV-positive population. In addition, there is an increased risk of
progression from low-grade to high-grade lesions,[6] and HAART has shown little
effect on the natural history of these lesions in some studies.[7,8]

The longer life expectancy of HIV-positive individuals with access to HAART
may increase their cumulative risk of developing cancer. In this context, we may
see an increase in incidence of the following: (1) non-AIDS-defining cancers
including Hodgkin’s disease and lung cancer (Hodgkin’s disease is currently
the most frequently diagnosed non-AIDS-defining cancer that is clearly related
to immunosuppression)[9,5]; (2) progression of high-grade squamous
intraepithelial lesions to cancer; (3) T-cell NHL[10]; and (4) possibly a
resurgence of Kaposi’s sarcoma. Advances in the understanding of the
pathogenesis of AIDS malignancies have allowed the development of targeted
treatment strategies. This, coupled with the decreased morbidity from cancer
therapies in HAART-treated HIV-positive patients, provides the opportunity for
more targeted or more aggressive regimens that have the potential to lengthen
the patient’s survival.

Treatments of AIDS malignancies have followed conventional cytotoxic
chemotherapy approaches and also newer, targeted approaches aimed at intervening
in critical pathogenic pathways. The following examples are given for Kaposi’s
sarcoma, NHL, and the anogenital dysplasias.

AIDS-Related Kaposi’s Sarcoma

AIDS-related Kaposi’s sarcoma is a tumor of the vascular endothelium that
may present with cutaneous lesions, either with or without visceral organ
involvement, or with lymphadenopathy. The etiology of the disease includes an
intricate relationship between HHV-8/KSHV, aberrant cytokine production,
angiogenic factors, and immune dysregulation. Multiple treatment options aimed
at each of the players in the pathogenesis of Kaposi’ sarcoma are
available.[11,12] Local therapies include cryotherapy, laser therapy, local
radiation, intralesional injection of chemotherapy, topical alitretinoin gel,
and surgical excision. However, because Kaposi’s sarcoma is a systemic
disease, recurrence is common with local therapy.

Disseminated disease is treated with systemic agents, either with drugs or
biologic agents, such as the vinca alkaloids, liposomal anthracyclines,
paclitaxel, and interferon-alpha. Therapeutic approaches that target pathogenic
pathways have shifted the focus to include: (1) the antiangiogenesis compounds
thalidomide (Thalomid), COL-3, and IM862; (2) retinoids that inhibit interleukin
(IL)-6, a cytokine involved in tumor growth of Kaposi’s sarcoma; and
(3) IL-12, which has immunomodulatory, antiviral, and antiangiogenic
effects. Another intriguing but as yet untested possibility is the use of
antiviral agents to inhibit HHV-8/KSHV gene expression.

Systemic AIDS-NHL

Systemic AIDS-NHL is a histologically heterogeneous group of malignancies
normally of B-cell phenotype, although cases of T-cell AIDS-NHL have been
described.[9,10] Chronic B-cell stimulation from HIV infection, increased
expression of cytokines involved in B-cell proliferation, and expression of
certain EBV genes are involved in various aspects of the pathogenesis of NHL.
Standard treatment regimens include cyclophosphamide (Cytoxan, Neosar),
doxorubicin HCl, vincristine (Oncovin), and prednisone (CHOP), and variations of
CHOP with infusion regimens such as cyclophosphamide, doxorubicin, and etoposide
(CDE) and etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin
(EPOCH) with some studies reporting response rates above 70%.[13,9] However, the
relapse rate is high with most of the bolus CHOP regimens, and overall survival
rates are not clearly improved.

Cytotoxic regimens can be combined with immune system modulators such as IL-2
or IL-12, or with monoclonal antibodies against malignant cell targets such as
anti-CD20.[14] Other interesting approaches include stem cell transplantation to
both restore immune function and treat lymphoma via a graft-vs-lymphoma
effect[15], or generation of cytotoxic T lymphocytes against EBV genes expressed
in NHL.[16]

Anal and Cervical Cancer

Anal and cervical cancers are thought to arise from the progression of
squamous intraepithelial lesions to invasive tumors. Progression correlates with
persistence of high-risk HPV genotypes. HPV oncogenes E6 and E7 bind to and
inactivate the key cell-cycle regulatory proteins p53 and Rb, resulting in
dysregulated cellular proliferation and transformation.[17] However, a fully
malignant phenotype occurs only in a subset of chronically infected cells,
presumably resulting from an accumulation of additional mutations.[18] Treatment
of HPV-related lesions might include surgical removal or local destruction.[19]
However, surgery for anal high-grade intraepithelial lesions is not as
successful as that for cervical high-grade squamous intraepithelial lesions.

The induction of a cell-mediated response to human papillomavirus type 16
(HPV16), specifically to the viral protein E7, appears to be protective against
cervical intraepithelial neoplasia (CIN).[20] Thus, vaccines designed to elicit
cell-mediated immunity to E6 and E7 may be a basis for immunotherapy of
HPV-related cancers.[21] The AIDS Malignancy Consortium (described below) is
currently developing a trial to treat anal intraepithelial neoplasia using a
therapeutic vaccine designed to elicit a humoral and cellular response to
E7-expressing cells in the anal lesion.

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