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HIV-Associated Malignancies

Epidemiology of HIV and Neoplasias

Kaposi's sarcoma

Non-Hodgkin's Lymphoma

Squamous carcinoma conjunctiva

Hodgkin's disease

Plasmacytoma

Leiomyosarcoma (Pediatric)

Kaposi's Sarcoma

Kaposi's sarcoma (KS) is the most common neoplasm affecting HIV-infected individuals.

Risk greatest in homosexual male population (up to 73,000 fold risk) but high among all

Impact of HAART highly significant with well-documented decline on incidence of les after 1995. Since 1995, overall oncudence of KS has declined 61% in

The pathogenesis of KS in HIV-infected patients is complex and may involve infectious and cytokine-mediated processes.

Confinement to the homosexual male population with recent declining    incidence, its occurrence in non-HIV infected gay men and in female sexual partners of bisexual men have all

Laboratory investigations have identified a novel herpesvirus (HHV-8, KSHV) associated with majority of HIV, lymphoma, kaposi, Kaposis, kaposes, Malignancies, AIDS, caposi's, caposis

Virus present in KS from patients with epidemic (HIV), endemic (African), classical and transplant-associated KS>

 Seropositivity observed in approximately 80% of HIV-KS patients, 30% of HIV+KS patients and 1% of blood donors.

Seropositivity strongly correlated with number of several partners

50% will develop les within 10 years of seroconversion

HHV-8 present in peripheral blood mononuclear cells from patients with HIV-KS and predicts subsequent development of KS. f.    HHV-8 gene encodes homologues of several cell cycle regulatory proteins (cyclin D, IL-6, DHFR Mip-lX).

Laboratory evidence suggests that at some level Kaposi's sarcoma is also a cytokine-driven process. A number of cytokines have been identified which enhance in vitro growth of KS cells. Specific inhibitors of these cytokines are associated with a decline in growth.

 Interleukin-6 (IL-6) may act in an autocrine fashion. It is produced by KS spindle cells in culture. Several other cytokines may enhance growth of KS by increasing IL-6 production.    

Basic fibroblast growth factor bFGF), a cytokine which enhances angiogenesis, a common component of Kaposi's sarcoma.

The HIV tat protein. Synergy with bFGF.

Other cytokines: oncostatin-m, IL-I, TNF, VEGF.

KS in the HIV-infected individual is usually an aggressive and unpredictable mucocutaneous disease.

Palpable, firm, non-tender, cutaneous nodules, ranging from .5 to 2 cm in diameter, are frequently observed. However, early, small, non-palpable lesions, often resembling small ecchymoses, may be observed.

Lesions may appear as small raised plaques, nodules or large bulky plaques.

Pain: as lesions progress at any site they may become painful or

Edema: lower extremity and facial edema are the most common sites and edema formation may be

Infection: cellulitis may develop in areas that are extensively involved with KS, particularly if edema is present.

Presumptive diagnoses of KS are discouraged. Biopsy is recommended.

Differential diagnosis includes bacillary angiomatosis, cutaneous micobacterial disease, cutaneous fungal disease and angiosarcoma.

A.    Systems based purely upon tumor bulk are unhelpful.

B.    In addition to tumor bulk important prognostic factors include: level of immune function (CD4 count), complications of KS such as edema or visceral disease and the presence of opportunistic infection.

C.    The currently used ACTG staging system is shown below: this system was recently validated in prospective clinical trials.

**"B" symptoms are unexplained fever, night sweats, >10% involuntary weight loss, or diarrhea persisting more than 2 weeks.

KS is a systemic disease and requires some form of systemic therapy (could be antiviral)

Local therapy: the appropriate choice for symptomatic local involvement or small lesions which are

Systemic therapy (chemotherapy): indicated for widespread symptomatic disease, rapidly progressive disease and visceral disease. Active single agents and commonly employed combination regimens are shown below.

Liposomal anthracyclines: First-line therapy for advanced cutaneous or visceral disease. Liposomal preparations of both doxorubicin and daunorubicin appear to be highly efficacious, as single agents, and both are 

The doxorubicin, bleomycin, vincristine (ABV) is less commonly employed for patients with advanced symptomatic disease and is more toxic than the liposonnal agents.

Regimens such as vincristine and bleomycin may be used for less advanced symptomatic disease than are doxorubicin-containing regimens, but are

Paclitaxel (Toxol): Highly active agent used as second-line therapy in

Response rate to liposomal doxombicin significantly higher than ABV in 

Single Agent

Agent

Dose

Reported Response

Recommended Use

Vincristine

2 mg/wk

20-59%

Rarely used alone, nonmyelosuppressive

Vinblastine

0.5-1 mg/kg/wk

25-30%

Rarely used alone

Etoposide

50 mg po qd, alternate

weeks or 150 mgJm3 IV qd

for 3d q 3-4 wks

36-75%

As single agent for prior treatment failure

Adriamycin

20 mg/m2 c10W

53%

Rarely used alone

Bleomycin

10-15 u/m2q 2 wks

or

20 mg/m2/d x 3d

65%

Nonmyelosuppressive; use if intolerance to other agents

Paclitaxel

100 mg/mq= 2 wks

53 %

Treatment failures*

Liposomal

Doxorubicin

20 mg/m2 q 2-3 wks

45-74%

Single agent

Refractory disease*

Daunorubicin

40 mg/m2 q 2 wks

28-55 %

Single agent

First line therapy*

Vinorelbine

30 mg/m2 q 2 w ks

40%

Treatment Failures

*FDA-approved indications

1.    An active regimen for treating Kaposi's sarcoma.

2.    Drug requires some level of intact immune function in order to achieve response. Those with < 200 CD4

VIII.   Therapeutic complications

A.    Neutropenia: patients with poor bone-marrow reserve may be treated with bleomycin and vincristine, neither of which are myelosuppressive.

        A.    Investigational approaches at present are pathogenesis-based:

1.    Angiogenesis inhibitors: rPF4, Tecogalan, TNP470

2.    Retinoids: All trans-RA, 9-cis-RA, Liarozole

3.    Cytokine inhibitors: IL4-, pentoxyfillene, SU101

4.     Antivirals: Foscarnet, Protease Inhibitors

X. Antiretroviral Therapy

A.    KS responses have been observed to protease inhibitor or combination antiviral therapies in many patients.