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Therapeutic Approaches to AIDS-Related Malignancies

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Therapeutic Approaches to AIDS-Related Malignancies Oncogene (2003) 22, 6646–6659 & 2003 Nature Publishing Group All rights reserved 0950-9232/03 $25.00 www.nature.com/onc Therapeutic approaches to AIDS-related malignancies Massimiliano Berretta1,2, Roberta Cinelli1,2, Ferdinando Martellotta1,2, Michele Spina1, Emanuela Vaccher1 and Umberto Tirelli*,1 1Division of Medical Oncology A, Centro di Riferimento Oncologico, National Cancer Institute, Via Pedemontana Occ.Le 12, Aviano (PN) 33081, Italy The introduction of highly active antiretroviral therapy In addition, Hodgkin’s disease (HD) has been (HAART) has changed dramatically the landscape of increasingly described in the HIV setting with peculiar HIV disease. Deaths from AIDS-related diseases have clinicopathologic features. Possible in anal, head and been reduced by 75% since protease inhibitor therapy and neck, lung and testicular carcinoma, melanoma and combination antiretroviral therapy came into use in late plasma cell myeloma have recently been reported (Spina 1995. While KS is declining, the situation for non- et al., 1999). Hodgkin’s lymphoma is more complex with a reduced incidence of primary central nervous system lymphoma, but a relatively stability in the number of patients de- Kaposi’s sarcoma veloping systemic NHL. AIDS related NHL appears not to be markedly decreased by the introduction of HAART The introduction of highly active antiretroviral therapy and it is the greatest therapeutic challenge in the area of (HAART) has had a dramatic impact on the morbidity AIDS oncology. The emphasis has now shifted to cure and mortality of individuals living with HIV. The while maintaining vigilance regarding the unique vulner- incidence of KS, the most common malignancy ability of HIV-infected hosts. Furthermore, also for the observed in patients with HIV infection, has dropped prolongation of the survival expectancy of these patients, precipitously since the introduction of HAART in other non AIDS-defining tumors, such as Hodgkin’s 1996–1997 (Gates and Kaplan, 2002). In particular, disease, anal and head and neck, lung and testicular since the use of protease inhibitors (PI), a 30–50% cancer, and melanoma have been recently reported with reduction of KS has been observed in both the USA and increased frequency in patients with HIV infection. Europe. On the other hand, morbidity and mortality for Oncogene (2003) 22, 6646–6659. doi:10.1038/sj.onc.1206771 KS are increasing. KS in the 1990s different from what happened at the beginning of the epidemics, occurs in Keywords: AIDS; HIV infection; malignancies; treatment; more than 50% of cases in late stages of HIV infection HAART and is characterized by an extremely aggressive clinical course. The risk of KS among male homosexuals is 5–10-fold higher in comparison with other groups of Introduction persons with other HIV-risk behaviours. In Italy and Spain, where intravenous drug user cases predominate, Approximately 30–40% of patients with human the proportion of patients with KS tends to be much immunodeficiency virus (HIV) infection are likely to lower than in the USA and northern Europe where develop malignancies during the course of their disease. homosexuals account for the majority of reported cases With the improved survival of HIV patients, due to the of AIDS (Serraino et al., 1992). better prevention and treatment of infectious complica- KS is an angioproliferative disease of multifactorial tions, as well as the development of more effective origin characterized by angiogenesis, endothelial spin- antiretroviral therapies, there may be an increase of dle-cell growth, inflammatory-cell infiltration and oede- malignant tumours, in particular those nondiagnostic of ma. Recently, it has been hypothesized that KS cells AIDS. may originate from a mesenchymal progenitor cell of Three malignancies are currently considered to be either endothelial or monocyte–macrophage lineage AIDS-defining conditions: (Toschi et al., 2002). The pathogenesis of KS is better understood since 1994 (Chang et al., 1994) when Chang Kaposi’s sarcoma (KS); and Moore discovered a new human herpesvirus (HHV- intermediate or high-grade B-cell non-Hodgkin’s 8), also known as KS-associated herpesvirus (KSHV), lymphoma (NHL); strongly associated with all subtypes of KS, multicentric invasive cervical cancer (ICC). Castleman’s disease and a rare form of B-cell lymphoma named primary effusion lymphoma (PEL). HHV-8 is a *Correspondence: U Tirelli; E-mail: [email protected] transforming virus transmitted both sexually and 2These three authors contributed equally to this work through body fluids such as saliva or blood, it has been AIDS-related malignancies M Berretta et al 6647 detected in biopsy samples of more than 90% of KS does not seem to provide prognostic information. The lesions and KSHV DNA sequences have also been median survival for patients with T1S1 was significantly found in peripheral blood mononuclear cells of more lower (38 months) compared to the median survival for than 50% of KS patients (Ablashi et al., 2002). Viral patients with T0S0, T1S0 and T0S1 (good risk). oncogenesis (v-IL-6; v-BCL-2; v-cyclin D, The pace of KS is quite variable, ranging from a very G-protein-coupled receptor and antiapoptosis genes), indolent process requiring little, if any, therapy to a cytokine-induced growth (b-FGF and VEGF), immu- rapidly progressive disease leading to patient demise nodysregulated state (immunosuppression due to HIV, (Levine and Tulpule, 2003). Treatment decisions must organ transplantion, congenital disorders and cancer be made taking into consideration the extent and the and its therapy) and HIV transactivating protein Tat rate of tumour growth, patient’s symptoms, immune (increase the proliferation of KS-derived spindle cells) system conditions and concurrent complications of HIV represent fundamental conditions for the development infection. The main problems in the treatment of KS are of KS (Ensoli et al., 1990; Barillari et al., 1992). represented by the short duration of response despite a KS ranges from an indolent to an aggressive disease remarkable percentage of complete remissions (CRs) with significant morbidity and mortality. Typically, the obtained with standard chemotherapy (CT), the high disease presents with disseminated and pigmented skin incidence of opportunistic infections during and after lesions, in size from a few millimetres to several CT and the reduced haematological tolerance to centimetres with a characteristic appearance ranging conventional doses of CT. from pink to purple or brown often associated with Localized KS cutaneous lesions are treated with local oedema, lymph node and visceral involvement. The oral radiation (20–70% complete response rate with muco- cavity (palate and gingiva) occurs in approximately 35% sitis and tissue fibrosis), HAART alitretinoid gel applied of patients at the time of initial diagnosis (Ficarra et al., to affected areas two to four times daily, and surgical 1998). Visceral involvement occurs in over 50% of cases; excision (Stelzer and Griffin, 1993; Conant, 1999). any segment of gastrointestinal tract may be involved, in Systemic CT is reserved for patients who do not particular stomach and duodenum (abdominal pain, respond to HAART and/or with widespread, sympto- weight loss, malabsorption with diarrhoea or obstruc- matic, rapidly progressive, life-threatening disease and tion). Pulmonary KS (shortness of breath or cough or in particular with visceral involvement. Several single- haemoptysis) is the second most common site of agent therapies have been reported to be active in AIDS- extracutaneous involvement and is the most life- related KS including the vinca alkaloids (vincristine, threatening form of the disease (Gill et al., 1984; vinblastine and vinorelbine), epipodophilotoxins (etopo- Mitsuyasu, 1993). Radiographic findings (nodular or side), anthracyclines (adriamycin and epirubicin), bleo- interstitial or alveolar infiltrates, pleural effusion or mycin and taxol. The overall response rate ranges from isolated pulmonary nodule) are indistinguishable from 10to 76%, although most have been partial responses. those of more common opportunistic infections. In the early 1990s, a combination of bleomycin and Gallium and thallium scans may differentiate KS from vincristine, either combined or not with doxorubicin other infectious aetiologies; in fact, KS is thallium (ABV or BV), every 2 weeks was the standard therapy positive and gallium negative, whereas infections are for rapidly progressive mucocutaneous or visceral gallium positive and thallium negative (Turoglu et al., disease with 25–88% overall response rate (ABV) and 1998). significant myelotoxicity. The liposomal anthracyclines In the pre-HAART era, the AIDS Clinical Trials are now considered as first-line therapy in the treatment group (ACTG) devised a staging system based upon the of patients with advanced AIDS-KS. In the liposomal extent of tumour (T), the status of the immune system in preparation, doxorubicin or daunorubicin have been terms of CD4 cell count (I) and the presence of systemic entrapped into small unilamellar vescicles with a illness (S). These classifications identified two different prolonged half-life and an increased accumulation in risk categories: a good risk (T0I0S0) with skin7 KS tissues. In randomized phase III studies in KS, both lung7minimal oral disease, CD44150 ml, no OI/b- liposomal daunorubicin (40mg/m 2 i.v. every 2 weeks) symptoms and performance status (PS)470, and poor and doxorubicin (20mg/m 2 i.v. every 2 weeks) as single risk (T1I1S1)
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