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) with oedema or ulcerations or extensive agents had activity, respectively, equivalent or superior oral KS and visceral involvement, CD4o150 ml, OI and/ to combinations ABV or BV with substantially reduced or B symptoms and PSo70(Krown et al., 1997). In the toxicity and an overall response rate of 46% (Kaplan HAART era, a refiniment of ACTG staging system is et al., 1986; Gill et al., 1996; Tavio et al., 1996). needed. Nasti et al. (submitted for publication) collected Paclitaxel, at a dose of 135 mg/m2 given every 3 weeks as epidemiological, clinical, staging and survival data from a 3 h infusion, is considered the treatment of choice after 211 patients with the diagnosis of AIDS-KS from failure of first-line chemotherapy with 59–71% response January 1996, enrolled in two prospective Italian HIV rate and bone marrow suppression, peripheral neuro- cohort studies: the Italian Cooperative Group on AIDS pathy, renal disfunction (Saville et al., 1995). Immuno- and Tumors (GICAT) and the Italian Cohort of patients suppression is a major problem in patients treated with naı¨ ve from antiretrovirals (ICONA). In the multivariate cytotoxic chemotherapy and because of immunodepres- analysis, only the combination of poor tumour stage sion, patients may develop OI. The use of recombinant (T1) and poor systemic disease (S1) risk identifies haematopoietic growth factors to support KS patients patients with unfavourable prognosis, while CD4 level undergoing CT has been evaluated as a means of

Oncogene AIDS-related malignancies M Berretta et al 6648 preventing bacterial infectious complications and now is beginning of the AIDS epidemic in 1984 and in 1986, the standard practice (Gill et al., 1992). Centers for Disease Control recognized NHL as an At present, the new findings on KS pathogenesis have AIDS-defining illness (Centers for Disease Control, prompted investigators to study the anti-KS activity of 1986). The relative risk of NHL in people with AIDS the new antiretroviral combination therapy. HAART ranges between 15 for low-grade and T-cell NHL and must be considered as a major treatment for all KS 400 for high-grade NHL (Dal Maso and Franceschi, patients. Alone it may be used as first-line anti-KS 2003). However, the incidence of AIDS-related tumours therapy in the early stages of disease (T0) and/or for has been substantially underestimated because of several slowly proliferating disease (when the tumour load is factors. First, national agencies collected data on initial low and/or the tumour growth is consistent with a long AIDS-defining events only. This is relevant because time interval to the development of HAART anti-KS these tumours appear most commonly in the end stages activity). In patients with T1 and/or rapidly proliferat- of AIDS, when the immune system is markedly ing disease, the first-line treatment is chemotherapy with impaired. Second, most primary lymphomas of the antiretroviral therapy followed by maintenance therapy central nervous system (CNS) are diagnosed only at the with HAART. A study from GICAT on 53 patients of a time of autopsy, and certainly many other cases of NHL slowly progressive disease (stage I–III according to outside the CNS are not diagnosed. NHLs occur among NYU), detectable HIV-RNA viraemia and HAART all population groups and in different countries with naı¨ ve, treated with HAART including PI as first-line similar epidemiologic and clinicopathologic features. treatment for KS concluded that HAART is an effective Systemic NHLs constitute 70% of all cases and the antineoplastic therapy in a high percentage of cases remaining 30% are primary CNS lymphomas (PCNSL) (overall response rate of 35%). The anti-KS activity of (Spina et al., 1999). In the era preceding the introduction HAART correlates with immune restoration in patients of HAART (pre-HAART era), NHLs represented the with anti-HIV response. The complete response to second most frequent cancer associated with AIDS, HAART after partial remission following chemotherapy after KS. In contrast to KS, which predominated in has convinced the GICAT investigators to perform a homosexual individuals, NHLs distributed homoge- phase II study on the role of maintenance (M)-HAART neously throughout the spectrum of HIV risk groups after systemic chemotherapy in advanced (stage III–IV (Tirelli et al., 2000). Recently, the use of HAART has acc. to NYU) KS patients, HAART naive or with been associated with significant reductions in various virological response to HAART. The results of this opportunistic illnesses in HIV-infected patients; despite study indicate that HAART, in patients with good a significant reduction of KS incidence, the magnitude compliance to antiretroviral therapy, is an effective anti- of reduction in the incidence of NHLs appears to be less KS therapy after debulking CT (overall response rate of significant, except for PCNSL. It is possible that 91%) (Tirelli et al., 2001). KS cells secrete angiogenic patients treated with HAART have an improved factors and cytokines that are critical for the growth and immune function, with reduced B cells stimulation but spread of KS and have been targeted for new they may survive longer, with continued B-cell stimula- therapeutic development as antiangiogenic agents, tion and dysregulation, resulting in an increased retinoic acids and antiviral agents. Thalidomide (40% incidence of lymphoma over time (Tirelli et al., 2001). partial response) has been shown to block TNF-a In developing countries, the risk of HIV-associated production and to inhibit basement membrane forma- NHL appears to be much lower than in developed tion and intercellular adhesion molecules. Toxicities countries, but earlier death from other AIDS manifesta- include neutropenia, depression and fever. Oral 9-cis- tions may explain the lack of HIV-associated lympho- retinoic acid (33% response rate in combination with mas in Africa (Franceschi et al., 1999). The risk of HAART with better responses at higher CD4 þ cell developing lymphomas in patients with symptomatic count) and all-trans retinoic acid (ATRA) have been HIV infection appears to be approximately 1.6% per show to inhibit of IL-6 production with no apparent year; further, the chance of developing lymphoma in effect on the IL-6 receptor and to be effective in the patients with AIDS, alive on HAART for 3 years is treatment of cutaneous lesions of KS. The discovery of estimated to be approximately 19% (Tulpule and HHV-8 as the aetiologic agent for KS has raised the Levine, 1999). possibility of the use of antiviral agents as treatment or AIDS-related NHL (AIDS-NHL) are characterized prophylaxis for AIDS-related KS. Interferon-a has been by a diffuse growth pattern, cellular pleomorphism, shown to have immunomodulatory, antiviral and high-grade morphology and B-cell derivation. Low- antiangiogenic effects, with a 10–40% overall response grade B-cell and T-cell NHL, which may occasionally rate when high doses are administered as a single agent develop in the HIV-infected population, are not or combined with antiretroviral therapy. Significant considered AIDS-related tumours because their inci- toxicity includes flu-like symptoms and bone marrow dence has not significantly increased since the start of suppression (Levine and Tulpule, 2001). the AIDS epidemic. AIDS-NHL traditionally included systemic and PCNSL, but nowadays their updated Non-Hodgkin’s lymphoma clinicopathologic spectrum also comprises two novel entities, namely, primary effusion lymphoma (PEL) and The incidence of NHL among people at risk for AIDS in plasmablastic lymphoma of the oral cavity (Spina et al., the United States has significantly increased since the 1999a-c). The overwhelming majority of systemic AIDS-

Oncogene AIDS-related malignancies M Berretta et al 6649 NHL are small noncleaved-cell lymphomas (SNCCL), The optimal treatment for HIV-associated NHL which include diffuse large-B-cell lymphomas (DLCL) remains unclear; despite significant efforts to improve (70%), including large noncleaved-cell lymphoma the outcome of AIDS-NHL, it continues to limit the life (LNCCL, 25%), immunoblastic lymphoma plasmocy- expectancy of affected individuals more significantly toid (IBL-P, 25%) and CD30 þ anaplastic large-cell than any single AIDS-defining condition, except for lymphoma (ALCL), which is a heterogeneous group of multifocal encephalopathy. Median survival times for high-grade lymphomas at the borderline between HD HIV-NHL are less than 18 months in most series in the and NHL (Tirelli et al., 1995a, b, 2000, 2002) and pre-HAART era, even for patients with good prognosis Burkitt’s or Burkitt-like lymphoma (30%). An intri- characteristics. Early in the AIDS epidemic it was guing pathologic characteristic common to systemic recognized that in addition to opportunistic infections, lymphomas in HIV patients is the occurrence of cases patients also developed lymphomas. At that time, there having some overlap between established histologic was no effective therapy for the underlying immune subtypes (Raphael et al., 1991). The best example is depletion resulting from the disease and prophylaxis represented by the so-called intermediate lymphoma, against opportunistic infections had not yet been defined which exhibits features ‘intermediate’ between SNCCL as standard practice (Little et al., 2000). and IBL-P (Carbone et al., 1995; Said, 1997). Chemotherapy regimens similar to those used for Recently, both in the US and Europe, a peculiar type NHL not associated with HIV infection have been used of primary lymphomatous effusion has been recognized for treating patients with AIDS-NHL, with less success. as an individual entity based on its distinctive biologic With combination chemotherapy regimens of the CHOP features and its consistent infection by a novel (cyclophosphamide, doxorubicin, vincristine and pre- herpesvirus, termed HHV-8 (Cesarman et al., 1995; dnisone)-type, CRs were obtained in 32–56% of patients Carbone and Gaidano, 1997). Owing to its peculiar and (Straus, 1997). Moreover, the use of aggressive CT in predominant tropism for the serous cavities of the body, patients with HIV and NHL resulted in an increased this type of NHL has been provisionally designated incidence of opportunistic infections secondary to body cavity-based lymphoma (BCBL). Although BCBL exacerbation of the immunodeficient state. A total of exhibits an undeterminate phenotype, immunophenoty- 20–80% of patients with HIV-related NHL treated with pic studies have confirmed its B-cell origin. BCBL has a variety of chemotherapeutic agents developed oppor- also been termed as PEL. The overall pattern of BCBL/ tunistic infections. CT-induced myelosuppression and PEL is a lymphoma of the serous membranes typically possible interference with monocyte–macrophage func- giving rise to lymphomatous effusions without mass tion may increase the susceptibility of these patients to formation (Tirelli et al., 2002). A particular type of opportunistic infections (Tan and Ratner, 1997). During lymphoma has been recently identified as a specific the pre-HAART era, preliminary phase II data for NHL entity among AIDS-DLCL involving the oral cavity. in HIV-negative people have suggested better efficacy This lymphoma has been designated as plasmablastic for the second- and third-generation lymphoma regi- lymphoma (PBL) according to a plasmablastic mor- mens, such as m-BACOD (methotrexate, bleomycin, phology and immunoblastic features. The blastoid doxorubicin, cyclophosphamide, vincristine and dexa- morphology and immunophenotype of these tumours methasone), ProMACE-CytaBOM (prednisone, doxor- indicate that they are most similar to plasmablasts, that ubicin, cyclophosphamide, etoposide, cytarabine, is, cells that still have the blastoid feature of immuno- bleomycin, vincristine and methotrexate with leucovor- blasts, but otherwise have already acquired the antigen in) and MACOP-B (methotrexate with leucovorin, profile of plasma cells. The clear separation of PBL from doxorubicin, cyclophosphamide, vincristine, prednisone plasmacytoma is reinforced by the high rate of associa- and bleomycin) as compared with CHOP. tion of PBL with Epstein–Barr virus (EBV), whereas Oncologists who treated a HIV-NHL used these more plasmacytomas have been rarely found to carry the complex regimens, but also recognized that patients genome of the virus. The real incidence of this new frequently tolerated chemotherapy poorly and that CR entity is still unknown (Delecluse et al., 1997). occurred in only a minority of HIV-NHL patients and From a molecular point of view, AIDS-NHL are a were usually of short duration (Little et al., 2000; Tirelli heterogeneous group of malignancies. In the last few et al., 2002). Efforts to improve patients’ tolerance years, several studies have shown that the pathologic stimulated interest in the role of low-dose chemother- heterogeneity of AIDS-NHL correlates with heteroge- apy. One particularly important study in this regard neity of the molecular lesions associated with these was a large, randomized trial comparing standard to lymphomas. Burkitt’s lymphoma selectively associates low-dose m-BACOD. This trial showed equivalent with the activation of c-myc, whereas rearrangements of results in patients receiving full- and low-dose bcl-6 are restrictive to a subset of DLCL. Infection by m-BACOD, with complete responses ranging from 41 HHV-8 clusters with BCBL/PEL; conversely, infection to 52%, but with lower incidence of febrile neutropenia by EBV occurs, although at different rates, in different in the low-dose group. However, the incidence of lymphoma types, being always associated with AIDS- opportunistic infections was equivalent in both groups PCNSL, but with a minority of systemic lymphomas. and the low-dose arm was not shown to yield an However, only immunoblastic lymphoma, included in improved survival outcome (Kaplan et al., 1997). DLCL, expresses the EBV-encoded latent membrane Another approach to reduce myelosuppression was the protein-1 (LMP-1) (Gaidano et al., 1998). use of sargramostim (GM-CSF) associated with stan-

Oncogene AIDS-related malignancies M Berretta et al 6650 dard-dose chemotherapy; in a small randomized trial tics: CD4 cell count 4100/mm3, histology other than using CHOP with or without GM-CSF, comparable immunoblastic variant of DLCL, good performance treatment results were achieved with the addition of status and no prior AIDS diagnosis. Straus et al. (1998) GM-CSF to CHOP as with CHOP alone, with showed that long-term survival is associated with certain significantly less neutropenia (Kaplan et al., 1991). A pretreatment patient’s characteristics, such as tumour phase I trial of m-BACOD escalated from a low- to stage I/II, CD4 cell count 4100/ml, age o35 years, no standard-dose along with GM-CSF was conducted by history of intravenous drug use. This study also the ACTG. Dose-limiting haematologic toxicity was not demonstrated the utility of the International Prognostic observed with standard doses, although other toxicities Index (IPI) and the age-adjusted IPI for patients occurred (Walsh et al., 1993). An attempt to facilitate with HIV-associated NHL, although it was originally administration of chemotherapy was made with a trial designed for patients with intermediate- and high-grade of completely orally administered combination (lomus- NHL not associated with HIV. This study had tine, etoposide, cyclophosphamide and procarbazine), also underscored the importance of LDH levels, which with results comparable to those obtained using other is one of the parameters considered by IPI, in combination regimens (CR 39%, media survival of 7 determining a patient’s prognosis, elevated LDH levels months); toxicities aside from myelosuppression were being an adverse prognostic factor for progression-free mild and the costs were less than those for standard- survival in multivariate analysis. Similar findings have dose CHOP or m-BACOD (Remik et al., 1993). been reported by Vaccher et al. (1996) in a retrospective Another trial conducted by Sparano et al. (1996) multivariate analysis, in which elevated LDH and age obtained promising results in the pre-HAART era, greater than 40years, as well as CD4 cell count o100/ml, employing cyclophosphamide, doxorubicine and etopo- were independent predictors of survival in a Cox side (CDE) as continuous infusion for 4 days along with proportional-hazards analysis of patients with didanosine; 58% of patients achieved a CR and the AIDS-NHL. The 1-year survival rate of patients median survival was 18.4 months. Despite these results, with none of these adverse factors was 73% as compared the fact remained that the majority of patients with with 24% for patients with one or more adverse HIV-associated NHL did not fare well with conven- factors. tional chemotherapy. For this reason, a number of HAART can suppress HIV viraemia to levels below investigators looked for newer therapeutic approaches. the detection limits of sensitive quantitative polymerase In a small study from Bologna, 12 patients with HIV- chain reaction (PCR) essays for prolonged periods. Low associated NHL were treated with interleukin-2 (IL-2) viral burden is associated with increased CD4 counts at dose of 6 mUI/m2/day by continuous intravenous and improved prognosis in HIV infection (Mellors et al., infusion for 5 days for four courses along with 1997). The development of HAART has resulted in zidovudine; 50% of patients achieved a CR and the substantial improvement in the survival of patients with others achieved a partial remission. Elevation in CD4, AIDS. More recently, the optimism has been tempered natural killer and lymphokine-activated killer cells were by the observation that prolonged viral suppression seen at the end of treatment (Mazza et al., 1992). does not appear to be achievable in a substantial Interleukin-6 (IL-6) produced by lymphoma and sur- number of patients for a variety of reasons, such as rounding cells may play a role in the growth of HIV- the difficulty of complying with complex regimens, drug associated NHL and in the production of symptoms in intolerance, and the developing of HIV genomic patients, so that Emilie et al. (1994) treated 11 patients mutations conferring resistance, so that HIV eradication with an anti-IL-6 monoclonal antibody; five patients using current therapy is now considered to be very progressed, five had stable disease and one achieved a unlikely by many researchers, because ongoing localized partial remission, but there was a clear decrease in fever HIV replication occurs even during HAART and viral and cachexia. reservoirs are likely to persist for a lifetime (Tirelli and The treatment of HIV infection has evolved very Bernardi, 2001). rapidly over the past several years and there are reasons One potential advantage of HAART is that viral to believe that these advantages may also benefit cancer suppression may further limit immune damage by HIV treatment in the HIV-infected patients; some lymphoma during chemotherapy and may even permit the devel- remissions have been attributed to HAART (Oksen- opment of antitumour immune responses. It may also hendler et al., 1998, Viciana et al., 1998). Thus, reduce HIV-associated production of proinflammatory important work has been initiated in an attempt to cytochines, such as IL-6, which have been proposed as a better define the role of combined antiretroviral therapy potential cofactor in lymphomagenesis in AIDS-NHL and cytotoxic chemotherapy for AIDS-NHL. More- (Levine, 1993). In addition, it is theoretically possible over, emphasis has been given by different authors to that in the absence of HAART, HIV could transactivate prognostic factors. Prior to AIDS diagnosis, Karnofky oncogenic viruses, such as HHV-8, that play a role in Performance Status less than 70%, CD4 cell count lymphomagenesis (Varthakavi et al., 1999). In contrast, less than 100/ml, the presence of extranodal disease, there is concern that overlapping toxicities and pharma- according to Kaplan are predictive of a worse outcome cokinetic interactions between antiretroviral drugs and in AIDS-NHL patients (Kaplan et al., 1989). chemotherapy may affect the therapeutic index of the Gisselbrecht et al. (1993) identified a subgroup of various drugs. The possibility of substantial and patients with AIDS-NHL with favourable characteris- unexpected drug interaction is increased in the setting

Oncogene AIDS-related malignancies M Berretta et al 6651 of HAART, because most protease inhibitors (PI) and between the two groups. CR occurred in 50% of non-nucleoside reverse transcriptase inhibitors patients treated with CHOP-HAART and in 36% of (NNRTIs) are methabolized by and have substantial evaluable patients treated with CT alone. Toxicity, effects on the cytochrome P4503A; anthracyclines, the however, was greater in the patients treated with vinca alkaloids and etoposide are metabolized via the combined therapy compared with patients treated with cytocrome P4503A too (Tan and Ratner, 1997; Little CHOP alone; grade 3–4 anaemia was seen in 33 and 7%, et al., 2000). Increased toxicity may lead to a delay of respectively, grade 3–4 neurotoxicity was observed in 17 chemotherapy cycles or prompt dose reduction, possibly and 0%, respectively. Leucopenia was similar between compromising the curative potential of the lymphoma. the two groups, but filgrastim (G-CSF) support was Toxicity can also adversely affect antiretroviral therapy significantly higher in the CHOP-HAART group than in compliance, posing a danger of emergence of resistant the control group (92 vs 63%). There appeared to be a HIV. Also, from a practical stand point, chemotherapy survival advantage for patients receiving combined is lymphocytotoxic and can deplete CD4 cell counts by therapy and there was a trend for more patients upwards of 50% independent of HIV infection, limiting receiving CHOP alone to experience opportunistic the relative CD4 protective effect of antiretroviral infections compared to those with combined therapy therapy. Ultimately, the relative impact of these various (52 vs 18%, respectively). The conclusion of the authors factors must be balanced by considering their contribu- was that CHOP-HAART patients had a better survival tion to the lethality of lymphoma and the underlying than CHOP patients, suggesting that the reduction of AIDS condition (Tirelli and Bernardi, 2001; Tirelli et al., opportunistic infections morbidity by HAART may 2002). So, many investigators have investigated and are improve the overall outcome of the combined treatment still investigating the feasibility of concomitant patients. In fact, in our case series of 235 patients administration of chemotherapy and HAART in affected by AIDS-NHL, the actuarial 3-year disease-free AIDS-NHL. survival for a subgroup of 88 patients achieving CR Ratner et al. (2001) presented preliminary data on a after chemotherapy was significantly longer for those trial of reduced- vs standard-dose CHOP with stavudine, who had been treated with HAART than for the lamivudine and indinavir in patients with previously HAART-naı¨ ve patients (86 vs 57%, P ¼ 0.004) (Vaccher untreated aggressive lymphoma. The low-dose arm E, data not shown). These findings have important received 50% reduced doses of cyclophosphamide implications for the management of AIDS-NHL; how- (375 mg/m2), and doxorubicin (25 mg/m2) with a stan- ever, careful attention must be directed towards the dard dose of vincristine and prednisone; 63 patients with crosstoxicity and the possible pharmacokinetic interac- a median CD4 cell count of 136/mm3 were enrolled. In tions of antiretroviral and antineoplastic drugs. all, 33% of patients in the low-dose arm and 32% of Concerns with the chemotherapy–HAART combined those in the standard-dose arm achieved a CR, results approach have been raised by a small report of 12 that are similar to those previously reported using patients treated with combined antiretroviral therapy CHOP without HAART (Vaccher et al., 2001). A total and CT utilizing infusional CDE þ G-CSF. In this trial, of 50% of the patients in low-dose arm had grade 3 or 4 patients received saquinavir and one or two nucleoside neutropenia and 28% had hyperbilirubinaemia, whereas analogue anti-HIV drugs concomitant with CDE. 28% of the patients in the full-dose arm had grade 3 or 4 Severe mucositis occurred in 67% of patients treated neutropenia and 20% had hyperbilirubinaemia. Viral with CDE plus saquinavir compared with 12% of loads generally remained stable during treatment, with patients treated on a previous trial of CDE without 77% of the patients maintaining fewer than 1000 copies saquinavir. A particular concern regarding mucositis in of HIV-RNA/ml plasma. Pharmacokinetic analysis was this setting is that it can substantially impair compliance performed and the findings compared with those from with HAART dosing (Sparano et al., 1998). In another historical control patients not receiving anti-HIV trial of CDE and antiretroviral therapy, plasma etopo- therapy. The cyclophosphamide clearance rate was side levels were decreased by 11–38% on CT cycles reduced to 39 ml/min/m2, compared with 70ml/min/m 2 administered with didanosine, compared to cycles with- in the historical control groups, whereas the doxorubicin out didanosine (Sparano et al., 1996). In a study clearance rate was unchanged (475 vs 500 ml/min/m2). conducted by the Eastern Cooperative Oncology Group Additionally, the area under the curve for indinavir was (ECOG), the efficacy of CDE and didanosine mono- unchanged. The investigators concluded that the therapy was evaluated (Sparano et al., 1999); in this decreased clearance of cyclophosphamide was not study, 48 patients received continuous didanosine with associated with adverse effects and that either low- or up to 8 monthly cycles of CDE and G-CSF and full-dose CHOP combined with HAART could be safely intrathecal cytarabine if the bone marrow was positive and effectively administrated to patients with AIDS-NHL. and the histology was small noncleaved-cell lymphoma. Vaccher et al. (2001) have assessed the impact of Overall, 46% achieved a CR. The median time to HAART on CT in a matched case control retrospective progression was 14.9 months, median survival was 8.2 analysis of 24 patients with AIDS-NHL treated with months and survival at 1 year was 48%. The role of dose CHOP and HAART compared with 80patients treated intensity and antiretroviral therapy remains unclear in with CHOP or CHOP-like regimens without HAART. AIDS-NHL. A method to investigate this relationship Antiretroviral regimens were selected based on the partially has been given by Tirelli and the European patient’s prior therapy. Response rates were similar Intergroup Study of HIV-NHL (Tirelli et al., 1999). In

Oncogene AIDS-related malignancies M Berretta et al 6652 this study, patients were randomized into stratified have reported the case of a man with relapsed AIDS- groups based on the number of adverse prognostic NHL, successfully treated with ESHAP (etoposide, factors defined as the presence or absence of prior methylprednisolone, cytarabine and cisplatine) che- AIDS-defining events, CD4 cell count o100/mm3 and motherapy followed by BEAM (BCNU, cytarabine, performance status score greater than 1. Patients with etoposide, melphalan) high-dose chemotherapy and no adverse prognostic factors were defined as low risk autologous bone marrow transplantation (ABMT) in and were randomized to receive either the intensive the pre-HAART era. The patients achieved CR, but he ACBVP regimen (doxorubicin, cyclophosphamide, vin- experienced many opportunistic complications, such as desine, and prednisolone) (80patients) or CHOP regi- atypical Mycobacteria pneumonia, intestinal cryptospor- men (79 patients). All patients received G-CSF support. idiosis, CMV retinitis and colitis, due to the high Complete responses were seen in 66 and 60% of patients immunosuppression state (Gabarre et al., 1996). The treated with ACBVP and CHOP, respectively. Survival introduction of HAART, by restoring the immune was similar in both groups. Patients with at least one system defect in HIV patients has allowed the explora- adverse prognostic factor were included in the inter- tion of more dose-intensive therapy such as ABMT in mediate-risk disease and were randomized to receive selected patients with AIDS-NHL. Molina et al. (2000) either full-dose CHOP (59 patients) or 50% dose- reported two cases of patients with AIDS-NHL reduced CHOP (51 patients). The complete response successfully treated with high-dose chemotherapy rate was 63% for the full-dose arm and 39% for the followed by ABMT; both patients were receiving half-dose arm. However, the improved response rate did HAART during chemotherapy. G-CSF was employed not significantly affect overall survival because of a for CD34 þ peripheral blood stem cells (PBSC) relapse and death from AIDS progression, confirming mobilization and prompt haematopoietic recovery was the need for more effective treatments for both observed after ABMT. Both patients achieved a durable lymphoma and the underlying immunosuppression. CR from their lymphoma. The authors concluded that Another important area of investigation is the role of ABMT is feasible in patients with AIDS-NHL. Gabarre CNS prophylaxis in AIDS-NHL. In HIV-negative et al. (2000) have recently reported eight cases of patients, CNS prophylaxis is usually limited to patients patients with HIV and lymphoma (both NHL and with Burkitt’s lymphoma and DLCL with multiple HD) treated with ABMT. Four patients died (one of extranodal disease sites such as the bone marrow (van opportunistic infection, the others of disease progres- Besien et al., 1998). However, routine CNS prophylaxis sion), but four are alive and in CR from their is now considered standard practice in HIV-NHL, based lymphoma. All patients except one have received on the findings of a high percentage (15–20%) of HAART during the treatment. The authors conclude patients with CNS involvement at presentation (Levine, that collection and grafting of stem cells is feasible and 1991). Some investigators have questioned the routine seems appropriate in CT-sensitive HIV-1-associated use of intrathecal prophylaxis in cases with intermedi- lymphoma (Gabarre et al., 2000). Krishnan et al. ate-grade histology and uninvolved bone marrow. This (2001) reported the cases of nine patients with HIV was based on a series of 26 patients who did not receive and HD or NHL, who mobilized a median of 10.6 Â 106 CNS prophylaxis, of whom none developed isolated CD34 þ cells/kg and engrafted after ABMT. CD4 CNS disease (Deasi et al., 1999). However, CNS counts recovered to pretransplantation levels and HIV progression is an important cause of both morbidity viral loads (VL) were controlled in patients compliant and mortality, and as treatments improve, CNS relapse with HAART; seven of nine patients remained in may become a relatively more important issue; thus, remission from their lymphoma at a median of 19 many authors continue to believe that CNS prophylaxis months after transplantation. Six patients had a rise in with intrathecal methotrexate or cytarabine is a useful their HIV VL in the first month following the adjunct for all patients with AIDS-NHL and its transplantation, whereas three patients maintained an omission has to be best explored in many research undetectable VL. In five of the seven evaluable patients, settings (Little et al., 2000). HIV VL was undetectable at 12 months from trans- There exist no standard options for the treatment of plantation. The authors concluded that patients with relapsed or refractory disease, but two publications AIDS-NHL on HAART can engraft following ABMT; suggest that second-line chemotherapy can be beneficial. prolonged lymphoma remissions without significant One regimen combined etoposide with continuous compromise of immune function can be seen. Re et al. infusion ifosfamide and mesna; although the first 14 of (2002) have started a programme of PBSC mobilization the 27 reported patients were treated on a dose and collection with subsequent high-dose chemotherapy escalation trial, the overall response rate was 59%, with and transplantation as salvage therapy for patients with 42% achieving a CR and 17% achieving partial relapsed or refractory HIV lymphomas. In all, 10 remission. In those treated at the higher dose level, the patients were enrolled, seven with HD and three with CR rate was 62%. The median duration of response was NHL. All patients were on HAART. After a median of 12.5 weeks (range 4–78 weeks), with a median survival three aphaeresis, a median of 5.9 (range 4.1–8.3) Â 106/ of 16 weeks (range 2–168 weeks) (Kaplan et al., 1998). kg CD34 þ cells were collected after cyclophosphamide Our group found that second-line chemotherapy with 4 g/m2 þ G-CSF in two or G-CSF-supported standard- etoposide, mitoxantrone and prednimustine can be dose chemotherapy in five cases. Six patients underwent beneficial (Tirelli et al., 1996). Gabarre et al. (1996) high-dose chemotherapy with BEAM and ABMT.

Oncogene AIDS-related malignancies M Berretta et al 6653 Prompt haematologic recovery was observed in all does not appear to be a restriction of the disease to this patients. Treatment-related toxicities included two group alone (Rubio, 1994; Koblin et al., 1978). WHO three and one WHO two oral mucositis and one Recently, Franceschi et al. (1998) reported a relative WHO three reaction to DMSO. Infectious complica- risk of 7.9 in a European series from Italy. tions during neutropenia included one facial cellulites, Whether this evidence is sufficient to consider HD, an one S. epidermidis sepsis and two Clostridium colitis; all AIDS-defining illness, remains a matter of controversy. patients responded to treatment. HIV VL remained The histological diagnosis of HD is still based on the undetectable in patients receiving HAART before and presence of classical Reed–Sternberg (RS) cells in an after ABMT. No HCV reactivations were seen. Five/six appropriate cellular background. HD occurring in the patients achieved CR and three were alive and disease HIV population exhibits pathological features that are free at 2, 3 and 9 months from ABMT. The authors different from those of HD in the general population concluded that adequate number of CD34 þ cells can be (Harris et al., 1994). In fact, the distribution of HD collected in most patients with AIDS-NHL even after subtypes in the HIV population is characterized by the intensive first-line chemotherapy and high-dose chemo- predominance of unfavourable histological subtypes, therapy with ABMT is feasible, with rapid haematologic and mixed cellularity is the most frequently diagnosed recovery and acceptable toxicity. Interest has also been subtype (Tirelli et al., 1995a, b). generated in the potential role of anti-CD20monoclonal A high frequency of EBV association has been shown antibody, rituximab, in HIV-NHL. When rituximab is in HD tissue from HIV population (Boiocchi et al., used alone in relapsed lymphomas, it has activity, yet 1993). The EBV genomes in such cases have been there is particular interest in exploring its activity in reported to be episomal and clonal, even when detected combination with chemotherapy, based on evidence that in multiple independent lesions. it is well tolerated and effective (Little et al., 2000). On the other hand, EBV association with HD Spina et al. (2003) report the results of a trial in which 41 occurring in HIV-uninfected population have been patients with AIDS-NHL CD20positive were enrolled; shown to be globally lower than 50%, although a the patients received a combination of rituximab þ CT higher association of EBV has been found with mixed with CDE every 4 weeks for up to six cycles; HAART cellularity subtype. was given concomitantly. In all, 38 patients were One of the most peculiar features of HD in the HIV evaluable for response and toxicity; 76% achieved CR, population is the widespread extent of the disease at 5% had partial remission and seven patients progressed. presentation and the frequency of systemic ‘B’ symp- With a median follow-up of 12 months, only three toms, including fever, night sweats and/or weight patients out of 29 complete responders (10%) had loss 410% of the normal body weight (70–96% of relapsed and 32 out of 41 patients are alive. Grade 3–4 patients). neutropenia, anaemia and thrombocytopenia were Around 75% of patients had advanced disease observed in 80, 37 and 29% of the patients, respectively. stages (stage III–IV according to Ann Arbor staging The authors concluded that the combination of ritux- classification) with a frequent involvement of extra imab plus CDE seems to be very active, with a CR rate nodal sites, and the most common being the bone of 76%, much higher than that reported so far in AIDS- marrow, liver and spleen. Bone marrow involvement NHL (45–65%), also with a significant increase of occurs in 40–50% of patients, and may be the first overall survival (70% at 2 years vs a median of 7–18 indication of the presence of HD in 20% of cases (Ree months), so the association of rituximab þ CT should be et al., 1991; Rubio, 1994; Errante et al., 1994; Tirelli strongly recommended as a front line treatment for et al., 1995a, b). patients with CD20 þ NHL and HIV. HD as Burkitt’s-type NHL tend to develop as an earlier manifestation of HIV infection with a higher median CD4 cell count (around 300/mm3), than HIV diffuse large-cell lymphoma (Andrieu et al., 1993; Hodgkin’s disease Rubio, 1994; Tirelli et al., 1995a, b). Staging evaluation of patients should include a bone HD is the most common non-AIDS defining tumour marrow biopsy, CT scan of the chest, abdomen and among HIV-infected individuals. pelvis, and other tests as clinically indicated. The majority of recent studies demonstrate an Optimal therapy for HD in the HIV population has increased incidence of HD in HIV-infected individuals. not been defined yet. As most patients had advanced In particular, data from AIDS cohort and registry disease, they were treated with combination chemother- matching studies showed a relative risk of HD in the apy regimens, that is, MOPP (mechlorethamine, vincris- HIV setting ranging from 2.5 to 8.5 (Franceschi et al., tine, procarbazine and dacarbazine), and more recently 1998; Spina et al., 1999a-c). with ABVD (doxorubicin, bleomycin, vinblastine and Thus, an association between HD and HIV infection dacarbazine), but the CR rate remains lower than that seems to be well established, although with a relative of HD in the general population. Moreover, the therapy much lower than that for NHL (IARC, 1996). of HD-HIV population presents many problems. The Although the majority of the evidence suggests that main one is represented by immunosuppression induced HD may be more common in HIV-infected intravenous by antineoplastic treatment that can further compromise drug users than in other groups at risk for HIV, there the immunocellular deficit of HIV-infected patients, and

Oncogene AIDS-related malignancies M Berretta et al 6654 can facilitate the onset of opportunistic infections and/ survival for all patients was 18 months (Levine et al., or the evolution of HIV infection itself. Furthermore, 2000). although CD4 þ cell counts in these patients are usually Recently, Horning et al. (2002) reported the results of normal or slightly decreased at diagnosis, they may a prospective phase II study using Stanford V regimen become severely depressed during and after treatment, (doxorubicin, vinblastine mecloretamine, etoposide, leading to a higher susceptibility to opportunistic vincristine, bleomycine and prednisone) consisting of infections. Finally, leucopenia, frequently present in short-term chemotherapy (12 weeks) with adjuvant patients with HIV-HD due to previous therapy with radiotherapy, in HIV-negative patients with locally nucleoside analogues and/or to HIV-related myelodys- extensive and advanced HD. In unfavourable HD, high plasia, sometimes makes conventional dosage of CT CR rate and disease-free survival rate have been difficult to administer. Retrospective evaluations of shown. therapy reported in the literature have revealed that GICAT data (Spina et al., 2002) show that Stanford V the CR rate (range 46–65%) is far below that reported in regimen with concomitant HAART is feasible and patients with HD without HIV infection, with a median highly active in the setting of HIV-related HD. survival of one year and the 2-year disease-free survival Furthermore, the concomitant use of HAART does rate of 50% (Tirelli et al., 1992, 2001; Errante et al., not seem to increase chemotherapy toxicity. In conclu- 1994, 1999). sion, the outcome of patients with HIV-associated HD We reported the results of a prospective nonrando- should be improved with better combined antineoplastic mized trial with epirubicin, bleomycin, vinblastine and and retroviral approaches. The results of these studies prednisone (EBVP) chemotherapy in combination with are summarized in Table 1. antiretroviral therapy primary use of G-CSF, and In the HAART era, new therapeutic strategies need Pneumocystis carinii pneumonia (PCP) prophylaxis in to be explored, such as high-dose chemotherapy, 35 previously untreated patients with HD and HIV. The concomitant with antiretroviral therapy, autologous majority of patients (83%) had advanced stages of HD stem cell transplantation should be used to improve at diagnosis, 26% of the patients had an AIDS diagnosis the response rate and disease-free survival of these for opportunistic infection before the onset of HD and patients. 90% had B symptoms. An overall response rate of 91% was observed with a CR rate of 74%. The toxicity was moderate, with a grade 3–4 leucopenia and thrombocy- Anogenital malignancies topenia of 32 and 10%, respectively. Of 26, 10 (38%) patients who had achieved a CR relapsed. In all, 23 Cervical cancer patients died of HD progression alone or in association with opportunistic infections, the cause of death in 48 In the early years of the AIDS epidemic in the United and 9% of patients, respectively. The median survival States, relatively few women were diagnosed with was 16 months, with a survival rate of 32% and a cervical cancer. Cervical intraepithelial neoplasia disease-free survival of 53% at 36 months (Errante et al., (CIN) has been increasingly diagnosed in HIV-infected 1999). The ACTG reported the results of a phase II women (Maiman et al., 1990; Mandelblatt et al., 1992; study in 21 patients treated with ABVD chemotherapy Fructher et al., 1994; Klein et al., 1994; Wright et al., for four to six cycles and primary use of G-CSF. 1994) and invasive cervical cancer (ICC) is currently Antiretroviral therapy was not used during the treat- considered an AIDS-defining condition (Centers for ment, but it was started at the end of chemotherapy. The Disease Control, 1993a). CIN in HIV-infected women is vast majority (90%) of patients had systemic ‘B’ usually associated with high-grade histology (CIN symptoms at diagnosis and 67% had stage IV disease. II–III) more extensive and/or mutlifocal disease and The CR rate, on an intent-to-treat analysis, was 42% disseminated lower genital tract human papilloma virus with an overall objective response rate of 62%. Median (HPV)-related lesions (Maiman et al., 1991; Vermund

Table 1 EBVP Errante et al. (1999) ABVD Levine et al. (2000) Stanford V Spina et al. (2002)

No patients 35 21 58 Median CD4 cell count (ml) 219 113 259 Prior AIDS 26% 29% 19% Antiretroviral therapy Concomitant zidovudine or didanosine HAART at the end of chemotherapy Concomitant HAART Stage III–IV 83% 81% 71% B symptoms 88% 90% 74% Overall response 91% 62% 91% CRa 74% 43% 81% Overall survival 16 months 18 months Not reached 68% at 2 years DFSb 53% at years 57 weeks 70% at 2 years

aComplete remission. bDisease-free survival

Oncogene AIDS-related malignancies M Berretta et al 6655 et al., 1991). Immunosuppression not related to HIV limitations of traditional screening strategies are better infection has been associated with development of lower understood. A thorough annual examination including genital tract tumours as well (Penn, 1986). Furthermore, visual inspection of the anus, vulva and vagina, as well other risk factors such as multiple sexual partners, early as Pap smear and screening colposcopy should be parity, early coitarche, cigarette smoking, sexually considered the minimal appropriate evaluation of the transmitted disease are often present in these women. lower tract in these patients. The molecular mechanism for the pathogenesis of Standard treatments for CIN have utilized excisional cervical carcinoma in both HIV-infected and -uninfected or ablative techniques and include cryosurgery, laser women is incompletely understood. However, both viral ablation, loop electrosurgical excision procedure and cellular factors appear to be involved. A strong and (LEEP) excision and cone biopsy. cellular factors appear to be involved. A strong Observation of early lesions for a period of 3–6 epidemiological association exists between several types months may also be appropriate, because early CIN of HPV (subtype 16, 18, 31, 33 and 35) and cervical may regress spontaneously and is unlikely to progress to carcinoma. This risk is particularly elevated in woman invasive disease. with AIDS who have a higher incidence of coinfection Overall, current treatment strategies for CIN appear by HPV and who may lack sufficient immune surveil- to be less effective in HIV-infected women than in lance of HPV infection owing to HIV-associated T-cell historical populations of unknown, but presumed HIV- immunodeficiencies. HPV integration into host DNA negative serostatus. The more severely imunosuppressed alters the viral E1/E2 genes, allowing uncontrolled women (CD4 cell count o500/ml) are most likely to expression of the E6/E7 transforming genes. Increased develop recurrent disease, but even those with CD4 expression of E6 and E7 oncoproteins that bind the count 4500 ml have higher recurrence rates than non- products of the tumour suppressor genes, may HIV-infected women. The increase in recurrence rate contribute to malignant transformation (Laimons, seems to occur with all standard techniques, although it 1993). Squamous neoplasia of the cervix is best under- seems more frequent with cryotherapy. Loop excision stood as a continuum of a single disease approach. This may be most appropriate for HIV-infected patients continuum is histologically represented as a progression because it eliminates the risk of vapourizing a small of changes beginning with CIN1 (mild displasia), invasive cancer, which may be more likely in HIV- followed by CIN2 (moderate displasia) and CIN3 infected patients owing to the more aggressive course (severe displasia), and eventually resulting in invasive and because the cost in time and money compares cervical cancer. These histologic changes are thought to favourably with that for cone biopsy. regenerate at the squamocolumnar epithelial junctions, Therapeutic recommendations for HIV-infected because these cells are likely to be the most vulnerable to women with invasive cervical cancer should be the same environmental neoplastic/oncogenic stimuli, including as for non-HIV-infected women, because most HIV- HPV infection. The histological changes associated with infected women will die from cervical cancer rather than HPV including koilocytosis, multinucleation and in- from other AIDS-related disease. In addition, it appears creased mitoses may, in fact, be indistinguishable from that elective gynaecologic surgery may be undertaken in early CIN. The median time of progression of CIN1 to asymptomatic HIV-infected women with no greater risk CIN3 is approximately seven years (Barron and Richart, of complications than in non-infected women. As with 1971), whereas the development of invasive carcinoma any serious illness, it is appropriate to counsel the from CIN3 may require an additional 5–7 years patients regarding the aggressive nature and poor (Kolstad and Klem, 1976; McIndoe et al., 1984). prognosis of cervical cancer in this setting. Until now, The degree of immunosuppression appears to be gynaecologists played a relatively small part in the related to the occurrence and severity of CIN as well. In evaluation and treatment of women with HIV infection. fact, CIN is more common in symptomatic or severely However, as improvements in the treatment of other CD4-depleted patients and appear to be at highest risk HIV-related illness and HIV infection itself increase life for the development of ICC. expectancy, and the number of infected women rises, In 1993, the CDC recommended annual Papanicolau more attention is being paid to traditional gynaecologic smears for HIV-infected women who have had two issues such as sexually transmitted disease and genital successive adequate and normal smears more than 6 neoplasms. It is hoped that gynaecologists, serving as months apart (Centers for Disease Control, 1993b). primary advocates for women’s health care, can play a However, many clinicians have opted to perform leading role in developing innovative investigational semiannual or more frequent Pap testing with or strategies for HIV-related diseases. without colposcopy. The rationale for this approach includes the fact that HIV-infected women are usually Anal cancer being seen in the health-care system more often than once a year for other reasons, and the high rate of There is strong evidence of a relationship between HIV- inflammation that may obscure a small lesion and the induced immunodeficiency, HPV infection and the high incidence of concurrent vulvar, vaginal and anal development of anal intraepithelial neoplasia (AIN) neoplasia seen in this group. It seems prudent to (Frazer et al., 1986; Carter et al., 1995) also termed recommend a low threshold for performing Pap smear squamous intraepithelial lesion (SIL). Patients with HIV and colposcopy in HIV-infected women until the infection are more likely to have both HPV infection

Oncogene AIDS-related malignancies M Berretta et al 6656 and AIN than are non-HIV infected persons with persons with HSIL is justified. Data from literature similar demographic characteristics. Moreover, AIN is support the use of anal cytology as a screening test for more common among HIV-infected persons with low detection of ASIL (Palefsky et al., 1998a) as well as the CD4 cell count and more advanced clinical stage of HIV use of anoscopy to detect HSIL and distinguish it from disease. The incidence of anal cancer in men with a LSIL (Palefsky et al., 1998b). A recent cost-effective history of receptive anal intercourse has been estimated analysis published by Goldie et al. (1999) demonstrated to be 35 per 100 000 person year, prior to the AIDS that such screening programme are comparable in cost epidemic (Daling et al., 1987; Biggar and Rabkin, to other preventative measures accepted as standard of 1996). Recent estimates of incidence rates of anal care for HIV-infected persons. cancer in HIV-positive men may be about twice that Treatment of anal dysplasia in HIV-infected persons is of HIV-negative homosexual men (Biggar and Rabkin, controversial. Low-grade lesions can be followed clini- 1996). cally with serial anoscopy and biopsy, while high-grade A history of receptive anal intercourse, genital lesions, when immune function is still preserved, can be condylomata, other sexually transmitted diseases and treated with surgical excision and laser ablation if the persistence of HPV infection are associated with dysplasia is limited. Those with extensive disease or increased risk of anal cancer in HIV-infected indivi- advanced immunosuppression can be managed with close duals, similarly as in HIV-negative persons (Northfelt clinical follow-up and biopsy of any suspicious lesions. et al., 1996, Goedert et al., 1998). Specific types of HPV, Anal cancer is very sensitive to chemotherapy and such as six and 11 have been associated with low-grade radiotherapy, being a highly curable cancer. In the SIL (LSIL) that rarely progresses to invasive cancer. general population, the overall rate of long-term HPV types 16 and 18 are associated with invasive survival with any preservative approach is 65–75%. anogenital cancers and the lesions with the potential to Recent data suggest that HIV-infected patients progress to invasive cancer, such as anal or cervical with anal cancer should be treated with the same high-grade (HSIL) (Palefsky and Holly, 1995). Several approach as HIV-negative individuals (Peddada et al., different cohorts of HIV-positive and HIV-negative 1997). In association with HAART, an aggressive homosexual men have been observed, primarily in San approach to the treatment of anal cancer in HIV- Francisco, CA, and Seattle, WA, USA. These data were infected patients is warranted. Patients with CD4 cell collected mostly before the introduction of HAART. counts less than 200/ml may experience considerable Results from cross-sectional analyses of the prevalence toxicities, but the majority will have their disease of anal HPV infection have shown that anal HPV controlled with standard therapy. Patients with CD4 infection is found in nearly all HIV-positive men as well cell counts greater than 200/mm3 seem to have less as a substantial proportion of HIV-negative homosexual treatment-related morbidity and excellent clinical out- men (Palefsky et al., 1991, 1997). In one recent study in comes (Hoffman et al., 1999). San Francisco, 93% of the HIV-positive men and 61% of the HIV-negative men had anal HPV infection detected by PCR. Infection with multiple types of HPV was more frequent in the HIV-positive men Other tumors compared with the HIV-negative men and was more common in those with lower CD4 cell counts. Con- As the AIDS epidemic advances, other tumours are sistent with the HPV infection data, the prevalence of being increasingly recognized in HIV-infected indivi- anal squamous intraepithelial lesions (ASIL) was also duals including skin cancer, testicular cancer, lung higher among HIV-positive homosexual men than HIV- cancer, and head and neck tumours. negative homosexual men, particularly those with lower HIV-infected patients are at increased risk for the CD4 cell counts (Melbye et al., 1996). LSIL and HSIL development of cutaneous neoplasm. Basal cell carcino- were present in 36% of HIV-positive men and 7% of ma is likely seen in increased incidence in HIV-infected HIV-negative men. The relative risk of ASIL inversely individuals (Lobo et al., 1992). These tumours are correlated with CD4 cell counts and compared with mostly superficial, multicentric and located on the HIV-negative men was 3.8 for those with CD4 counts trunk. Of interest is the association between the degree 4500 cells/mm3 and 7.3 for those with CD4 counts of immunosuppression and the number of cutaneous o200 cells/mm3. neoplasm or the recurrence of squamous cell carcinoma. The impact of HAART on the natural history of Although there have been more than 120reported cases ASIL is not yet known (Palefsky, 1998). It is possible of lung cancer in HIV-infected patients, epidemiological that successful suppression of HIV replication by data do not support the existence of an increased risk for HAART will be accompanied by restitution of immune development of this tumour in an HIV setting. Many response to HPV and regression of HSIL to LSIL or features of lung cancer in HIV-infected individuals differ normal. However, early data suggest that most cases of from the disease in the general population. Adenocarci- HSIL will not regress after initiation of HAART noma predominates as histological subtype; this feature (Palefsky, 2000). differs from the usual distribution of tumour type in Given the success of the Pap-smear screening pro- most lung cancer series of the general population, where gramme in reducing the incidence of cervical cancer, it is adenocarcinoma, squamous cell and small-cell carcino- likely that a similar approach in identifying and treating ma each account for approximately one-third of the

Oncogene AIDS-related malignancies M Berretta et al 6657 cases. Overall, tobacco smoking appears to be the major should be offered the standard therapeutical approach, carcinogenic agent in HIV-infected patients, being since the majority can be cured of their tumours and present in more than 90% of cases as in the general have a good quality of life. Attention should be paid to population. More than 70% of HIV-infected patients effective therapeutical options for the underlying HIV present with advanced stages or inoperable disease, infection and for opportunistic infections prophylaxis. including 55% with metastases at the time of diagnosis (Spina et al., 1999a-c). Diagnosis of lung cancer may be delayed in HIV-infected patients, because signs and symptoms of the disease may be similar to those of Conclusions common pulmonary opportunistic infections. The survival of patients with lung cancer and HIV infection The spectrum of cancers in patients with HIV infection is very poor, with a median survival of around 6 months may further develop since these patients survive longer and with 10% of survivors at 1 year from diagnosis. As with HAART and with a better control of opportunistic regards the management of patients with lung cancer infections. Several questions such as feasibility and and HIV infection, we believe that they can be toxicity, drug–drug interactions face the oncologists approached with the same therapeutical strategies as in using the combination of HAART and chemotherapy the general population, if HIV seropositive homosexual for the management of patients with malignancies and men have a significant increase in the incidence of HIV infection. With the increasing use of HAART, the testicular cancer as compared to data of the general dilemma is of instituting or continuing protease population (Lyter et al., 1998). The median CD4 cell inhibitors use while chemotherapy is started. Most count of 260/ml reported in an Italian series of 26 clinicians would recommend continuation of HAART patients affected by germ cell testicular cancer is not until unacceptable toxicity occurs. Based on the directly related to the level of immune function advances in our understanding of HIV viral dynamics (Bernardi et al., 1995). The majority of HIV-infected and the availability of newer antiretroviral therapies, patients with germ cell tumours tolerate standard the choice for anti-HIV agents in patients receiving therapy and obtain a cure rate similar to that of HIV- CT is important (Vaccher et al., 2001). Continuation of infected patients. Survival of HIV-infected patients with HAART with prophylaxis against opportunistic testicular tumours closely parallels the natural history of infections in patients receiving CT may be beneficial. HIV disease. A 1 year of survival is not different from With recent data emerging on the role of HIV in that reported for HIV-infected patients without testi- oncogenesis, the use of HAART may improve the cular tumours with a similar CD4 cell count. Therefore, treatment outcomes of patients with HIV infection and patients with HIV infection affected by testicular cancer malignancy.

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