Nagy JA, Masse EM, Herzberg KT, et al. months (range, 3 to 36 months). Of 16 assessable patients, best tumor responses observed were complete response (CR) in three patients (19%), partial response (PR) in two patients (12%), stable disease in nine patients (56%), and progressive disease in two patients (12%). GZD824 Overall response rate (CR + PR) was 31% (95% CI, 11% to 58.7%). Four of five responders had received prior chemotherapy for KS. Over 202 cycles, grade 3 to 4 4 adverse events at least possibly attributed to therapy included hypertension (n = 7), neutropenia (n = 5), cellulitis (n = 3), and headache (n = 2). Conclusion Bevacizumab is tolerated in patients with HIV-KS and has activity in a subset of patients. INTRODUCTION Kaposi’s sarcoma (KS) is a multifocal angioproliferative malignancy characterized by endothelial-derived spindle cells, vascular slits with enhanced permeability, and local inflammatory infiltrate. KS-associated herpes virus (KSHV), also called human herpesvirus-8, is a necessary but insufficient cause of KS.1C3 The majority of cells in KS lesions are KSHV infected. HIV is a cofactor that increases KS risk.4 Despite decline in KS incidence associated with highly active antiretroviral therapy (HAART) availability in the developed world, HIV-infected individuals remain at a markedly elevated risk of KS. In the United States, KS remains the second most common cancer among people with HIV.5 KS is one of the most common cancers in sub-Saharan Africa6 and is a major public health problem as a result of epidemic HIV.7 KS incidence increases with age, and the effect of an aging US HIV-positive population on KS incidence remains to be seen. HAART is essential to HIV-associated KS (HIV-KS) therapy.8C10 Its effectiveness is largely a result of control of HIV and resulting improved KSHV-specific cellular immunity.11 In controlled KS trials, HAART alone induced responses in approximately 20% of patients,9,10,12,13 depending partly on immune reconstitution potential and extent of KS. Addition of systemic cytotoxic chemotherapy is indicated for GZD824 advanced or symptomatic KS. Liposomal anthracyclines, with an overall response rate (ORR) of 55% to 76% in the HAART era,13C17 are considered first-line agents. However, KS is not curable, and 1-year progression-free survival (PFS) with GZD824 liposomal doxorubicin is approximately 70%.17 Long-term administration of continuous or intermittent chemotherapy is often required. Given substantially improved survival of HIV-positive patients on HAART, long-term toxicities of anti-KS therapies must be considered. Indeed, cumulative therapy-associated toxicity, rather than therapy-refractory disease, frequently limits long-term KS management. High cumulative doses of anthracyclines are associated with irreversible cardiac toxicity.18 Although drugs such as interferon alfa, vincristine, vinblastine, etoposide, and paclitaxel are active in KS, they have lower activity than liposomal anthracyclines and/or greater toxicity. Improved therapies are urgently GZD824 needed.19C21 Rabbit polyclonal to POLR3B KS, characterized by angiogenic proliferation of endothelial-derived cells, is a rational and potentially optimal tumor in which to consider antiangiogenic approaches. Vascular endothelial growth factor-A (VEGF-A) is an important paracrine and autocrine growth factor in KS.22,23 KSHV has developed redundant mechanisms for upregulation of VEGF-A. Viral gene products, including viral G proteinCcoupled receptor, viral interleukin (IL) -6, latency-associated GZD824 nuclear antigen (LANA), and K1, all directly or indirectly upregulate VEGF-A production.24C29 VEGF-A seems to be responsible for leaky blood vessels, a common pathologic feature, as well as some clinical features, including tumor-associated edema and effusions.30C33 Given the role of VEGF-A in KS pathogenesis, we performed a phase II study of the humanized, monoclonal, antiCVEGF-A antibody, bevacizumab, in patients with HIV-KS. PATIENTS AND METHODS Eligibility Patients were adults with pathologically confirmed KS and at least five evaluable cutaneous lesions. HIV-positive patients must have been on HAART for at least 1 month with evidence of progressive disease (PD) or for at least 4 months without disease regression. Additional requirements included the following: Eastern Cooperative Oncology Group performance status of 2, life expectancy of at least.