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Clinicopathological characteristics and management of prostate cancer in the human immunodeficiency virus (HIV)-positive population: experience in an Australian major HIV centre Wee Loon Ong*†, Paul Manohar*, Jeremy Millar†‡ and Peter Royce*§ *Department of Urology and ‡William Buckland Radiation Oncology Service, Alfred Health, and Departments of † Epidemiology and Prevention Medicine and §Surgery, Monash University, Melbourne, Vic, Australia Objectives To characterise clinicopathological characteristics of prostate cancer among human immunodeficiency virus (HIV)-positive men and to evaluate the current practice patterns in the management of prostate cancer in these men. Patients and Methods We retrospectively reviewed all patients with HIV in the State-wide HIV referral centre in Victoria, who were diagnosed with prostate cancer from 2000 onwards. In all, 12 patients were identified, and the medical records were reviewed to collect data on HIV parameters at the time of prostate cancer diagnosis, as well as prostate cancer clinicopathological characteristics, treatment details and outcomes. Results At the time of prostate cancer diagnosis, eight patients had undetectable viral load, and the median cluster of differentiation 4 (CD4) count was 485 cells/μL. The average age at diagnosis of prostate cancer was 63 years and the median prostate-specific antigen (PSA) level of 11.1 ng/mL. Four patients had Gleason 6 prostate cancer, four Gleason 7, one Gleason 8 and three Gleason 9. Seven of the 12 patients Introduction HIV-positive patients are at increased risk of developing certain cancers, especially AIDS-defining cancers (i.e. Kaposi sarcoma, non-Hodgkin lymphoma and invasive cervical carcinoma), as well as other HIV-related cancers, such as anal cancer. However, prostate cancer has been reported to be less common in the HIV-positive population [1,2]. HIV-positive patients who were diagnosed with prostate cancer had been reported to have very rapid cancer progression, due to the severely depressed immune system, as well as poor response to © 2015 The Authors BJU International © 2015 BJU International | doi:10.1111/bju.13097 Published by John Wiley & Sons Ltd. www.bjui.org had a positive family history for prostate cancer. Of the patients with clinically localised prostate cancer (10), most were treated with radiotherapy (RT): one permanent seed brachytherapy (BT), five external beam RT (EBRT), two open radical prostatectomies (RP), one active surveillance (AS), and one on watchful waiting (WW). For the two patients with metastatic disease, one had androgen-deprivation therapy and EBRT, while the other had a combination of EBRT and chemo-hormonal therapy with doxetacel. All patients were followed for a median of 46 months, with three deaths reported, none of which was a prostate cancer-specific death. Conclusions This is the first Australasian series on prostate cancer management in a HIV population. With the prolonged survival among HIV-positive men in the highly active anti-retroviral therapy era, PSA testing should be offered to this group of patients, especially those with a positive family history. HIV-positive men should also be offered all treatment options in the same manner as men in the general population. Keywords prostate cancer, HIV, treatment androgen-deprivation therapy (ADT) due to their hypogonadal state [3]. Before highly active anti-retroviral therapy (HAART) was available, the management of prostate cancer among HIV-positive men was often considered secondary to the management of HIV infection, given the poor prognosis from HIV infection and AIDS illnesses. However, with the advent of HAART, HIV-positive patients are living longer [4], and HIV infection is gradually evolving into a chronic disease. In a multinational study by the Antiretroviral Therapy Cohort BJU Int 2015; 116, Supplement 3, 5–10 wileyonlinelibrary.com © 2015 The Authors 6 BJU International © 2015 BJU International Yes Yes 9 Yes – RP + PLND 26 Dx, diagnosis; Int. intermediate; PLND, pelvic lymph node dissection. #, fractions; CTx, chemotherapy. 1116 19 High 0 0 2b 5+4 2013 12 53 7.6 4 2013 11 54 269 5+4 1 1 High 8 792 <20 ADT + EBRT + CTx Surgical specimen: Gleason score 4 + 3, pT2c, clear margin ADT + 50 Gy/20# + six cycle docetaxel Surgical specimen: Gleason score 5 + 4, pT2b, clear margin 9 Yes Yes Yes No – No 1c 1c 2b 2012 2012 2013 8 9 10 68 58 46 3.9 11.5 9.0 3+3 3+3 4+3 0 0 0 0 0 0 Low Int Int 6 5 23 485 485 672 <20 <20 <20 EBRT AS RP + PLND 46 Gy/23# + HDR (17 Gy/2#) 74 Gy/37# 28 23 13 No No Yes No – – No 60 58 103 87 81 67 34 145 Gy (125I) 70 Gy/35# 70 Gy/35# 74 Gy/37# ADT + 50Gy/20# BT EBRT EBRT EBRT ADT + EBRT WW EBRT <20 <20 810 <20 56 200 <20 49 900 586 – 471 235 405 – 347 7 9 – 22 – 20 0.25 Int Int Int Int High Int High 0 0 0 0 0 0 0 2a 1c 1c 1c 4 1c 1c 2002 2002 2004 2007 2008 2008 2011 1 2 3 4 5 6 7 68 70 66 61 63 79 66 8.8 8.4 12.2 11.7 134 10.8 57 3+3 4+3 3+3 4+3 5+4 3+4 4+4 0 0 0 0 1 0 0 BCF Follow-up, months Treatment details Primary treatment Viral load, copies/mL NCCN M N cT Gleason score PSA level at Dx, ng/mL Age at DX, years Year of Dx Prostate cancer characteristics Of the 5334 HIV-positive men treated at our institution, 12 with a prostate cancer diagnosis were included in the present study. Table 1 summarises the HIV parameters, prostate cancer characteristics, treatment details and oncological outcomes in our cohort of patients. The mean (SD) age at prostate cancer diagnosis was 62.7 (8.9) years. At the time of prostate cancer diagnosis, the median (range) CD4 count was 485 (235–1116) cells/μL, with eight of the 12 patients having undetectable viral load (<20 copies/mL). One patient had a history of AIDS defining illness, Kaposi sarcoma, treated with radiotherapy (RT) ≈ 16 years before their prostate cancer diagnosis. All 12 patients were on HAART treatment. ID Results Table 1 Prostate cancer and HIV infection characteristics. We retrospectively reviewed all HIV-positive patients treated at the Alfred Health. The Alfred Health, through its infectious disease unit, provides treatment and care for HIV patients for the entire state of Victoria. HIV-positive patients who were diagnosed with prostate cancer in the HAART era, from 2000 onwards were identified through the health informatics unit at the Alfred Health. The medical records for patients who were identified were reviewed for collection of data on HIV-related and prostate cancer-related variables. HIV-related variables of interest were: date of diagnosis of HIV infection, cluster of differentiation 4 (CD4) count, and viral load at the time of prostate cancer diagnosis, treatment details for HIV, and any history of AIDS defining illnesses. Prostate cancer-related variables of interest included: date of prostate cancer diagnosis, clinicopathological characteristics of cancer (i.e. PSA level at diagnosis, Gleason score of diagnostic biopsy, TNM staging), treatment details and oncological outcomes. The study was approved by the Alfred Health Ethics Committee (Project no. 307/14). HIV infection characteristics at the time of prostate cancer Dx Patients and Methods CD4, cells/μL The aim of our present study was to characterise the clinicopathological features of prostate cancer among HIV-positive men, in a major HIV referral centre in the state of Victoria, Australia. We also aimed to evaluate the current practice pattern in the management of prostate cancer in this population, as well as the oncological outcomes. Duration of HIV, years Prostate cancer treatment Follow-up Alive Collaboration, it has been reported that compared with the early HAART era (1996–1999), the life-expectancy among HIV patients at age 35 years has increased from 25 to 37.3 years in the late HAART era (2003–2005) [4]. Alongside the prolonged survival of HIV-positive men and the widespread use of serum PSA testing, prostate cancer is likely to become more prevalent among the HIV-positive men, and increasingly, urologists and oncologists will have to care for HIV-positive men with prostate cancer. However, data on the management of prostate cancer in this population are extremely limited, with only a few published series, each reporting only a handful of patients [5–10]. No No No Yes Yes Yes Yes Ong et al. Clinicopathological characteristics and management of prostate cancer among HIV-positive men Prostate Cancer Characteristics At the time of prostate cancer diagnosis, the median (range) serum PSA level was 11.1 (3.9–269) ng/mL. Histopathology of the diagnostic biopsy showed four of the 12 patients with Gleason 3 + 3 disease, one (8%) Gleason 3 + 4, three (25%) Gleason 4 + 3, one (8%) Gleason 4 + 4, and three (25%) Gleason 5 + 4. Seven patients of the 12 had benign DRE at diagnosis (cT1c). Based on the National Comprehensive Cancer Network (NCCN) classification, 10 of the 12 patients had clinically localised prostate cancer (one low-risk, seven intermediate-risk, and two high-risk), while the other two had metastatic disease at diagnosis. More than half of the patients (seven) had a positive family history of prostate cancer. Treatment After diagnosis, eight of the 10 patients with clinically localised prostate cancer proceeded to have curative treatment with surgery or RT. Two patients had open radical prostatectomy (RP) as their primary treatment. Both had pT2 disease on the RP surgical specimen, with clear surgical margin, and no lymph nodes involvement. Of the patients who had RT, one had low-dose-rate brachytherapy (LDR-BT) with 125I seed, while five had external beam RT (EBRT), one of which was in conjunction with high-dose-rate BT (HDR-BT) (17 Gy/2 fractions). One patient with low-volume Gleason 3 + 3 disease was put on active surveillance (AS) after their prostate cancer diagnosis, while the other remaining patient, who was diagnosed with Gleason 3 + 3 prostate cancer at the age of 79 years, was put on watchful waiting (WW), and was alive at last follow-up. One of the patients with nodal involvement (cT2N1M0) was initially treated with ADT alone. However, he was noted to have pT4 disease with bladder invasion on TURP performed for LUTS 6 years later. He was subsequently treated with EBRT (50 Gy/20 fractions) for local control. Another patient with metastatic disease (cT4N1M1) was treated with a combination of chemo-hormonal therapy, with six cycles of docetaxel, and EBRT. Oncological Outcomes All patients were followed for a median (range) of 46 (9–103) months. The LDR-BT patient has remained free of biochemical recurrence (BCR) at 5 years follow-up. One of the five patients treated with curative EBRT developed BCR, based on the Phoenix definition, ≈ 7 years after completion of EBRT. One RP patient has remained BCR-free at 1 year, while another RP patient had a persistently elevated serum PSA level postoperatively and was treated with salvage EBRT (60 Gy/30 fractions). The patient on AS had another repeat transperineal saturation biopsy 2 years after diagnosis, again, confirming low-volume Gleason 3 + 3 disease and he has remained on AS at last follow-up. During the follow-up period, there were three deaths reported, none of which were prostate cancer-related deaths: one anal cancer and two ischaemic heart disease. Discussion We reported on the clinicopathological characteristics, management and the oncological outcomes of prostate cancer in a cohort of HIV-positive men based on our experience in a major HIV centre in Australia. While this is a single institutional study, it is likely to be representative of the current practice patterns in the population, given that the Alfred Health is the state-wide HIV treatment centre, and we would have captured most, if not all, HIV patients with prostate cancer in the state of Victoria. This is to our best knowledge, one of the few published series, and the first Australasian series to date. Similar to findings in population-based studies in the USA [1], the incidence of prostate cancer in HIV-positive men in Australia was reported to be relatively low. Data-linkage between the Australia National HIV/AIDS Registry and the Australasian National Cancer Statistics Clearing House (NCSCH) reported only 24 incident cases of prostate cancer in 18 794 HIV-positive men between 1982 and 2004: 10 in the pre-HAART era (1982–1995), six in early-HAART era (1996–1999) and eight in late-HAART era (2000–2004) [2]. The population-based study also reported significant decline (Ptrend = 0.026) in the standardised incidence ratio (SIR) of prostate cancer in HIV-positive men over that period, with a decline in the SIR to 0.27 (95% CI 0.11–0.52) compared with the general population in the late-HAART era. However, these numbers need to be interpreted cautiously, as they do not necessarily represent a ‘true’ reduced risk of prostate cancer in the HIV-positive men with HAART treatment, but instead, it could represent an artefact driven by other development in prostate cancer diagnosis and/or treatment around the same period. The rapid uptake of HAART in the HIV-populations in the 1990s [11] corresponds with the rapid rise in PSA testing in the general population in Australia around the same period. Since the listing of PSA testing on the Australia’s Medical Benefits Schedule in 1988, Smith et al. [12] reported a continuous rise in PSA testing in a population-based study in the state of New South Wales, from 1284/100 000 men in 1989 to 6908/100 000 men in 1995 and 12 119/100 000 men in 2005. This has resulted in a corresponding rise in the incidence of prostate cancer in the general population (non-HIV). However, given the poor prognosis from HIV infection in the pre/early HAART era, screening for non-AIDS defining illnesses, such as prostate cancer, has been controversial [13]; hence PSA testing was not as commonly utilised in HIV-positive men. One feature suggesting the © 2015 The Authors BJU International © 2015 BJU International 7 Ong et al. under-utilisation of PSA testing in this population is the higher grade or stage of prostate cancer diagnosed in our present cohort of HIV-positive patients with prostate cancer. The introduction of PSA testing has resulted in a stage migration in prostate cancer in the general population, with early and more frequent detection of low-grade, low-volume disease. Data from the population-based Victorian Prostate Cancer Registry reported that one in four patients with prostate cancer in the general population had NCCN low-risk prostate cancer [14]. However, in our present cohort of HIV-positive patients with prostate cancer, we observed a lower proportion of patients with low-risk prostate cancer (one in 12) and as many as three patients were diagnosed with Gleason 5 + 4 prostate cancer, two of whom had metastatic disease with PSA levels of >100 ng/mL at the time of diagnosis. This is probably secondary to a lack of PSA testing, resulting in a potential delay in cancer detection, and subsequent diagnosis of higher grade prostate cancer in the HIV-positive men. Given that HIV-positive men are living longer in the HAART era, this approach will probably change, and PSA testing in HIV-positive population is likely to become more common [15]. This is especially true for patients with risk factors for prostate cancer, such as those with a positive family history. Family history has long been recognised as one of the strongest risk factors for prostate cancer, and having an affected first-degree relative increases one’s risk by two- to three-fold [16]. The fact that more than half of the HIV-positive patients with prostate cancer in our present cohort reported having a family history of prostate cancer further highlights the need for PSA testing among HIV-positive men with risk factors for prostate cancer. After the diagnosis, there is no universally accepted consensus about management of prostate cancer in the HIV-positive men. Data in the literature appeared to suggest that RT has conventionally been the treatment method of choice for HIV-positive patients with prostate cancer. Half of our present cohort had curative RT with either EBRT or BT, and reported excellent long-term oncological outcomes, with only one BCR reported at 7 years follow-up. However, there is lack of detailed treatment-related toxicities documented in our present cohort of patients. The few published data have reported that HIV-positive patients with prostate cancer do not have increased incidence of treatment-related toxicities, compared with the general population. Ng et al. [10] reported one of the largest series of HIV-positive patients with prostate cancer treated with RT based on a single institution experience in the USA. The study included 14 patients: four treated with 103Pd seeds, eight with EBRT + BT and two with EBRT alone, and reported primarily on the gastrointestinal and genitourinary toxicity. The study showed that treatment-related complications in HIV-positive patients with © 2015 The Authors 8 BJU International © 2015 BJU International prostate cancer are similar to those seen in non-HIV patients with prostate cancer, giving no evidence that HIV-positive patients with prostate cancer should be treated differently from non-HIV patients when considering RT. This is consistent with a more recent matched-cohort analysis by Kahn et al. [17], which reported comparable disease control and toxicity outcomes after curative EBRT in 13 HIV-positive patients with prostate cancer and 26 matched non-HIV patients with prostate cancer. While data in the Victorian Prostate Cancer Registry reported >40% of patients with prostate cancer (regardless of NCCN risk categories) in the non-HIV population in the state of Victoria were treated primarily with RP [14], we reported a much lower proportion of patients with prostate cancer who were treated with RP in our present cohort of HIV-positive patients with prostate cancer, with only two of the 12 having RP, and both occurred in very recent years. This is similar to the proportion reported in the literature. In a recent study of 43 HIV-positive and 86 matched HIV-negative patients with prostate cancer treated in a single institution in the USA, there were a significantly lower proportion of HIV-positive patients who had open RP (16%) compared with HIV-negative prostate cancer patients (57%) (P < 0.001) [18]. In other smaller studies, Levinson et al. [5] reported only one of 10 HIV-positive patients with prostate cancer treated in a single institution in the USA had RP, while in another multi-institutional cohort of 17 HIV-positive patients with prostate cancer in the USA, Pantanowitz et al. [6] reported three (18%) patients who had RP. The lower proportion of utility of surgery for prostate cancer management in HIV-positive men is probably due to a combination of factors including the potentially higher perioperative complication rates in the immunosuppressed population, and the concern of occupational risk to the surgical team. In a retrospective review of RP performed in five HIV-positive patients at the Memorial Sloan Kettering Cancer Centre, Huang et al. [7] reported two patients with wound infections, including one (who had the lowest CD4 counts) requiring hospitalisation for i.v. antibiotics. It has been suggested that with the use of minimally invasive surgical approaches, which may reduce the healthcare workers’ exposure to HIV-positive material, and careful selection of surgical candidate, including assessment of CD4 counts and viral loads, RP could potentially be offered to more HIV-positive patients with prostate cancer in the future [7]. Apart from curative treatment with RT and surgery, we also reported one patient who was put on AS and another on WW. Patients with HIV often have underlying anxiety, which might precede their HIV infection, triggered by the HIV diagnosis, or develop over the course of their dealing with the HIV infection [19]. There were concerns in the past that putting patients on AS might evoke psychological stress, given that Clinicopathological characteristics and management of prostate cancer among HIV-positive men patients are living with ‘untreated’ prostate cancer. Hence, putting HIV-positive patients on AS could potentially aggravate the underlying anxiety. However, a recent review by Bellardita et al. [20] showed that patients with prostate cancer on AS can have favourable anxiety scores, and a relatively good quality of life. In fact, the HIV-positive patient in our present cohort has remained on AS for >2 years since his initial diagnosis of low-volume low-grade prostate cancer. Despite the lack of guidelines on prostate cancer management specific to the HIV-positive population, a recent study reported that HIV-positive men were mostly treated in accordance with the NCCN guideline recommendation [18]. In a cohort of 43 HIV-positive patients with prostate cancer treated in a single institution in the USA, Murphy et al. [18] reported two patients who were deemed to have received inappropriate treatment: one patient was over-treated, due to presence of other medical comorbidities, while another patient who was put on WW was considered under-treated. The author concluded that the difficulty in life-expectancy estimation in this group of patients as the cause of under- or over-treatment of prostate cancer. This highlighted the need for a multidisciplinary approach, not only involving urologists and oncologists but HIV specialists, in the management of prostate cancer among HIV-positive patients. It has been previously reported that input from a multidisciplinary team has led to high impact changes in the management plan in about one quarter of the uro-oncological cases [21]. This will definitely help minimise the likelihood of inappropriate management among HIV-positive men. In conclusion, our present study showed a lower proportion of low-risk prostate cancer in the HIV-positive population compared with the general population in the state of Victoria. HIV-positive patients were offered the full spectrum of prostate cancer treatment options (ranging from AS to radical surgery to palliative chemotherapy), with most patients being treated with RT. We think our review suggest that in Australia, as men with HIV are living longer, well into their 70s [4], they should be offered PSA testing and all potential treatment options in the same manner as men in the general population: that is, taking into account all co-morbidities and their life-expectancy in a shared decision-making framework. Acknowledgements The authors would like to thank Paul Hougham (Information Analyst at the Clinical Performance Unit/ Health Informatics, Alfred Health) and Robin Smith (Research Manager at the William Buckland Radiotherapy Centre, Alfred Health) for assistance with patient identification and data extraction from the Alfred Health electronic medical records. Conflict of Interest Nil to disclose. References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Shiels MS, Goedert JJ, Moore RD, Platz EA, Engels EA. Reduced risk of prostate cancer in U.S. Men with AIDS. Cancer Epidemiol Biomarkers Prev 2010; 19: 2910–5 van Leeuwen MT, Vajdic CM, Middleton MG et al. Continuing declines in some but not all HIV-associated cancers in Australia after widespread use of antiretroviral therapy. AIDS 2009; 23: 2183–90 Kwan DJ, Lowe FC. Genitourinary manifestations of the acquired immunodeficiency syndrome. Urology 1995; 45: 13–27 Antiretroviral Therapy Cohort Collaboration. 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Prostate carcinoma among men with human immunodeficiency virus infection. Cancer 2004; 101: 294–9 Goldgar DE, Easton DF, Cannon-Albright LA, Skolnick MH. Systematic population-based assessment of cancer risk in first-degree relatives of cancer probands. J Natl Cancer Inst 1994; 86: 1600–8 Kahn S, Jani A, Edelman S et al. Matched cohort analysis of outcomes of definitive radiotherapy for prostate cancer in human immunodeficiency virus-positive patients. Int J Radiat Oncol Biol Phys 2012; 83: 16–21 Murphy AB, Bhatia R, Martin IK et al. Are HIV-infected men vulnerable to prostate cancer treatment disparities? Cancer Epidemiol Biomarkers Prev 2014; 23: 2009–18 Clucas C, Sibley E, Harding R, Liu L, Catalan J, Sherr L. A systematic review of interventions for anxiety in people with HIV. Psychol Health Med 2011; 16: 528–47 © 2015 The Authors BJU International © 2015 BJU International 9 Ong et al. 20 Bellardita L, Valdagni R, van den Bergh R et al. How does active surveillance for prostate cancer affect quality of life? A systematic review. Eur Urol 2015; 67: 637–45 21 Rao K, Manya K, Azad A et al. Uro-oncology multidisciplinary meetings at an Australian tertiary referral centre–impact on clinical decision-making and implications for patient inclusion. BJU Int 2014; 114 (Suppl. 1): 50–4 Correspondence: Wee Loon Ong, Department of Urology, Alfred Health, Commercial Road, Prahran, VIC 3181, Australia. e-mail: [email protected] 10 © 2015 The Authors BJU International © 2015 BJU International Abbreviations: ADT, androgen-deprivation therapy; AS, active surveillance; BCR, biochemical recurrence; (HDR)(LDR)-BT, (high-dose-rate) (low-dose-rate) brachytherapy; CD4, cluster of differentiation 4; (EB)RT, (external beam) radiotherapy; HAART, highly active anti-retroviral therapy; NCCN, National Comprehensive Cancer Network; RP, radical prostatectomy; SIR, standardised incidence ratio; WW, watchful waiting.