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HIV and prostate cancer: a systematic review of the literature
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Prostate Cancer and Prostatic Diseases advance online publication 19 August 2008; doi: 10.1038/pcan.2008.44
J Silberstein1, T Downs1,2,3, C Lakin1,3 and C J Kane1,3
1. 1Division of Urology, Department of Surgery, University of California, San Diego, Medical Center, San Diego, CA, USA
2. 2Moores Comprehensive Cancer Center, University of California, San Diego, San Diego, CA, USA
3. 3Veterans Affairs Medical Center, San Diego, CA, USA
"......Hypogonadism may result in or contribute to reduced bone mineral density and muscle mass, poor mood, anemia, decreased libido and erectile dysfunction. Testosterone replacement therapy helps improve these conditions and is often prescribed for hypogonadal men with HIV. Hypogonadism is more prevalent in the HIV-positive population, with prevalence rates about 20% higher than age-matched controls. Testosterone replacement has been linked, albeit not definitely, to an increased risk of development of PCa....If HIV truly does represent a risk for PCa, then more rigorous screening may be necessary in this group as a whole, and especially in those on testosterone replacement therapy. At this point in time no definitive recommendations can be offered but it should be noted that many men with HIV are receiving testosterone replacement and are not adequately being screened......Interestingly HIV protease inhibitors have been demonstrated to decrease proliferation of PCa cells via inhibition of nuclear factor-B.42 HAART may prove to be protective against the development of PCa and this may in part explain the reduced incidence of PCa seen in several of the large epidemiological studies outlined earlier.....Some have suggested that HIV-positive cohorts are inadequately screened for PCa, but in the few prospective screening studies a higher prevalence of PCa has not been detected.....Future studies should be aimed at using age-appropriate PSA screening and characterizing long-term outcomes of this patient population...."
ABSTRACT
Malignancy occurs with increased frequency in the HIV-positive population. The true incidence of prostate cancer in this population is unknown. In the few cases that have been presented in the literature, prostate cancer in HIV-positive men appears to behave much like it does in HIV-negative men. Prostate cancer is the most common malignancy in men and the second leading cause of cancer death. Approximately 800 000 men in the United States are HIV positive, and innovative therapies have dramatically improved survival. HIV disproportionately impacts ethnic groups with increased risk of prostate cancer and has been associated with increases in the incidence of certain malignancies. Despite the high prevalence of both diseases, there is relatively little literature about prostate cancer in HIV-positive patients. There is no consensus on how to screen or treat this patient population. We review the literature with regards to incidence, screening, treatment, and outcomes of this poorly characterized population. We briefly discuss the impact of highly active antiretroviral therapy and testosterone supplementation in the development of prostate cancer. A systematic review of the literature was conducted using MEDLINE key words 'HIV,' 'prostate,' 'prostate cancer' and 'AIDS.' Manual bibliographic review of cross-referenced items was also performed. A total of 176 unique abstracts and publications were reviewed; many authors provided data on the incidence of HIV and various malignancies including prostate cancer. Twelve unique publications providing detailed information on 60 patients with HIV and prostate cancer were identified. Prostate cancer is a common malignancy in HIV-positive men. With improved therapies for HIV and increasing survival, the importance for screening and treating prostate cancer is increasing. Acute outcomes of treatment do not demonstrate increased acute morbidity; however long-term outcomes have not been reported.
INTRODUCTION
Tumor registries have demonstrated that HIV is associated with an increased incidence of certain malignancies such as Kaposi sarcoma, non-Hodgkin lymphoma and cervical cancer.1 These so-called AIDS-defining malignancies make up approximately two-thirds of all cancers among people with AIDS.1 In addition, several genitourinary malignancies have been demonstrated to have an increased incidence in the HIV-positive population including seminoma and possibly renal cell carcinoma.1, 2 Interestingly, some malignancies such as breast cancer have been shown to occur at a reduced rate in this population.3
According to the Centers of Disease Control, at the end of 2003 an estimated 1 039 000-1 185 000 persons in the United States were living with HIV/AIDS and about three quarters of these patients were men.4 More than half of all newly diagnosed HIV patients are African American and more then a quarter are over the age of 45.5, 6 With the advent of highly active antiretroviral therapy (HAART), the overall progression of HIV infection to AIDS and from AIDS to death has slowed, and survival has increased dramatically.7
Prostate cancer (PCa) is the most common malignancy in men. Its incidence increases as men age and it is more prevalent in African Americans.8 Men with HIV represent a unique cohort of patients to whom urologists must be able to offer appropriate information regarding incidence, screening, treatment and outcomes with respect to PCa.
Though there are several epidemiologic studies that estimate the incidence of PCa in HIV-positive men, there is a paucity of data that examine specific characteristics of this patient population. To this end, we performed a systematic review of all studies on HIV-positive men who were diagnosed with PCa. Twelve studies included data on 60 unique patients diagnosed with PCa and HIV (Table 1). The age range (average) at the time of diagnosis was 40-79 years (57.8). Most men were identified because of an elevated prostate-specific antigen (PSA; 52%) and had no palpable tumor on digital rectal examination (DRE; T1c 27/52 patients); 18 patients were determined to have localized palpable tumors (35%), 3 patients (5.8%) had locally advanced PCa and 4 patients (7.7%) had metastatic disease at the time of diagnosis. The average number of years with HIV before diagnosis was 8.8 years (6 months-20 years), the average viral load at the time of diagnosis was 10 006 copies per ml (undetectable set at 25 copies per ml to >100 000 copies), and average CD4 count was 425.2 cells per l (24-1070). The average Gleason score was 6.57 (5-8).
INCIDENCE
Prostate cancer
Approximately 220 000 men are diagnosed with PCa annually and PCa is expected to account for 29% of new cancer cases in men in 2007.21, 22
HIV
Approximately 37 000 new cases of HIV were reported in the United States in 2006.5 Hessol et al.7 identified more than 14 000 adults diagnosed with AIDS in San Francisco between 1990 and 2001 and identified 482 non-AIDS-defining cancers in the 60 months before or after the diagnosis of AIDS was made. They reported 32 cases of PCa and found significantly increased standardized incidence ratios of PCa when compared to the general population (SIR=1.7).7 However similar studies have noted disparate results.
Biggar et al.23 linked more then 8000 patients who were over the age of 60 and carried a diagnosis of AIDS to cancer registries and found 1142 cases of malignancy from 60 months before the diagnosis of HIV to 27 months after AIDS onset. Non-AIDS-defining malignancies were identified in 548 patients. Although PCa was the most common (118 cases), the risk of PCa was lower than expected in both overall (relative risk (RR) 0.8; 95% CI 0.6-0.9) and post-AIDS onset periods (RR 0.5; 95% CI 0.3-0.8).23 A similar linkage-based population study examining more than 300 000 people throughout the United States aged 15-69 years demonstrated a lower than expected incidence of PCa both in the overall (RR 0.7; 95% CI 0.6-0.9) and post-AIDS onset period (RR 0.5; 95% CI 0.4-0.7).24
Based on these and several other large retrospective population-based studies, it is difficult to determine if there is an increased or decreased incidence of HIV in an age-matched general population.25, 26 These observation-based, epidemiologic studies simply look at incidence of PCa in an HIV-positive cohort which is dependent on detection and, thus, PSA and DRE screening. It has been hypothesized that reports of lower incidence of PCa in HIV positive individuals may be due to decreased screening of this group.16, 23
Table 1. HIV positive men diagnosed with prostate cancer
DETECTION
Current PCa screening requires digital rectal exam and PSA determination. Screening protocols have unquestionably led to increased detection of cancer and a migration to lower-stage and lower-volume tumors.23, 27 It has yet to be proven in large randomized control studies that PSA screening significantly reduces mortality from PCa; however two studies are anticipated to answer this question in the near future.28, 29 Detecting cancer at lower stages and volumes has led to improved survival for other malignancies.30
The American Urologic Association (AUA) recommends beginning PSA screening in all men aged 50 years or more with a life expectancy of more than 10 years.31 Men with increased risk of PCa should begin earlier screening; no formal recommendations are made by the AUA with respect to HIV or AIDS.31 Because of the relatively long latency period of PCa, a survival of greater than 10 years is thought to be necessary for screening to provide information that may impact survival. Recently, the life expectancy of a newly diagnosed 25-year-old HIV-infected individual was estimated to be 39 years.32 Other studies from the US have suggest that from the time of entering HIV care, per person projected life expectancy is 24.2 years.33 Although exact figures are not known, most estimates are beyond 10 years.
Under the current standard of care, an elevated PSA or abnormal DRE result prompts a transrectal ultrasound (TRUS)-guided biopsy of the prostate for tissue diagnosis. Immunosupression resulting from HIV could theoretically increase the morbidity of prostate biopsy. To our knowledge, however, there are no reports in the literature of any complications as a result of TRUS biopsies of the prostate in HIV-positive men. Furthermore, Wammack et al.34 performed a prospective study on 59 patients receiving immunosupressive therapy after renal transplants and compared their complications rates after TRUS biopsy with 1051 men in the European Prostate Cancer Detection Study. These investigators found no increased morbidity in the immunosupressed group, which indirectly suggests that TRUS biopsy is safe in HIV-positive patients.34
Prospective HIV/prostate cancer screening studies
In order to evaluate the usefulness of PSA as a screening tool and determine the rates of PCa in a screened cohort of HIV-positive individuals, two studies have been conducted. Crum et al.17 initiated PCa screening protocol on an HIV-positive cohort of men >35 years of age over an 18-month period. All 269 men underwent DRE and none had abnormal results. Of these patients, 80% also had PSA testing. Elevated PSA levels were found in seven patients. Of these, six patients had normalization of their PSA values on repeat PSA testing and did not receive a prostate biopsy. One patient underwent prostate biopsy and was found to have high-grade prostatic intraepithelial neoplasia. No patients in this screening cohort were noted to have biopsy-proven PCa. These authors did note that, in the 2 years before initiating their screening protocol, they diagnosed four men with PCa, all of whom were over the age of 60. They found that age, African-American ethnicity and number of years of HIV infection were positively associated with the development of PCa. They concluded that HIV-positive men aged 60-70 years had a 20.5 times higher rate of adenocarcinoma compared to an age-matched US general population rate.17
A similar study was performed by Vianna and Klein35 of 534 men enrolled in the Cohort of HIV at-risk Ageing Men's Prospective Study. Men aged 49 years or more who engaged in high-risk behaviors for HIV were eligible for enrollment in the study regardless of HIV status. There were 9 of 310 (2.9%) HIV-positive men and 11 of 224 (4.9%) HIV-negative men who had PSA values greater than 4.0 ng ml-1. Of these 20 patients with elevated PSA levels, the authors were only able to obtain biopsy information on 5. PCa was present in one HIV-positive patient and one HIV-negative patient. Details on the HIV status of the remaining three patients were not provided. HIV status was not associated with elevated PSA. These authors suggest that PSA screening protocols need not be modified for those with HIV infection.35 Notably, these authors waited until PSA values reached 4.0 before recommending urologic evaluation to their patients regardless of age or PSA velocity. Furthermore, only 25% of patients whose PSA values were determined to be greater than 4 ng ml-1 subsequently received biopsies.
Symptomatic detection
PCa was detected in HIV-positive men through a screening study, either DRE or PSA determination in the majority of cases in the literature, however several men have been reported to have vague symptoms that were ultimately determined to be related to metastatic disease (Table 1). Manfredi et al.12 reported on a 53-year-old HIV-positive man who presented with fever, weight loss, generalized fatigue, and exertional dyspnea. As part of a work-up for his fever of unknown origin, a bone marrow biopsy was obtained, revealing metastatic PCa. The patient died 4 weeks after diagnosis due to coagulative complications from disseminated intravascular coagulation (DIC) as a result of his metastatic disease.12 Schwartz and Prince20 reported a 43-year-old HIV-positive man who presented with DIC, hematochezia, lower back pain and progressive weakness. Bone marrow biopsy revealed metastatic PCa. The patient survived his acute event and was started on androgen deprivation therapy.20 Quatan et al.15 present a 58-year-old man who was hospitalized with infective myositis of the left iliacus muscle and was found to have a PSA of 5638 ng ml-1. A bone scan confirmed metastatic disease throughout his axial skeleton. The patient had a good initial response to androgen deprivation therapy but developed androgen-insensitive PCa approximately 1 year after diagnosis.15
TREATMENT & OUTCOMES
It has been suggested that PCa is more aggressive in HIV-positive men. Kwan and Lowe36 noted that, in their experience, progression of PCa was more virulent in HIV-positive patients because of its lack of response to hormonal manipulation and that this was secondary to the hypogonadal status of HIV-positive men. These authors did not present any data from which they drew these conclusions. As then there have been a variety of case series of HIV-positive men with PCa describing treatment and short-term outcomes. Notably there are no long-term outcomes for HIV-positive patients with biopsy-proven PCa.
Radical prostatectomy
HIV-positive men with biopsy-proven localized PCa have undergone a variety of interventions; Huang et al.13 have published the largest series of radical prostatectomies in HIV-positive individuals to our knowledge. They retrospectively reviewed all patients who had undergone prostatectomy at Memorial Sloan-Kettering Cancer Center over a two-and-a-half-year period and identified five men who had HIV before prostatectomy. Age (mean) ranged from 45 to 59 years (52); PSA levels ranged from 4.1 to 30.8 ng ml-1 (11.26 ng ml-1), biopsy Gleason score ranged from 6 to 7 (6.8); three patients had clinical stage T1c and two had clinical stage T2a. Viral load ranged from undetectable to 18 700 copies per ml (4475 copies per ml) and CD4 count from 269 to 870 cells per mm3 (617 cells per mm3). Duration from HIV diagnosis ranged from 2 to 14 years (8.75 years); duration for one patient was not known. All five patients underwent a radical retropubic prostatectomy with negative margin status although one patient was noted to have a positive lymph node and extraprostatic extension. The patients were followed for 11-32 months (median 26 months). All had undetectable PSA following their intervention and none had PSA recurrence. No patients had progression from HIV to AIDS during the course of the study. These authors reported no major complications in their cohort but did note wound infections in two of these five patients, one of whom required rehospitalization for intravenous antibiotics. These authors concluded that in patients with CD4 counts greater than 500 cells per ul and asymptomatic HIV infection, prostatectomy is well tolerated and a reasonable treatment option.
Radiation therapy
Radiation therapy has also been used for treatment of PCa in HIV-positive patients. O'Connor et al.14 described three patients with HIV and localized PCa who received external beam radiation therapy (EBRT). These authors noted excellent acute tolerance to the EBRT when compared with other published series.14 All three patients were noted to have mild dysuria and urinary frequency. Two patients experienced nocturia, one developed mild diarrhea and another experienced mild rectal burning and hemorrhoidal bleeding. The authors note that HIV-positive men have much better tolerance of radiotherapy for PCa than for rectal cancer. They attributed this to less rectal radiation, lack of concurrent chemotherapy, and use of conformal techniques, such as intensity-modulated radiation therapy.
Brachytherapy
Staiman and Lowe19 reported on a patient with HIV and adenocarcinoma of the prostate who underwent brachytherapy and subsequently developed a prostatic abscess. Transrectal and transperineal drainage of the prostate were performed in addition to prostate biopsy. The patient abscess was caused by Enterococcus as well as underlying squamous cell carcinoma of the prostate and rectum.
In a more recent study evaluating the role of brachytherapy and radiotherapy in HIV/PCa patients, Ng et al.9 demonstrated that brachytherapy is a safe short-term intervention. They conducted a retrospective study of 14 PCa/HIV patients; 2 received EBRT, 4 received brachytherapy and 8 underwent a combination of the two. Several of these patients received adjuvant hormonal therapy but it was unclear which patients and for what duration. The age range (mean) was 49-71 years (61 years); the Gleason score range was 6-8 (6.5); mean PSA was 14.3 ng ml-1 (median 5.8 ng ml-1); CD4 counts ranged from 200-946 cells per mm3. Viral load was undetectable in nine patients and ranged from 1600 to 27 000 copies per ml. There were six patients with T1c tumors, five with stage T2b and three with stage T2c tumors. The patients were followed for 8-73 months (mean 26). One patient died at 15 months after treatment secondary to heart failure. Thirteen patients demonstrated decrease of PSA value to 1.1 ng ml-1 or below. One patient had an increasing PSA and a subsequent bone scan showed a likely metastatic lesion. Seven months after treatment one patient demonstrated a dramatic decline in CD4 count and an increase in his viral load for unknown reasons. CD4 counts and viral loads in the remaining patients remained relatively stable. All patients were assessed for urinary, bowel and sexual symptoms after treatment and these authors concluded that these patients fared well when compared with other series. These authors concluded that radiation therapy and brachytherapy of the prostate were not contraindicated in HIV-positive patients.9
Different treatments of study populations
Levinson et al.16 performed a retrospective analysis of 10 patients with HIV and localized PCa who presented to a single urologist over a 2-year period. The age at diagnosis of PCa ranged from 41-69 years (mean 54 years); PSA ranged from 4.5-19.9 ng ml-1. Duration from HIV status to PCa diagnosis was 0.5-19 years (mean 8.75 years). The CD4 count ranged from 76-1070 cells per ul (mean 417 cells per ul) and the viral load ranged from undetectable to 501 copies per ml (mean 141.67 copies per ml) for the patients receiving HAART therapy. The average Gleason score was 6: two patients had a score of 5, six had a score of 6 and two had a score of 7. Six of these patients were African Americans, 2 were Hispanic and 2 were white. All 10 patients had clinical stage T1c or T2 disease. The patients received a variety of interventions: one underwent laparoscopic radical prostatectomy, one underwent cryosurgery, one chose androgen deprivation therapy, two underwent brachytherapy, three underwent EBRT and two elected watchful waiting. All patients who elected intervention did well, with minimal side effects of treatment. They were followed between 1.4 and 3 years (mean 2.3 years) after PCa diagnosis. The two patients who elected watchful waiting had stable PSA levels without progression at last follow-up and the eight patients who underwent intervention had PSA levels lower than baseline.16
Pantanowitz et al.10 recently performed a retrospective multi-institutional study involving HIV-positive men with PCa. They identified 17 patients with HIV and PCa; 13 were known to be HIV-positive before being diagnosed with PCa (range 2-20 years, mean 8.5 years), 2 were found to be HIV-positive years after a diagnosis of PCa and in 2 patients HIV status could not be determined at the time of PCa diagnosis. Findings from DRE were abnormal in six men. The race of two of the patients was unknown, eight patients were white, three were black, two were Hispanic and one was Haitian. The age at diagnosis of PCa ranged from 46 to 79 (mean 59). CD4 count ranged from 24 to 759 cells per l (mean 336 cells per l). HIV viral load ranged from undetectable to >100 000 copies per ml (mean 17 319 copies per ml). PSA at diagnosis ranged from 4.5 to 77 ng ml-1 (mean 30 ng ml-1). The Gleason score ranged from 6 to 8 (mean 6.8): seven tumors were pT1, two were pT2 and one was pT3. One patient had evidence of distant metastasis and one had regional lymph node involvement. Three patients received surgical intervention, three received brachytherapy, seven received androgen suppression and radiation therapy, and 2 received androgen suppression alone. One patient received no treatment and subsequently died secondary to dementia. The authors noted no serious treatment-related side effects, however five patients subsequently died of causes unrelated to PCa. These authors concluded that in HIV-positive men on HAART, PSA levels, clinical presentation and outcomes from treated PCa do not appear to be noticeably altered by HIV status. Unfortunately these authors did not record the duration of follow-up for these patients. They noted that CD4 counts were relatively preserved but the mean duration of HIV infection was 8.5 years before diagnosis of PCa and concluded that duration of HIV infection and not degree of immunodeficiency may be crucial in carcinogenesis.
Testosterone
Hypogonadism is more prevalent in the HIV-positive population, with prevalence rates about 20% higher than age-matched controls.37 The etiology of this hypogonadism is unclear but may be related to a combination of factors, including HIV, HAART, malnutrition and opportunistic infections. Hypogonadism may result in or contribute to reduced bone mineral density and muscle mass, poor mood, anemia, decreased libido and erectile dysfunction. Testosterone replacement therapy helps improve these conditions and is often prescribed for hypogonadal men with HIV. Testosterone replacement has been linked, albeit not definitely, to an increased risk of development of PCa. Although it is universally agreed that men with elevated PSA or abnormal DRE findings should undergo a prostate biopsy before initiating testosterone replacement therapy, there is no generally agreed upon monitoring regimen for PCa in patients with normal PSA and DRE findings. Some authors advocate a prostate biopsy before initiating testosterone replacement therapy even in men with normal DRE results and PSA levels.38 This is a particularly important and difficult issue in the HIV-positive population because the incidence and relationship between PCa and HIV are unclear. There are very limited data on this topic but Pantanowitz et al.10 reported that in their series of 13 men with a known diagnosis of HIV before a diagnosis of PCa, 3 had received testosterone therapy. If HIV truly does represent a risk for PCa, then more rigorous screening may be necessary in this group as a whole, and especially in those on testosterone replacement therapy. At this point in time no definitive recommendations can be offered but it should be noted that many men with HIV are receiving testosterone replacement and are not adequately being screened.
Highly active antiretroviral therapy
Current treatment for HIV includes the use of multiple medications aimed at suppression of the viral load below the limit of detection and increasing the number of CD4 cells. This is most commonly referred to as HAART; the synergistic use of several medications aimed at preventing viral replication, incorporation into host DNA, cleavage of a precursor polyprotein into active viral proteins and inhibition of fusion of the viral envelope into host cells.39 These therapies have transformed AIDS from an inevitably fatal condition to a chronic, manageable disease. Furthermore, HAART has been demonstrated to reduce the incidence of Kaposi sarcoma and non-Hodgkin lymphoma.40
The effect of HAART on the incidence or progression of PCa is not yet known. Viral infections have been implicated in the development of several malignancies including PCa. Recently a novel retrovirus has been identified from prostate tissue of men with known PCa and it may be crucial in tumorigenesis.41 Interestingly HIV protease inhibitors have been demonstrated to decrease proliferation of PCa cells via inhibition of nuclear factor-B.42 HAART may prove to be protective against the development of PCa and this may in part explain the reduced incidence of PCa seen in several of the large epidemiological studies outlined earlier.23, 24, 25 It is interesting to note that several of the recently published studies of HIV-positive men with PCa did occur while these patients were receiving HAART. Pantanowitz et al. noted that 82% of the men with HIV and PCa were receiving HAART, and Ng et al. noted that 79% were receiving HAART.10, 11 Clearly more investigation is needed before definitive conclusions can be reached.
Conclusion
Patients with HIV are living longer in large part because of new innovations of viral treatment. As this trend continues, these patients are at risk of secondary malignancies. The incidence of PCa may theoretically be increased in HIV-positive patients because of immunosupression and because other tumors occur with increased frequency. There is mixed evidence of a relationship between HIV and PCa incidence. Some have suggested that HIV-positive cohorts are inadequately screened for PCa, but in the few prospective screening studies a higher prevalence of PCa has not been detected. The HIV-positive men who are diagnosed with PCa often have tumors and demographics that are not dissimilar to age-matched cohorts. The life expectancy of modern HIV-positive men warrants consideration for treatment for PCa similar to age- and comorbidity-matched men. Although there are limited data on outcomes, HIV-positive men do appear to tolerate surgical or radiotherapeutic interventions with little increased morbidity. Future studies should be aimed at using age-appropriate PSA screening and characterizing long-term outcomes of this patient population.
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