Objectives: We reviewed the incidence, management, and survival outcomes of prostate cancer among kidney transplant recipients and compared these characteristics with a national population (nonrecipients).

Materials and Methods: A retrospective study was performed on all kidney transplant recipients from a National Kidney Transplant Centre who were subsequently diagnosed with prostate cancer. Primary outcome variables included comparisons of incidence and 5-year overall survival in kidney transplant recipients versus nonrecipients after treatment of prostate cancer. Secondary outcome variables were prostate-specific antigen levels at diagnosis, Gleason grade, treatment strategy, and morbidity from treatment among kidney transplant recipients.

Results: Of 4048 kidney transplants performed, 3020 were male recipients (63.9%). In total, 34 kidney transplant recipients (1.1%) were diagnosed with prostate cancer 109 ± 83 months (range, 7-372 mo) after transplant. The mean age at prostate cancer diagnosis was 64 ± 7 years, median prostate-specific antigen level was 10 ng/dL (range, 2.6-771 ng/dL), and 76% (n = 26/34) were diagnosed with localized disease. The incidence of prostate cancer was 1126/100 000 in kidney transplant recipients compared with 160/100 000 nonrecipients in Ireland (P = .01). Treatment strategies included curative radiotherapy (n = 18), curative surgery (n = 2), androgen deprivation therapy (n = 8), and watchful waiting (n = 6). Overall survival rates at 1, 3, and 5 years were not significantly different between kidney transplant recipients with prostate cancer versus nonrecipients with prostate cancer (98% vs 98%, 80% vs 79%, and 77% vs 72%, respectively, P = .8).

Conclusions: The incidence of prostate cancer is significantly higher among kidney transplant recipients compared with nonrecipients in the general population, with most diagnosed with localized disease. Definitive management guidelines should be developed to increase awareness and optimize treatment options in this unique patient cohort.

Key words : Malignancy posttransplant, Prostate-specific antigen, Renal allograft, Renal transplant

Introduction

Prostate cancer (PCa) is the most common non-cutaneous malignancy in male kidney transplant recipients (KTRs), and its incidence is increasing.¹ Risk factors for PCa such as sex, age, and race/ethnicity are particularly relevant with regard to KTRs, as approximately two-thirds of donor kidneys are transplanted into male recipients and most patients who receive kidney transplants are between 50 and 65 years of age.² Furthermore, the number of African American KTRs has increased significantly in the past 10 years.²

The life expectancy among KTRs has improved in recent years due to improved immunosuppressive protocols and better perioperative and postoperative medical care.³ Therefore, urologists will inevitably more frequently care for KTRs with PCa. However, there are no urologic guidelines or randomized controlled trials that have evaluated the treatment of PCa among KTRs.4 Furthermore, studies have not related renal transplant to increased PCa risk or aggressiveness. Features and outcomes of PCa among KTRs need to be investigated to provide urologists with data on appropriate management strategies. In the present study, we reviewed the incidence, treatment, and survival outcomes of PCa among KTRs versus a national population.

Materials and Methods

Overview of study design
A retrospective institutional review board-approved study was performed on all KTRs from a National Kidney Transplant Centre (Beaumont Hospital, Dublin, Ireland) between 1994 and 2016 who were subsequently diagnosed with PCa. Primary outcome variables included comparisons of incidence and 5-year overall survival after treatment in KTRs with PCa versus a general population with PCa. Prostate cancer outcome variables among the general population were obtained from the National Cancer Registry in Ireland (www.ncri.ie). The National Cancer Registry of Ireland electronically registers all histologically confirmed cancers. Secondary outcome variables were prostate-specific antigen (PSA) at diagnosis, Gleason grade, treatment strategy, and morbidity from treatment among KTRs.

Perioperative and postoperative immunosup-pression in kidney transplant recipients
During the perioperative period, immunosup-pressive agents given to KTRs included prednisone, tacrolimus, mycophenolic mofetil, and basiliximab. Tacrolimus levels were maintained between 10 and 15 ng/mL (microparticle enzyme immunoassay; Abbot IMX, Fujisawa Healthcare Incorporated, Co., Kerry, Ireland) during the first 6 weeks after transplant and between 8 and 12 ng/mL thereafter. All patients received standard antiviral and Pneumocystis prophylaxis. Prednisolone was given as a 500-mg intravenous infusion 12 hours after transplant. This dose was then tapered to 250 mg twice daily intravenously for 2 days until reduced to a daily morning dose of 250 mg intravenously for another 2 days. Patients were then switched to a daily dose of 20 mg oral prednisolone, which was gradually tapered to a daily maintenance dose of 5 mg of oral prednisolone by month 2 posttransplant.

Diagnosis of prostate cancer in kidney transplant recipients
Prostate cancer screening was routinely performed on all KTRs before transplant and offered during follow-up. Screening consisted of an annual PSA and digital rectal examination. Prostate cancer was histologically proven with transrectal ultrasonography-guided 12-core prostate biopsies with antibiotic prophylaxis. After diagnosis, PCa assessment for staging and treatment was consistent with the contemporary National Cancer Control Programme guidelines for the general population in Ireland diagnosed with PCa.⁵ Clinical stage was defined by digital rectal examination or magnetic resonance imaging when performed and updated in accordance with TNM classification of 2009.⁶ Risk groups for biochemical recurrence were classified according to the D’Amico classification as follows: low risk was defined as PSA ≤ 10 ng/mL, biopsy Gleason score < 7, and stage ≤ cT2a; intermediate risk was defined as PSA between 10 and ≤ 20 ng/mL, biopsy Gleason score = 7, and stage cT2b; and high risk was defined at PSA > 20 ng/mL, biopsy Gleason score > 7, and stage ≥ cT2c.⁶

Statistical analyses
Unless otherwise stated, data are shown as means ± standard deviation, and “n” represents the number of patients included in the analysis. We used t tests with unequal variances for pairwise comparisons. Kaplan-Meier estimates were used to compare overall survival of PCa in KTRs with the general Irish population after 1, 3, and 5 years from 2000 to 2005 and from 2006 to 2011, respectively (SPSS, Inc, Chicago, IL, USA).

Results

Prostate cancer in kidney transplant recipients
Of 4048 kidney transplants performed during the study period, 3020 (63.9%) were male recipients. The mean male recipient age was 55 ± 12 years (range, 23-70 y). In total, 34 KTRs (1.1%) were diagnosed with PCa during follow-up. The incidence of PCa was 1126/100 000 male KTRs compared with 160/100 000 male nonrecipients in Ireland (P = .01).5,7 The relevant patient demographics of KTRs with PCa are shown in Table 1. Thirty-one patients underwent deceased-donor kidney transplant and 3 underwent related living-donor kidney transplant. Prostate cancer was diagnosed 109 ± 83 months (range, 7-372 mo) after kidney transplant. The mean age at PCa diagnosis was 64 ± 7 years (range, 53-78 y) in KTRs compared with 65 years among the general population (P = .9).^5,7

Fifteen allograft failures occurred during the follow-up period. One renal allograft failed due to chronic rejection 124 months after PCa treatment. The remaining 14 grafts failed due to patient mortality. Mortalities in the KTR group were due to metastatic PCa (n = 5), cardiovascular disease (n = 4), prog-ressive dementia (n = 4), and spontaneous esophageal rupture (n = 1). Mortality occurred 34 ± 40 months (range, 1-140 mo) after PCa diagnosis in KTRs.

Overall patient survival
Overall survival rates at 1, 3, and 5 years for KTRs diagnosed with PCa between 2000 and 2005 were 100%, 93%, and 80% (Figure 1). Between 2000 and 2005, overall survival rates at 1, 3, and 5 years in Irish males diagnosed with PCa were 98%, 90%, and 78%.5,7 We observed no significant differences in overall survival rate for PCa at 5 years between groups diagnosed from 2000 to 2005 (P = .9).

Between 2006 and 2011, the 1-, 3-, and 5-year overall survival rates for KTRs diagnosed with PCa were 98%, 80%, and 77% (Figure 1). In Irish males diagnosed with PCa between 2006 and 2011, 1-, 3-, and 5-year overall survival rates were 98%, 79%, and 72%.^5,7 We observed no significant differences in overall survival rate for PCa at 5 years between groups between 2006 and 2011 (P = .8).

Management of prostate cancer in kidney transplant recipients
Management options for KTRs with PCa were discussed at multidisciplinary team meetings with input from consultant urologists, nephrologists, radiation oncologists, medical oncologists, radio-logists, and histopathologists. In total, 18 patients were treated with curative radiotherapy, 2 under-went curative surgery, 8 were treated with androgen deprivation therapy (ADT), and 6 were managed with watchful waiting protocols.

Radiotherapy
Among the 18 patients treated with radiotherapy, 16 underwent external beam radio-therapy (EBRT) and 2 underwent brachytherapy. Prostate-specific antigen levels at diagnosis, Gleason grade, and duration of follow-up are shown in Table 2. External beam radiotherapy consisted of 3-dimensional conformal radiotherapy with a total delivery dose of 74 Gy in 37 fractions delivered 5 times per week. When indicated, ADT consisted of 6 months or 3 years of luteinizing hormone-releasing hormone analog (leuprolide, triptorelin, or goserelin) in combination with radiation therapy. Brachytherapy consisted of transperineal iodine 125 brachytherapy seeds with transrectal ultrasonograph guidance. Brachytherapy with permanent iodine 125 seeds was performed with a prescribed dose of 145 Gy to the prostate. Needles were inserted into the prostate through the perineum under transrectal ultrasonog-raphic imaging control. One patient had alteration to the EBRT delivery method and underwent volume-mediated arc therapy approach due to prostato-megaly (77 cm3) and proximity (ie, < 1 cm) of the transplanted ureter to the enlarged prostate gland on imaging. This patient had an undetectable PSA at his 3-year follow-up appointment. One transplant ureteric stricture occurred 18 months after EBRT and is currently being treated with ureteral stent changes every 6 months.

Surgery
Radical curative surgery was performed in 2 patients. One patient underwent open radical retropubic prostatectomy via a conventional extra-peritoneal approach with early identification and protection of the transplanted ureter for the duration of the procedure. Lymphadenectomy was unilateral and contralateral to the kidney graft. The second patient underwent transperineal prostatectomy without pelvic lymphadenectomy as his relevant past urologic history included 2 previous kidney transplants with allograft failure and he was awaiting a third transplant. A transperineal approach was selected to preserve his remaining retro-peri-toneal space in anticipation of the future transplant. Prostate-specific antigen levels at diagnosis, surgical histopathology, and duration of follow-up of both patients are summarized in Table 2.

Androgen deprivation therapy with or without palliative radiotherapy
Eight patients were treated with ADT with or without palliative radiotherapy. Their characteristics are summarized in Table 3. The age at PCa diagnosis in this cohort was 72 ± 4 years, and PSA was 130 ± 282 ng/dL (range, 8-771 ng/dL). Seven patients were diagnosed with metastatic PCa on presentation. The duration from transplant to PCa diagnosis was 112 ± 52 months (range, 49-218 mo).

Watchful waiting
Six patients underwent watchful waiting with PSA checks every 6 months. All patients undergoing watchful waiting were diagnosed with low-volume Gleason score (3 + 3 = 6). Their relevant demographic characteristics are summarized in Table 4. The mean American Society for Anesthesiologists (ASA) grade was 3.8 ± 1.2, and none required treatment for symptomatic PCa. There were 5 mortalities due to cardiovascular disease (n = 3), spontaneous esop-hageal rupture (n = 1), and progressive dementia (n = 1) after 44 ± 38 months (Table 4).

Discussion

Treatment of PCa in KTRs is challenging due to anatomic and clinical management-related issues, including the immunosuppression protocol, the pelvic location of the renal allograft, and the absence of robust data on the natural history of PCa in this patient cohort.⁸ This retrospective study, in which we report on the incidence, natural history, manage-ment, and outcomes of 34 KTRs with PCa, is the largest series to date on this topic. We also compared characteristics of KTRs with PCa versus a national population with PCa. Our main finding is that PCa treatment in KTRs yielded 5-year overall survival rates similar to the general PCa population. Important secondary findings are that the incidence of PCa is significantly higher among KTRs and that radical radiotherapy and surgery are curative treatment options with low rates of biochemical recurrence for localized disease.

The incidence of PCa in KTRs has not been widely studied, and we noted a 7-fold increased risk of PCa among KTRs compared with the general population. The calculated incidence of PCa in KTRs was 1.1% in our center, which is consistent with other series with incidences ranging from 0.3% to 2% or a 2-5-fold higher incidence in KTRs.^8-10 There is no nationalized screening program for PCa in Ireland; however, PCa screening is routinely performed on all potential transplant recipients and offered at follow-up. In other transplant centers around the world, mass PCa screening in kidney transplant candidates is also routinely performed.^11-13 This systematic use of annual screening by PSA and digital rectal examination among KTRs may partly explain the higher incidence of PCa in KTRs compared with the general population. The median time between renal transplant and PCa diagnosis was approximately 12 years (144 ± 98 mo), suggesting that PCa is not an early event after transplant.

The risk of malignancy among solid-organ transplant recipients is 4 to 5 times greater than in the general population due to transplant-specific risk factors, including chronic long-term immunosup-pression and oncoviruses.^14,15 Specifically, azathioprine and calcineurin inhibitors are associated with an increased risk of cancer and enhanced in vitro and in vivo PCa aggressiveness, respectively.^16-18 Conversely, mycophenolic mofetil and mammalian target of rapamycin inhibitors have been associated with a reduced incidence of malignancies in transplant recipients.^19,20 In our study, most KTRs (76%; n = 26/34) were diagnosed with PCa at an early stage with localized disease compared with 24% (n = 8/34) who had locally advanced and/or metastatic disease at presentation. Pettenati and associates described similar findings in their series, in which 87.5% of KTRs with PCa had localized disease at presentation compared with 12.5% who presented with locally advanced disease, indicating that the risk of aggressive PCa among KTRs is similar to that shown in the general population.⁸

In our series, radiotherapy with transient hor-monal deprivation was the most frequently utilized curative treatment option, resulting in low incidence of biochemical recurrence at follow-up (n = 1/18 [5.5%] after 57 ± 41 mo). Furthermore, toxicity- and radiotherapy-associated complications were low in our cohort. One radiotherapy-associated transplant ureteral stricture and 1 allograft failure occurred 18 months and 18 years, respectively, after treatment. Three-dimensional conformal radiotherapy with transient hormonal deprivation is an established curative treatment option for localized PCa in KTRs.¹⁹ The main objective of this modality is to optimize tumor control while preventing early and late adverse effects.¹⁹ Kidneys are extremely radiosensitive, and obvious concerns related to radiation nephritis and ureteral anastomotic strictures exist in the treatment of KTRs with PCa.¹⁹ In addition, chronic immunosuppressive protocols increase the risk of avascular necrosis in the femoral head, and the addition of hip irradiation may increase its incidence.^19,21

Radical prostatectomy has been described as a safe procedure for KTRs with various techniques reported.^22-24 No clear benefits of one technique over another have been described, and the surgical approach should be guided by surgeon experience and preference. No statistical differences in urinary continence, potency, and overall complication rates have been shown between KTRs with PCa versus nontransplant patients with PCa.^22,25 Positive surgical margins and biochemical recurrence have been recorded in < 20% and 10%, respectively, and cancer-specific survival is almost 100%.^23,26 The presence of the renal allograft in the pelvis necessitates awareness, as its location increases the risk of injury. Technical modifications have been reported, with 1 group suggesting that the blade of the self-retaining retractor be placed above the rectus muscle to avoid unnecessary pressure on the allograft.²⁷ Another modification is cranial mobili-zation of the urinary bladder to protect the transplanted ureter.²⁷

Data are sparse on watchful waiting and treatment of locally advanced/metastatic PCa among KTRs. Management strategies are similar to the general population for metastatic PCa in KTRs. Complete androgenic blockade with hormonal therapy is feasible, as metabolism is hepatic and does not involve the kidneys.¹¹ This ensures that the safety profile for these agents among KTRs is similar to the general population. Importantly, the risk of osteoporosis is increased among KTRs due to long-term corticosteroid therapy.²⁸ Kidney transplant recipients on hormonal therapy for PCa should be monitored clinically and with radiologic imaging on a regular basis.²⁸ We considered watchful waiting appropriate in 6 patients with low-risk PCa as no cases of rapid PCa progression in low-risk patients have previously been described. The ASA grade in this subgroup was 3.8 ± 1.2, and there were 5 mortalities due to associated medical comorbidities after 44 ± 38 months.

Limitations of the present study are that it is a single center, retrospective analysis of a prospectively maintained database. However, our study was a comprehensive follow-up of all KTRs diagnosed and treated for PCa over a prolonged period, with no patients lost to follow-up.

Conclusions

The incidence of PCa is significantly higher among KTRs compared with nontransplant patients with PCa, with mostly localized disease at diagnosis. Despite challenges with chronic immunosuppression and the anatomic location of the renal allograft, treatment of PCa in KTRs results in similar overall survival rates compared with nontransplant patients. Definitive management guidelines need be developed to increase awareness and to optimize treatment options in this unique patient cohort.

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