The Role of Remote Interactions in Genitourinary Oncology: Implications for Practice Change in Light of the COVID-19 Pandemic

The rapid spread of Coronavirus Disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) has dramatically reshaped the structure of Western society, including on health care delivery.1 While care for patients with cancer has been prioritized in nearly every guideline and recommendation, data suggest that among patients with COVID-19, those with a history of cancer have significantly increased risk of severe outcomes.2 Further, patients most at risk of a severe SARS-CoV-2 phenotype are men and those of advanced age or comorbidity,1,3-6 demographics which mirror the patient population with genitourinary cancers.
Written by: Christopher J.D. Wallis, MD, PhD and Zachary Klaassen, MD, MSc
References:
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Prostate Cancer Survivorship

Physical Side Effects


Urinary Dysfunction

Urinary dysfunction is a side effect of both surgical and radiotherapy (RT) for local treatment of prostate cancer (PCa). Surgical side effects typically include a period of urinary incontinence for several months postoperatively followed by a degree of stress urinary incontinence that may persist for months or even years. RT-induced urinary dysfunction typically manifests as bladder irritability/overactivity either during treatment or shortly thereafter. Longer-term urinary dysfunction issues after RT may include urethral strictures necessitating periodic interventions and/or catheterization.

The ProtecT trial randomized 1,643 men from 1999 to 2009 to undergoing either active monitoring (n=545), surgery (n=553), or RT (n=545), finding that at a median 10 years of follow-up, PCa-specific mortality was low irrespective of treatment.2 As part of this trial, patient-reported outcomes were collected and have now become one of the benchmarks for counseling patients with regards to long-term side effects of treatment for localized PCa treatment.3 Questionnaires were completed at the time of diagnosis, at 6 and 12 months after randomization, and annually thereafter. Patients completed validated measures that assessed urinary, bowel, and sexual function and specific effects on quality of life, anxiety, and depression, and general health. The rate of questionnaire completion during follow-up was outstanding at >85% for most measures. Regarding urinary dysfunction, radical prostatectomy (RP) had the greatest negative effect on urinary continence, and although there was some recovery over time, these patients remained worse throughout follow-up compared to patients undergoing active monitoring or RT. Interestingly, RT had little effect on urinary incontinence, and there was a gradual decrease in urinary function over time for the men undergoing active monitoring. Urinary voiding and nocturia were worse in the radiotherapy group at 6 months but then mostly recovered and were similar to the other groups after 12 months. Urinary incontinence has been cited as being the most important factor for decision regret among receiving local therapy for PCa and may be incompletely explained/discussed with ~80% of patients prior to undergoing treatment.4

Sexual Dysfunction

Similar to urinary dysfunction, sexual dysfunction is a common side effect of localized therapy for PCa. Patients undergoing RP will suffer a degree of sexual dysfunction in the immediate postoperative period with a degree of recovering over 12-24 months after surgery. Many studies have been published assessing predictors of postoperative recovery of sexual function, commonly highlighting younger age and adequate function pre-operatively as predictors of post-operative recovery. Men undergoing RT, similar to urinary dysfunction, will not notice an immediate effect on sexual function during the treatment phase, but generally, suffer sexual dysfunction in the years post-radiation.

In the ProtecT trial, RP incurred the greatest degree of sexual dysfunction among all three treatment arms, with some recovery of function over time.3 The negative effect of RT on sexual function was greatest at 6 months, but sexual function then recovered somewhat and was stable thereafter. Sexual dysfunction also declined in the active monitoring group over time.

Primarily secondary to the sexual side effects of localized treatment for PCa, many cancer centers now have fellowship-trained experts that see these patients concomitantly with the oncologist. There are a variety of treatment options offered, including oral PDE-5 inhibitors (sildenafil, tadalafil, etc.), intracavernosal injection therapy, and penile prosthetics.

Bowel Dysfunction

Bowel dysfunction is typically low for patients undergoing RP or active surveillance (AS) but may be a detrimental side effect among men undergoing RT. In the ProtecT trial, bowel function was worse in the RT group at 6 months than in the other groups but then recovered somewhat, except for the increasing frequency of bloody stools; bowel function was unchanged in the active monitoring and RP groups.3

Bowel dysfunction and rectal toxicity has improved with the recent FDA approval of hydrogel rectal spacers. Prior to RT, patients may have a hydrogel rectal spacer (SpaceOAR®) placed in a transperineal fashion in the fat between the rectum and Denonvilliers' fascia. In the pivotal clinical trial assessing hydrogel spacers, 114 patients were enrolled between 2010 and 2011 with 54 patients selected for a hydrogel injection before the beginning of RT.5 Patients were surveyed at various time-points with the EPIC PCa questionnaire – among patients treated with a hydrogel spacer, mean bowel function and bother score changes of >5 points in comparison with baseline levels were found only at the end of RT (10-15 points; p < 0.01). Mean bowel bother score changes of 21 points at the end of RT, 8 points at 2 months, 7 points at 17 months, and 6 points at 63 months after RT were found for patients treated without a spacer. These bowel quality of life results have given hydrogel spacers an option among patients considering RT.

Other health-related effects

There is evidence that both RT and androgen deprivation therapy (ADT) may contribute to the development of coronary heart disease, sudden cardiac death, myocardial infarction, and skeletal-related events such as fracture.6

Psychological Side Effects

Depression and Anxiety

Depression is the most common psychiatric comorbidity among cancer patients, including patients with PCa. Ravi et al.7 previously utilized the SEER-Medicare database to assess the burden of mental health issues (anxiety, major depressive disorder, suicide) in patients with localized PCa. Among 50,586 men >65 years of age without a diagnosis of mental illness, 20.4% of men developed a mental illness with a median 55-month follow-up. Interestingly, patients undergoing WW (29.7%) and RT (29.0%) had a significantly increased incidence of mental illness compared to patients undergoing RP (22.6%; p<0.001). A systematic review of depression and anxiety in patients with PCa identified 27 articles comprising 4,494 patients.8 The meta-analysis of prevalence rates identified pretreatment prevalence of depression of 17.27% (95% confidence interval (CI) 15.06%-19.72%), on-treatment prevalence of 14.70% (95% CI 15.06%-19.72%) and post-treatment prevalence of 18.44% (95% CI 15.18%-22.22%). For anxiety, pretreatment prevalence was 27.04% (95% CI 24.26%-30.01%), on-treatment was 15.09% (95% CI 12.15%-18.60%) and post-treatment was 18.49% (95% CI 13.81%-24.31%). For patients undergoing AS, nearly one-third of patients (29%) report cancer-specific anxiety in the year following diagnosis.9 Interestingly, over time, this anxiety decreased significantly.

There is also increasing evidence that ADT for locally advanced and metastatic PCa is associated with depression. A study from 2016 using SEER-Medicare data found that men that received ADT, compared with patients who did not receive ADT, had higher 3-year cumulative incidences of depression (7.1% v 5.2), inpatient psychiatric treatment (2.8% v 1.9%), and outpatient psychiatric treatment (3.4% v 2.5%).10 Furthermore, the risk of depression increased with the duration of ADT, from 12% with ≤ 6 months of treatment, 26% with 7 to 11 months of treatment, to 37% with ≥ 12 months of treatment. A recent meta-analysis of 18 studies among 168,756 men found that ADT use conferred a 41% increased risk of depression (RR 1.41, 95%CI 1.18-1.70).11 These results were consistent when limiting the analysis to studies in localized disease (relative risk (RR) 1.85, 95%CI 1.20-2.85). Interestingly, this analysis did not find an association for continuous ADT with depression risk compared to intermittent ADT (RR 1.00, 95%CI 0.50-1.99).

Suicidal Risk

Patients with PCa have been shown to be at increased risk of suicide across several population-level studies. In a SEER analysis assessing suicide risk among patients with genitourinary malignancies from 1988-2010, Klaassen et al.12 found an age-adjusted standardized mortality ratio (SMR) of 1.37 for patients with PCa (95%CI, 0.99-1.86) Increasing age, metastatic disease and Caucasian race were risk factors for suicide among these patients. Interestingly, even patients >15 years after diagnosis were at increased risk of suicide compared to the general population (SMR 1.84, 95%CI 1.39-2.41). In an assessment of PCa suicidal risk compared to individuals with other malignancies, Dalela et al.13 found that risk of suicidal death was no different in men with PCa (1,165 [0.2%]) compared to men with other cancers (2,232 [0.2%]), However, within the first year of diagnosis, men with PCa had an increased risk of suicide (absolute risk reduction (ARR) 3.98, 95% CI 3.02-5.23 0-3 months after diagnosis). Furthermore, men with non-metastatic PCa who were Caucasian, uninsured, or recommended but did not receive treatment (hazard ratio (HR) vs treated 1.44, 95%CI 1.20-1.72) were at increased risk of suicidal death.

A meta-analysis of observational studies assessing incidence and risk factors of suicide after PCa diagnosis was recently published.14 This study included 8 observational studies involving 1,281,393 men diagnosed with PCa and 842,294 matched PCa-free men. Guo et al. found an overall increased relative risk of suicide of 2.01 (95% CI 1.52-2.64) among men diagnosed with PCa compared with those without PCa during the first year after diagnosis, particularly during the first 6 months after diagnosis (RR   2.24, 95%CI 1.77-2.85). Additionally, PCa patients were at an increased risk of suicide among men aged 75 years or older (RR  1.51, 95% CI 1.04-2.18) and for those treated with ADT (RR  1.80, 95% CI 1.54-2.12).

Until recently, all population-level studies assessing risk of suicide among PCa patients have not accounted for psychiatric comorbidities at the time of diagnosis. This is important, considering that being unable to adjust for psychiatric comorbidities makes it impossible to assess the true risk associated with a PCa diagnosis on suicidal risk. At the AUA 2019 annual meeting, Klaassen et al.15 presented data assessing all residents of Ontario, Canada diagnosed with either prostate, bladder or kidney cancer (1997-2014). Each patient was assigned a psychiatric utilization gradient (PUG) score in the five years prior to cancer diagnosis: 0 (none), 1 (outpatient), 2 (emergency department), 3 (hospital admission). Non-cancer controls were matched 4:1 to cancer patients based on sociodemographic variables and a marginal cause-specific hazard model was used to assess the effect of cancer on the risk of suicidal death. Among 191,068 patients included (137,699 PCa, 29,884 bladder cancer, 23,485 kidney cancer), 109,154 (57.1%) were PUG score 0, 79,553 (41.6%) PUG score 1, 1,596 (0.84%) PUG score 2, and 765 (0.40%) PUG score 3. Patients with genitourinary cancer had a higher risk of dying of suicide compared to controls (HR 1.16, 95%CI 1.00-1.36). Specifically, among individuals with PUG score 0, those with cancer were significantly more likely to die of suicide compared to patients without cancer (HR 1.39, 95%CI 1.12-1.74).

Guideline Recommendations

The Commission on Cancer requires cancer programs to develop and implement processes to monitor formation and dissemination of a survivorship care plan for all cancer patients with stage I-III disease treated with curative intent, and to have this plan in place within 1-year of diagnosis of cancer and no later than 6 months after completing adjuvant therapy.16 Guideline recommendations for PCa survivorship have primarily been driven by the American Cancer Society (ACS) and the American Society of Clinical Oncology (ASCO). The ACS noted in their 2014 guideline that survivorship should promote comprehensive follow-up care and optimal health and quality of life for the post-treatment PCa survivor.17 The guidelines also address health promotion, surveillance for PCa recurrence, screening for second primary cancers, long-term and late effects assessment and management, psychosocial issues, and care coordination among the oncology team, primary care clinicians, and non-oncology specialists. Subsequently, the ASCO Endorsement Panel reviewed the ACS guidelines, endorsing these guidelines with the following recommendations:18

• Measure PSA level every 6 to 12 months for the first 5 years and then annually, considering more frequent evaluation in men at high risk for recurrence and in candidates for salvage therapy. 

• Refer survivors with elevated or increasing PSA levels back to their primary treating physician for evaluation and management.

• Adhere to ACS guidelines for the early detection of cancer.

• Assess and manage physical and psychosocial effects of PCa and its treatment.

• Annually assess for the presence of long-term or late effects of PCa and its treatment.

Screening Measures

There are several screening tools to assess for quality of life, depression and suicidal risk. A study from 2017 assessed differences in the scores, relative severity and major depressive disorder from three standardized self-report scales for depression in PCa patients [The Hospital Anxiety and Depression Scale Depression subscale (HADS-D), the Self-rating Depression Scale (SDS) and the Patient Health Questionnaire (PHQ-9) for depression].19 Among 138 PCa patients, despite significant correlations between the total scores from the three scales, severity classification differed across the three scales. Furthermore, there was considerable underestimation of depression by the HADS-D compared to the PHQ-9 and a similar tendency for the SDS. This study highlights that scale construction and depression items included can produce different results across scales, making inter-study comparisons difficult. Despite these findings, we recommend that at minimum oncologists should be using at least one depression index to assess patient well-being at each clinic visit.

In addition to the aforementioned HADS-D, SDS, and PHQ-9 metrics, the National Comprehensive Cancer Network (NCCN) provides a guideline for identifying and explaining risk factors in patients with cancer, in addition to providing a “distress thermometer”. The NCCN defines distress, in the setting of cancer, as a multifactorial emotional experience of a psychological, social, and/or spiritual nature that may interfere with the ability to cope effectively with the diagnosis.20 Distress can range from sadness and fear to more disabling symptoms such as anxiety and depression. Furthermore, the time periods at which patients are at increased vulnerability begin with the realization of a suspicious symptom, all the way through to failure/disease recurrence and near the end of life. The NCCN recommends screening all patients for distress to recognize, monitor, and treat patients effectively.20

Previous work has also suggested that screening for depression and erectile dysfunction may be a way to decrease suicidal risk among PCa patients.21 A proposed algorithm allows for an initial evaluation with the EPIC-CP and PHQ-9 tools to assess for health-related quality of life and depression, respectively. If the EPIC-CP or PHQ-9 are negative for depression or erectile dysfunction, these tools should still be used at each visit to regularly evaluate patients. If EPIC-CP or PHQ-9 suggest problems with depression or erectile dysfunction, then an 8-question suicidal ideation questionnaire (adapted from Recklitis et al.22) should be completed. If the suicidal ideation questionnaire demonstrates any level of suicidal ideation, clinicians should make an urgent referral for psychiatric evaluation. This is particularly true when the patient has the concomitant high-risk suicidal risk profile of being elderly, white, single, or with high-risk or disease progression. Given that, at maximum, the patient must answer a 27-point composite questionnaire, this should be feasible in the busy clinical setting and can be provided to the patient at appointment check-in and completed in the waiting room before the physician-patient encounter. Regardless of the results from these screening tools, if any member of the healthcare team has an index of suspicion for suicidal ideation, the physician should immediately make a referral for psychiatric evaluation.

Conclusions

With nearly 3 million men in the United States living with PCa, survivorship programs are now mandated by the Commission on Cancer and play an integral role in health and well-being of men with PCa. In addition to the physical side effects of treatment that should be addressed at each clinic visit, there are crucial psychiatric side effects, including depression, anxiety, and suicidal ideation that should be screened for and recognized by all members of the healthcare team.

Published Date: December 2019
Written by: Zachary Klaassen, MD, MSc and Christopher J.D. Wallis, MD, PhD
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17. Skolarus TA, Wolf AM, Erb NL, et al. American Cancer Society prostate cancer survivorship care guidelines. CA Cancer J Clin. 2014;64(4):225-249.
18. Resnick MJ, Lacchetti C, Bergman J, et al. Prostate cancer survivorship care guideline: American Society of Clinical Oncology Clinical Practice Guideline endorsement. J Clin Oncol. 2015;33(9):1078-1085.
19. Sharpley CF, Bitsika V, Christie DR, Hunter MS. Measuring depression in prostate cancer patients: does the scale used make a difference? Eur J Cancer Care (Engl). 2017;26(1).
20. National Comprehensive Cancer N. Distress management. Clinical practice guidelines. J Natl Compr Canc Netw. 2003;1(3):344-374.
21. Klaassen Z, Arora K, Wilson SN, et al. Decreasing suicide risk among patients with prostate cancer: Implications for depression, erectile dysfunction, and suicidal ideation screening. Urol Oncol. 2018;36(2):60-66.
22. Recklitis CJ, Zhou ES, Zwemer EK, Hu JC, Kantoff PW. Suicidal ideation in prostate cancer survivors: understanding the role of physical and psychological health outcomes. Cancer. 2014;120(21):3393-3400.

PARP Inhibitors in Prostate Cancer

Prostate cancer is a clinically heterogeneous disease with many patients having an indolent course requiring no interventions and others who either present with or progress to metastasis. While underlying dominant driving mutations are not widespread, there have been a number of key genomic mutations that have been consistently identified in prostate cancer patients, across the disease spectrum including gene fusion/chromosomal rearrangements (TMPRSS2-ERG), androgen receptor (AR) amplification, inactivation of tumor suppressor genes (PTEN/PI3-K/AKT/mTOR, TP53, Rb1) and oncogene activation (c-MYC, RAS-RAF).1
Written by: Christopher J.D. Wallis, MD, PhD and Zachary Klaassen, MD, MSc
References:
  1. Rubin MA, Maher CA, Chinnaiyan AM. Common gene rearrangements in prostate cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29(27):3659-3668.
  2. Kunkel TA, Erie DA. DNA mismatch repair. Annu Rev Biochem. 2005;74:681-710.
  3. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. The New England journal of medicine. 2016;375(5):443-453.
  4. Castro E, Romero-Laorden N, Del Pozo A, et al. PROREPAIR-B: A Prospective Cohort Study of the Impact of Germline DNA Repair Mutations on the Outcomes of Patients With Metastatic Castration-Resistant Prostate Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2019;37(6):490-503.
  5. Nicolosi P, Ledet E, Yang S, et al. Prevalence of Germline Variants in Prostate Cancer and Implications for Current Genetic Testing Guidelines. JAMA Oncol. 2019;5(4):523-528.
  6. Dantzer F, de La Rubia G, Menissier-De Murcia J, Hostomsky Z, de Murcia G, Schreiber V. Base excision repair is impaired in mammalian cells lacking Poly(ADP-ribose) polymerase-1. Biochemistry. 2000;39(25):7559-7569.
  7. McCabe N, Turner NC, Lord CJ, et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res. 2006;66(16):8109-8115.
  8. Gudmundsdottir K, Ashworth A. The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability. Oncogene. 2006;25(43):5864-5874.
  9. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917-921.
  10. Ashworth A. A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J Clin Oncol. 2008;26(22):3785-3790.
  11. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361(2):123-134.
  12. Mateo J, Carreira S, Sandhu S, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. The New England journal of medicine. 2015;373(18):1697-1708.
  13. Mateo J, Porta N, McGovern U, et al. TOPARP-B: A phase II randomized trial of the poly(ADP)-ribose polymerase (PARP) inhibitor olaparib for metastatic castration resistant prostate cancers (mCRPC) with DNA damage repair (DDR) alterations. J Clin Oncol. 2019;37(15_suppl):5005.
  14. de Bono J, Mateo J, Fizazi K, et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. The New England journal of medicine. 2020.
  15. de Wit R, de Bono J, Sternberg CN, et al. Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer. The New England journal of medicine. 2019;381(26):2506-2518.
  16. Clarke N, Wiechno P, Alekseev B, et al. Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial. The lancet oncology. 2018;19(7):975-986.
  17. Abida W, Bryce AH, Vogelzang N, et al. Preliminary Results From TRITON2: A Phase II Study of Rucaparib in Patients with mCRPC Associated with Homologous Recombination Repair Gene Alterations. Ann Oncol. 2018;29(suppl_8):viii271.
  18. Smith MR, Sandhu S, Kelly WK, et al. Phase II study of niraparib in patients with metastatic castration-resistant prostate cancer (mCRPC) and biallelic DNA-repair gene defects (DRD): Preliminary results of GALAHAD. J Clin Oncol. 2019;37(7_suppl):202.
  19. Hussain M, Daignault-Newton S, Twardowski PW, et al. Targeting Androgen Receptor and DNA Repair in Metastatic Castration-Resistant Prostate Cancer: Results From NCI 9012. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2018;36(10):991-999.
  20. Hussain M, Carducci MA, Slovin S, et al. Targeting DNA repair with combination veliparib (ABT-888) and temozolomide in patients with metastatic castration-resistant prostate cancer. Invest New Drugs. 2014;32(5):904-912.
  21. Yu EY, Massard C, Retz M, et al. Keynote-365 cohort a: Pembrolizumab (pembro) plus olaparib in docetaxel-pretreated patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC). J Clin Oncol. 2019;37(7_suppl):145.

The Current Status of Immunotherapy for Prostate Cancer

The Prostate Cancer Immune Microenvironment

The microenvironment associated with prostate cancer includes low cytolytic activity of natural killer (NK) cells,5 high secretion of TGF-beta by prostate tissue (which inhibits NK and lymphocyte function),6 and recruitment of T regulatory cells that down-regulate antitumor immunity.7 As such, the prostate cancer microenvironment has been described as an immunosuppressive state. Furthermore, based on the chronicity of the prostate cancer disease spectrum, the immune microenvironment is likely dynamic, with changes over time/clinical states and with treatment exposure.8 For example, there are increased tumor-infiltrating lymphocytes in the prostate bed following androgen deprivation therapy,9 and higher levels of PD-1 ligand and PD-L2 expression on the surface of enzalutamide-treated prostate cancer cells.10 Several aspects make prostate cancer attractive for immunotherapy-based treatment options, including a high-level of tumor-associated antigens such as prostate-specific antigen (PSA), prostate acid phosphatase (PAP), and prostate-specific membrane antigen (PSMA).

Cell-based vaccines

Cell-based vaccines consist of whole cells that are modified in order to induce anti-tumor immune responses. Sipuleucel-T is an autologous vaccine processed following peripheral dendritic cell collection via leukapheresis. This is then incubated with GCS-F and PAP protein, followed by reinfusion into the patient (after a 36-44 hour period) in order to generate a PAP-specific CD4+ and CD8+ T cell response.11,12

Sipuleucel-T was FDA approved based on results of the Phase III IMPACT clinical trial.1 This trial enrolled 512 patients with mCRPC who had asymptomatic disease/minimally symptomatic with no visceral metastases, randomizing men to three infusions of sipuleucel-T (n=341) or placebo (n=171). The IMPACT trial noted a 4.1-month improvement in overall survival (OS) for those taking sipuleucel-T compared to placebo and a 22% reduction in risk of death. There was no difference between the groups with regards to objective disease progression or PSA response (secondary endpoints). An assessment of safety profile for patients in this study found that the treatment was overall well tolerated with minimal concern for severe adverse events.13 Furthermore, immunologic assessment showed that patients with high antibody titers against PA2024 benefited the most from treatment, noting longer survival.1 Despite the results and safety profile of IMPACT, reported nearly a decade ago, the use of sipuleucel-T has not been widely adopted primarily due to the lack of cost-effectiveness and the infrastructure required to administer this treatment.

Vector-based vaccines

Vector-based vaccines consist of genetically engineered nucleic acids that encode specific tumor-associated antigens transmitted by vectors such as bacterial plasmids or viruses. DNA-based vaccines can be incorporated by host cells and generate an immune response to recruiting antigen-presenting cells. pTVG-HP is a DNA plasmid vector vaccine that encodes PAP protein. pTVG-HP has been tested in the non-metastatic CRPC setting, demonstrating increased PSA doubling time from 6.5 months to 9.3 months after one year of treatment.14

PROSTVAC is a PSA-target pox-virus-based vaccine. PROSTVAC was tested in a Phase II study of 125 patients with minimally symptomatic mCRPC who were randomized to receive the vaccine or placebo.15 Although the study was negative for its primary endpoint of progression-free survival (PFS), OS after 3 years of follow-up was significantly increased by 8.5 months (25.1 vs 16.6 months; HR 0.56; p=0.0061).

PROSTVAC was subsequently tested in a Phase III trial that reported results earlier this year.16 Patients were randomly assigned to PROSTVAC (n = 432), PROSTVAC plus granulocyte-macrophage colony-stimulating (GMCS) factor (n = 432), or placebo (n = 433), stratified by PSA (< 50 ng/mL vs. >= 50 ng/mL) and lactate dehydrogenase (< 200 vs >= 200 U/L). The primary endpoint for this trial was OS, and secondary endpoints were patients alive without events (AWE): radiographic progression, pain progression, chemotherapy initiation, or death at 6 months. Unfortunately, neither active treatment had an effect on median OS: (i) PROSTVAC: 34.4 months, hazard ratio (HR) 1.01, 95% confidence interval (CI) 0.84-1.20 (ii) PROSTVAC plus GMCS factor: 33.2 months, HR 1.02, 95% CI 0.86-1.22 (iii) placebo: 34.3 months. Furthermore, AWE at 6 months was similar between the arms. Based on these results, the authors noted that focus is currently ongoing for combination therapies.

DCVAC/PCa is an autologous dendritic cell vaccine derived from mononuclear cells that are pulsed with killed prostate cancer cells. In a Phase I/II trial, there were 25 men with mCRPC that received DCVAC/PCa plus docetaxel, demonstrating good tolerability and a median OS of 19 months.17 Currently, there is a Phase III (VIABLE) trial of DCVAC/PCa ongoing, which began accrual in 2014, with a target of 1,170 patients and planned completion date in 2020.

Immune Checkpoint inhibitors

Checkpoint inhibitors are antibodies that target molecules, such as cytotoxic T-lymphocyte protein 4 (CTLA-4) or PD-1 and its ligand PD-L1. Among men with mCRPC, ipilimumab was tested in the Phase III for those who had progressed on docetaxel chemotherapy, randomizing 799 patients to ipilimumab or placebo after bone-directed radiotherapy.18 The primary endpoint was OS, with no difference between the groups (ipilimumab 11.2 months vs placebo 10 months; HR 0.85, p=0.053); however, there was a small benefit in PFS favoring ipilimumab (4.0 vs 3.1 months; HR 0.70, p < 0.0001). More recently, Beer et al.19 reported findings of another Phase III trial randomizing 602 patients (2:1) with metastatic chemotherapy-naïve CRPC to ipilimumab vs placebo. Similar to the post-docetaxel patients, there was no difference in OS between the groups (HR 1.11, 95% CI 0.88-1.39), however men receiving ipilimumab had improved PFS (5.6 months vs 3.8; HR 0.67, 95% CI 0.55-0.81) compared to those receiving placebo.

Pembrolizumab has recently moved into the mCRPC arena, receiving FDA approval in a tumor agnostic indication for MSI-high (MSI-H) mutation CRPC patients in 2017. A study from the Memorial Sloan Kettering Cancer Center assessed the prevalence of MSI-H/dMMR prostate cancer among 1,033 patients treated at their institution,20 finding that 32 (3.1%) had MSI-H/dMMR disease. This included 23 patients (2.2%) that had tumors with high MSIsensor scores, and 7 of the 32 MSI-H/dMMR patients (21.9%) with pathogenic germline mutation in a Lynch syndrome-associated gene. Eleven patients with MSI-H/dMMR CRPC received anti-PD-1/PD-L1 therapy and six of these had a greater than 50% decline in PSA levels. Based on these data, experts in the field of advanced prostate cancer feel that every mCRPC patient should be tested for MSI-H status and potential pembrolizumab eligibility.

The KEYNOTE-028 study was a trial of pembrolizumab in advanced solid tumors among patients with PD-1 expression ≥1% of tumor or stromal cells. Among 245 men screened, there were 35 PD-1% (14.3%) and 23 patients who enrolled.21 There were four partial responses, for an objective response rate of 17.4% and 8 of 23 (34.8%) patients had stable disease. Median duration of response was 13.5  months, and median PFS and OS were 3.5 and 7.9 months, respectively. Furthermore, the 6-month PFS and OS rates were 34.8% and 73.4%, respectively. Recently, off-label use of pembrolizumab among a heavily pre-treated population of mCRPC patients has recently been reported. At the 2019 ASCO GU meeting, Tucker and colleagues presented data on 51 patients, 86% of which had received three or more prior lines of therapy. Most patients had previously received abiraterone (88%), docetaxel (86%), enzalutamide (80%), and sipuleucel-T (74%). Among these patients, 16% had a >50% confirmed PSA decline with pembrolizumab, with 8% having >90% PSA decline. Fifty-nine percent of men were treated with some form of concurrent therapy along with pembrolizumab, most commonly enzalutamide (47%).

At the 2019 ASCO GU meeting, results of the Phase II KEYNOTE-650 were also presented. This trial tested the combination of nivolumab plus ipilimumab for men with mCRPC. There were two cohorts for this study: cohort 1 – asymptomatic or minimally symptomatic, who had progressed after at least 1 second generation hormone therapy with no prior chemotherapy, and cohort 2 – progression after chemotherapy. Overall response rates were 26% in cohort 1 and 10% in cohort 2, including two patients in each cohort who had a complete response. Median time to response was approximately two months. PSA response rate was 18% in cohort 1 and 10% in cohort 2.

Future Directions

Unlike many other tumor sites, to date, there has not been robust data to demonstrate a large role for immunotherapy in patients with mCRPC. However, there are several potential ways to increase immunotherapy response with the goal of improving the outcomes of immunotherapy for prostate cancer: (i) combination therapy, (ii) immune modulation, (iii) biomarkers for improving patient selection.

Options for combination therapies:

1) Combination of immunotherapies: multiple vaccines, vaccine plus an immune checkpoint inhibitor, or an immunocytokine plus an immune checkpoint inhibitor. KEYNOTE-650 combining nivolumab plus ipilimumab is an example of improved efficacy among patients receiving combination therapy.

2) Combinations with therapies to capitalize on immunologic synergy: these studies assess the effect of the addition of other accepted treatments such enzalutamide, poly ADP ribose polymerase PARP inhibitors, radium-223, and docetaxel to immunotherapy regimens.

3) Given the changing microenvironment of prostate cancer across disease states, beginning combination immunotherapy earlier (castration-sensitive) may improve the immunotherapeutic benefit.

There are several options of immunomodulatory agents that target the tumor microenvironment to improve immunotherapy efficacy. Docetaxel has been proven to induce immunogenic modulations, such as increasing expression of ICAM-1, MUC-1, and MHC class 1 molecules.22 Additionally, tasquinimod is an immunomodulatory agent that blocks S100A9, a key regulatory molecule of myeloid cells. In a Phase II trial of 206 asymptomatic chemotherapy-naïve mCRPC patients randomized to tasquinimod vs placebo, men receiving tasquinimod had significantly improved disease progression (7.6 vs 3.3 months, p = 0.0042).23 Unfortunately, a Phase III trial assessing tasquinimod did not improve OS (21.3 for tasquinimod vs 24 months for placebo, HR 1.10, p=0.25), however, there was an improvement in radiographic PFS (7.0 months vs 4.4 months, HR 0.64, p = 0.001).24

Biomarkers continue to be an active area of research, not just for the selection of appropriate patients for immunotherapy, but also for other treatment regimens for advanced prostate cancer (ie. BRCA status for selecting patients for PARP inhibitors).

As follows is a summary of several of the current biomarkers as related to immunotherapy and prostate cancer (adapted from Maia and Hansen8):

current biomarkers as related to immunotherapy and prostate cancer

As follows is a summary of ongoing, recruiting phase III trial assessing immunotherapy in prostate cancer:

ongoing recruiting phase III trial assessing immunotherapy in prostate cancer

Conclusion 

To date, immunotherapy in prostate cancer has been less successful than other cancer types, with only Sipuleucel-T demonstrating an OS advantage of 4.1 months in a Phase III trial. Given the plethora of other treatment options, Sipuleucel-T is uncommonly used. However, with improved combination therapy, immunomodulation and biomarkers in addition to ongoing Phase III trials, there are additional assessments and results in upcoming that may improve the immunotherapy landscape and add to the armamentarium of treatment options for men with advanced prostate cancer.

Published Date: November 2019

Written by: Zachary Klaassen, MD, MSc
References: 1. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411-422.
2. Ryan CJ, Smith MR, Fizazi K, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015;16(2):152-160.
3. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376(9747):1147-1154.
4. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.
5. Pasero C, Gravis G, Guerin M, et al. Inherent and Tumor-Driven Immune Tolerance in the Prostate Microenvironment Impairs Natural Killer Cell Antitumor Activity. Cancer Res. 2016;76(8):2153-2165.
6. Flavell RA, Sanjabi S, Wrzesinski SH, Licona-Limon P. The polarization of immune cells in the tumour environment by TGFbeta. Nat Rev Immunol. 2010;10(8):554-567.
7. Sfanos KS, Bruno TC, Maris CH, et al. Phenotypic analysis of prostate-infiltrating lymphocytes reveals TH17 and Treg skewing. Clin Cancer Res. 2008;14(11):3254-3261.
8. Maia MC, Hansen AR. A comprehensive review of immunotherapies in prostate cancer. Crit Rev Oncol Hematol. 2017;113:292-303.
9. Thoma C. Prostate cancer: Towards effective combination of ADT and immunotherapy. Nat Rev Urol. 2016;13(6):300.
10. Bishop JL, Sio A, Angeles A, et al. PD-L1 is highly expressed in Enzalutamide resistant prostate cancer. Oncotarget. 2015;6(1):234-242.
11. Drake CG. Prostate cancer as a model for tumour immunotherapy. Nat Rev Immunol. 2010;10(8):580-593.
12. Ren R, Koti M, Hamilton T, et al. A primer on tumour immunology and prostate cancer immunotherapy. Can Urol Assoc J. 2016;10(1-2):60-65.
13. Hall SJ, Klotz L, Pantuck AJ, et al. Integrated safety data from 4 randomized, double-blind, controlled trials of autologous cellular immunotherapy with sipuleucel-T in patients with prostate cancer. J Urol. 2011;186(3):877-881.
14. McNeel DG, Dunphy EJ, Davies JG, et al. Safety and immunological efficacy of a DNA vaccine encoding prostatic acid phosphatase in patients with stage D0 prostate cancer. J Clin Oncol. 2009;27(25):4047-4054.
15. Kantoff PW, Schuetz TJ, Blumenstein BA, et al. Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol. 2010;28(7):1099-1105.
16. Gulley JL, Borre M, Vogelzang NJ, et al. Phase III Trial of PROSTVAC in Asymptomatic or Minimally Symptomatic Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol. 2019;37(13):1051-1061.
17. Podrazil M, Horvath R, Becht E, et al. Phase I/II clinical trial of dendritic-cell based immunotherapy (DCVAC/PCa) combined with chemotherapy in patients with metastatic, castration-resistant prostate cancer. Oncotarget. 2015;6(20):18192-18205.
18. Kwon ED, Drake CG, Scher HI, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15(7):700-712.
19. Beer TM, Kwon ED, Drake CG, et al. Randomized, Double-Blind, Phase III Trial of Ipilimumab Versus Placebo in Asymptomatic or Minimally Symptomatic Patients With Metastatic Chemotherapy-Naive Castration-Resistant Prostate Cancer. J Clin Oncol. 2017;35(1):40-47.
20. Abida W, Cheng ML, Armenia J, et al. Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade. JAMA Oncol. 2018.
21. Hansen AR, Massard C, Ott PA, et al. Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study. Ann Oncol. 2018;29(8):1807-1813.
22. Hodge JW, Garnett CT, Farsaci B, et al. Chemotherapy-induced immunogenic modulation of tumor cells enhances killing by cytotoxic T lymphocytes and is distinct from immunogenic cell death. Int J Cancer. 2013;133(3):624-636.
23. Pili R, Haggman M, Stadler WM, et al. Phase II randomized, double-blind, placebo-controlled study of tasquinimod in men with minimally symptomatic metastatic castrate-resistant prostate cancer. J Clin Oncol. 2011;29(30):4022-4028.
24. Sternberg C, Armstrong A, Pili R, et al. Randomized, Double-Blind, Placebo-Controlled Phase III Study of Tasquinimod in Men With Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol. 2016;34(22):2636-2643.

The Impact of COVID-19 on Oncology Clinical Trials

Since the beginning of the COVID-19 pandemic in early 2020, the diagnosis, treatment and surveillance of cancer has been transformed globally. The heavy demand for resources, exacerbated by limited excess health system capacity, means that health care systems have become quickly overwhelmed and hospitals have become sources for virus transmission.

Written by: Zachary Klaassen, MD, MSc and Christopher J.D. Wallis, MD, PhD
References:

1. COVID, CDC, and Response Team. "Severe outcomes among patients with coronavirus disease 2019 (COVID-19)—United States, February 12–March 16, 2020." MMWR Morb Mortal Wkly Rep 69, no. 12 (2020): 343-346.
2. Thornton, Jacqui. "Clinical trials suspended in UK to prioritise covid-19 studies and free up staff." BMJ 368 (2020): m1172.
3. Majumdar, Sumit R., Matthew T. Roe, Eric D. Peterson, Anita Y. Chen, W. Brian Gibler, and Paul W. Armstrong. "Better outcomes for patients treated at hospitals that participate in clinical trials." Archives of internal medicine 168, no. 6 (2008): 657-662.
4. Skrutkowska, Myriam, and Charles Weijer. "Do patients with breast cancer participating in clinical trials receive better nursing care?." In Oncology nursing forum, vol. 24, no. 8, pp. 1411-1416. 1997.
5. McDermott, Mary M., and Anne B. Newman. "Preserving clinical trial integrity during the coronavirus pandemic." Jama (2020).
6. Marandino, Laura, Massimo Di Maio, Giuseppe Procopio, Saverio Cinieri, Giordano Domenico Beretta, and Andrea Necchi. "The Shifting Landscape of Genitourinary Oncology During the COVID-19 Pandemic and how Italian Oncologists Reacted: Results from a National Survey." European Urology (2020).
7. Wallis, Christopher JD, Giacomo Novara, Laura Marandino, Axel Bex, Ashish M. Kamat, R. Jeffrey Karnes, Todd M. Morgan et al. "Risks from Deferring Treatment for Genitourinary Cancers: A Collaborative Review to Aid Triage and Management During the COVID-19 Pandemic." European Urology (2020).
8. Segelov, Eva, Hans Prenen, Daphne Day, C. Raina Macintyre, Estelle Mei Jye Foo, Raghib Ali, Quanyi Wang et al. "Impact of the COVID-19 Epidemic on a Pan-Asian Academic Oncology Clinical Trial." JCO global oncology 6 (2020): 585.
9. Wang, Hongkai, Junlong Wu, Yu Wei, Yao Zhu, and Dingwei Ye. "Surgical Volume, Safety, Drug Administration, and Clinical Trials During COVID-19: Single-center Experience in Shanghai, China." European Urology (2020).
10. Waterhouse D, Harvey RD, Hurley P, Levit LA, Klepin HD. "Early Impact of COVID-19 on the Conduct of Oncology Clinical Trials and Long-term Opportunities for Transformation: Findings from an American Society of Clinical Oncology Survey." JCO Oncology Practice. 2020.
11. US Food and Drug Administration. "FDA guidance on conduct of clinical trials of medical products during COVID-19 pandemic: guidance for industry, investigators, and institutional review boards." (2020).
12. Tan, Aaron C., David M. Ashley, and Mustafa Khasraw. "Adapting to a pandemic-conducting oncology trials during the SARS-CoV-2 pandemic." Clinical Cancer Research (2020).
13. Khozin, Sean, and Andrea Coravos. "Decentralized Trials in the Age of Real-World Evidence and Inclusivity in Clinical Investigations." Clinical pharmacology and therapeutics 106, no. 1 (2019): 25-27.
14. Galsky, Matthew D., Mohamed Shahin, Rachel Jia, David R. Shaffer, Kiev Gimpel-Tetra, Che-Kai Tsao, Charles Baker et al. "Telemedicine-enabled clinical trial of metformin in patients with prostate cancer." JCO clinical cancer informatics 1 (2017): 1-10.
15. Borno, Hala T., and Eric J. Small. "Does the COVID-19 outbreak identify a broader need for an urgent transformation of cancer clinical trials research?." Contemporary Clinical Trials 92 (2020).
16. Duley, Lelia, Karen Antman, Joseph Arena, Alvaro Avezum, Mel Blumenthal, Jackie Bosch, Sue Chrolavicius et al. "Specific barriers to the conduct of randomized trials." Clinical Trials 5, no. 1 (2008): 40-48.
17. Uren, Shannon C., Mitchell B. Kirkman, Brad S. Dalton, and John R. Zalcberg. "Reducing clinical trial monitoring resource allocation and costs through remote access to electronic medical records." Journal of oncology practice 9, no. 1 (2013): e13-e16.

Prostate Cancer and Utilization of Multi-Parametric MRI

Over the last decade, imaging for prostate cancer has improved immensely. Specifically, prostate multiparametric MRI (mpMRI) has improved primarily as a result of an increase in magnet strength from 1 to 3-tesla. mpMRI consists of anatomic and functional imaging techniques: anatomic imaging includes T1- and T2-weighted images, and functional imaging includes diffusion-weighted imaging (DWI) and dynamic contrast-enhanced (DCE) sequences. Currently, the recommendation is for a 1.5 tesla MRI with an endorectal coil or a 3-tesla MRI with no endorectal coil.1 

Initial T1-weighted images are performed first to determine if hemorrhage is present in the prostate. As such, most experts recommend waiting 3-8 weeks after a prostate biopsy to decrease artifact associated with hemorrhage from the biopsy.2 Subsequently, T2-weighted images provide anatomic configuration of the prostate gland: the normal peripheral zone appears as areas of high signal intensity, whereas areas of low signal intensity may represent prostate cancer, prostatitis, BPH, etc. T2-weighted images also provide information regarding extraprostatic extension (EPE) or seminal vesical invasion (SVI), which are represented by areas of low signal intensity. DWI assess the diffusion of water within the magnetic field—the closer the cells are together (ie. for a prostate cancer nodule), the lower the motion of water, which leads to a high signal intensity in this phase. The DCE phase is a T1-weighed image with gadolinium-based contrast, which assesses vascular permeability of the prostate over a period of typically 5-10 minutes. Importantly, the combination of T2, DCE, and DWI phases yields both a NPV and PPV of >90%.3


table-1-prostate-cancer-utilization@2x.jpg


The objective of this article is to focus on indications for mpMRI use in the localized prostate cancer setting, specifically exploring its use before prostate biopsy, after a negative biopsy, on active surveillance, and prior to radical prostatectomy for surgical planning purposes.

Before Prostate Biopsy

Until recently, the utilization of mpMRI as a “triage test” prior to transrectal ultrasound (TRUS)-guided prostate biopsy was a contentious topic, relying on single centers suggesting that such an approach may decrease unnecessary biopsies.5,6 However, in 2017, the PROMIS trial provided level 1b evidence for utilizing mpMRI prior to TRUS-guided biopsy among men with elevated PSA.7 PROMIS was a multi-center, paired-cohort study to assess the diagnostic accuracy of mpMRI and TRUS biopsy against a gold-standard reference template mapping biopsy. Men were included (n=576) if they had a PSA <15 ng/ml and no history of the previous biopsy. On mapping biopsy, 71% of men had cancer, including 40% with clinically significant prostate cancer (Gleason score ≥4+3 or maximum cancer length ≥6 mm). For clinically significant disease, mpMRI was more sensitive (93%) than TRUS-biopsy (48%), albeit less specific (41% for mpMRI; 96% for TRUS-biopsy). Based on these data, a triage mpMRI would allow 25% of men to safely avoid a prostate biopsy, while at the same time reducing detection of clinically insignificant prostate cancer. Importantly, secondary to the poor specificity and positive predictive value, this study does not suggest that mpMRI should replace prostate biopsy and that men with suspicious lesions should still have histologic confirmation of prostate cancer.

Shortly after PROMIS was published, PRECISION reported results of their trial which assigned 500 men with a clinical suspicion of prostate cancer who had not previously undergone a prostate biopsy to undergo MRI with or without a targeted biopsy vs standard TRUS-guided biopsy.8 Men in the MRI group underwent a targeted biopsy if there was a suspicion of prostate cancer on imaging and did not undergo a biopsy if the MRI was negative. The primary outcome for this randomized clinical trial was a diagnosis of clinically significant prostate cancer. In the MRI-targeted biopsy group, 28% had a negative MRI and thus no biopsy. Among men undergoing targeted biopsy, 38% had clinically significant cancer, compared to 26% in the TRUS-guided biopsy group (p=0.005). Furthermore, fewer men in the MRI-targeted biopsy group had clinically insignificant prostate cancer compared to the TRUS-guided biopsy group.

Since the publication of these two trials, debate regarding the implementation of mpMRI prior to biopsy has ensued. Detractors have mentioned that the negative predictive value of mpMRI in PROMIS for detecting Gleason grade group ≥2 was only 76%, albeit no grade group ≥3 were missed on mpMRI.7 mpMRI prior to prostate biopsy has already been widely accepted in the UK and Australia where mpMRI is reimbursed in this setting.9 There is evidence to suggest that men with a negative mpMRI should not be biopsied unless caveats such as a strong family history, abnormal digital rectal exam, or BRCA mutation are present. At present, experts have pressed for a new paradigm for prostate cancer detection in which an abnormal mpMRI should have a targeted biopsy performed; if the mpMRI is negative then a routine follow-up protocol should be employed.9 It is noteworthy to mention that widespread dissemination will undoubtedly rely on (i) affordability/reimbursement of mpMRI, (ii) quality of the mpMRI, and (iii) skill of the radiologist.

After Negative Prostate Biopsy

It is generally accepted that men with a history of negative TRUS-guided biopsy and persistently elevated or increasing PSA should undergo a mpMRI prior to consideration of a second (or in some cases third or fourth) prostate biopsy. In a study of 265 patients with a PSA >4.0 ng/ml and one negative TRUS-biopsy mpMRI detected prostate cancer in 41% of men, including 87% with clinically significant prostate cancer.10 

mpMRI has been shown in the previous negative biopsy setting to detect tumors in up to 40% of cases, often in the anterior region of the prostate.11-14 An advantage of mpMRI fusion biopsy in patients with prior negative biopsy is the ability of MRI to identify suspicious lesions in areas not normally sampled by standard TRUS-guided biopsy, specifically the anterior and apical parts of the prostate. Thus, the benefit of fusion biopsy is particularly accentuated in the prior negative biopsy cohort. Furthermore, a study by Kongnyuy et al.15 suggested that there may be racial differences with regards to anterior tumors. In a cohort of 195 African-American men matched 1:1 to white men undergoing mpMRI, 47.7% of African-American men had anterior prostate lesions. Amongst these men, a history of prior negative biopsy was significantly associated with an anterior prostate lesion (OR 1.81, 95%CI 1.03-3.20). Despite an overall higher cancer detection rate among African American than white men, the presence of anterior prostate lesions and lesions harboring clinically significant cancer were not different between races.

On Active Surveillance

Over the last decade, adoption of active surveillance as a management strategy for men with clinically low-risk prostate cancer has appropriately continued to increase. However, until recently, the utilization of mpMRI in active surveillance management has been somewhat discretionary and clinician dependent.16

Earlier this year the European Association of Urology (EAU) released a position statement for active surveillance, which included 10 recommendation statements;17 the 3rd statement assessed “use and timing of MRI in active surveillance.” mpMRI can be used to increase clinically significant cancer detection, thus ensuring men are appropriately included in surveillance regimens and those with potentially threatening disease can have appropriate and timely intervention. The statement recommends that mpMRI can be performed at several time points during active surveillance:

  1. At the time of initial diagnosis – the EAU statement recommends that men diagnosed with a low-risk disease without a prior mpMRI should under a mpMRI prior to enrolment to ensure no significant disease was missed on initial biopsy. In cases of initial targeted mpMRI biopsy, both targeted and systematic biopsies should be performed.17 In addition to the excitement generated by PROMIS 7 and PRECISION,8 a recent systematic review assessed the role of mpMRI among active surveillance patients, noting that a lesion suspicious for prostate cancer was found in nearly two-thirds of men otherwise suitable for surveillance.18
  2. Before confirmatory biopsy – the EAU statement recommends that a mpMRI be performed before the confirmatory biopsy, within 12 months from initial diagnosis, and to include targeted and systematic biopsies.17 The rate of reclassification after targeted biopsies among men on active surveillance without a prior mpMRI may be as high as 22%.18-20 A recent publication assessed the value of serial mpMRI imaging among 111 men on active surveillance with > 1-year of follow-up, noting that among 33 reclassifications after one year, 55% were reclassified on only TRUS-guided biopsy.21 As such, the value of serial mpMRI in active surveillance algorithms remains unclear.
  3. During follow-up – the EAU statement does not support the use of solely using mpMRI instead of repeat biopsy in active surveillance follow-up.17 As mentioned, the use of serial mpMRIs over long-term follow-up is not currently recommended, however it may be used in situations where a targeted lesion is being followed. This is an area of great research interest considering that institutional studies with vast experience with mpMRI suggest that mpMRI supplanting follow-up biopsies is safe and feasible.22  
Last month, the ASIST trial published results of the randomized, multicenter, prospective trial assessing if mpMRI with targeted biopsy could identify a greater proportion of men with grade group ≥2 cancer on confirmatory biopsy compared with systematic biopsies.23 Among 273 men included in the study, 64% in the MRI group had a suspicious region of interest. Unfortunately, no difference was observed in the rate of grade group ≥2 upgrading in the intention to treat or per protocol cohort, grade group ≥2 upgrading within each stratum separately, or grade group ≥3. This trial confirms that there is still a role for TRUS-guided biopsy among active surveillance patients, in addition to tempering the current role for targeted biopsies in this setting.

Before Radical Prostatectomy

With improved mpMRI technology has come an interest in more precise clinical staging of localized prostate cancer, particularly before performing radical prostatectomy. Ultimately, the patient and urologist are concerned about the risk of EPE preoperatively, which dictates the degree of nerve-sparing performed at the time of radical prostatectomy. Somford et al.24 assessed mpMRI images among 183 men to determine the positive and negative predictive values of mpMRI for EPE at radical prostatectomy for different prostate cancer risk groups. The overall prevalence of EPE at radical prostatectomy was 49.7% (24.7% low-risk; 77.1% high-risk) – the overall staging sensitivity was 58.2%, specificity was 89.1%, positive predictive value was 84.1% and a negative predictive value was 68.3%. The positive predictive value was best in the high-risk cohort (88.8%) and a negative predictive value was best in the low-risk cohort (87.7%).

Data regarding whether preoperative imaging influences surgical planning is limited. However, Schiavina et al.25 assessed the impact of mpMRI on preoperative decision making among 137 patients planned for radical prostatectomy who underwent mpMRI. They found that mpMRI changes robotic surgeon’s initial surgical plan with regards to the degree of nerve-sparing in nearly half of patients. Interestingly, there was an equal alteration in surgical planning when considering a more aggressive (to less aggressive) and less aggressive (to more aggressive) preliminary plan. Although the above results for EPE prediction and tailored surgical planning are encouraging, this degree of advanced mpMRI interpretation should be reserved for expert radiologists where sensitivities and specificities for predicting EPE are typically both >80%.26

Conclusions

The improvement of MRI technology and development of mpMRI for prostate imaging is one of the most important technologic advancements in urologic oncology over the past decade. The PROMIS and PRECISION trials have delineated the utility of mpMRI among men considering a prostate biopsy. Likely the most accepted and concrete indication for utilization of mpMRI is in men with a negative prostate biopsy and persistent/increasingly elevated PSA, specifically to enhance the ability to detect previously unsampled (often anterior) tumors. The recent EAU statement on active surveillance has provided much-needed guidance as to when to include mpMRI in the surveillance algorithm; work is still necessary to delineate who benefits from serial mpMRI, particularly after 1 year on active surveillance. Finally, there is increased utilization of mpMRI among patients planned for radical prostatectomy to assess the degree of acceptable nerve sparing without compromising oncologic efficacy, however the high-level of mpMRI interpretation to accurately assess EPE in these instances requires expert radiologic experience.

Published Date: April 16th, 2019
Written by: Zachary Klaassen, MD, MSc
References: 1. Muller BG, Futterer JJ, Gupta RT, Katz A, Kirkham A, Kurhanewicz J, et al. The role of magnetic resonance imaging (MRI) in focal therapy for prostate cancer: recommendations from a consensus panel. BJU Int. 2014;113:218-27.
2. Rosenkrantz AB, Kopec M, Kong X, Melamed J, Dakwar G, Babb JS, et al. Prostate cancer vs. post-biopsy hemorrhage: diagnosis with T2- and diffusion-weighted imaging. J Magn Reson Imaging. 2010;31:1387-94.
3. Abd-Alazeez M, Kirkham A, Ahmed HU, Arya M, Anastasiadis E, Charman SC, et al. Performance of multiparametric MRI in men at risk of prostate cancer before the first biopsy: a paired validating cohort study using template prostate mapping biopsies as the reference standard. Prostate Cancer Prostatic Dis. 2014;17:40-6.
4. Barentsz JO, Weinreb JC, Verma S, Thoeny HC, Tempany CM, Shtern F, et al. Synopsis of the PI-RADS v2 Guidelines for Multiparametric Prostate Magnetic Resonance Imaging and Recommendations for Use. Eur Urol. 2016;69:41-9.
5. Thompson JE, Moses D, Shnier R, Brenner P, Delprado W, Ponsky L, et al. Multiparametric magnetic resonance imaging guided diagnostic biopsy detects significant prostate cancer and could reduce unnecessary biopsies and over detection: a prospective study. J Urol. 2014;192:67-74.
6. Thompson JE, van Leeuwen PJ, Moses D, Shnier R, Brenner P, Delprado W, et al. The Diagnostic Performance of Multiparametric Magnetic Resonance Imaging to Detect Significant Prostate Cancer. J Urol. 2016;195:1428-35.
7. Ahmed HU, El-Shater Bosaily A, Brown LC, Gabe R, Kaplan R, Parmar MK, et al. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet. 2017;389:815-22.
8. Kasivisvanathan V, Rannikko AS, Borghi M, Panebianco V, Mynderse LA, Vaarala MH, et al. MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis. N Engl J Med. 2018;378:1767-77.
9. Nzenza T, Murphy DG. PRECISION delivers on the PROMIS of mpMRI in early detection. Nat Rev Urol. 2018.
10. Hoeks CM, Schouten MG, Bomers JG, Hoogendoorn SP, Hulsbergen-van de Kaa CA, Hambrock T, et al. Three-Tesla magnetic resonance-guided prostate biopsy in men with increased prostate-specific antigen and repeated, negative, random, systematic, transrectal ultrasound biopsies: detection of clinically significant prostate cancers. Eur Urol. 2012;62:902-9.
11. Kirkham AP, Haslam P, Keanie JY, McCafferty I, Padhani AR, Punwani S, et al. Prostate MRI: who, when, and how? Report from a UK consensus meeting. Clin Radiol. 2013;68:1016-23.
12. Lawrentschuk N, Fleshner N. The role of magnetic resonance imaging in targeting prostate cancer in patients with previous negative biopsies and elevated prostate-specific antigen levels. BJU Int. 2009;103:730-3.
13. Hambrock T, Somford DM, Hoeks C, Bouwense SA, Huisman H, Yakar D, et al. Magnetic resonance imaging guided prostate biopsy in men with repeat negative biopsies and increased prostate specific antigen. J Urol. 2010;183:520-7.
14. Zugor V, Kuhn R, Engelhard K, Poth S, Bernat MM, Porres D, et al. The Value of Endorectal Magnetic Resonance Imaging of the Prostate in Improving the Detection of Anterior Prostate Cancer. Anticancer Res. 2016;36:4279-83.
15. Kongnyuy M, Sidana A, George AK, Muthigi A, Iyer A, Fascelli M, et al. The significance of anterior prostate lesions on multiparametric magnetic resonance imaging in African-American men. Urol Oncol. 2016;34:254 e15-21.
16. Scarpato KR, Barocas DA. Use of mpMRI in active surveillance for localized prostate cancer. Urol Oncol. 2016;34:320-5.
17. Briganti A, Fossati N, Catto JWF, Cornford P, Montorsi F, Mottet N, et al. Active Surveillance for Low-risk Prostate Cancer: The European Association of Urology Position in 2018. Eur Urol. 2018;74:357-68.
18. Schoots IG, Petrides N, Giganti F, Bokhorst LP, Rannikko A, Klotz L, et al. Magnetic resonance imaging in active surveillance of prostate cancer: a systematic review. Eur Urol. 2015;67:627-36.
19. Recabal P, Assel M, Sjoberg DD, Lee D, Laudone VP, Touijer K, et al. The Efficacy of Multiparametric Magnetic Resonance Imaging and Magnetic Resonance Imaging Targeted Biopsy in Risk Classification for Patients with Prostate Cancer on Active Surveillance. J Urol. 2016;196:374-81.
20. Pessoa RR, Viana PC, Mattedi RL, Guglielmetti GB, Cordeiro MD, Coelho RF, et al. Value of 3-Tesla multiparametric magnetic resonance imaging and targeted biopsy for improved risk stratification in patients considered for active surveillance. BJU Int. 2017;119:535-42.
21. Hamoen EHJ, Hoeks CMA, Somford DM, van Oort IM, Vergunst H, Oddens JR, et al. Value of Serial Multiparametric Magnetic Resonance Imaging and Magnetic Resonance Imaging-guided Biopsies in Men with Low-risk Prostate Cancer on Active Surveillance After 1 Yr Follow-up. Eur Urol Focus. 2018.
22. Walton Diaz A, Shakir NA, George AK, Rais-Bahrami S, Turkbey B, Rothwax JT, et al. Use of serial multiparametric magnetic resonance imaging in the management of patients with prostate cancer on active surveillance. Urol Oncol. 2015;33:202 e1- e7.
23. Klotz L, Loblaw A, Sugar L, Moussa M, Berman DM, Van der Kwast T, et al. Active Surveillance Magnetic Resonance Imaging Study (ASIST): Results of a Randomized Multicenter Prospective Trial. Eur Urol. 2018.
24. Somford DM, Hamoen EH, Futterer JJ, van Basten JP, Hulsbergen-van de Kaa CA, Vreuls W, et al. The predictive value of endorectal 3 Tesla multiparametric magnetic resonance imaging for extraprostatic extension in patients with low, intermediate and high risk prostate cancer. J Urol. 2013;190:1728-34.
25. Schiavina R, Bianchi L, Borghesi M, Dababneh H, Chessa F, Pultrone CV, et al. MRI Displays the Prostatic Cancer Anatomy and Improves the Bundles Management Before Robot-Assisted Radical Prostatectomy. J Endourol. 2018;32:315-21.
26. Tay KJ, Gupta RT, Brown AF, Silverman RK, Polascik TJ. Defining the Incremental Utility of Prostate Multiparametric Magnetic Resonance Imaging at Standard and Specialized Read in Predicting Extracapsular Extension of Prostate Cancer. Eur Urol. 2016;70:211-3.

Androgen Receptor Signaling in Castration-Resistant Prostate Cancer

While androgen deprivation therapy (ADT) is nearly ubiquitously successful in suppressing testosterone to castrate levels with resultant declines in prostate-specific antigen (PSA) levels, the development of resistance is nearly as inevitable. While the natural history is variable, evidence suggests that most patients with advanced or metastatic prostate cancer will have disease progression within two to three years after initiation of androgen deprivation therapy, resulting in so-called “castration-resistant prostate cancer.”
Written by: Zachary Klaassen, MD, MSc and Christopher J.D. Wallis, MD, PhD
References: 1. Huggins, Charles, and Clarence V. Hodges. "Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate." The Journal of urology 167, no. 2 Part 2 (2002): 948-951.
2. Coutinho, Isabel, Tanya K. Day, Wayne D. Tilley, and Luke A. Selth. "Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence." Endocrine-related cancer 23, no. 12 (2016): T179-T197.
3. Visakorpi, Tapio, Eija Hyytinen, Pasi Koivisto, Minna Tanner, Riitta Keinänen, Christian Palmberg, Aarno Palotie, Teuvo Tammela, Jorma Isola, and Olli-P. Kallioniemi. "In vivo amplification of the androgen receptor gene and progression of human prostate cancer." Nature genetics 9, no. 4 (1995): 401-406.
4. Chen, Charlie D., Derek S. Welsbie, Chris Tran, Sung Hee Baek, Randy Chen, Robert Vessella, Michael G. Rosenfeld, and Charles L. Sawyers. "Molecular determinants of resistance to antiandrogen therapy." Nature medicine 10, no. 1 (2004): 33-39.
5. Wyatt, Alexander W., and Martin E. Gleave. "Targeting the adaptive molecular landscape of castration‐resistant prostate cancer." EMBO molecular medicine 7, no. 7 (2015): 878-894.
6. Robinson, Dan, Eliezer M. Van Allen, Yi-Mi Wu, Nikolaus Schultz, Robert J. Lonigro, Juan-Miguel Mosquera, Bruce Montgomery et al. "Integrative clinical genomics of advanced prostate cancer." Cell 161, no. 5 (2015): 1215-1228.
7. Grasso, Catherine S., Yi-Mi Wu, Dan R. Robinson, Xuhong Cao, Saravana M. Dhanasekaran, Amjad P. Khan, Michael J. Quist et al. "The mutational landscape of lethal castration-resistant prostate cancer." Nature 487, no. 7406 (2012): 239-243.
8. Cai, Changmeng, Housheng Hansen He, Sen Chen, Ilsa Coleman, Hongyun Wang, Zi Fang, Shaoyong Chen et al. "Androgen receptor gene expression in prostate cancer is directly suppressed by the androgen receptor through recruitment of lysine-specific demethylase 1." Cancer cell 20, no. 4 (2011): 457-471.
9. Antonarakis, Emmanuel S., Changxue Lu, Hao Wang, Brandon Luber, Mary Nakazawa, Jeffrey C. Roeser, Yan Chen et al. "AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer." New England Journal of Medicine 371, no. 11 (2014): 1028-1038.
10. Chmelar, Renée, Grant Buchanan, Eleanor F. Need, Wayne Tilley, and Norman M. Greenberg. "Androgen receptor coregulators and their involvement in the development and progression of prostate cancer." International Journal of cancer 120, no. 4 (2007): 719-733.
11. Zoubeidi, Amina, Anousheh Zardan, Eliana Beraldi, Ladan Fazli, Richard Sowery, Paul Rennie, Colleen Nelson, and Martin Gleave. "Cooperative interactions between androgen receptor (AR) and heat-shock protein 27 facilitate AR transcriptional activity." Cancer research 67, no. 21 (2007): 10455-10465.
12. Gregory, Christopher W., Bin He, Raymond T. Johnson, O. Harris Ford, James L. Mohler, Frank S. French, and Elizabeth M. Wilson. "A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen deprivation therapy." Cancer research 61, no. 11 (2001): 4315-4319.
13. Qin, Jun, Hui-Ju Lee, San-Pin Wu, Shih-Chieh Lin, Rainer B. Lanz, Chad J. Creighton, Francesco J. DeMayo, Sophia Y. Tsai, and Ming-Jer Tsai. "Androgen deprivation–induced NCoA2 promotes metastatic and castration-resistant prostate cancer." The Journal of clinical investigation 124, no. 11 (2014): 5013-5026.

Prostate Cancer and Tumor Markers

The discovery of prostate-specific antigen (PSA) in the late 1970s and its widespread application and adoption in the 1980s and 1990s ushered in the prostate cancer screening and disease monitoring era. As the first tumor marker for prostate cancer, it is organ specific but not cancer specific.1 thus providing the opportunity for further tumor marker investigation. A potential biomarker must go through a rigorous vetting process from discovery → differentiation of case from control → ability to detect preclinical disease (defining a positive test) → indications for application and validation → cancer control studies.2 Secondary to the cost and time involved, biomarkers are rarely tested in large randomized controlled trials (RCTs). However, the development of the Prospective Randomized Open, Blinded Endpoint (PROBE) initiative for biomarker studies was designed to overcome spectrum and ascertainment bias and give guidance for validation studies.3 Biomarkers are typically evaluated based on their positive predictive value (probability that a positive test indicates the presence of disease) and negative predictive value (probability that a negative test indicates the absence of disease), entities that rely on the test’s specificity, sensitivity, and prevalence of the disease. This article will focus on briefly reviewing the clinical utility of several commonly used tumor markers associated with prostate cancer detection.

Blood

PSA
PSA is part of the kallikrein gene family located on chromosome 19 and functions as a serine protease, predominantly produced by prostate luminal cells. PSA in the serum is typically bound to proteins (~80% of PSA; complexed) or unbound (free PSA). The production of PSA is androgen dependent4 and in the absence of cancer varies with age,5 race,6, 7 and prostate volume.8 African-American men without prostate cancer have a higher PSA level compared to similar Caucasian men when assessed on a volume-to-volume ratio.9 Additionally, many studies have suggested that PSA in men with higher body mass index (BMI) have lower PSAs, a concept referred to as “hemodilution”:10 a greater plasma volume leading to lower hematocrit and PSA. Recent studies have provided further support for the hemodilution theory, in that only a fraction of lower PSA values in obese men are attributed to testosterone and dihydrotestosterone levels, with the remaining lower PSA explained presumably by hemodilution.11 The greatest contributor to elevated PSA is prostatic diseases, namely prostatitis, BPH and prostate cancer. Without question, the decrease in specificity associated with PSA and prostate cancer is an elevated PSA in men with prostatitis and/or BPH.

Free PSA (fPSA)
fPSA is PSA that is enzymatically inactive and non-complexed, making up 4-45% of total PSA;12 men with PSA from prostate cancer cells have a lower percentage of total PSA that is free, compared to those without prostate cancer.13 fPSA has FDA approval for men with a negative digital rectal examination (DRE) and total PSA level of 4-10 ng/mL, largely on the basis of a prospective study of men demonstrating a %fPSA (fPSA/total PSA) cutoff of 25% detecting 95% of prostate cancers, while avoiding 20% of biopsies.14 A generally acceptable cut-point ranges from 15-25%. Twenty years later, %fPSA is still used for clinically appropriate men, most commonly used in those with an elevated PSA and a negative prostate biopsy. In these men, studies have reported a 5% cancer under-detection rate and 21% cutoff for repeating prostate biopsy.15

Kallikreins
PSA, also known as human kallikrein 3 (hK3), is the most famous of the kallikreins, however, there are other kallikreins that have recently been explored as prostate cancer tumor markers. hK2 shares 80% amino acid homology with PSA, however, is weakly expressed in benign tissue and intensely expressed in prostate cancer tissue.16 Low-grade disease generally has low expression of hK2, whereas aggressive disease has high levels of expression.16 Recently, the hK2 kallikrein has been incorporated into a panel of kallikrein markers (total PSA, free PSA, intact PSA, and hK2, along with clinical information), commercially available as the 4KScore Test, used for calculating a patient’s percent risk for aggressive prostate cancer. First described in 2008, Vickers et al.17 tested the utility of the kallikrein panel in 740 men in the Swedish arm of the ERSPC screening trial. They found that adding free and intact PSA with hK2 to total PSA improved the clinical area under the curve (AUC) from 0.72 to 0.84. When the authors applied a 20% risk of prostate cancer as the threshold for biopsy, 424 (57%) of biopsies would have been avoided, missing 31 of 152 low-grade and 3 of 40 high-grade cancers.17 Since this study a decade ago, many studies have validated these findings, including among 6,129 men participating in the ProtecT study:18 the AUC for the four kallikreins was 0.719 (95%CI 0.704-0.734) vs 0.634 (95%CI 0.617-0.651, p<0.001) for PSA and age alone for any-grade cancer, and 0.820 (95%CI 0.802-0.838) vs 0.738 (95%CI 0.716-0.761) for high-grade prostate cancer. 

Prostate Health Index (phi)
The phi test combines total, free and [-2]proPSA into a single score for improving the accuracy of prostate cancer detection. In the seminal study leading to FDA approval, Catalona et al.19 assessed phi scores among 892 patients without prostate cancer and a PSA between 2-10 ng/mL. They found that an increasing phi score was associated with a 4.7-fold increased risk of prostate cancer and a 1.6-fold increased risk of Gleason score ≥ 4+3 disease at prostate biopsy. Furthermore, the phi score AUC exceeded that of %fPSA (0.72 vs 0.67) to discriminate high vs low-grade disease or negative biopsy. In a subsequent study, Loeb et al.20 confirmed the phi score’s ability to outperform total, free and [-2]proPSA for identifying clinically significant prostate cancer.

Urine

Prostate Cancer Antigen 3 (PCA3)
PCA3 is a long noncoding RNA shed into the urine that is not expressed outside the prostate and is associated with much higher expression in malignant than benign prostate tissue.21 Prior to collecting urine for a PCA3 test, a “rigorous” DRE is performed in order to enhance the sensitivity of the test. The commercial PCA3 score is reported as a ratio of urine PCA3 mRNA to urine PSA mRNA x 1000. The optimal cutoff is still debated, however in a contemporary comparative effectiveness review, Bradley et al.22 showed that a PCA3 threshold of 25 resulted in a sensitivity of 74% and specificity of 57% for a positive biopsy. This threshold led to FDA approval of the PCA3 test in 2012 among men with a prior negative prostate biopsy.

Since then, several groups have reported results of PCA3 in biopsy naïve men. In a retrospective review of 3,073 men undergoing initial biopsy, Chevli et al.23 found that the mean PCA3 was 27.2 for those without, and 52.5 for patients with prostate cancer. Prostate cancer was identified in 1,341 (43.6%) men; on multivariable analysis, PCA3 was associated with any (OR 3.0, 95%CI 2.5-3.6) and high-grade (OR 2.4, 95%CI 1.9-3.1) prostate cancer after adjusting for clinicopathologic variables. Furthermore, PCA3 outperformed PSA in the prediction of prostate cancer (AUC 0.697 vs 0.599, p<0.01) but did not for high-grade disease (AUC 0.682 vs 0.679, p=0.702).23

microRNAs (miRNAs)
miRNAs are small, noncoding single-stranded RNAs involved in the regulation of mRNA. Due to their short sequence (typically 19-22 nucleotides), miRNAs are highly stable in most body fluids (including urine) as they are resistant to RNase degradation.24 Several miRNAs have been implicated as potential biomarkers in prostate cancer diagnosis and management, including miRNA-141, miRNA-375, miRNA-221, miRNA-21, miRNA-182 and miRNA-187.25, 26 miR-187 detected in urine has been suggested as a candidate for improving the predictive value for a positive biopsy; a prediction model including serum PSA, urine PCA3, and miR-187 provided 88.6% sensitivity and 50% specificity (AUC 0.711, p = 0.001) for a positive biopsy.26 Ultimately, these miRNAs need to be further validated in terms of their ability to regulate various pathways important for prostate cancer management and their potential role as tumor markers.

Combining Tumor Markers

In an effort to improve the predictive accuracy of a positive biopsy, the last several years have seen a plethora of studies combining biomarkers to not only improve predictive accuracy above that offered by PSA, but also individual, newer biomarkers. As previously mentioned, the decrease in specificity associated with PSA and prostate cancer is secondary to an elevated PSA in men with prostatitis and/or BPH. The “perfect” biomarker (or combination) would delineate prostate cancer (and ultimately high-grade prostate cancer) from other benign entities.

Vedder et al.27 assessed the added value of %fPSA, PCA3, and 4KScore Test to the ERSPC prediction models among men in the Dutch arm of the ERSPC screening trial. Prostate cancer was detected in 119 of 708 men – adding %fPSA did not improve the predictive value of the risk calculators, however, the 4KScore discriminated better than PCA3 in univariate models (AUC 0.78 vs. 0.62; p=0.01). In the overall population, there was no statistically significant difference between the multivariable model with PCA3 (AUC 0.73) versus the model with the 4KScore (AUC 0.71; p=0.18). Among 127 men with a previous negative biopsy, Auprich et al.28 compared the performance of total PSA, %fPSA, PSA velocity (PSAV), and PCA3 at first, second and ≥ third repeat biopsy. At first repeat biopsy, PCA3 predicted prostate cancer best (AUC 0.80) compared with total PSA. A second repeat biopsy, %fPSA demonstrated the highest accuracy (AUC 0.82), and again at ≥ third repeat biopsy %fPSA demonstrated the highest accuracy (AUC 0.70).28 

This sampling of studies demonstrates that many combinations of biomarkers are being studied in an effort to improve detection of high-grade cancer and decrease the number of unnecessary biopsies. The next generation of biomarker combinations has and will continue to incorporate multi-parametric prostate MRI into predictive algorithms for clinically significant prostate cancer.29-31

Conclusions

For over four decades, research efforts have been directed towards improving the detection of prostate cancer and attempting to build on the predictive accuracy of the first prostate cancer tumor marker, PSA. With the United States Preventative Services Task Force’s 2012 recommendation for the urgent need to identify new screening efforts to better identify indolent versus aggressive disease, the last several years have seen a dramatic increase in prostate cancer biomarker options. As briefly highlighted, biomarker combinations studies have demonstrated improved predictive accuracy of positive biopsies; however, these combinations are far from perfect, are expensive and much work remains to be done. Furthermore, the specific indication (pre-biopsy, post-negative biopsy, active surveillance, etc) and a combination of tumor markers remain to be fully elucidated.

Published Date: April 16th, 2019
Written by: Zachary Klaassen, MD, MSc
References: 1. Partin AW, Carter HB, Chan DW, Epstein JI, Oesterling JE, Rock RC, et al. Prostate specific antigen in the staging of localized prostate cancer: influence of tumor differentiation, tumor volume and benign hyperplasia. J Urol. 1990;143:747-52.
2. Srivastava S. The early detection research network: 10-year outlook. Clin Chem. 2013;59:60-7.
3. Pepe MS, Feng Z, Janes H, Bossuyt PM, Potter JD. Pivotal evaluation of the accuracy of a biomarker used for classification or prediction: standards for study design. J Natl Cancer Inst. 2008;100:1432-8.
4. Henttu P, Liao SS, Vihko P. Androgens up-regulate the human prostate-specific antigen messenger ribonucleic acid (mRNA), but down-regulate the prostatic acid phosphatase mRNA in the LNCaP cell line. Endocrinology. 1992;130:766-72.
5. Partin AW, Criley SR, Subong EN, Zincke H, Walsh PC, Oesterling JE. Standard versus age-specific prostate specific antigen reference ranges among men with clinically localized prostate cancer: A pathological analysis. J Urol. 1996;155:1336-9.
6. Smith DS, Carvalhal GF, Mager DE, Bullock AD, Catalona WJ. Use of lower prostate specific antigen cutoffs for prostate cancer screening in black and white men. J Urol. 1998;160:1734-8.
7. Espaldon R, Kirby KA, Fung KZ, Hoffman RM, Powell AA, Freedland SJ, et al. Probability of an abnormal screening prostate-specific antigen result based on age, race, and prostate-specific antigen threshold. Urology. 2014;83:599-605.
8. Naya Y, Stamey TA, Cheli CD, Partin AW, Sokoll LJ, Chan DW, et al. Can volume measurement of the prostate enhance the performance of complexed prostate-specific antigen? Urology. 2002;60:36-41.
9. Fowler JE, Jr., Bigler SA, Kilambi NK, Land SA. Relationships between prostate-specific antigen and prostate volume in black and white men with benign prostate biopsies. Urology. 1999;53:1175-8.
10. Ohwaki K, Endo F, Muraishi O, Hiramatsu S, Yano E. Relationship between prostate-specific antigen and hematocrit: does hemodilution lead to lower PSA concentrations in men with a higher body mass index? Urology. 2010;75:648-52.
11. Klaassen Z, Howard LE, Moreira DM, Andriole GL, Jr., Terris MK, Freedland SJ. Association of Obesity-Related Hemodilution of Prostate-Specific Antigen, Dihydrotestosterone, and Testosterone. Prostate. 2017;77:466-70.
12. McCormack RT, Rittenhouse HG, Finlay JA, Sokoloff RL, Wang TJ, Wolfert RL, et al. Molecular forms of prostate-specific antigen and the human kallikrein gene family: a new era. Urology. 1995;45:729-44.
13. Catalona WJ, Beiser JA, Smith DS. Serum free prostate specific antigen and prostate specific antigen density measurements for predicting cancer in men with prior negative prostatic biopsies. J Urol. 1997;158:2162-7.
14. Catalona WJ, Partin AW, Slawin KM, Brawer MK, Flanigan RC, Patel A, et al. Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. JAMA. 1998;279:1542-7.
15. Stephan C, Lein M, Jung K, Schnorr D, Loening SA. Re: Editorial: can prostate specific antigen derivatives reduce the frequency of unnecessary prostate biopsies? J Urol. 1997;157:1371.
16. Darson MF, Pacelli A, Roche P, Rittenhouse HG, Wolfert RL, Saeid MS, et al. Human glandular kallikrein 2 expression in prostate adenocarcinoma and lymph node metastases. Urology. 1999;53:939-44.
17. Vickers AJ, Cronin AM, Aus G, Pihl CG, Becker C, Pettersson K, et al. A panel of kallikrein markers can reduce unnecessary biopsy for prostate cancer: data from the European Randomized Study of Prostate Cancer Screening in Goteborg, Sweden. BMC Med. 2008;6:19.
18. Bryant RJ, Sjoberg DD, Vickers AJ, Robinson MC, Kumar R, Marsden L, et al. Predicting high-grade cancer at ten-core prostate biopsy using four kallikrein markers measured in blood in the ProtecT study. J Natl Cancer Inst. 2015;107.
19. Catalona WJ, Partin AW, Sanda MG, Wei JT, Klee GG, Bangma CH, et al. A multicenter study of [-2]pro-prostate specific antigen combined with prostate specific antigen and free prostate specific antigen for prostate cancer detection in the 2.0 to 10.0 ng/ml prostate specific antigen range. J Urol. 2011;185:1650-5.
20. Loeb S, Sanda MG, Broyles DL, Shin SS, Bangma CH, Wei JT, et al. The prostate health index selectively identifies clinically significant prostate cancer. J Urol. 2015;193:1163-9.
21. de Kok JB, Verhaegh GW, Roelofs RW, Hessels D, Kiemeney LA, Aalders TW, et al. DD3(PCA3), a very sensitive and specific marker to detect prostate tumors. Cancer Res. 2002;62:2695-8.
22. Bradley LA, Palomaki GE, Gutman S, Samson D, Aronson N. Comparative effectiveness review: prostate cancer antigen 3 testing for the diagnosis and management of prostate cancer. J Urol. 2013;190:389-98.
23. Chevli KK, Duff M, Walter P, Yu C, Capuder B, Elshafei A, et al. Urinary PCA3 as a predictor of prostate cancer in a cohort of 3,073 men undergoing initial prostate biopsy. J Urol. 2014;191:1743-8.
24. Schwarzenbach H, Nishida N, Calin GA, Pantel K. Clinical relevance of circulating cell-free microRNAs in cancer. Nat Rev Clin Oncol. 2014;11:145-56.
25. Sharma N, Baruah MM. The microRNA signatures: aberrantly expressed miRNAs in prostate cancer. Clin Transl Oncol. 2018.
26. Casanova-Salas I, Rubio-Briones J, Calatrava A, Mancarella C, Masia E, Casanova J, et al. Identification of miR-187 and miR-182 as biomarkers of early diagnosis and prognosis in patients with prostate cancer treated with radical prostatectomy. J Urol. 2014;192:252-9.
27. Vedder MM, de Bekker-Grob EW, Lilja HG, Vickers AJ, van Leenders GJ, Steyerberg EW, et al. The added value of percentage of free to total prostate-specific antigen, PCA3, and a kallikrein panel to the ERSPC risk calculator for prostate cancer in prescreened men. Eur Urol. 2014;66:1109-15.
28. Auprich M, Augustin H, Budaus L, Kluth L, Mannweiler S, Shariat SF, et al. A comparative performance analysis of total prostate-specific antigen, percentage free prostate-specific antigen, prostate-specific antigen velocity and urinary prostate cancer gene 3 in the first, second and third repeat prostate biopsy. BJU Int. 2012;109:1627-35.
29. Johnston E, Pye H, Bonet-Carne E, Panagiotaki E, Patel D, Galazi M, et al. INNOVATE: A prospective cohort study combining serum and urinary biomarkers with novel diffusion-weighted magnetic resonance imaging for the prediction and characterization of prostate cancer. BMC Cancer. 2016;16:816.
30. Sciarra A, Panebianco V, Cattarino S, Busetto GM, De Berardinis E, Ciccariello M, et al. Multiparametric magnetic resonance imaging of the prostate can improve the predictive value of the urinary prostate cancer antigen 3 test in patients with elevated prostate-specific antigen levels and a previous negative biopsy. BJU Int. 2012;110:1661-5.
31. Perlis N, Al-Kasab T, Ahmad A, Goldberg E, Fadak K, Sayid R, et al. Defining a Cohort that May Not Require Repeat Prostate Biopsy Based on PCA3 Score and Magnetic Resonance Imaging: The Dual Negative Effect. J Urol. 2018;199:1182-7.

The Genetics of Prostate Cancer

Germline mutations in prostate cancer carcinogenesis

Some of the first data to delineate the value of assessment of inherited genetic changes in prostate cancer came from Pritchard and colleagues who assessed the prevalence of mutations in 20 DNA-repair genes among 692 patients with metastatic prostate cancer8. They identified such mutations in 82 men (11.8%).

Written by: Zachary Klaassen, MD, MSc
References: 1. Kang ZJ, Liu YF, Xu LZ, et al. The Philadelphia chromosome in leukemogenesis. Chin J Cancer 2016; 35:48.
2. An X, Tiwari AK, Sun Y, et al. BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: a review. Leuk Res 2010; 34(10):1255-68.
3. Lichtenstein P, Holm NV, Verkasalo PK, et al. Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 2000; 343(2):78-85.
4. Stanford JL, Ostrander EA. Familial prostate cancer. Epidemiol Rev 2001; 23(1):19-23.
5. Carter BS, Bova GS, Beaty TH, et al. Hereditary prostate cancer: epidemiologic and clinical features. J Urol 1993; 150(3):797-802.
6. Bostwick DG, Burke HB, Djakiew D, et al. Human prostate cancer risk factors. Cancer 2004; 101(10 Suppl):2371-490.
7. Alvarez-Cubero MJ, Saiz M, Martinez-Gonzalez LJ, et al. Genetic analysis of the principal genes related to prostate cancer: a review. Urol Oncol 2013; 31(8):1419-29.
8. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med 2016; 375(5):443-53.
9. Castro E, Romero-Laorden N, Del Pozo A, et al. PROREPAIR-B: A Prospective Cohort Study of the Impact of Germline DNA Repair Mutations on the Outcomes of Patients With Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol 2019; 37(6):490-503.
10. Nicolosi P, Ledet E, Yang S, et al. Prevalence of Germline Variants in Prostate Cancer and Implications for Current Genetic Testing Guidelines. JAMA Oncol 2019; 5(4):523-528.
11. Mateo J, Carreira S, Sandhu S, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N Engl J Med 2015; 373(18):1697-708.
12. Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer. Cell 2015; 161(5):1215-1228.
13. Giri VN, Knudsen KE, Kelly WK, et al. Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017. J Clin Oncol 2018; 36(4):414-424.
14. Wallis CJ, Nam RK. Prostate Cancer Genetics: A Review. EJIFCC 2015; 26(2):79-91.
15. Ahmad AS, Vasiljevic N, Carter P, et al. A novel DNA methylation score accurately predicts death from prostate cancer in men with low to intermediate clinical risk factors. Oncotarget 2016; 7(44):71833-71840.
16. Majumdar S, Buckles E, Estrada J, et al. Aberrant DNA methylation and prostate cancer. Curr Genomics 2011; 12(7):486-505.

Diagnosing and Staging of Prostate Cancer

Secondary to the introduction of prostate specific antigen (PSA) screening in the 1980’s/1990’s, symptomatic presentation of prostate cancer has become less frequent. Symptoms of locally advanced prostate cancer may include obstructive urinary symptoms, gross hematuria, and/or upper tract urinary obstruction leading to renal failure. Once the diagnosis of prostate cancer is made, staging is important, which may include imaging studies in cases of high-risk disease. This article will focus on contemporary diagnosis/screening modalities in addition to the staging of localized prostate cancer.

Diagnosis

Screening

The goal of screening for any malignancy is early detection with the hopes of intervening with treatment at an earlier time period in order to reduce cancer-specific mortality. Screening for prostate cancer involves a digital rectal examination (DRE) and a serum PSA blood test. Screening in certain instances may lead to over treatment of clinically insignificant disease, for which urologists have been criticized with regards to prostate cancer over treatment.1, 2 Notwithstanding, during the PSA screening era for prostate cancer, disease mortality has declined by ~40% with a substantial decrease in men presenting with advanced malignancy.3

Two randomized control trials (RCTs) were initiated in 1993 to compare prostate cancer-specific mortality between prostate cancer screened and unscreened men.4, 5 The European Randomized Study of Screening for Prostate Cancer (ERSPC) trial identified 182,000 men (ages 50-74 years) who were randomly assigned to a group that was offered PSA screening once every four years or to a control group that did not receive screening4. During a median follow-up of 9 years, the cumulative incidence of prostate cancer was 8.2% in the screening group and 4.8% in the control group. The rate ratio (RR) for death from prostate cancer in the screening vs control group, was 0.80 (95%CI 0.65-0.98). This correlated to 1410 men needing to be screened and 48 additional cases of prostate cancer treated to prevent one death from prostate cancer. The Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial randomly assigned men in the US to receive either annual screening (n=38,343) or usual care (n=38,350).5 Importantly, in this trial “usual care” occasionally included screening; rates of screening in the control group increased from 40% in the first year to 52% in the sixth year for PSA testing. After seven years of follow-up, the incidence of prostate cancer per 10,000 person-years was 116 in the screening group and 95 in the control group (RR 1.22; 95CI 1.16-1.29). The incidence of death per 10,000 person-years was 2.0 in the screening group and 1.7 in the control group (RR 1.13; 95%CI 0.75-1.70), thus the results of the study suggested that prostate cancer screening did not reduce cancer-specific mortality.

Since the initial reporting of these two RCTs nearly a decade ago, several follow-up iterations have been published for the ERSPC6, 7 and PLCO8, 9 trials, confirming initial results: a screening benefit in the ERSPC trial and no benefit in the PLCO trial. These trials have been thoroughly analyzed as to potential reasons for differing results. The PLCO trial had (i) a shorter screening interval, (ii) higher threshold for prostate biopsy, (iii) halted regular screening after six rounds, and had (iv) “contamination” in the control group, considering that these men often received screening. As such, the PLCO has been described as organized screening vs opportunistic screening, rather than screening vs no screening.8, 9 

Recommendations for Screening

The United States Preventative Services Task Force (USPSTF) has been highly critical of PSA screening and relied heavily on results of the PLCO trial for their recommendations against routine screening for prostate cancer.2, 10 The American Urological Association (AUA) guidelines for prostate cancer screening were most recently released in 2013 and revalidated in 2018,11 suggesting shared decision making for men 55-69 years of age who are considering PSA-based screening. These recommendations were based on the benefits outweighing the harms of screening in this age group. Other organizations, such as the European Association of Urology (EAU), recommend a baseline PSA test at age 40-45, which is then used to guide a subsequent screening interval.12 Most recently, the USPSTF changed their recommendation against PSA screening for men aged 55-69 (Grade D) to a Grade C recommendation for prostate cancer screening: clinicians should not screen men who do not express a preference for screening.13

Triggers for Biopsy

Various “triggers” for prostate biopsy have been proposed with no consensus agreement. Generally, urologists agree that a positive DRE finding should be followed by a prostate biopsy. When the DRE is unremarkable, PSA thresholds are primarily used to guide recommendations for consideration of a prostate biopsy. The upper limit of a normal PSA has historically been set at 4 ng/mL, however the ERSPC has suggested this level should be lowered to 2.5-3.0 ng/mL. A recent study suggested that men <50 years of age with a PSA >1.5 ng/mL should consider a prostate biopsy, as more than half of these patients diagnosed with prostate cancer exceed the Epstein criteria for active surveillance.14 Furthermore, in an ad hoc analysis of the placebo arm of the Prostate Cancer Prevention Trial (PCPT), Thompson et al.15 showed a continuum of prostate cancer risk at all PSA values: PSA cutoff values of 1.1, 2.1, 3.1, and 4.1 ng/mL yielded sensitivities of 83.4%, 52.6%, 32.2%, and 20.5%, and specificities of 38.9%, 72.5%, 86.7%, and 93.8%, respectively, for detecting any prostate cancer. Undoubtedly, there is no perfect trigger for deciding whether to perform a prostate biopsy, as all factors must be taken into account, including age, race, family history, PSA trend, etc.

Staging


The clinical staging of prostate cancer relies on factors prior to treatment, such as PSA, DRE, prostate biopsy results, and imaging findings. Pathologic staging of prostate cancer relies on the stage of disease after surgical extirpation of the prostate. The following discussion will primarily focus on clinical staging.

Prostate Biopsy and Gleason Classification

At the time of prostate biopsy, a “systematic sampling” of the prostate is undertaken, typically consisting of 10-12 biopsy cores of tissue. Positive samples are then scored a primary and secondary Gleason score: 3+3, 3+4, 4+3, 4+4, 4+5, 5+4, or 5+5. Over the last 20 years, the D’Amico risk stratification has been commonly used to guide treatment16 Low-risk disease (cT1-2a, PSA ≤10 ng/mL, and Gleason ≤6), intermediate-risk disease (T2b or PSA >10 ng/ml but <20 ng/ML, or Gleason score 7), and high-risk disease (T2c, or PSA >20 ng/mL or Gleason 8-10), conferred freedom of disease 10-years after radical prostatectomy rates of 83%, 46%, and 29%, respectively.16

Several years ago, the Gleason Grade Group (GGG) was proposed to better reflect the true cancer biologic aggressiveness and better guide treatment: GGG 1 is Gleason 6, GGG 2 is 3+4=7, GGG 3 is Gleason 4+3=7, GGG 4 is Gleason 8, GGG 5 is Gleason 9-10.17 In a Swedish population-level database of 5,880 men diagnosed with prostate cancer, using the GGG schema demonstrated four-year biochemical recurrence-free survival rates of 89% (GGG 1), 82% (GGG 2), 74% (GGG 3), 77% (GGG 4), and 49% (GGG 5) on biopsy, and 92% (GGG 1), 85% (GGG 2), 73% (GGG 3), 63% (GGG 4), and 51% (GGG 5) based on prostatectomy data18 Generally, the GGG classification offers a simplified nomenclature with predictive accuracy comparable to previously used classification schemes.

Classification

table 1 diagnosing staging prostate cancer2x

table 2 diagnosing staging prostate cancer2x

Imaging

Several imaging modalities have been used to radiographically stage prostate patients. Generally, staging studies have included a radionuclide bone scan (to assess for skeletal metastases) and a computed tomography (CT) scan of the abdomen and pelvis (to assess for lymphadenopathy). Selecting appropriate patients for imaging is a point of much debate. The general consensus is that there is no role for imaging patients with low-risk disease, whereas imaging is appropriate for patients with either PSA >20 ng/mL, GGG 4-5, cT3-T4 or clinical symptoms of bone metastases.11

The improvement in multi-parametric MRI (mpMRI) technology has allowed, not only the ability to perform targeted prostate biopsies but also to stage patients for locoregional extent of disease. mpMRI comprises anatomic sequences (T1/T2) supplemented by functional imaging techniques such as diffusion-weighted and dynamic contrast-enhanced (DCE) imaging. When performed at high resolution, DCE facilitates detection of disease, as well as an assessment of extracapsular extension, urethral sphincter, and seminal vesicles involvement.20 Furthermore, mpMRI may provide accurate information for planning robotic prostatectomy. In a study assessing the ability of mpMRI to assist with planning neurovascular bundle preservation, mpMRI results changed preoperatively planning in 26% of cases based on the extent of disease.21

Conclusions  

Prostate cancer screening has been crucial to decreasing the burden of disease and improving mortality rates. However, early practices of over-screening and over-treatment have led to strong recommendations from non-urologic governing bodies recommending against prostate cancer screening, which has just recently changed to provide screening options for certain men (55-69 years of age). Prostate cancer screening should be based on a shared decision-making model, allowing patients to make educated decisions that best fit their healthcare needs. As prognostic tools continue to be refined and imaging technology improves, diagnosis and staging of prostate cancer will hopefully lead to an improved selection of men that need screening and ultimately those who may benefit from treatment.

Published Date: April 16th, 2019
Written by: Zachary Klaassen, MD, MSc
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Oligometastatic Prostate Cancer – Treatment of the Primary Tumor and Metastasis Directed Therapy

In 2018 1.3 million prostate cancer (PCa) cases were diagnosed worldwide, with approximately 20% having metastatic disease.1 Oligometastatic PCa is defined as a state of low-volume metastatic disease that appears to be prognostically different and likely amenable to different treatment options, which could potentially change the disease trajectory when compared with high-volume metastatic disease.2 
Written by: Hanan Goldberg, MD
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12. Gandaglia G, Karakiewicz PI, Briganti A, et al. Impact of the Site of Metastases on Survival in Patients with Metastatic Prostate Cancer. European urology 2015; 68(2): 325-34.
13. Gakis G, Boorjian SA, Briganti A, et al. The role of radical prostatectomy and lymph node dissection in lymph node-positive prostate cancer: a systematic review of the literature. European urology 2014; 66(2): 191-9.
14. von Bodman C, Godoy G, Chade DC, et al. Predicting biochemical recurrence-free survival for patients with positive pelvic lymph nodes at radical prostatectomy. The Journal of urology 2010; 184(1): 143-8.
15. Briganti A, Karnes JR, Da Pozzo LF, et al. Two positive nodes represent a significant cut-off value for cancer specific survival in patients with node positive prostate cancer. A new proposal based on a two-institution experience on 703 consecutive N+ patients treated with radical prostatectomy, extended pelvic lymph node dissection and adjuvant therapy. European urology 2009; 55(2): 261-70.
16. Francini E, Gray KP, Xie W, et al. Time of metastatic disease presentation and volume of disease are prognostic for metastatic hormone sensitive prostate cancer (mHSPC). 2018; 78(12): 889-95.
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26. Kalina JL, Neilson DS, Comber AP, et al. Immune Modulation by Androgen Deprivation and Radiation Therapy: Implications for Prostate Cancer Immunotherapy. Cancers (Basel) 2017; 9(2): 13.
27. Heidenreich A, Pfister D, Porres D. Cytoreductive radical prostatectomy in patients with prostate cancer and low volume skeletal metastases: results of a feasibility and case-control study. The Journal of urology 2015; 193(3): 832-8.
28. Bianchini D, Lorente D, Rescigno P, et al. Effect on Overall Survival of Locoregional Treatment in a Cohort of De Novo Metastatic Prostate Cancer Patients: A Single Institution Retrospective Analysis From the Royal Marsden Hospital. Clinical genitourinary cancer 2017; 15(5): e801-e7.
29. Gratzke C, Engel J, Stief CG. Role of radical prostatectomy in metastatic prostate cancer: data from the Munich Cancer Registry. European urology 2014; 66(3): 602-3.
30. Culp SH, Schellhammer PF, Williams MB. Might men diagnosed with metastatic prostate cancer benefit from definitive treatment of the primary tumor? A SEER-based study. European urology 2014; 65(6): 1058-66.
31. O'Shaughnessy MJ, McBride SM, Vargas HA, et al. A Pilot Study of a Multimodal Treatment Paradigm to Accelerate Drug Evaluations in Early-stage Metastatic Prostate Cancer. Urology 2017; 102: 164-72.
32. Satkunasivam R, Kim AE, Desai M, et al. Radical Prostatectomy or External Beam Radiation Therapy vs No Local Therapy for Survival Benefit in Metastatic Prostate Cancer: A SEER-Medicare Analysis. The Journal of urology 2015; 194(2): 378-85.
33. Loppenberg B, Dalela D, Karabon P, et al. The Impact of Local Treatment on Overall Survival in Patients with Metastatic Prostate Cancer on Diagnosis: A National Cancer Data Base Analysis. European urology 2017; 72(1): 14-9.
34. Boeve LMS, Hulshof M, Vis AN, et al. Effect on Survival of Androgen Deprivation Therapy Alone Compared to Androgen Deprivation Therapy Combined with Concurrent Radiation Therapy to the Prostate in Patients with Primary Bone Metastatic Prostate Cancer in a Prospective Randomised Clinical Trial: Data from the HORRAD Trial. European urology 2019; 75(3): 410-8.
35. Parker CC, James ND, Brawley CD, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet (London, England) 2018; 392(10162): 2353-66.
36. Sweeney CJ, Chen Y-H, Carducci M, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. New England Journal of Medicine 2015; 373(8): 737-46.
37. Burdett S, Boeve LM, Ingleby FC, et al. Prostate Radiotherapy for Metastatic Hormone-sensitive Prostate Cancer: A STOPCAP Systematic Review and Meta-analysis. European urology 2019; 76(1): 115-24.
38. Potters L, Kavanagh B, Galvin JM, et al. American Society for Therapeutic Radiology and Oncology (ASTRO) and American College of Radiology (ACR) practice guideline for the performance of stereotactic body radiation therapy. International journal of radiation oncology, biology, physics 2010; 76(2): 326-32.
39. De Bleser E, Tran PT, Ost P. Radiotherapy as metastasis-directed therapy for oligometastatic prostate cancer. Current opinion in urology 2017; 27(6): 587-95.
40. Decaestecker K, De Meerleer G, Lambert B, et al. Repeated stereotactic body radiotherapy for oligometastatic prostate cancer recurrence. Radiat Oncol 2014; 9: 135-.
41. Palma DA, Salama JK, Lo SS, et al. The oligometastatic state - separating truth from wishful thinking. Nature reviews Clinical oncology 2014; 11(9): 549-57.
42. Riva G, Marvaso G, Augugliaro M, et al. Cytoreductive prostate radiotherapy in oligometastatic prostate cancer: a single centre analysis of toxicity and clinical outcome. Ecancermedicalscience 2017; 11: 786.
43. Ost P, Reynders D, Decaestecker K, et al. Surveillance or Metastasis-Directed Therapy for Oligometastatic Prostate Cancer Recurrence: A Prospective, Randomized, Multicenter Phase II Trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2018; 36(5): 446-53.
44. Nguyen PL, Alibhai SM, Basaria S, et al. Adverse effects of androgen deprivation therapy and strategies to mitigate them. European urology 2015; 67(5): 825-36.
45. Duchesne GM, Woo HH, Bassett JK, et al. Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial. The Lancet Oncology 2016; 17(6): 727-37.
46. Ost P, Bossi A, Decaestecker K, et al. Metastasis-directed therapy of regional and distant recurrences after curative treatment of prostate cancer: a systematic review of the literature. European urology 2015; 67(5): 852-63.
47. Steuber T, Jilg C, Tennstedt P, et al. Standard of Care Versus Metastases-directed Therapy for PET-detected Nodal Oligorecurrent Prostate Cancer Following Multimodality Treatment: A Multi-institutional Case-control Study. European urology focus 2018.
48. Siva S, Bressel M, Murphy DG, et al. Stereotactic Abative Body Radiotherapy (SABR) for Oligometastatic Prostate Cancer: A Prospective Clinical Trial. European urology 2018; 74(4): 455-62.
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Epidemiology and Etiology of Prostate Cancer

In 2018 in the United States, there will be an estimated 164,690 new cases of prostate cancer (19% of all male cancer incident cases, 1st) and an estimated 29,430 prostate cancer mortalities (9% of all male cancer deaths, 2nd only to lung/bronchus cancer).1 Over the last four decades, there was a spike in prostate cancer incidence in the late 1980’s/early 1990’s secondary to the widespread adoption of prostate-specific antigen (PSA) testing for the asymptomatic detection of prostate cancer.2 Since 1991, prostate cancer mortality has decreased by more than 40% due to a combination of increased PSA screening and improvement in treatment.3 This article will discuss the epidemiology of prostate cancer, as well as focus on several important etiologic risk factors associated with the disease.

Epidemiology

Incidence
For the last 30+ years, prostate cancer has been the most common noncutaneous malignancy among men in the United States, with 1 in 7 men being diagnosed with the disease.4 Similar to the United States, prostate cancer is the second most commonly diagnosed malignancy among men worldwide, with 1.1 million new cases diagnosed per year.5 In developed countries, the age-standardized rate (ASR) of prostate cancer incidence is 69.5 per 100,000 compared to 14.5 per 100,000 in developing countries.5 Crude differences in incidence between developed and developing countries are likely secondary to poor use of screening6 and lower life expectancies in developing countries.

Mortality
Among all men in the United States, 1 in 38 men will die from prostate cancer.4 Prostate cancer ranks as the leading cause of cancer death globally, with the highest mortality rates noted in the Caribbean and Southern/Middle Africa.5 Furthermore, the ASR for mortality in developed countries is 10.0 per 100,000 compared to 6.6 per 100,000 in developing countries.5 Many hypotheses have been considered as to the decline in mortality seen in the United States after 1991, with the most commonly accepted (in addition to utilization of screening) being an increase in aggressive curative treatment of prostate cancer diagnosed in the 1980s.7,8

A Global Perspective
The incidence and epidemiology from a global perspective is much different than what may typically be seen in the United States and Europe. For example, in India the incidence of prostate cancer is a fraction (1.7-5.3 per 100,000) of other first world countries (North America: 83.2-173.7 per 100,000),6 but secondary to the sheer size of the population (1.2 billion) the crude prevalence of prostate cancer is on par with countries such as the United States, UK, France, and Italy. Despite greater awareness of prostate cancer screening, data from India suggest that 4% of patients <50 years of age present with metastatic disease. Among worldwide prostate cancer incidence, 14% of cases are diagnosed within the Asia-Pacific region, with a wide variation of incidence rates across the Asian-Pacific countries. In Latin American countries, prostate cancer represents 28% of all incidence cancers (highest) and 13% of all cancer mortalities (second after lung cancer). Specifically, in Trinidad and Tobago, Guyana and Barbados, the incidence is 3-4x that of the United States. Particularly in Cuba, the mortality rates continue to increase, despite greater adoption of screening.  The incidence of prostate cancer in the Middle East is higher than the Asian countries, specifically in Lebanon (37.2 per 100,000), Jordan (15.3 per 100,000), and Palestine (15.2 per 100,000). A closer look at the demographics at presentation among Middle Eastern men shows that 25% present with metastatic disease, with rates as high as 58% among men from Iraq. There are several hypotheses for the shift in incidence and prevalence of prostate cancer among non-North America/European countries, including (1) an increased awareness of prostate cancer leading to greater utilization of PSA testing, and (2) adoption of a more “Western” diet/lifestyle and less the traditional Indian/Asian/Mediterranean diet, particularly in the urban centers.

Unfortunately, a greater burden of disease among non-North American/European regions has presented several problems:

  1. A wide variation in incidence/prevalence across countries in these regions, particularly in Asia-Pacific and Latin America
  2. Huge discrepancies in quality and access to care between the private and public sector
  3. Poor access to newer standards of care, leading to high rates of surgical castration and limited access to radiation therapy (ie. for treatment of bone metastases)
  4. Limited organized cancer registries, thus grossly underestimating the true incidence and prevalence of prostate cancer
Age and Family History
Age is an established risk factor for prostate cancer, as men <40 years of age are highly unlikely to be diagnosed with prostate cancer, whereas men >70 years of age have a 1 in 8 chance of prostate cancer diagnosis.1 In a population-based analysis of more than 200,000 patients, increasing age was associated with higher 15-year cancer-specific mortality (CSM) rates: 2.3% for men diagnosed ≤50 years of age, 3.4% for men 51-60 years of age, 4.6% for men 61-70 years of age, and 6.3% for men ≥71 years of age.9

A family history of prostate cancer is also strongly predictive of a prostate cancer diagnosis. To be considered hereditary prostate cancer, a family must have three affected generations, three first-degree relatives affected, or two relatives diagnosed prior to age 55.10 Men with one first-degree relative previously diagnosed with prostate cancer have a risk of a prostate cancer diagnosis that is 2-3x that of individuals with no family history.11 Data on 65,179 white men from the PLCO cancer screening trial showed that men with a family history of prostate cancer had a significantly higher incidence of prostate cancer (16.9% vs 10.8%, p<0.01) and higher cancer-specific mortality (0.56% vs 0.37%, p<0.01).12

Race
Both prostate cancer incidence and mortality have been shown to be significantly related to race. African-Americans and Jamaicans of African descent have the highest incidence of prostate cancer in the world.1 Despite decreases in mortality since the 1990s among all races, death rates of African Americans are still 2.4x higher than Caucasian patients.13 Several studies have assessed possible reasons for this discrepancy. In an ad hoc analysis of the REDUCE trial, African American men had greater non-compliance with study-mandated2 and 4-year prostate biopsies, despite having greater prostate cancer risk (at 2-year biopsy),14 suggesting that population-level estimates of the excess prostate cancer burden in African American men may underestimate the degree of prostate cancer disparity. Gene expression assessment of prostate cancer specimens has noted numerous differentially expressed genes between African American and white patients, suggesting that there may be racial differences in androgen biosynthesis and metabolism.15 However, studies in mCRPC patients assessing clinical response to the potent anti-androgen abiraterone have not demonstrated racial differences when prospectively evaluated.16

The incidence of prostate cancer among races other than African-American and Caucasians is lower, including men of Asian descent living in the United States, although their incidence of prostate cancer is higher than those living within continental Asia.17 Interestingly, men moving from developing countries to high prostate cancer incidence countries demonstrate a shift in prostate cancer risk similar to that of their new country of residence.18 Ultimately, the relative components of genetics, socioeconomic factors, cultural, and environmental factors associated with racial differences observed are poorly understood.   

Trends
There has been a significant drop in prostate cancer incidence in the last decade (~10% annually per year from 2010-2014), likely secondary to a decrease in PSA testing after the US Preventative Services Task Force (USPSTF) Grade D recommendation for screening of men older than 75 years of age (2008) and subsequently all men (2012) due to concern for overdiagnosis and overtreatment.13,19 Following the USPSTF recommendations, an analysis of the National Cancer Database suggested that in the month after the recommendation, incident prostate cancer diagnoses decreased by 1,363 cases, followed by a drop of 164 cases per month thereafter for the first year (28% decrease in incident cases).20 There has been considerable debate as to whether patients present with the more advanced disease since the USPSTF recommendations with no general consensus.21 Recently, the USPSTF changed their recommendation for PSA screening among men aged 55-69 years of age to a Grade C, suggesting that men in this age bracket should undergo periodic PSA-based screening for prostate cancer based on a decision after discussion regarding the potential benefits and harms of screening with their clinician.22

Etiology and Risk Factors

Diet and Obesity
Initial evidence that diet and lifestyle may have a role in prostate cancer epidemiological outcomes was provided by ecological studies which demonstrated that men in Western countries had higher rates of prostate cancer than developing/non-Western countries.6 To strengthen this possible association, subsequent studies demonstrated that men from non-Western countries migrating to Western countries adopted similar lifestyle and prostate cancer risk as those in Western countries.23 Nonetheless, several prospective studies since these ecologic descriptions assessing self-reported dietary patterns of healthy foods and the risk of prostate cancer have failed to show an association with diet and risk of prostate cancer.24,25 Epidemiological evidence suggesting that statins reduce the risk of advanced stage prostate cancer suggests a possible role of cholesterol and prostate cancer risk.26 Regardless, the complexity of the Western diet and the association/interaction with healthier lifestyles are limitations to understanding how diet influences prostate cancer risk.  

Obesity has become an epidemic in the United States, and observational studies have suggested a modest increase in the risk of prostate cancer among obese individuals.27,28 The pathophysiology between obesity and prostate cancer is likely secondary to higher levels of estradiol, insulin, and free IGF-1 levels, as well as lower free testosterone and adiponectin levels.29 However, a clear pathophysiological explanation between obesity and prostate cancer is still uncertain and may be associated with lower serum PSA and larger prostates leading to fewer prostate biopsies.30   

Inflammation
Chronic inflammation has been implicated in the development of several cancers and may also be associated with prostate cancer. Possible etiologic factors suggested include: infectious agents, dietary carcinogens, hormonal imbalances, as well as physical and chronic trauma.31 As a result, intra-prostatic inflammation may lead to DNA damage, epithelial proliferation, cellular turnover, and angiogenesis.31 In men part of the placebo arm of the Prostate Cancer Prevention Trial (PCPT), those with at least one biopsy core of inflammation had an odds ratio (OR) of 1.78 (95%CI 1.04-3.06) for prostate cancer compared to men with no cores of inflammation.32 Furthermore, this association was even higher when considering a high-grade prostate cancer diagnosis (OR 2.24, 95%CI 1.06-4.71).32

Medications
As mentioned, there has been emerging evidence that HMG-CoA reductase inhibitors (statins) may be associated with a lower risk of prostate cancer mortality following diagnosis.33 Although there have been disparate results for the beneficial nature of statins and prostate cancer, a recent meta-analysis from observational studies of nearly 1 million patients noted that both post- and pre-diagnosis use of statins are beneficial for both overall survival (HR 0.81, 95%CI 0.72-0.91) and cancer-specific survival (HR 0.77, 95%CI 0.66-0.85).34 Nonetheless, the exact role statins play in prostate carcinogenesis/protection is still widely debated.

Similar optimism with statins has been associated with metformin use and prostate cancer outcomes. Among patients with diabetes, metformin has been associated with a significant dose-dependent benefit for both prostate cancer-specific (HR 0.76, 95%CI 0.64-0.89 for each additional six months of metformin use) and all-cause mortality.35 In a systematic review and meta-analysis of observational studies assessing clinical outcomes of patients with prostate cancer and metformin, medication use was marginally associated with a reduction in risk of biochemical recurrence (HR 0.82, 95%CI 0.67-1.01), but not associated with metastasis, prostate-cancer mortality or all-cause mortality.36

Genetics
Prostate cancer is known to have an extraordinarily complex genetic makeup, including somatic copy number alterations, point mutations, structural rearrangements, and changes in chromosomal number.37 It is estimated that 5-10% of all prostate cancers may be caused by dominantly inherited genetic factors.11 These include, but are not limited to HPC1, HPC2, HPC20, HPCX, PCAP, and CAPB.38 More famously are the mutations associated with BRCA1 and BRCA2 and the associated increase in the risk of clinically significant prostate cancer, and prostate cancer-specific mortality among men with screen-detected prostate cancer.39-41 Recent research has evaluated epigenetic markers for prostate cancer such as miRNA. The first report of miRNA and prostate cancer was reported in 2007,42 and since then many reports have implicated over 30 unique miRNAs and prostate carcinogenesis.

Conclusions

The epidemiology and etiology of prostate cancer are complex and multi-factorial. Prostate cancer remains a malignancy spanning the spectrum of localized/indolent disease to de novo advanced disease that is ultimately fatal. Although there are accepted differences in race and geography, the ultimate interplay between sociodemographic factors, environmental/lifestyle factors, and genetic differences remains to be fully elucidated.

Published Date: April 16th, 2019
Written by: Zachary Klaassen, MD, MSc
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