Robert K. Nam

Clinical Results of Long-Term Follow-Up of a Large, Active Surveillance Cohort With Localized Prostate Cancer

PURPOSE We assessed the outcome of a watchful-waiting protocol with selective delayed intervention by using clinical prostate-specific antigen (PSA), or histologic progression as treatment indications for clinically localized prostate cancer. PATIENTS AND METHODS This was a prospective, single-arm, cohort study. Patients were managed with an initial expectant approach. Definitive intervention was offered to those patients with a PSA doubling time of less than 3 years, Gleason score progression (to 4 + 3 or greater), or unequivocal clinical progression. Survival analysis and Cox proportional hazard model were applied to the data. Results A total of 450 patients have been observed with active surveillance. Median follow-up was 6.8 years (range, 1 to 13 years). Overall survival was 78.6%. The 10-year prostate cancer actuarial survival was 97.2%. Overall, 30% of patients have been reclassified as higher risk and have been offered definitive therapy. Of 117 patients treated radically, the PSA failure rate was 50%, which was 13% of the total cohort. PSA doubling time of 3 years or less was associated with an 8.5-times higher risk of biochemical failure after definitive treatment compared with a doubling time of more than 3 years (P < .0001). The hazard ratio for nonprostate cancer to prostate cancer mortality was 18.6 at 10 years. CONCLUSION We observed a low rate of prostate cancer mortality. Among the patients who were reclassified as higher risk and who were treated, PSA failure was relatively common. Other-cause mortality accounted for almost all of the deaths. Additional studies are warranted to improve the identification of patients who harbor more aggressive disease despite favorable clinical parameters at diagnosis.

Increasing Hospital Admission Rates for Urological Complications After Transrectal Ultrasound Guided Prostate Biopsy

PURPOSE Transrectal ultrasound guided prostate biopsy is widely used to confirm the diagnosis of prostate cancer. The technique has been associated with significant morbidity in a small proportion of patients. MATERIALS AND METHODS We conducted a population based study of 75,190 men who underwent a transrectal ultrasound guided biopsy in Ontario, Canada, between 1996 and 2005. We used hospital and cancer registry administrative databases to estimate the rates of hospital admission and mortality due to urological complications associated with the procedure. RESULTS Of the 75,190 men who underwent transrectal ultrasound biopsy 33,508 (44.6%) were diagnosed with prostate cancer and 41,682 (55.4%) did not have prostate cancer. The hospital admission rate for urological complications within 30 days of the procedure for men without cancer was 1.9% (781/41,482). The 30-day hospital admission rate increased from 1.0% in 1996 to 4.1% in 2005 (p for trend <0.0001). The majority of hospital admissions (72%) were for infection related reasons. The probability of being admitted to hospital within 30 days of having the procedure increased 4-fold between 1996 and 2005 (OR 3.7, 95% CI 2.0-7.0, p <0.0001). The overall 30-day mortality rate was 0.09% but did not change during the study period. CONCLUSIONS The hospital admission rates for complications following transrectal ultrasound guided prostate biopsy have increased dramatically during the last 10 years primarily due to an increasing rate of infection related complications.

Systematic Review of Complications of Prostate Biopsy

CONTEXT Prostate biopsy is commonly performed for cancer detection and management. The benefits and risks of prostate biopsy are germane to ongoing debates about prostate cancer screening and treatment. OBJECTIVE To perform a systematic review of complications from prostate biopsy. EVIDENCE ACQUISITION A literature search was performed using PubMed and Embase, supplemented with additional references. Articles were reviewed for data on the following complications: hematuria, rectal bleeding, hematospermia, infection, pain, lower urinary tract symptoms (LUTS), urinary retention, erectile dysfunction, and mortality. EVIDENCE SYNTHESIS After biopsy, hematuria and hematospermia are common but typically mild and self-limiting. Severe rectal bleeding is uncommon. Despite antimicrobial prophylaxis, infectious complications are increasing over time and are the most common reason for hospitalization after biopsy. Pain may occur at several stages of prostate biopsy and can be mitigated by anesthetic agents and anxiety-reduction techniques. Up to 25% of men have transient LUTS after biopsy, and <2% have frank urinary retention, with slightly higher rates reported after transperineal template biopsy. Biopsy-related mortality is rare. CONCLUSIONS Preparation for biopsy should include antimicrobial prophylaxis and pain management. Prostate biopsy is frequently associated with minor bleeding and urinary symptoms that usually do not require intervention. Infectious complications can be serious, requiring prompt management and continued work into preventative strategies.

Expression of the TMPRSS2:ERG fusion gene predicts cancer recurrence after surgery for localised prostate cancer

The prostate-specific gene, TMPRSS2 is fused with the gene for the transcription factor ERG in a large proportion of human prostate cancers. The prognostic significance of the presence of the TMPRSS2:ERG gene fusion product remains controversial. We examined prostate cancer specimens from 165 patients who underwent surgery for clinically localised prostate cancer between 1998 and 2006. We tested for the presence of TMPRSS2:ERG gene fusion product, using RT–PCR and direct sequencing. We conducted a survival analysis to determine the prognostic significance of the presence of the TMPRSS2:ERG fusion gene on the risk of prostate cancer recurrence, adjusting for the established prognostic factors. We discovered that the fusion gene was expressed within the prostate cancer cells in 81 of 165 (49.1%) patients. Of the 165 patients, 43 (26.1%) developed prostate-specific antigen (PSA) relapse after a mean follow-up of 28 months. The subgroup of patients with the fusion protein had a significantly higher risk of recurrence (58.4% at 5 years) than did patients who lacked the fusion protein (8.1%, P<0.0001). In a multivariable analysis, the presence of gene fusion was the single most important prognostic factor; the adjusted hazard ratio for disease recurrence for patients with the fusion protein was 8.6 (95% CI=3.6–20.6, P<0.0001) compared to patients without the fusion protein. Among prostate cancer patients treated with surgery, the expression of TMPRSS2:ERG fusion gene is a strong prognostic factor and is independent of grade, stage and PSA level.

Do Older Men Benefit From Curative Therapy of Localized Prostate Cancer

PURPOSE Prior decision-analytic models are based on outdated or suboptimal efficacy, patient preference, and comorbidity data. We estimated life expectancy (LE) and quality-adjusted life expectancy (QALE) associated with available treatments for localized prostate cancer in men aged >/= 65 years, adjusting for Gleason score, patient preferences, and comorbidity. METHODS We evaluated three treatments, using a decision-analytic Markov model: radical prostatectomy (RP), external beam radiotherapy (EBRT), and watchful waiting (WW). Rates of treatment complications and pretreatment incontinence and impotence were derived from published studies. We estimated treatment efficacy using three data sources: cancer registry cohort data, pooled case series, and modern radiotherapy studies. Utilities were obtained from 141 prostate cancer patients and from published studies. RESULTS For men with well-differentiated tumors and few comorbidities, potentially curative therapy (RP or EBRT) prolonged LE up to age 75 years but did not improve QALE at any age. For moderately differentiated cancers, potentially curative therapy resulted in LE and QALE gains up to age 75 years. For poorly differentiated disease, potentially curative therapy resulted in LE and QALE gains up to age 80 years. Benefits of potentially curative therapy were restricted to men with no worse than mild comorbidity. When cohort and pooled case series data were used, RP was preferred over EBRT in all groups but was comparable to modern radiotherapy. CONCLUSION Potentially curative therapy results in significantly improved LE and QALE for older men with few comorbidities and moderately or poorly differentiated localized prostate cancer. Age should not be a barrier to treatment in this group.

Assessing individual risk for prostate cancer.

PURPOSE To construct a clinical nomogram instrument to estimate individual risk for having prostate cancer (PC) for patients undergoing prostate specific antigen (PSA) screening, using all risk factors known for PC. PATIENTS AND METHODS We conducted a cross-sectional study of 3,108 men who underwent a prostate biopsy, including a subset of 408 volunteers with normal PSA levels. Factors including age, family history of PC (FHPC), ethnicity, urinary symptoms, PSA, free:total PSA ratio, and digital rectal examination (DRE) were incorporated in the model. A nomogram was constructed to assess risk for any and high-grade PC (Gleason score >or= 7). RESULTS Of the 3,108 men, 1,304 (42.0%) were found to have PC. Among the 408 men with a normal PSA (< 4.0 ng/mL), 99 (24.3%) had PC. All risk factors were important predictors for PC by multivariate analysis (P, .01 to .0001). The area under the curve (AUC) for the nomogram in predicting cancer, which included age, ethnicity, FHPC, urinary symptoms, free:total PSA ratio, PSA, and DRE, was 0.74 (95% CI, 0.71 to 0.81) and 0.77 (95% CI, 0.74 to 0.81) for high-grade cancer. This was significantly greater than the AUC that considered using the conventional screening method of PSA and DRE only (0.62; 95% CI, 0.58 to 0.66 for any cancer; 0.69; 95% CI, 0.65 to 0.73 for high-grade cancer). From receiver operating characteristic analysis, risk factors including age, ethnicity, FHPC, symptoms, and free:total PSA ratio contributed significantly more predictive information than PSA and DRE. CONCLUSION In a PC screening program, it is important to consider age, family history of PC, ethnicity, urinary voiding symptoms, and free:total PSA ratio, in addition to PSA and DRE.

Expression of TMPRSS2:ERG gene fusion in prostate cancer cells is an important prognostic factor for cancer progression

The prostate-specific gene, TMPRSS2, is fused with the transcription factor gene, ERG in a high proportion of prostate cancers. However, the clinical significance of TMPRSS2:ERG gene fusion among prostate cancer patients is unknown. We assayed for the presence of the TMPRSS2:ERG gene fusion product among 26 patients who underwent surgery for clinically localized prostate cancer using RT-PCR and direct DNA sequencing, and evaluated its prognostic significance. All 26 patients had cancers of the same histologic grade (Gleason score 7). The fusion protein was present within prostate cancer tumor cells in eleven patients (42.3%). Nine patients experienced biochemical disease relapse (elevated PSA) after a mean follow-up of 12 months (range 1 to 48 months). Patients with the fusion protein had a significantly higher rate of recurrence (5-year recurrence rate 79.5%) compared to patients who lacked the fusion protein (5-year recurrence rate 37.5%, p=0.009). The adjusted hazard ratio for disease relapse for patients with the fusion protein was 7.1 (95% C.I.: 1.1 - 45, p = 0.03) compared to patients without the fusion protein. In multivariate analysis, the presence of gene fusion was the single most important prognostic factor. Our study indicates that the expression of TMPRSS2:ERG fusion gene among prostate cancer patients treated with surgery is a strong prognostic factor for disease relapse, and may have important clinical implications.

PREVALENCE AND PATTERNS OF THE USE OF COMPLEMENTARY THERAPIES AMONG PROSTATE CANCER PATIENTS: AN EPIDEMIOLOGICAL ANALYSIS

PURPOSE We determine the prevalence and patterns of the use of complementary therapies among patients with and those at high risk for prostate cancer. MATERIALS AND METHODS A cross-sectional survey was performed of men presenting to 2 urban tertiary urology clinics for prostate cancer evaluation or followup, and those attending a prostate cancer support group. All men diagnosed with and those at high risk (positive family history or abnormal prostate specific antigen) for prostate cancer were eligible for study. A 9-item self-administered, anonymous questionnaire about complementary therapies was administered. RESULTS Of 357 patients who received the survey 155 from the urology clinics and 113 from the support group responded, for a total response rate of 75%. Of the patients presenting to urology clinics and the support group 27.4 and 38.9% with and 25.8 and 80% at high risk for prostate cancer, respectively, used some form of complementary therapy. The use significantly differed according to disease status (p = 0.001), and was highest among men who were clinically disease-free after radical therapy. Of the patients 24% did not inform the urologist of using alternative therapy. CONCLUSIONS The prevalence of the use of complementary therapy among patients with or at increased risk for prostate cancer was high and dependent on the disease state. Urologists should be aware of this pattern of use, and consider the potential effects when assessing patients for and with prostate cancer.

Screening for Prostate Cancer with Prostate-Specific Antigen Testing: American Society of Clinical Oncology Provisional Clinical Opinion

PURPOSE An American Society of Clinical Oncology (ASCO) provisional clinical opinion (PCO) offers timely clinical direction to the ASCO membership after publication or presentation of potentially practice-changing data from major studies. This PCO addresses the role of prostate-specific antigen (PSA) testing in the screening of men for prostate cancer. CLINICAL CONTEXT Prostate cancer is the second leading cause of cancer deaths among men in the United States. The rationale for screening men for prostate cancer is the potential to reduce the risk of death through early detection. RECENT DATA Evidence from a 2011 Agency for Healthcare Research and Quality systematic review primarily informs this PCO on the benefits and harms of PSA-based screening. An update search was conducted to March 16, 2012, for additional evidence related to the topic. RESULTS In one randomized trial, PSA testing in men who would not otherwise have been screened resulted in reduced death rates from prostate cancer, but it is uncertain whether the size of the effect was worth the harms associated with screening and subsequent unnecessary treatment. Although there are limitations to the existing data, there is evidence to suggest that men with longer life expectancy may benefit from PSA testing. Adverse events associated with prostate biopsy are low for the majority of men; however, several population-based studies have shown increasing rates of infectious complications after prostate biopsy, which is a concern.

Incidence of complications other than urinary incontinence or erectile dysfunction after radical prostatectomy or radiotherapy for prostate cancer: a population-based cohort study

BACKGROUND Studies of complications resulting from surgery or radiotherapy for prostate cancer have mainly focused on incontinence and erectile dysfunction. We aimed to assess other important complications associated with these treatments for prostate cancer. METHODS We did a population-based retrospective cohort study, in which we used administrative hospital data, physician billing codes, and cancer registry data for men who underwent either surgery or radiotherapy alone for prostate cancer between 2002 and 2009 in Ontario, Canada. We measured the 5-year cumulative incidence of five treatment-related complication endpoints: hospital admissions; urological, rectal, or anal procedures; open surgical procedures; and secondary malignancies. FINDINGS In the 32 465 patients included in the study, the 5-year cumulative incidence of admission to hospital for a treatment-related complication was 22·2% (95% CI 21·7-22·7), but was 2·4% (2·2-2·6) for patients whose length of stay was longer than 1 day. The 5-year cumulative incidence of needing a urological procedure was 32·0% (95% CI 31·4-32·5), that of a rectal or anal procedure was 13·7% (13·3-14·1), and that of an open surgical procedure was 0·9% (0·8-1·1). The 5-year cumulative incidence of a second primary malignancy was 3·0% (2·6-3·5). These risks were significantly higher than were those of 32 465 matched controls with no history of prostate cancer. Older age and comorbidity at the time of index treatment were important predictors for a complication in all outcome categories, but the type of treatment received was the strongest predictor for complications. Patients who were given radiotherapy had higher incidence of complications for hospital admissions, rectal or anal procedures, open surgical procedures, and secondary malignancies at 5 years than did those who underwent surgery (adjusted hazard ratios 2·08-10·8, p<0·0001). However, the number of urological procedures was lower in the radiotherapy than in the surgery group (adjusted hazard ratio 0·66, 95% CI 0·63-0·69; p<0·0001) INTERPRETATION: Complications after prostate cancer treatment are frequent and dependent on age, comorbidity, and the type of treatment. Patients and physicians should be aware of these risks when choosing treatment for prostate cancer, and should balance them with the clinical effectiveness of each therapy. FUNDING Ajmera Family Chair in Urologic Oncology.