Prostate ...

[Michael Scally MD]

Testosterone Slows Prostate Cancer Recurrence in Low-Risk Patients
Testosterone Slows Prostate Cancer Recurrence in Low-Risk Patients

San Francisco, CA, USA (UroToday.com) -- In the largest such study so far undertaken, US researchers have shown that testosterone replacement slows the recurrence of prostate cancer in low-risk patients. This may call into question the general applicability of Nobel-Prize winning hormonal prostate treatment. The work is presented at the European Association of Urology congress in Barcelona.

Doctors have long regarded testosterone as a hormone which promotes prostate cancer. The 1941 work of Huggins and Hodges won Huggins the 1966 Nobel Prize for Medicine1, for reporting the dramatic impact of testosterone reduction on prostate cancer. Since then, medicines which reduce levels of the hormone testosterone have become a standard option for many patients2.

However, in the late 1990s to 2000s, doctors discovered that although men on long term anti-testosterone treatments were not dying from prostate cancer, they were dying prematurely of cardiovascular disease. It seemed that although anti-testosterone therapies were treating the prostate cancer, the extremely low testosterone levels were significantly worsening metabolic complications such as elevated blood sugar, diabetes, elevated cholesterol, mid-abdomen visceral fat, etc. Low testosterone also caused a loss of sexual function in many men on anti-androgen treatment. This led some doctors3 to suggest testosterone treatment of some low-risk men after radiation or surgical treatment.

What have they done?

Starting in 2008 a team of doctors from the University of California, Irvine, led by Professor Thomas Ahlering, began to carefully select patients for testosterone replacement after primary treatment of prostate cancer with robotic radical prostatectomy, in hopes of improving recovery of sexual function.

The team worked with 834 patients undergoing radical prostatectomy. They treated 152 low-risk patients with no evidence of disease with testosterone replacement therapy. After a median of 3.1 years following surgery, they tested the patients for biochemical recurrence of the cancer, as indicated by measurement of the Prostate Specific Antigen (PSA) levels. They found that the cancer had recurred in only approximately 5% of treated patients, whereas the cancer had recurred in 15% of the patients who did not receive testosterone. Overall, after accounting for differences between the groups, they found nearly a three-fold reduction by three years.


Thomas Ahlering commented “This is not what we set out to prove, so it was a big surprise: not only did testosterone replacement not increase recurrence, but it actually lowered recurrence rates. While the testosterone is not curing cancer per se, it is slowing the growth of cancer, giving an average of an extra 1.5 years before traces of cancer can be found. We already know that testosterone can help with physiological markers such as muscle mass, better cholesterol and triglyceride levels, and increased sexual activity, so this seems to be a win-win”.

He continued, “There have been smaller studies which have hinted that testosterone may not be risky for certain patient groups, but this is the largest such study ever conducted. We’re not suggesting that treatment methods be changed just yet, but this puts us at the stage where we need to question the taboo against testosterone use in prostate cancer therapy – especially for low-risk patients after radical prostatectomy. We need the oncology/urology community to begin to review testosterone use”.

Commenting, Professor Francesco Montorsi (Milano), European Association of Urology’s Adjunct Secretary General for Science said:

“The paper is indeed important, as it stresses the importance of checking testosterone levels as a part of the management of patients with sexual disorders following radical prostatectomy. Obviously selection of the right patients is vital, but if confirmed, this may have immediate benefits on quality of life; the possibility of reducing mortality would be an unexpected bonus. We now need bigger studies to support this work”.

 

[Michael Scally MD]

Melloni C, Roe MT. Androgen deprivation therapy and cardiovascular disease. Urologic oncology 2019. https://www.sciencedirect.com/science/article/pii/S1078143919300651?via=ihub

Highlights
· Prostate cancer is the most common cancer among men.
· Androgen deprivation therapy (ADT) is the mainstay treatment of advanced prostate cancer.
· ADT seems to be linked with increased cardiovascular morbidity and mortality.
· The underlying mechanism is multifactorial, including type of ADT and cardiovascular history.

Prostate cancer (PCa) is the most common cancer among men. Advances in early detection and successful treatments have improved cancer-specific survival. With prolonged survival, PCa patients now suffer from the effects of aging and are at increasing risk for the development of cardiovascular (CV) risk factors and CV disease. Androgen deprivation therapy (ADT) is the mainstay treatment of advanced PCa.

There is conflicting evidence about whether or not ADT is associated with increased CV morbidity and mortality. Metabolic abnormalities such as increasing body weight, reduced insulin sensitivity, dyslipidemia, and activation of T cells to the Th1 phenotype, resulting in atherosclerotic plaque destabilization, have been proposed as possible mechanisms by which ADT may increase the risk of CV events.

Type of ADT and preexisting CV history also seem to play a major role in the risk of subsequent CV events. Ongoing prospective clinical trials will help define whether there is any difference between gonadotropin-releasing hormone agonists and antagonists in terms of CV morbidity and mortality.

 

[Michael Scally MD]

EAU 2019: Case Based Debate: Hypogonadal Prostate Cancer Patient Following Treatment with Curative Intent: Pro versus Con
EAU 2019: Case Based Debate: Hypogonadal Prostate Cancer Patient Following Treatment with Curative Intent: Pro versus Con

Barcelona, Spain (UroToday.com) In this debate, Drs. Mulhall and Tombal debated the safety of testosterone replacement therapy in a prostate cancer patient. The index patient was a 58-year-old male with a pre-treatment PSA of 7.6 who, was 6 months status post radical prostatectomy for Gleason 4+3 prostate cancer with negative margins and an undetectable PSA, but symptomatic hypogonadism and erectile dysfunction despite tadalafil 5mg daily.

It was noted that physicians concerns regarding testosterone replacement therapy are worldwide, stemming from the original Huggins and Hodges data that reduction of testosterone to castrate levels caused prostate cancer to regress whereas administration of exogenous testosterone caused prostate cancer to grow. However, more contemporary data shows no strong evidence on testosterone replacement therapy and prostate cancer and current EAU evidence-based guidelines is listed as “weak”.

Dr. Mulhall argued in favor of administering testosterone replacement therapy in the post-prostatectomy patient. Risks of testosterone therapy include polycythemia, gynecomastia, and an absence of long term safety data in prostate cancer population. Benefits include reduction of cardiovascular events, improved glycemic control, bone density, and nerve recovery. Dr. Mulhall then explained the prostate cancer saturation model, where the receptors become saturated at a specific level and added testosterone does no harm. He explained in vitro and in vivo models which support this data. There is also data that supports testosterone as a neurogenic modulator and supports nerve recovery after prostatectomy.

He reviewed a 2017 multivariate analysis demonstrating that patients treated with neoadjuvant ADT were 13 times more likely to have severe ED following prostatectomy. Dr. Mulhall also reviewed the newest MSKCC data which will be released at the upcoming 2019 AUA conference, in which 360 patients status post radical prostatectomy for pT2 Gl 6-7 prostate cancer and undetectable PSA were treated with TRT. Only one patient had a biochemical recurrence at a median follow up of 66 months. Dr. Mulhall concluded that a shared decision making is essential and treatment may be necessary depending upon the patient's specific signs and symptoms of testosterone deficiency.

Dr. Tombal argued the contrary: that he would be reluctant to give this patient testosterone replacement. A 2017 multi-institutional study demonstrated that patients with pT2N0 Gl 7 prostate cancer have an approximately 15% and 20% recurrence and 5 and 10 years, respectively. This is also confirmed via MSKCC nomograms. Existing evidence supporting testosterone replacement therapy is very weak, consisting of small retrospective series with short follow up and most of the patients were Gl 6 disease.

Furthermore, Dr. Tombal refuted Dr. Mulhall’s analysis of the saturation model, due to the ignoring of the Coffey Paradox, and believe that prostate cancer is an extremely heterogeneous disease. In summary, Dr. Tombal believes that testosterone replacement therapy may add fuel to the fire – proceed with caution.

 

[Michael Scally MD]

[OA] epiCaPture: A Urine DNA Methylation Test for Early Detection of Aggressive Prostate Cancer

Purpose: Liquid biopsies that noninvasively detect molecular correlates of aggressive prostate cancer (PCa) could be used to triage patients, reducing the burdens of unnecessary invasive prostate biopsy and enabling early detection of high-risk disease. DNA hypermethylation is among the earliest and most frequent aberrations in PCa.

We investigated the accuracy of a six-gene DNA methylation panel (Epigenetic Cancer of the Prostate Test in Urine [epiCaPture]) at detecting PCa, high-grade (Gleason score greater than or equal to 8) and high-risk (D'Amico and Cancer of the Prostate Risk Assessment] PCa from urine.

Patients and Methods: Prognostic utility of epiCaPture genes was first validated in two independent prostate tissue cohorts. epiCaPture was assessed in a multicenter prospective study of 463 men undergoing prostate biopsy. epiCaPture was performed by quantitative methylation-specific polymerase chain reaction in DNA isolated from prebiopsy urine sediments and evaluated by receiver operating characteristic and decision curves (clinical benefit). The epiCaPture score was developed and validated on a two thirds training set to one third test set.

Results: Higher methylation of epiCaPture genes was significantly associated with increasing aggressiveness in PCa tissues. In urine, area under the receiver operating characteristic curve was 0.64, 0.86, and 0.83 for detecting PCa, high-grade PCa, and high-risk PCa, respectively.

Decision curves revealed a net benefit across relevant threshold probabilities. Independent analysis of two epiCaPture genes in the same clinical cohort provided analytical validation. Parallel epiCaPture analysis in urine and matched biopsy cores showed added value of a liquid biopsy.

Conclusion: epiCaPture is a urine DNA methylation test for high-risk PCa. Its tumor specificity out-performs that of prostate-specific antigen (greater than 3 ng/mL). Used as an adjunct to prostate-specific antigen, epiCaPture could aid patient stratification to determine need for biopsy.

O'Reilly E, Tuzova AV, Walsh AL, et al. epiCaPture: A Urine DNA Methylation Test for Early Detection of Aggressive Prostate Cancer. JCO precision oncology 2019;2019. https://ascopubs.org/doi/full/10.1200/PO.18.00134

 

[Michael Scally MD]

Overturning Dogma -- Using Testosterone in Prostate Cancer

Introduction & Objectives: The use of testosterone replacement therapy (TRT) is currently not recommended in patients with a history of prostate cancer. However, recent data has shown that higher levels of free testosterone (FT) are associated with lower grade cancers, and may be protective against early biochemical recurrence (BCR). We present a study examining the use of TRT in patients with prostate cancer undergoing radical prostatectomy (RP) and its effect on disease progression.

Materials & Methods: 850 patients who underwent robot-assisted RP for primary treatment of localized prostate cancer by a single surgeon between December 2009 and June 2018 were included. Prostate Specific Antigen (PSA), pathological grade, and pathological stage were prospectively collected. Post-operative PSA levels were used to assess BCR status (defined as 2 consecutive PSA values of 0.2 ng/dL or greater). Median follow up time after RARP was 2.75 years. Univariate and multivariate comparisons between patients on TRT and those not on TRT were used to assess differences in rates of BCR and time to BCR. Patients in the TRT group remained on TRT up until date of last follow up or until date of BCR.

Results: Out of 850 patients, 834 had values recorded for all pre-specified variables and 152 (18.2%) were treated with TRT. Of the patients on TRT, 15/152 (9.9%) developed BCR compared with 160/682 (23.5%) patients in the group not on TRT (p<0.001). Overall, 85 patients experienced BCR within a year after surgery, and 4 (4.7%) of those patients were on TRT compared to 81 (95.3%) not on TRT (p<0.0001). In multivariate analysis, being placed on TRT predicted a longer time to BCR and delayed progression by a median of 1.5 years, after adjusting for pathological grade and stage (p=0.005).

Conclusions: The use of TRT in patients with prostate cancer was shown to be beneficial by delaying time to BCR. In all patients that experienced BCR, those that were on TRT had a median 1.5 year longer latency of disease progression. These results provide further evidence that testosterone replacement may be beneficial in prostate cancer patients.

Towe M, Huynh LM, El-Khatib FM, Yafi FA, Ahlering T. 646 - Testosterone replacement therapy prevents disease progression in men undergoing radical prostatectomy. European Urology Supplements 2019;18:e859-e60. https://www.sciencedirect.com/science/article/pii/S1569905619306281

 

[Michael Scally MD]

Low Free Testosterone Is an Independent Risk Factor for High Grade Prostate Cancer.

Introduction & Objectives: The role of testosterone in prostate growth and the development of prostate cancer is a controversial topic. Most current data suggest that lower testosterone leads to higher grade conversion, whereas higher testosterone may serve a protective role in preventing both development and recurrence. We seek to analyze whether free testosterone (FT) values can predict aggressiveness in prostate cancers.

Materials & Methods: We retrospectively reviewed 830 patients who presented to a single surgeon for evaluation and management of prostate cancer. FT values were obtained on each patient at initial visit. All patients underwent radical prostatectomy and samples from surgery were sent for grading and staging.

Mean FT values for each Gleason score (GS) and stage were calculated and compared by in univariate and multivariate analysis. Patients were then stratified by FT quartile (25th [≤ 4.42 ng/dL], 50th [4.43 – 5.60 ng/dL], 75th [5.61 – 6.95 ng/dL], and 100th [≥ 6.96 ng/ dL]).

Results: Of 830 patients, 168 (22.2%), 330 (39.8%), 188 (22.7%), 46 (5.5%), and 98 (11.8%) had GS ≤3+3, 3+4, 4+3, 4+4, and ≥4+5, respectively. Mean FT values were significantly different in univariate analysis (p = 0.008).

In terms of stage, 553 (66.1%), 272 (32.5%), and 11 (1.3%) were T2, T3, and T4 at presentation, respectively, and mean FT was also lower in patients with higher stage disease (p = 0.01). Figure 1 depicts proportion of Gleason grade by level of FT.

Patients who had a FT level in the lowest quartile (≤ 4.42 ng/dL) had a higher proportion of Gleason grade group 5 (15.6%) than patients in the highest quartile (≥ 6.96 ng/dL) (6.2%) (p = 0.002). After adjusting for age and PSA in multivariate analysis, lower FT was a significant predictor of high-risk score 9-10 (OR: 0.912, 95% CI: 0.836-0.994, p=0.036).

These trends showed strong correlation in pathologic stage (p = 0.057), but larger numbers are needed to gauge effect size.

Conclusions: Based on our data, biochemically low FT may be a risk factor for high grade and high stage cancer. These results have implications for the current recommendations for testosterone therapy, which is contraindicated in men with prostate cancer.

Towe M, Huynh LM, El-Khatib FM, Osman M, Yafi F, Ahlering T. 107 - Low free testosterone is an independent risk factor for high grade prostate cancer. European Urology Supplements 2019;18:e137-e8. https://www.sciencedirect.com/science/article/pii/S156990561930106X

 

[Michael Scally MD]

Prostate Cancer (PCa) Incidence and Severity In 823 Hypogonadal Men with and Without Testosterone Therapy (TTh)

Introduction & Objectives: Guidelines by AUA and EAU state that there is no evidence for an increased PCa risk for testosterone therapy (TTh) in hypogonadal men.

Materials & Methods: In a registry study initiated in 2004 in a urology practice, 428 hypogonadal men (T≤350 ng/dL) received testosterone undecanoate (TU) 1000 mg every 3 months following an initial 6-month interval for up to 13 years (T-group). 395 hypogonadal men (age range 51-74) opted against TTh (CTRL).

Suspicion of or active PCa was excluded by transrectal ultrasound, digital rectal examination and PSA before treatment/observation initiation. Examinations were repeated between one and four times per year. Biopsies were performed when indicated according to EAU Guidelines.

Results: In the T-group, 12 men (2.8%) were diagnosed with PCa. In CTRL, 44 (11.1%) were diagnosed with PCa. The mean baseline age of PCa patients was 64.9 years in the T-group and 64.1 in CTRL. In the T-group, the average time span between the day of first injection and positive biopsy was 14.2 months (range: 5-18). No patient was diagnosed with PCa beyond 18 months of TTh. In CTRL, PCa was diagnosed at any time during the observation time.

In the T-group, radical prostatectomy (RP) was performed in all men. All but 3 patients had a Gleason score (GS) ≤6, and all but 1 had a primary GS of 3. Tumor grade was G2 in all 12 (100%), tumor stage T2a in 7 (58%), T2b in 3 (25%), and T2c in 2 (17%) patients. All but 2 patients are back on TTh after an average time of 25 months.

In CTRL, RP was performed in all but 8 patients who primarily received radiation therapy (RT; 6) or hormonal therapy (HT; 2). GS was ≤6 in 2 patients, 7 men had a GS of 7, 21 a GS of 8, and 14 a GS of 9. 4 men had a primary Gleason score of 3, 31 had 4, and 9 had 5. Tumor grade was G2 in 8 (18%) and G3 in 36 (82%) patients, tumor stage T2a in 2 (5%), T2c in 1 (2%), T3b in 15 (34%) and T3c in 26 (59%) patients.

In CTRL, biochemical recurrence occurred in 14 (32%) patients. These patients received androgen deprivation therapy (ADT). 12 (27%) patients died of whom 7 were on ADT. In the T-group, no biochemical recurrences or deaths occurred during the observation time.

Conclusions: Less PCa occurred and severity was lower in testosterone-treated hypogonadal patients compared to untreated hypogonadal controls.

Haider A, Haider KS. 106 - Prostate cancer (PCa) incidence and severity in 823 hypogonadal men with and without testosterone therapy (TTh) in a controlled, observational registry study over up to 14 years. European Urology Supplements 2019;18:e136. https://www.sciencedirect.com/science/article/pii/S1569905619301058

 

[Michael Scally MD]

The Association of Metabolic Syndrome and Its Components with Serum Prostate-Specific Antigen Levels

Metabolic syndrome (MetS) can increase the risk of prostate cancer. Prostate-specific antigen (PSA) is the marker for prostate cancer puncture screening. The aim of our study was to investigate the association between MetS and its components with PSA levels.

Data were obtained from 482 943 healthy men who underwent routine health check-ups from January 2010 to December 2017. We used linear regression analysis to evaluate the effects of MetS and its components on PSA levels. To explore the cumulative effect of MetS components, analysis of variance trend analysis was carried out.

The PSA levels in the group with MetS were significantly lower than those without MetS (P=0.001).

In the multivariate regression model,
· age (P<0.001) and
· hypertension (P<0.001)

were correlated positively with PSA levels;

nevertheless,
· obesity (P<0.001),
· hypertriglyceridemia (P<0.001),
· hyperglycemia (P<0.001), and
· low high-density lipoprotein cholesterol level (P<0.001)

had a negative correlation.

In addition, after adjustment for age, increasing sums of positive MetS components were associated with a linear decrease in PSA levels (P<0.001).

In conclusion, MetS, obesity, hypertriglyceridemia, hyperglycemia, and low high-density lipoprotein cholesterol levels are associated with decreased PSA levels. For patients with PSA levels at the critical value of prostate puncture, the effect of these diseases in reducing PSA levels should be taken into account.

Gao X, Bao T, Yang H, et al. The association of metabolic syndrome and its components with serum prostate-specific antigen levels. European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation (ECP) 2019. The association of metabolic syndrome and its components... : European Journal of Cancer Prevention

 

[Michael Scally MD]

Testosterone Supplementation in Relation to Prostate Cancer In A US Commercial Insurance Claims Database
Program Planner

Background: Testosterone supplementation (TS) has dramatically increased in the United States (US). We conducted a study of TS and prostate cancer risk using a large US commercial insurance research database.

Methods: From the HealthCore Integrated Research Database (HIRDSM), we selected men aged 30 years or greater who were new users of TS during 2007-2015. We selected two male comparison groups:
1) unexposed (matched 10:1);
2) new users of a phosphodiesterase type 5 inhibitor (PDE5i).

Incident prostate cancer was defined as diagnosis of prostate cancer within four-weeks following prostate biopsy.

Propensity scores and inverse probability of treatment weights were used in Poisson regression models to estimate adjusted incidence rates, incidence rate ratios (IRRs) and 95% confidence intervals (CI) using doubly robust estimation. Subgroup analyses included stratification by prostate cancer screening, hypogonadism, and follow-up time.

Results: The adjusted prostate cancer IRR was 0.77 (95%CI: 0.68, 0.86) when comparing TS with the unexposed group and 0.85 (95%CI: 0.79, 0.91) in comparison with the PDE5i group. Inverse associations between TS and prostate cancer were observed in a majority of subgroup analyses, although in both comparisons estimates generally attenuated with increasing time following initial exposure. Amongst TS users, duration of exposure was not associated with prostate cancer.

Conclusion: In this study, men who received TS did not have a higher rate of prostate cancer compared with the unexposed or PDE5i comparison groups. The inverse association between TS and prostate cancer could be the result of residual confounding, contraindication bias, or undefined biologic effect.

 

[Michael Scally MD]

Circulating Testosterone in Modifying the Association of BMI Change Rate with Serum PSA In Prostate Cancer-Free Men with Initial-PSA Less Than 4 ng/ml
Program Planner

Background: Body mass index (BMI)-adjusted prostate-specific antigen (PSA) model has been proposed to improve the predictive accuracy of serum PSA in prostate cancer (PCa) screening. However, how BMI change rate may influence PSA levels in PCa-free men has not been well studied. The current study is to examine the relationship between BMI change rate and serum PSA in PCa-free men and whether this relationship is modified by circulating testosterone.

Methods: We conducted this study at a tertiary hospital in the Southeastern US using the Electronic Medical Records of PCa-free men with initial PSA less than 4 ng/mL (cutoff for prostate biopsy), at least 1 testosterone measurement and at least 2 BMI measurements during the study period.

Time when the first BMI measurement was recorded served as the baseline, and the study period was defined from baseline to the most recent hospital visit. The included medical records ranged from Jun 2001 to Oct 2015. BMI change rate was created in two ways depending on the number of data points.

For men with only 2 BMI measurements, it was calculated by firstly subtracting baseline BMI from the second BMI, then dividing the difference by time interval (months) between the two BMI measurements. For men with more than 2 BMI measurements, we firstly regressed BMI to time interval (months) between that measurement and baseline, then took the β regression coefficient (slope) as the BMI change rate for that men.

Multivariable linear regression was used to assess the association of BMI change rate with three PSA measures, including peak, the most recent, and mean PSA during the study period. Effect modification by testosterone was assessed through stratified analysis by testosterone level of 280 ng/dL as cutoff.

Results: A total of 470 men with a mean study period of 97.6 months were included. Median age at baseline was 62 years. After adjusting for covariates including baseline BMI, no significant association of BMI change rate was observed with peak PSA (β =0.416, P =0.078), the most recent PSA (β =0.360, P =0.139), or mean PSA (β =0.405, P =0.064) in the overall sample.

However, testosterone-stratified analyses indicated that BMI change rate was positively associated with peak PSA (β =1.118, P =0.013), the most recent PSA (β =0.932, P =0.044), and mean PSA (β =1.034, P =0.013) in men with testosterone <280 ng/dL, but no significant association was observed in men with testosterone ≥280 ng/dL (for peak PSA, β =0.076, P =0.785; for the most recent PSA, β =0.072, P =0.802; for mean PSA, β =0.099, P =0.700).

Conclusion: Accelerated BMI increase in middle-to-late adulthood might correlate with higher PSA level if a low circulating testosterone occurred concurrently. Further studies are needed to confirm this finding.

 

[Michael Scally MD]

Zhang X, Zhong Y, Taylor N, Xu X. Family history of prostate cancer and age-related trend of testosterone levels among US males: NHANES 2003-2004. Andrology 2019. https://onlinelibrary.wiley.com/doi/abs/10.1111/andr.12609
BACKGROUND: Studies have suggested that rapid age-related declines of testosterone (T) level may play a critical role in the development of prostate cancer (PCa), and family history of PCa is another well-established risk factor of PCa, which have been reported to be associated with androgen metabolism-related genes.

However, few studies have ever investigated whether a family history of PCa influences the risk of PCa via regulating the age-related trend of T level among males over the life course.

OBJECTIVES: To examine the association between family history of PCa and age-related trend of T levels.

MATERIALS AND METHODS: We used National Health and Nutrition Examination Survey (NHANES) data from 2003 to 2004 (n = 322) to compare the age-specific T levels in males with a family history of PCa and those without.

RESULTS: We found that between two younger age groups (ages 20-39 and 40-59), there was a more pronounced drop-off in T levels among men with a family history of PCa compared to men without a family history.

DISCUSSION AND CONCLUSION: This preliminary analysis suggested that men with a family history of PCa may experience a sharper decline in T level over the life course as compared to males without a family history. However, no conclusions can be made due to small sample sizes. Further longitudinal studies with large sample sizes are needed.

 

[Michael Scally MD]

Safety of Testosterone Replacement Therapy after Radical Prostatectomy (RP) for Localized Prostate Cancer

INTRODUCTION AND OBJECTIVES: The safety of testosterone replacement therapy in men who have undergone radical prostatectomy (RP) for localized prostate cancer remains undefined.

METHODS: In a large national cohort, the Veterans Affairs Informatics and Computing Infrastructure, we identified node-negative and non-metastatic prostate cancer patients diagnosed between 2001-2015 treated with RP. We excluded patients for missing covariate and follow-up data. We then coded receipt of testosterone replacement after RP as a time-dependent covariate.

Other covariates included: age, Charlson Comorbidity index, diagnosis year, body mass index, race, PSA, clinical T/N/M stage, Gleason score, and receipt of hormone therapy. Biochemical recurrence was defined as a post-RP PSA≥0.2. We evaluated prostate cancer-specific survival, overall survival, and biochemical recurrence free survival using multivariable Cox regression.

RESULTS: Our cohort included 28,651 patients, of whom 469 (1.6%) received testosterone replacement after RP. Median follow up was 7.4 years. There were no differences in clinical T stage, median post-RP PSA (testosterone: 0 non-testosterone: 0; p=0.18), or hormone therapy use between treatment groups.

Testosterone patients were more likely to be of younger age, have higher comorbidity, non-black, have a lower median pre-treatment PSA (5.0 vs 5.8; p<0.001), and have higher BMI. The median time from RT to TRT was 3.0 years.

After controlling for potential confounders, we found no difference in prostate cancer specific mortality (HR 0.73; 95% CI 0.32-1.62; p=0.43), overall survival (HR 1.11; 95% CI 0.86-1.44; p=0.43), non-cancer mortality (HR 1.17; 95% CI 0.89-1.55; p=0.26) biochemical recurrence free survival (HR 1.07; 95% CI 0.84-1.36; p=0.59) between testosterone users and non-users.

CONCLUSIONS: To our knowledge, this cohort is the largest comparative analysis to date of testosterone therapy after RP. These data suggest that testosterone replacement is safe in patients who have undergone definitive management of localized prostate cancer with RP.

Sarkar R, Parsons JK, Einck J, et al. Safety of testosterone replacement therapy after radical prostatectomy (RP) for localized prostate cancer: A population-based analysis. Presented at the 2019 American Urological Association annual meeting held May 3-6 in Chicago. Abstract PD28-12. American Urological Association

 

[Michael Scally MD]

Safety of Testosterone Replacement After Radiation Therapy For Localized Prostate Cancer

INTRODUCTION AND OBJECTIVES: The safety of testosterone replacement therapy in men who have undergone radiation therapy (RT) for localized prostate cancer remains undefined.

METHODS: In a large national cohort, the Veterans Affairs Informatics and Computing Infrastructure, we identified node-negative and non-metastatic prostate cancer patients diagnosed between 2001-2015 treated with RT. We excluded patients for missing covariate and follow-up data. We then coded receipt of testosterone replacement after RP as a time-dependent covariate.

Other covariates included: age, Charlson Comorbidity index, diagnosis year, body mass index, race, PSA, clinical T/N/M stage, Gleason score, and receipt of hormone therapy. Biochemical recurrence was defined as a post-RP PSA≥ 0.2. We evaluated prostate cancer-specific survival, overall survival, and biochemical recurrence free survival using multivariable Cox regression.

RESULTS: Our cohort included 41,544 patients, of whom 544 (1.3%) received testosterone replacement after RT. There were no differences in Charlson comorbidity, clinical T stage, median pre-treatment PSA or Gleason score between treatment groups.

Testosterone patients were more likely to be of younger age, non-black, have a lower median post-treatment PSA nadir (0.1 vs. 0.2; p<0.001), have higher BMI, and have used hormone therapy (46.7% vs 40.3%; p=0.003). Median duration of ADT usage was equivalent between treatment groups (testosterone: 185 days vs. non-testosterone: 186 days, p=0.77). The median time from RT to TRT was 3.52 years.

After controlling for differences in covariates between treatment groups, we found no difference in prostate cancer specific mortality (HR 1.02; 95% CI 0.62-1.67; p=0.95), overall survival (HR 1.02; 95% CI 0.84-1.24; p=0.86), non-cancer mortality (HR 1.02; 95% CI 0.82-1.27; p=0.86) biochemical recurrence free survival (HR 1.07; 95% CI 0.90-1.28; p=0.45).

CONCLUSIONS: To our knowledge, this population-based cohort is the largest comparative analysis to date of testosterone therapy after RT. These data suggest that testosterone replacement is safe in patients who have undergone definitive management of localized prostate cancer with RT.

Sarkar R, Parsons J, Einck J, et al. Safety of testosterone replacement after radiation therapy for localized prostate cancer: A population-based analysis. Presented at the 2019 American Urological Association annual meeting held May 3-6 in Chicago. Abstract MP58-12. American Urological Association

 

[Michael Scally MD]

Biochemical Recurrence Rates in Men with High Grade Prostate Cancer on Testosterone Therapy

INTRODUCTION AND OBJECTIVES: Testosterone therapy (TTH) in men with prostate cancer is controversial especially in men with high risk prostate cancer. This study assessed biochemical recurrence (BCR) rates in men with high risk prostate cancer.

METHODS: We reviewed men who underwent radical prostatectomy (RP) with high risk prostate cancer (HRPC), defined as having a Gleason (GS) score of GS 6-7 with positive surgical margins (SMS+), lymph node involvement (LNI+), seminal vesicle involvement (SVI+) or GS ≥8 with any pathology status. BCR was defined as a prostate specific antigen (PSA) level of ≥ 0.1ng/mL.

Low T was defined as an early morning total T (TT) <300nd/dl. Men were divided into 3 groups based on T levels and TTH: those with normal TT levels and no TTH (NT); men with low TT who did not receive TTH; men with low TT who received TTH.

Clinical and pathological data were analyzed. Chi-square and ANOVA were performed for group comparisons. A series of proportional hazards models were estimated to assess the unadjusted and adjusted associations of predictors to time-to-BCR. Each predictor was fitted in an unadjusted model, then significant predictors from unadjusted models were included in a single adjusted model.

RESULTS: 1,407 men with HRPC were analyzed. Mean age = 61.7±7 years. 793 (56%) had normal TT (NT) levels with a mean TT of 481±156 ng/dL. 614 men had low TT levels (mean TT 136.2 ± 113.5 ng/dL), 590 not on TTH (LTNT), and 24 on TTH (LTT).

Among men with low TT levels, those on TTH did not differ significantly from those not on TTH, by pathology status, but had lower Gleason scores (p=0.010) and were less likely to be LNI positive (17% LTT, 41% LTNT, p =0.041).

Of the men on TTH, 25% were ≥ GS 8; of the GS 6-7 patients, 63% were SMS+, 42% SVI+, 17% LNI+.

In our cohort, a total of 906 (64%) patients experienced BCR within 0.1-15.3 years. 57% of the NT group, 75% in the LTNT group and 46% of men in the LTT group (LTNT compared to LTT p=0.001).

Older age, higher Gleason score, LNI+, SVI+, receipt of chemotherapy, radiation, or ADT, low T and TTH were associated with faster BCR rates in unadjusted models.

After adjustment, low T and TTH were not associated with BCR after covariate adjustment.

CONCLUSIONS: Men with HRPC with low T levels on TTH did not show an increased incidence of BCR when compared to men with HRPC who were not on TTH and men with normal TT levels.

Bernie HL, Salter CA, Schofield EA, et al. Biochemical recurrence rates in men with high grade prostate cancer on testosterone therapy. Presented at the 2019 American Urological Association annual meeting held May 3-6 in Chicago. Abstract MP58-10. American Urological Association

 

[Michael Scally MD]

Testosterone Therapy in Men with Gleason 6-7 Prostate Cancer

INTRODUCTION AND OBJECTIVES: The administration of exogenous testosterone (T) to men who have undergone radical prostatectomy (RP) for prostate cancer remains controversial. Besides small case series there are no large population, long-term studies assessing the safety of this treatment in this population.

We have adopted a policy of allowing the decision regarding T therapy in men post-RP to be a negotiated one with a comprehensive discussion of the data and the pros and cons of T therapy. This prospective study was undertaken to define the safety of exogenous T therapy in men post-RP.

METHODS: Men were considered candidates for T therapy if
(i) they had two early morning total T level <300 ng/dl
(ii) had symptoms/signs of TD
(iii) had pathologically organ-confined, Gleason 6-7 prostate cancer and
(iv) an undetectable PSA level post-RP pre-commencement of T therapy.

Once men opted for treatment they had labs tested 4 weeks later. T dose was titrated to achieve a serum level of 500-600ng/dl. Patients had serum T levels and PSA checked every 6 months.

RESULTS: A total of 360 patients have been prescribed T therapy to date. Mean age and pre-RP PSA levels were 59±12 years and 4±6 ng/dl respectively. Baseline total T levels were 228±94 (80-296) ng/dl. 48% had a Gleason Score (GS) of 6, 42% had GS 7 disease.

Median time post-RP before T therapy was commenced was 9 months (IQR 9, 112) months. 28% were using clomiphene, 56% transdermal T and 16% IM T to achieve therapeutic T levels.

Mean post-treatment total T was 520±280 (396-920) ng/dl. Median duration on T therapy at last follow-up was 38 (IQR 6, 112) months equating to mean duration post-RP of 66±41 months. A single man had a PSA recurrence at a time point 2.5 years post-RP.

CONCLUSIONS: In this series of carefully selected patients (G≤7, organ confined disease, post-RP undetectable PSA level)the administration of exogenous T for the treatment of TD appears to be safe 3 years post-T administration.

Mulhall J, Benfante N, Teloken, et al. Testosterone therapy in men with Gleason 6-7 prostate cancer. Presented at the 2019 American Urological Association annual meeting held May 3-6 in Chicago. Abstract MP58-13. American Urological Association

 

[Michael Scally MD]

Testosterone Therapy in Men on Active Surveillance for Prostate Cancer

INTRODUCTION AND OBJECTIVES: The role of testosterone (T) therapy in men with prostate cancer is debated. There is a paucity of long-term data in men on active surveillance (AS) for prostate cancer. This analysis attempted to define the safety of T therapy in this population.

METHODS: Men on active surveillance for prostate cancer who had T deficiency constituted the study population. Men were treated with exogenous T (topical, intramuscular) agents or clomiphene if they had low or low-normal LH levels.

T dose was titrated to achieve a serum level in the middle tertile of the reference range. Patients had serum T levels checked every 6 months and PSA levels checked every 3 months in the first year and every 6 months thereafter.

RESULTS: A total of 86 patients have been prescribed T therapy to date. Mean age and pre-RP PSA levels were 55±11 years and 5±2 ng/dl respectively. Baseline total T levels were 240±60 ng/dl. 92% had a Gleason Score (GS) of 6, 8% had GS 7 disease.

Mean duration on AS before T therapy was commenced was 13±15 months. Post-treatment total T levels were 515±190 ng/dl. Mean duration on T supplementation at last follow-up was 19±21 months.

Mean PSA level change per patient was 0.6±0.3 nd/dl with 26% of men experiencing a PSA level increase ≥1 (70% baseline total T levels <200 ng/dl). 16% of men on T therapy opted for definitive therapy for their prostate cancer.

CONCLUSIONS: These data suggest that T therapy does not result in significant PSA changes in men on active surveillance for prostate cancer. The rate of progression definitive therapy was similar to previously reported data.

Mulhall J, Benfante N, Teloken P, et al. Testosterone therapy in men on active surveillance for prostate cancer. Presented at the 2019 American Urological Association annual meeting held May 3-6 in Chicago. Abstract MP58-14. American Urological Association

 

[Michael Scally MD]

Association of Treatment With 5α-Reductase Inhibitors With Time to Diagnosis and Mortality in Prostate Cancer

Key Points

Question - Does prediagnostic 5α-reductase inhibitor use, with associated prostate-specific antigen suppression, lead to delayed diagnosis and increased risk of death from prostate cancer in a prostate specific antigen–screened population?

Findings - In this population-based cohort study of 80 875 men with prostate cancer, prediagnostic 5α-reductase inhibitor users had longer time from first elevated prostate-specific antigen test result to diagnosis, higher adjusted prostate-specific antigen at diagnosis, more advanced disease at diagnosis, and worse prostate cancer–specific and all-cause mortality compared with nonusers.

Meaning - Prediagnostic use of 5α-reductase inhibitors is associated with delayed prostate cancer diagnosis and increased mortality in men who underwent prostate-specific antigen screening.

Sarkar RR, Parsons JK, Bryant AK, et al. Association of Treatment With 5α-Reductase Inhibitors With Time to Diagnosis and Mortality in Prostate Cancer. JAMA internal medicine 2019. 5α-Reductase Inhibitors and Time to Diagnosis and Mortality in Prostate Cancer

Importance - 5α-Reductase inhibitors (5-ARIs), commonly used to treat benign prostatic hyperplasia, reduce serum prostate-specific antigen (PSA) concentrations by 50%. The association of 5-ARIs with detection of prostate cancer in a PSA-screened population remains unclear.

Objective - To test the hypothesis that prediagnostic 5-ARI use is associated with a delayed diagnosis, more advanced disease at diagnosis, and higher risk of prostate cancer–specific mortality and all-cause mortality than use of other or no PSA-decreasing drugs.

Design, Setting, and Participants - This population-based cohort study linked the Veterans Affairs Informatics and Computing Infrastructure with the National Death Index to obtain patient records for 80 875 men with American Joint Committee on Cancer stage I-IV prostate cancer diagnosed from January 1, 2001, to December 31, 2015. Patients were followed up until death or December 31, 2017. Data analysis was performed from March 2018 to May 2018.

Exposures - Prediagnostic 5-ARI use.

Main Outcomes and Measures - The primary outcome was prostate cancer–specific mortality (PCSM). Secondary outcomes included time from first elevated PSA (defined as PSA≥4 ng/mL) to diagnostic prostate biopsy, cancer grade and stage at time of diagnosis, and all-cause mortality (ACM). Prostate-specific antigen levels for 5-ARI users were adjusted by doubling the value, consistent with previous clinical trials.

Results - Median (interquartile range [IQR]) age at diagnosis was 66 (61-72) years; median [IQR] follow-up was 5.90 (3.50-8.80) years. Median time from first adjusted elevated PSA to diagnosis was significantly greater for 5-ARI users than 5-ARI nonusers (3.60 [95% CI, 1.79-6.09] years vs 1.40 [95% CI, 0.38-3.27] years; P < .001) among patients with known prostate biopsy date.

Median adjusted PSA at time of biopsy was significantly higher for 5-ARI users than 5-ARI non-users (13.5 ng/mL vs 6.4 ng/mL; P < .001). Patients treated with 5-ARI were more likely to have Gleason grade 8 or higher (25.2% vs 17.0%; P < .001), clinical stage T3 or higher (4.7% vs 2.9%; P < .001), node-positive (3.0% vs 1.7%; P < .001), and metastatic (6.7% vs 2.9%; P < .001) disease than 5-ARI nonusers. In a multivariable regression, patients who took 5-ARI had higher prostate cancer–specific (subdistribution hazard ratio [SHR], 1.39; 95% CI, 1.27-1.52; P < .001) and all-cause (HR, 1.10; 95% CI, 1.05-1.15; P < .001) mortality.

Conclusions and Relevance - Results of this study demonstrate that prediagnostic use of 5-ARIs was associated with delayed diagnosis and worse cancer-specific outcomes in men with prostate cancer. These data highlight a continued need to raise awareness of 5-ARI-induced PSA suppression, establish clear guidelines for early prostate cancer detection, and motivate systems-based practices to facilitate optimal care for men who use 5-ARIs.

 

[Michael Scally MD]

Nascimento B, Miranda EP, Jenkins LC, Benfante N, Schofield EA, Mulhall JP. Testosterone Recovery Profiles After Cessation of Androgen Deprivation Therapy for Prostate Cancer. The journal of sexual medicine 2019. https://www.jsm.jsexmed.org/article/S1743-6095(19)30735-0/abstract

INTRODUCTION: Androgen deprivation therapy (ADT) is frequently used in the treatment of prostate cancer worldwide. Variable testosterone (T) recovery profiles after ADT cessation have been cited.

AIM: To evaluate T recovery after cessation of ADT. METHODS: We reviewed our institutional prospectively maintained database of patients with prostate cancer who received ADT. Serum early morning total T (TT) levels, collected at baseline and periodically after ADT cessation, were analyzed. Patient age, baseline T level, duration of ADT, and presence of diabetes and sleep apnea were selected as potential predictors of T recovery.

3 metrics of T recovery after 24 months of ADT cessation were analyzed: return to non-castrate level (TT > 50 ng/dL), return to normal (T > 300 ng/dL), and return back to baseline level (BTB).

Multivariable time-to-event analysis (Cox proportional hazards), chi(2) test, logistic regression model, and Kaplan-Meier curve were performed to define impact of the above predictors on time and chance of T recovery.

MAIN OUTCOME MEASURES: Time and chance of T recovery to non-castrate level (TT > 50 ng/dL), return to normal (T > 300 ng/dL), and return BTB.

RESULTS: 307 men with a mean age of 65 +/- 8 years were included. Mean duration of ADT was 17 +/- 25 months, and median follow-up was 31 +/- 35 months. Mean TT values were 379 ng/dL at baseline and 321 ng/dL at >24 months.

At 24 months after cessation of ADT, 8% of men remained at castrate level, 76% returned to TT >300 ng/dL, and 51% had returned BTB. Lower baseline T levels (TT < 400 ng/dL) and ADT duration >6 months were associated with a lower likelihood of recovery to normal TT at 24 months. Age >65 years and receiving ADT for >6 months were significantly associated with a slower T recovery.

CLINICAL IMPLICATIONS: T recovery after ADT is not certain and may take longer than expected. Considering the range of side effects of low T, we believe that these findings must be discussed with patients before initiating such therapies.

STRENGTHS & LIMITATIONS: Our strengths consisted of a relatively large database, long follow-up, and clinically meaningful endpoints. Limitations included the retrospective design of the study.

CONCLUSION: T recovery rates after ADT cessation vary according to patient age, ADT duration, and baseline T levels. Approximately one-quarter of patients failed to normalize their TT level, and one-tenth of men remained at castrate levels 24 months after ADT cessation.

 

[Michael Scally MD]

[OA] Kadomoto S, Shigehara K, Iwamoto H, et al. Testosterone Replacement Therapy for Patients with Hypogonadism after High Dose-Rate Brachytherapy for High-Risk Prostate Cancer: A Report of Six Cases and Literature Review. World J Mens Health 2019. Testosterone Replacement Therapy for Patients with Hypogonadism after High Dose-Rate Brachytherapy for High-Risk Prostate Cancer: A Report of Six Cases and Literature Review

We had six cases of patients who were treated with long-term testosterone replacement therapy (TRT) after high dose-rate (HDR) brachytherapy and androgen deprivation therapy for high-risk prostate cancer.

All patients were given testosterone enanthate by intramuscular injection every 3 to 4 weeks. Blood biochemistry including prostate specific antigen (PSA) level was evaluated every 3 to 6 months after TRT, and radiological imaging was performed every 12 months.

All patients had slight increases in PSA within the normal range and not indicative of biochemical recurrence. A sudden increase in PSA was observed in one patient, but it finally decreased. Aging male symptoms scale and various metabolic factors were improved by TRT in all of cases. Although adverse events included polycythemia in one patient, no patients experienced disease recurrence or progression during TRT.

Our results suggest TRT for high risk-patients with HDR brachytherapy for prostate cancer may be beneficial and safe.

 

[Michael Scally MD]

The predictive power of free (vs. total) testosterone in aggressive prostate cancer.
The predictive power of free (vs. total) testosterone in aggressive prostate cancer. | 2019 ASCO Annual Meeting Abstracts

Background: The role of testosterone in prostate growth and the development of prostate cancer is a controversial topic. Most current data suggest that lower testosterone leads to higher grade conversion, whereas higher testosterone may serve a protective role in preventing both development and recurrence. We seek to analyze whether free testosterone (FT) values can predict aggressiveness in prostate cancers.

Methods: We retrospectively reviewed 830 patients who presented to a single surgeon for evaluation and management of prostate cancer. Total Testosterone (TT) and FT values were obtained on each patient at initial visit. All patients underwent radical prostatectomy and samples from surgery were sent for grading and staging. Patients were stratified by FT quartile (25th [≤ 4.42 ng/dL], 50th [4.43 – 5.60 ng/dL], 75th [5.61 – 6.95 ng/dL], and 100th [≥ 6.96 ng/dL]).

Results: Of 830 patients, 168 (22.2%), 330 (39.8%), 188 (22.7%), 46 (5.5%), and 98 (11.8%) had GS 3+3, 3+4, 4+3, 4+4, and ≥4+5, respectively.

Mean FT values for each Gleason grade group (GGG) were significantly different (p = 0.008). Mean FT was also lower in patients with higher stage disease (p = 0.01). In contrast, TT did not differ significantly among GGG (p = 0.489) or stage (p = 0.670). Patients who had a FT level in the lowest quartile (≤ 4.42 ng/dL) had a higher proportion of GGG 5 (15.6%) than patients in the highest quartile (≥ 6.96 ng/dL) (6.2%) (p = 0.002).

After adjusting for age, prostate specific antigen (PSA), and body mass index (BMI) in multivariate analysis, lower FT was a significant predictor of high-risk score 9-10 (OR: 0.912, 95% CI: 0.836-0.994, p = 0.036). These trends showed strong correlation in pathologic stage (p = 0.057), but larger numbers are needed to gauge effect size.

Conclusions: Based on our data, biochemically low FT may be a risk factor for high grade and high stage cancer. These results have implications for the current recommendations for testosterone therapy, which is contraindicated in men with prostate cancer.