Badar M. Mian, MD

offers perspective on noteworthy research in the peer-reviewed literature. Dr. Mian is professor of surgery in the division of urology at Albany Medical College, New York.

Active surveillance (AS) strategies for prostate cancer with low-risk features, such Grade Group 1 (GG1), are increasingly being utilized to avoid treatment-related complications. Due to the long natural history of prostate cancer and low risk of progression, long-term risk of metastasis or death is not well defined, resulting in some uncertainty about patient selection for AS. A recent study by Maggi et al noted that although reclassification of the initial biopsy Grade Group or switch from surveillance to active treatment occurred frequently, less than 1% of men died of prostate cancer.

 They analyzed the data from a large, prospectively maintained AS cohort to identify the variables associated with disease progression and metastases while on AS.

The investigators identified 1450 men on AS between 1990 and 2018 who met the inclusion criteria of low- or intermediate-risk prostate cancer. AS eligibility criteria included organ-confined disease with biopsy GG1, 33% or less positive biopsy cores, and PSA density (PSAD) lower than 0.15 ng/mL/cm3. However, few selected patients with GG2 and/or higher PSAD were also enrolled into the AS program. 1303 patients (90%) were diagnosed with initial biopsy GG1 and 147 (10%) with GG2. Median PSA at initial biopsy was 5.4 ng/mL, with median PSAD of 0.13 ng/mL/cm3. Median age was 62 years and median follow-up was 77 months. Additional testing such as Genomic Prostate Score (GPS) was performed in 34% of men (mean GPS 25), whereas multiparametric magnetic resonance imaging (mpMRI) was performed in 46% of men, of whom 24% had lesions classified as Prostate Imaging Reporting and Data System (PI-RADS) 4-5.

The primary outcome of interest was emergence of metastatic prostate cancer noted on imaging or pathology of delayed prostatectomy. Secondary outcomes included upgrading on surveillance biopsy to GG2 or greater, receipt of active treatment, and prostate cancer-specific and overall survival. For this analysis, patients were divided into 3 subgroups based on the initial biopsy GG and PSA. Of these, GG1 with PSAD lower than 0.15 was noted in 57%, GG1 with PSAD of 0.15 or higher in 32%, and GG2 in 10%.

At 7 years, biopsy GG upgrade-free survival was 40%, and median time to biopsy GG upgrade was 25 months. The 7-year upgrade-free survival was higher in patients with initial GG1 with PSAD lower than 0.15 (47%) compared with those with GG1 with PSAD of 0.15 or higher (28%) or initial GG2 (44%) (log rank 

 < .01). The 7-year treatment-free survival was 59%, with a median time to receiving active treatment of 32 months. The 7-year treatment-free survival was higher in patients with initial GG1 with PSAD lower than 0.15 (69%) compared with those with GG1 with PSAD of 0.15 or higher (46%) or initial GG2 (42%) (log rank 

At 7 years, metastasis-free survival was 99%, and median time to metastases was 62 months. Of the 15 patients who developed metastases, 2 were lost to follow-up, 9 had lymph node metastasis, 2 had lymph node and bone metastasis, 1 had bone metastasis, and 1 had bone and visceral organ metastasis. Initial biopsy GG2 disease was associated with lower 7-year metastasis-free survival (96%) than those with GG1 with PSAD lower than 0.15 (99 %) and with GG1 with PSAD of 0.15 or higher (100%) (log rank 

 < .01). On multivariable analysis, risk factors for increased risk of metastases included initial GG2, PSA velocity, and PI-RADS 4-5 lesion. However, age, PSAD, and GPS did not increase the risk of metastases. Of note, in those who did not develop metastases, the median follow-up was quite sufficient at 77 months.

Overall, 64 of 1450 patients died at a median of 84 months. The 7-year overall survival was 97% for the entire cohort. Overall survival rates differed by sub-groups: GG1 with PSAD lower than 0.15 (98%) compared to those with GG1 with PSAD of 0.15 or higher (96%) or initial GG2 (87%). Only 4 of 64 patients in this AS program died of advanced prostate cancer. The 7-year prostate cancer-specific survival was greater than 99%.

This report is based on one of the few large AS cohorts with long-term follow-up. Although 60% of patients experienced upgrading on subsequent biopsies, only 41% underwent deferred treatment, suggesting that upgrading alone may not necessitate immediate treatment. The goal of AS protocols is to avoid or delay treatment for those who may not benefit from it, and still maintain the curative intent through early capture of any disease progression. The success of AS protocol is evident from the data showing that 1% of men with low-risk prostate cancer developed metastases, and only 0.27% died of prostate cancer.

Further details about other prognostic variables in patients with initial GG2, such as age, focality, or percentage of Gleason pattern 4, would have been instructive in identifying the optimal candidates for AS. Additionally, this AS protocol included variable diagnostic testing and surveillance protocol during the study period. Should patients with GG2 on AS be managed with a more strict or intensive surveillance program than those with GG1? Although most of the patients in this study were Caucasian (92%) and the general applicability may be questioned, recent studies have highlighted the safety of AS in African American men with low-risk prostate cancer.

The boundaries of AS inclusion criteria are being expanded to include selected men with GG2 prostate cancer. Incorporating mpMRI, and perhaps genomic tests, will further facilitate the selection of appropriate candidates for AS, thus increasing its acceptability by urologists and patients. Despite some heterogeneity in the type and frequency of testing during the surveillance period, these results provide reassurance and increased confidence in the safe utilization of AS protocols for men with low-risk GG1, and selected GG2, prostate cancer.

1. Maggi M, Cowan JE, Fasulo V, et al. The long-term risks of metastases in men on active surveillance for early stage prostate cancer. 

. 2020;204(6):1222-1228. doi:10.1097/JU.0000000000001313

Articles

"Despite some heterogeneity in the type and frequency of testing during the surveillance period, these results provide reassurance and increased confidence in the safe utilization of AS protocols for men with low-risk GG1, and selected GG2, prostate cancer," Mian writes.

Active surveillance data in prostate cancer show frequent upgrading, rare mortality

Despite previous randomized controlled studies demonstrating a benefit from post-prostatectomy adjuvant radiation therapy (RT), urologists have been slow to adopt this approach. This may be related to inconsistencies in the reported outcomes as well as the timing of salvage RT, which was thought to have been initiated much later than the contemporary clinical practice. Consequently, 3 randomized controlled trials (RADICALS-RT, GETUG-AFU 17, and RAVES) were initiated nearly a decade ago to evaluate the oncologic outcomes after adjuvant RT or early-salvage RT in post-prostatectomy patients with high-risk and/or locally advanced pathology. Recently, a combined analysis of these 3 trials was reported, which did not demonstrate any advantage to adjuvant RT when compared to early-salvage RT; that is, following rise in prostate-specific antigen (PSA) level after prostatectomy.

Vale and colleagues prospectively planned a systematic review and meta-analysis of the combined data from the 3 trials before the final results were available to assess whether adjuvant RT was superior to early-salvage RT.

 Individually, the 3 trials were powered for different primary outcomes such as time free of metastases (RADICALS-RT), event-free survival (GETUG-AFU 176), and biochemical progression (RAVES). Inclusion criteria for the trials varied slightly but included the following: postoperative PSA less than 0.2 ng/mL, and one or more high-risk features including stage pT 3 or 4, Gleason score 7–10, or positive surgical margins.

After randomization, adjuvant RT was to be initiated within 6 months after surgery while early-salvage RT for biochemical recurrence was to be initiated at PSA level of 0.2 ng/mL (0.1 ng/mL for RADICALS-RT). The RT dose was quite similar in all 3 trials; that is, 64 to 66 Gy in 32 or 33 fractions. The concurrent use of hormone therapy was variable across the 3 trials. For this meta-analysis, the agreed-upon primary outcome measure was event-free survival. An event after randomization was defined as the first evidence of any 1 of the following: biochemical progression (PSA ≥ 0.4 ng/mL), clinical or radiological progression, initiation of additional treatment, and PSA level of at least 2.0 ng/mL at any time after randomization.

In the 3 trials combined, 2153 patients were recruited between November 2007 and December 2016. Of these, 1075 patients were randomly assigned to receive adjuvant RT and 1078 were assigned to early-salvage RT. Median age was 64 to 65 years. A majority of patients had either stage pT3a/b disease (79.8%), positive surgical margins (70.9%), and extracapsular extension (76.9%). The median follow-up ranged from 60 to 78 months.

There were 270 (12.5%) events recorded out of the 2153 randomized patients. The pooled event-free survival analysis yielded an overall hazard ratio of 0.95 (95% CI, 0.75-1.21; 

= 0.70) which translates into only a 1% absolute difference between adjuvant RT and early-salvage RT groups. Further, there was no advantage to adjuvant RT on event-free survival when analyzed based on pre-specified subgroups including pre-surgical PSA, Gleason score, seminal vesicle involvement, surgical margins, or CAPRA-S risk group. In the group assigned to early-salvage RT, only 421 (39.1%) had required RT at the time of this analysis. A majority of the men remained free of biochemical progression at 5 years (87% in RAVES, 88% in RADICALS-RT, and 94% in GETUG-AFU 17).

It seems clear from this meta-analysis that adjuvant RT for men with high-risk, localized, or locally advanced prostate cancer after prostatectomy does not improve event-free survival. These results are in contrast to the previous trials (from EORTC and SWOG), which had demonstrated improved biochemical recurrence rates following adjuvant RT in these men. However, the enthusiasm for adjuvant RT remained limited due to the timing of salvage RT in previous trials (which was initiated much later than the contemporary practice), and concerns about the risks of over-treatment and adverse effects of adjuvant RT (such as urinary, bowel, and sexual dysfunction).

The unique design of current meta-analysis can remove some of the biases associated with retrospective meta-analyses and provides an increased number of subjects to allow for sufficiently powered analysis of longer-term survival outcomes. The authors were able to include up-to-date, event-free survival results from 100% of patients randomized in all 3 trials. However, it should be noted that the recurrence events were dominated by biochemical recurrence and not clinical or radiological recurrence, and the overall event (recurrence) rates were low.

The results of additional analyses (which are pre-planned by the authors), of the effects of adjuvant vs early-salvage RT on metastases-free survival, prostate-cancer specific survival, and overall survival are awaited. It’s possible that after longer follow up, the timing of RT and the use of hormone therapy may yield different results in a subgroup with multiple high-risk features. For now, avoiding adjuvant RT (and associated adverse effects) in favor of PSA monitoring and early-salvage therapy appears to be the safest initial option for post-prostatectomy patients with adverse pathology.

1. Vale CL, Fisher D, Kneebone A, et al. Adjuvant or early salvage radiotherapy for the treatment of localised and locally advanced prostate cancer: a prospectively planned systematic review and meta-analysis of aggregate data. 

 Published online September 28, 2020. doi:10.1016/S0140-6736(20)31952-8

PSA monitoring and early salvage therapy appear to be safest in these patients.

Adjuvant RT after prostatectomy does not improve recurrence rate

Although the physiologic adverse effects of androgen-deprivation therapy (ADT), such as hot flashes, fatigue, osteoporosis, and sexual dysfunction, are regularly discussed with patients, the neurocognitive complications (such as depression, cognitive decline, and dementia) are often overlooked. Despite the reportedly strong association between ADT for prostate cancer and several psychological adverse effects, clinical guidelines to address these issues are lacking. Recently, Siebert et al performed a systematic review of the literature to demonstrate the strength of existing data and to offer recommendations regarding identification and management of neuropsychiatric adverse effects of ADT.

The authors summarized the findings from 48 articles outlining the current evidence for neuropsychiatric consequences of ADT and proposed interventions. They also performed 2 meta-analyses examining the risk of depression and dementia after initiating ADT. The data from prospective, controlled studies demonstrate a causal relationship between ADT initiation and incidence of clinical depression. Results suggest that ADT initiation not only worsens pre-existing depression (in as early as 1 month), but may also trigger the development of clinical depression after approximately 1 year on treatment.

A study of patients in the Danish Prostate Cancer Registry showed an association between ADT and depression (HR, 1.8; 

 <.001) after adjustment for comorbidities. Their data suggest that ADT exposure is a risk factor for the development of depression, especially when used with concurrent radiation therapy. Meta-analysis of studies in this report demonstrates 1.51 times (

 = .0002) increased risk of incident depression after ADT exposure.

A dose-dependent relationship between the duration of ADT and depressive symptoms has been demonstrated in several studies. Among prostate cancer patients in the TRICARE military database (n = 9117), ADT was associated with a higher incidence of depression (HR, 2.07; 

<.001), which worsened with the duration of therapy. This dose-response relationship between ADT and depression has also been demonstrated in Chinese and Australian populations. Cumulatively, these data demonstrate significant risk of incident depression and worsening symptoms in men with depressive disorder after initiating ADT.

The data on ADT-related cognitive impairment can vary, depending upon the study population and methodology used to measure the outcome. ADT, compared with healthy controls, was associated with decreased short-term memory and working memory (

<.02). A prospective study of men starting ADT compared with matched individuals undergoing prostatectomy showed higher rates of cognitive impairment at 6 and 12 months. Similarly, men initiating ADT (vs prostatectomy) had a negative impact on language ability and short-term memory capacity (

<.05). These findings suggest an association between ADT and cognitive impairment such as memory loss can be detected as early as 6 months after initiating ADT.

Several large, American studies have demonstrated a consistent association between ADT and subsequent development of Alzheimer dementia (AD). As compared with non-ADT prostate cancer controls, men receiving ADT were at increased risk of AD (HR, 1.14; 

 <.001) and all-cause dementia (HR, 1.20; 

 <.001), dependent upon the duration of ADT. A study of men in the SEER-Medicare database found that those receiving ADT were 20% more likely to develop AD, after controlling for race, ethnicity, prostate cancer stage, and comorbidities.

Another analysis of SEER data of men receiving ADT demonstrated a dose-dependent increased risk of all-cause dementia and AD at 22% and 29%, respectively. ADT exposure for at least 7 months was associated with a 41% increase in all-cause dementia and 30% increased risk of AD compared with prostate cancer controls without ADT. Meta-analysis of several non-American population data sets showed approximately 1.45 times (

 = .02) increased risk of all-cause dementia after ADT exposure.

The authors recommend brief baseline affect and cognitive screening assessments in all patients initiating ADT, particularly those with prior diagnosis or treatment for depression or cognitive impairment. One of the challenges in identifying neurocognitive dysfunction in men receiving ADT is that several of the symptoms overlap with the symptoms of hypogonadism (such as fatigue, lack of desire, and decreased mental sharpness). The authors recommend that all patients starting long-term ADT be counseled regarding possible neuropsychiatric adverse effects, and provided some information about the connection between ADT and mental health. Knowledge of these potential adverse effects can reduce the negative psychological impact or stigma associated with discussion of mental health issues.

Although urologists are quite adept at identifying and addressing the links between urologic conditions/treatments and non-urologic conditions (erectile dysfunction and coronary disease; ADT and osteoporosis), discussion about mental health are often omitted. In any patient receiving ADT for more than 6 months, a patient-administered assessment tool, the Patient Health Questionnaire-9, can be used to screen for depressive disorder. A simple query by the providers, such as “have you been feeling down,” can open the door to acknowledging mental health issues, facilitating a discussion or referral to a mental health professional. As the primary care physicians for prostate cancer, and the main prescribers of ADT, we, the urologists, owe it to our patients to address both the physiologic and the neuropsychiatric adverse effects.

1. Siebert AL, Lapping-Carr L, Morgans AK. Neuropsychiatric impact of androgen deprivation therapy in patients with prostate cancer: current evidence and recommendations for the clinician. 

 Published online July 17, 2020. S2405-4569(20)30149-8. doi:10.1016/j.euf.2020.05.014

Cognitive screening is recommended in patients receiving androgen-deprivation therapy.

Neuropsychiatric effects of ADT often overlooked 

Active surveillance of low-risk prostate cancer, with the intention to delay or avoid any treatment-related adverse effects, has been employed with increasing frequency over the past decade. However, concerns remain about disease progression and loss of opportunity to cure an otherwise curable disease. To address these concerns, Ahmad et al report on their experience and outcomes from delayed radical prostatectomy (RP) in men who were initially diagnosed with low-risk prostate cancer and managed with active surveillance (AS).

The authors reviewed their AS cohort of 1359 men from 1992 and 2015 at Princess Margaret Cancer Centre in Toronto, Ontario, Canada, and identified 294 (21.6%) who were treated with RP due to disease progression. Of these, 170 (12.5%) underwent RP due to progression of grade group (GG) 1 to GG2 and formed the study group, with a median age of 61.5 years and median PSA of 5.5 ng/mL. A matched group of men with GG2 or higher undergoing immediate RP served as the control group. The primary outcomes included the presence of adverse pathology defined as pT3 or greater, GG3 or greater, positive surgical margin, or nodal metastases. Secondary outcomes of interest included biochemical recurrence (BCR), overall survival (OS), and cancer-specific survival (CSS).

Of the 170 men undergoing RP, 91 (53%) demonstrated reclassification to GG2 on confirmatory biopsy and 79 (47%) demonstrated grade progression on surveillance biopsies. There were no significant differences in the pathologic parameters (T stage, margins, nodal involvement) on the RP specimens between the study and control groups. The delayed RP group had a smaller median cancer volume noted at final pathology than the control group with initial GG2. Overall, adverse final pathology at RP was present in 54% of men with delayed RP for GG2 and 59% of men with initial RP for GG2 or higher.

5-year OS, CSS not different between groups

Median time spent on AS in the study group was 31.0 months, and median follow-up after RP in both cohorts was 5.6 years. The 5-year OS and CSS were not different between the study and control groups (98.1% vs 99.7% and 100% vs 99.7%, respectively). BCR was also not significantly different between the delayed RP and immediate RP groups (15% vs 19%, respectively). Further, the 5-year BCR-free survival rate in the AS cohort undergoing delayed RP and the initial GG2 cohort undergoing immediate RP was quite similar (85.8% vs 82.4%, respectively).

These data clearly demonstrate that the pathologic and oncologic outcomes in patients who underwent RP for grade progression after a period of AS are similar to the matched controls undergoing immediate RP, and the time spent on AS did not appear to adversely affect the outcomes. For the study cohort, the time spent on AS, roughly 2.5 years, appears to be relatively short, considering the longevity of this data set. One reason may be that nearly half (53%) of the cohort had grade reclassification on first repeat (ie, confirmatory) biopsy and may be not true grade progression over time during AS. This may lend support to the idea of a confirmatory biopsy before assigning to an AS strategy, especially if the diagnostic biopsy did not use a targeted biopsy approach. Another explanation may be that the majority of disease progression occurs early in the course of active surveillance.

It is often stated that earlier identification of those men is required who are either misclassified at onset or experience early grade progression in order to avoid adverse outcomes. However, it appears that these inherent limitations of the AS paradigm did not compromise the survival outcomes for these men. Direct comparison of the outcomes of various AS protocols from different institutions can be difficult due to significant heterogeneity in the inclusion criteria and surveillance intensity. Despite the variability, a consistent theme with increasing level of confidence has emerged over the past few years that a period of active surveillance for men with low-risk prostate cancer does not compromise the window of curability.

Going forward, our challenge is to devise less intensive surveillance strategies, with fewer biopsies and fewer complications. A fertile area for further research is the oncologic outcomes of contemporary low-risk prostate cancer, which is often diagnosed following an MRI targeted biopsy. This would facilitate the development and validation of a modern, less intensive AS protocol incorporating noninvasive methodologies such as advanced imaging and/or urine or serum markers to identify disease progression.

1. Ahmad AE, Richard PO, Leão R, et al. Does time spent on active surveillance adversely affect the pathological and oncologic outcomes in patients undergoing delayed radical prostatectomy? 

2020;204(3)476-482. doi:10.1097/JU.0000000000001070

Survival outcomes are not compromised in men undergoing active surveillance, a recent study finds.

Badar M. Mian, MD

Articles

Active surveillance data in prostate cancer show frequent upgrading, rare mortality

Adjuvant RT after prostatectomy does not improve recurrence rate

Neuropsychiatric effects of ADT often overlooked

Similar outcomes observed with immediate vs delayed radical prostatectomy