 is professor of surgery in the division of urology at Albany Medical College in New York.

Badar M. Mian, MD

Prostate-specific antigen (PSA)-based screening and detection of prostate cancer has remained an active area of research and debate since its widespread utilization began more than 3 decades ago. The imbalance between benefits and harms (overdetection and overtreatment) associated with PSA-based cancer detection, as gleaned from the early results of 2 large trials, resulted in the US Preventive Services Task Force (USPSTF) giving a grade D recommendation in its guideline—ie, recommending against PSA-based screening—in 2012. This quickly and significantly reduced PSA testing and biopsies. Although there was a decrease in overdetection of low-risk prostate cancer, there also were increasing rates of advanced and metastatic prostate cancer over the next few years.

A reassessment of the benefits of PSA-based screening in 2017, supported by long-term data from clinical trials, resulted in an upgrade of the USPSTF recommendations to grade C. The guidance was applicable only to men aged 55 to 69 years, with an individualized decision to undergo periodic PSA-based screening after a discussion of the potential benefits and harms. The USPSTF guidance did not address screening in men younger than 55 years and recommended against PSA-based screening for men 70 years and older. The effect of these changes in recommendations regarding PSA testing or cancer diagnosis is unclear.

A study by Leapman et al sought to evaluate the association between the current USPSTF grade C recommendation and national rates of PSA testing.

 The authors queried the administrative claims database Blue Cross Blue Shield Axis, which provides care to approximately one-third of the privately insured US population. Their goal was to identify patterns of testing in the age group (55-69 years) specifically addressed by the USPSTF guideline as well as among those men who are outside the recommended age range (40-54 years and 70-89 years).

From January 1, 2013, to December 31, 2019, PSA testing trends were studied in male beneficiaries aged 40 to 89 years. The overall median number of eligible beneficiaries for each bimonthly period was 8,087,565, more than 50% of whom were aged 40 to 54 years. The median number of eligible beneficiaries in the group aged 55 to 69 years was 3,372,772, and the median number of men in the group 70 to 89 years was 148,195.

For the entire cohort of patients aged 40 to 89 years, the mean rate of PSA testing increased from 32.5 per 100 person-years in 2016 to 36.5 per 100 person-years in 2019 (

 < .001), an absolute and relative increase of 4.0% and 12.5%, respectively. For the groups specified in the USPSTF statement, men aged 55 to 69 years, the mean rate of PSA testing increased from 49.8 per 100 person-years in 2016 to 55.8 per 100 person-years in 2019 (

 < .001), corresponding an absolute and relative increase of 6.0% and 12.1%, respectively. Among the group of men aged 40 to 54 years, the mean rates of testing increased from 20.6 per 100 person-years in 2016 to 22.7 per 100 person-years in 2019 (

 = .001), an absolute and relative increase of 2.1% and 10.1%, respectively.

For the group of men aged 70 to 89 years, rates of PSA testing increased from 38.0 per 100 person-years in 2016 to 44.2 per 100 person-years in 2019 (

 < .001), representing an absolute and relative increase of 6.2% and 16.2%, respectively. The largest absolute increase in PSA testing was noted in the group aged 70 to 74 years (8.2%, 

 < .001), and relative increases in PSA testing were observed in all subsets of patients 70 years or older.

The data presented by the authors clearly demonstrate that changes in the USPSTF’s prostate cancer screening guideline from a grade D to grade C recommendation (for men aged 55 to 69 years) was associated with an increase in PSA testing in all age groups. Despite maintaining a grade D recommendation (do not screen) in men aged 70 years or higher, this age group demonstrated the largest (up to 16.2% relative) increase in PSA testing. Although no specific recommendations were made for younger men aged between 40 and 54 years, a significant increase in PSA testing was also noted in this group. Whether this increase in PSA testing will reverse the previously reported increased rates of locally advanced and metastatic disease related to insufficient PSA testing remains to be determined.

This raises several clinically relevant questions, including the usefulness of the USPSTF recommendation and how it may affect clinical decision-making regarding PSA testing. It appears that changes to the USPSTF recommendations resulted in unanticipated, wide swings in PSA testing, ranging from insufficient testing after 2012 recommendations to excessive testing following 2017 guidance. Clearly, indiscriminate, population-level screening with the PSA test is inappropriate and harmful due to downstream consequences of overdetection and overtreatment. 

A nuanced approach to PSA-based screening requires assessment of life expectancy and a discussion of risks and benefits of screening 

 to PSA testing. It is a lot easier to include statements in guidelines regarding proper counseling, and shared decision-making, than it is practical in real life. Who should be responsible for the added requirement of thorough counseling? Should it be the urologists, who tend to favor PSA screening, or the primary care providers, who order the vast majority of screening PSA tests? Regardless, it is safe to state that PSA tests are obtained by both primary providers and urologists without specific or sufficient counseling to satisfy the intent of the guidelines.

It is worth remembering that injudicious use of PSA test, and the downstream consequences of overtreatment and complications, can obscure the benefits associated with PSA-based early detection of prostate cancer. The increased rate of PSA testing and resultant overtreatment increases the number needed to screen and the number needed to treat, potentially diluting the positive impact of PSA testing.

Several advances have been made since the 2012 USPSTF grade D recommendation. Risk calculators, additional biomarkers, genomic tests, multiparametric MRI with targeted biopsy, and increasing adoption of active surveillance have transformed the landscape prostate cancer detection and treatment. What was once thought of as a linear inevitability of PSA test resulting in biopsy, overdetection, overtreatment, and complications has been curbed to a some extent over the past decade. We have the ability to apply the brakes at any of these steps along the PSA screening paradigm to mitigate the harms associated with increased PSA testing.

1. Leapman MS, Wang R, Park H, et al. Changes in prostate-specific antigen testing relative to the revised US Preventative Services Task Force recommendation on prostate cancer screening. 

 Published online November 11, 2021.. doi:10.1001/jamaoncol.2021.5143

Articles

"It is worth remembering that injudicious use of PSA test, and the downstream consequences of overtreatment and complications, can obscure the benefits associated with PSA-based early detection of prostate cancer," writes Badar M. Mian, MD.

Unexpected increase in PSA testing after USPSTF recommendations 

Transrectal ultrasound–guided prostate needle (TR) biopsy has been the gold standard for the diagnosis of prostate cancer for nearly 3 decades. More recently, transperineal prostate (TP) biopsy has been gaining popularity because of possible improvement in postbiopsy complications, especially infections. However, studies have reported variable results that largely suggest that both biopsy techniques are quite comparable in their diagnostic and complications outcomes, except for pain during the procedure, which is often worse during the in-office TP biopsy. However, other short-term effects on quality of life related to these procedures (or tests) have not been studied in detail between the TR and TP procedures.

To measure the differences in the test-related quality of life between the 2 biopsy procedures, Shankar et al conducted postbiopsy surveys of men undergoing ultrasound-guided TR or TP biopsy.

 They included men undergoing an in-office, ultrasound-guided prostate biopsy, without MRI guidance or MR-ultrasound fusion, and without any history of Gleason score 7 or higher cancer.Over 77% of patients were biopsy-naïve.

Patients were recruited for participation in the study before the biopsy at 7 clinics, and 161 patients agreed to be contacted for the postbiopsy survey. Of these, 120 (60 TR, 60 TP) patients eventually completed the survey whereas the remainder either declined to complete the survey or could not be contacted. Biopsies were performed by 7 urologists, including some performing only the TR or the TP procedure. Average age of patients was 64.5 years, 81% were white, and 62% had a college degree. Most patients were biopsy-naïve, including 80% in the TR and 75% in the TP cohort.

The authors used 2 main survey instruments during the phone interview, including Testing Morbidities Index (TMI) and Short-Form 12 version 2 (SF-12). The TMI includes several domains including pain and anxiety before and during the procedure, embarrassment during the procedure, and any mental or physical impact the procedure. The mean baseline self-reported physical health, as determined by the SF-12 physical component score, were similar for both groups (TR: 50.6 [SD ± 9.8]; TP: 52.3 [SD ± 8.5]). Similarly, there was no difference in the mean baseline self-reported mental component scores between the TR and TP cohorts. The phone interviews to assess TMI were conducted 1 to 5 days after the biopsy (mean, 1.3 days).

The mean summary testing-related health utility score (scale: 0-1, where 1=perfect baseline health) was 0.86 (95% CI 0.84-0.88) for TR biopsy and 0.83 (95% CI 0.81-0.85) for TP biopsy (

 = .08). The only significant difference in the individual domain-level scores (scale: 1-5, with 1 = no health impact, 5 = extreme health impact), was related to more pain during TP biopsy (TR 2.3, 95% CI 2.1-2.4; TP 2.9, 95% CI 2.6-3.1; 

 = .0002). There were no significant test-related differences in other domains during the biopsy procedure. The overall cancer detection (52% and 53%) and high-grade cancer detection rates (23% and 20%) appeared similar between the TR and TP procedures, respectively. The complications rates, including hospitalizations and infections, were also similar between the TR and TP cohorts.

The temporary testing-related health impact between TR (86% of “perfect” health) and TP biopsy (83% of “perfect” health) were clinically and statistically similar, except for pain during the procedure, which was more painful for those undergoing TP biopsy.

It is not clear why the authors excluded patients undergoing MRI-US fusion biopsy and patients with prior biopsy with Gleason score higher than 6. The goal of the study was to evaluate procedure-related effect on short-term quality of life, which is not likely to be affected by the histology. Conversely, the image fusion targeted biopsy procedures take longer to complete than TRUS biopsy and thus, could have affected the patient experience during the procedure.

The study had a relatively small sample size and patients were not randomly assigned to TR or TP biopsy procedures. It’s possible that patients may have elected or favored 1 procedure over the other, and thus were more accepting of the procedure-related adverse experience. Similarly, the urologists with expertise and/or experience with exclusively performing TP biopsies could have mitigated any potential difference in patient experience between the 2 procedures.

It appears that the TR and TP biopsy procedures are essentially comparable in various aspects of the procedure. If the cancer detection rates, and complications including infection rates, and procedure related-effect on quality of life are similar, how does one recommend 1 procedure over the other to the patients? Despite our best efforts, the non-randomized study design can introduce a number of confounders that can affect the results. There are ongoing randomized control trials that should provide us with essential, high-quality data to inform the discussion regarding TR vs TP prostate biopsy.

1. Shankar PR, Ellimoottil C, George AK, et al. Testing-related health impact of transrectal and transperineal prostate biopsy as assessed by health utilities. 

2021;206(6):1403-1410. doi:10.1097/JU.0000000000002118

"It appears that the TR and TP biopsy procedures are essentially comparable in various aspects of the procedure," writes Badar M. Mian, MD.

Transrectal vs transperineal biopsy: Comparable outcomes and QoL

Radical cystectomy (RC) and urinary diversion are arguably the most life-altering therapeutic interventions undertaken by urologists. From the patient’s perspective, matters related to survivorship and health-related quality of life (HRQOL) may be as important as cancer control. The implication of postoperative HRQOL and functional status are such that most patients are initially reluctant to consider this surgery, with some refusing it altogether in favor of potentially less effective therapies. There has been a lack of prospective studies with longitudinal follow-up of the impact of RC on HRQOL, especially when compared to the preoperative, baseline features.

Many concerns about HRQOL are addressed in a recent report by Clement et al.

The authors conducted a prospective study to collect data using 14 patient-reported outcome measures and semistructured interviews over a 2-year follow-up period. Their aim was to describe the HRQOL and some functional outcomes following RC, to compare pre-RC HRQOL between patients undergoing different types of urinary diversions, and to quantify baseline differences in outcomes associated with the clinical selection biases for various diversion types. Several tools were utilized, including the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire, to assess various domains such as physical, emotional, social, urinary bowel, sexual, and global QOL. Because of the differences in selection criteria for continent diversion or ileal conduit, the patterns of recovery for each diversion type were reported separately.

Of the 462 patients enrolled from 2008 to 2014, 411 were evaluable for this report. Most procedures were performed using open technique (88%). In terms of survey participation, 292 (71%) completed the baseline questionnaires pre-RC and 196 (48%) completed follow-up surveys at 24 months. Only 178 (43%) received neoadjuvant chemotherapy. There were significant differences in baseline characteristics among patients undergoing continent diversion and ileal conduit. The continent diversion patients, compared with the ileal conduit cohort, were younger, healthier, employed, , and likely to have better renal function, nerve-sparing procedure and neoadjuvant chemotherapy.

In the continent diversion cohort, global QOL domain scores remained similar to the baseline score of 74 at 3 months and gradually improved to 80 at 12 months. In the ileal conduit cohort, scores at 3 months postoperatively were similar to baseline, then gradually increased slightly by 24 months. The mobility and activity scores decreased by only 5 points (scale, 0 to 100) in the continent diversion cohort at 3 months but returned to near preoperative levels by 12 months. In patients with ileal conduit, a similar early decrease of 5 points was noted, but function did not recover to baseline during follow-up.

When assessing the ability to perform work or other activities, patients with an ileal conduit were near their baseline by 24 months, and those with a continent diversion had improved to a higher score than the baseline pre-RC scores. In social functioning domains, no decrease, and an actual increase (by 10 points) from baseline, were reported in the continent diversion cohort at 12 months. In those with an ileal conduit, the initial mean decrease (from 81 to 77) by 6 months improved to near baseline by 24 months.

The bowel function index decreased modestly by 4 points at 6 months in continent diversion patients and then remained stable. Among the ileal conduit cohort, the scores remained within 2 points of baseline throughout follow-up. Despite using a much longer bowel segment in continent diversion, there was no significant difference in bowel function among the diversion types. Body image scores for the ileal conduit cohort decreased by 10 points at3 and 6 months and did not improve over time, whereas the scores remained unchanged in continent diversion cohort over time.

The mean scores on the sexual function domain in ileal conduit patients decreased from 37 at baseline to 27 at 6 months, with no further improvement. In continent diversion patients (nerve-sparing RC was more common), scores decreased from 48 to 28 at 6 months, recovered to 36 by 12 months, and showed no further improvement. In a subset of patients receiving continent diversion and nerve or vagina sparing, the scores decreased from 51 to 30 at 6 months, with recovery to 45 by 24 months.

It is important to note that any difference reported in HRQOL between continent diversion and ileal conduit are likely not related to the diversion itself but rather due to the differences in selection criteria (age, health, social status, renal function, nerve-sparing technique). Thus, one cannot conclude that one type of urinary diversion is associated with a better HRQOL over the other.

The authors noted that although there was an observed decrease in some physical health domains for up to 6 months, most HRQOL measures had returned to or exceeded baseline by 24 months except sexual function. For the psychosocial domains, scores remained stable or improved over time, although patients receiving ileal conduit showed decreases in body image. These data and previous studies suggest that there is a decrease in the physical functioning and some other QOL domains at 3 and 6 months, which tends to recover to baseline or at times even better than baseline.

Because this study includes patients from a single high-volume center with embedded resources, it is not clear whether similar outcomes can be reproduced at other hospital. However, studies have demonstrated that RC surgical volume is an important determinant of oncologic and functional outcomes, and one might expect most tertiary referral centers to be able to deliver similar HRQOL outcomes. Also, the mechanisms by which some HRQOL domains improved beyond the preoperative scores at 12 to 24 months are not discussed. Were these patients experiencing physical (or psychological) symptoms from the bladder cancer or the diagnostic procedures or systemic therapy at the time of the survey which could have lowered their reported baseline HRQOL scores?

A few studies have reported poor HRQOL after RC and diversion, which has prompted a more vigorous pursuit of nonsurgical therapies such as trimodal combination of endoscopic resection, chemotherapy, and radiation therapy. Previous post-RC HRQOL studies generally lacked longitudinal follow-up, not prospectively designed, and did not include baseline QOL data. This study provides credible support for the expectation that post-RC HRQOL should recover and improve over the first 2 years after RC, and provides a benchmark for comparisons with future bladder preservation strategies.

1. Clements MB, Atkinson TM, Dalbagni GM, et al. Health-related quality of life for patients undergoing radical cystectomy: results of a large prospective cohort. 

Published online October 8, 2021. doi:10.1016/j.eururo.2021.09.018

"This study provides credible support for the expectation that post-RC HRQOL should recover and improve over the first 2 years after RC, and provides a benchmark for comparisons with future bladder preservation strategies," writes Badar M. Mian, MD.

Patient-reported HRQOL is maintained after cystectomy

Active surveillance (AS) for the management of low-risk prostate cancer is slowly becoming the de facto standard of care. Although the adoption of AS has been increasing, still too many patients with low-risk prostate cancer appear to be undergoing active treatment. A frequently voiced concern by patients and physicians alike is the risk of disease progression and the need for active treatment. These issues were addressed in the recent study by Cooley et al of a large, multicenter cohort of men converting from AS to active treatment.

The investigators evaluated the clinical and pathologic parameters associated with the time to conversion from AS to treatment in the pooled cohort of 7279 patients from 28 institutions between 1991 and 2018. They also evaluated the association of germline genetic variants to conversion to treatment in a subset of patients. The primary question to be addressed was the time from prostate cancer diagnosis to conversion to treatment. Those men followed without a strict AS protocol were analyzed in the same manner as those on AS.

The patients were stratified into risk groups. Low-risk patients were Gleason grade group (GG) 1 (Gleason score 3+3) and had prostate-specific antigen (PSA) lower than 10 ng/mL, clinical-stage cT1, and 2 or fewer positive biopsy cores. Intermediate-risk patients were GG2 (Gleason 3+4) and had PSA 10 to 20 ng/mL, stage cT2, or 3 positive biopsy cores of any Gleason grade. High-risk patients were GG3 or higher and had cT3 or 4 positive cores of any GG.

The investigators compared low-volume GG1, high-volume GG1 (≥ 4 biopsy cores involved), intermediate-risk, and high-risk patients. Also, exploratory subgroup analysis including self-reported race and genetically-inferred ancestry was performed for time to conversion. The genetic inference was obtained from patient data of uncorrelated single nucleotide polymorphisms that were available for a subset of patients.

Of the 6775 men meeting the inclusion criteria, median PSA was 5.0 ng/mL, and GG1 was noted in 91.6%, stage cT1 in 79.5%, 1 to 2 positive biopsy cores in 77.6% of patients. There were 882 men (13.0%) who had some higher-risk features such as GG ≥ 3 (1.2%), cT3 (0.7%) or 4 or more positive cores of any GG (11.3%).

The median follow-up for the entire cohort was 6.7 years, during which 33.4% of men converted to treatment. The median time to conversion was 6.8, 6.1, and 7.0 years for low-, intermediate-, and high-risk/high-volume disease, respectively. The most common reasons for conversion were grade reclassification alone (48.8%), PSA progression (8.5%), tumor volume progression (7.2%), anxiety (5.0%), and other (9.0%). Of the men who died, less than 1% died of prostate cancer, whereas 1.3% died of other competing cause.

Multivariable analysis, including the self-reported race, demonstrated that higher GG, PSA, clinical tumor stage, number of positive biopsy cores, and more recent year of diagnosis were significantly associated with earlier time to conversion. Men with high-volume, 4 or more GG1 cores were more likely than those with 3 or fewer GG1 cores to convert to treatment (63.6% vs 26.0%). Further, the conversion rate was higher than those with intermediate-risk disease (63.6% vs 38.3%), but similar to men with other higher-risk features (63.6% vs 65.7%). Men with high-volume GG1 converted to treatment sooner than patients with low-volume GG1 (aHR 3.46, 95% CI: 2.92-4.10). The risk for conversion was higher than the intermediate-risk patients (aHR 1.78, 95% CI: 1.59-1.99) and similar to all other high-risk patients.

Age, race, and a positive family history of prostate cancer were not associated with the time to conversion. There was no difference in the time to conversion between Black and White men across various risk groups. Further, none of the genetic ancestry groups had a shorter time to conversion to treatment. Conversion to treatment was noted in 2260 men (1107 prostatectomy, 565 radiotherapy, and 588 other treatments), of whom 124 (5.5%) subsequently developed a PSA recurrence, 29 (1.3%) developed metastasis, and 11 (<1%) died of prostate cancer.

This study included patients from 28 centers to provide an analysis of more representative practice patterns. However, the attempt to assemble a large “real-world” cohort also may have introduced substantial heterogeneity that could confound the results and make it difficult to identify the most effective strategy. Some sites likely used watchful waiting instead of a strictly defined AS protocol. The intervals for PSA testing and biopsy are not available. Additionally, the data on comorbidity, life expectancy, and exact triggers for conversion to treatment were not provided.

The higher rate of conversion to treatment for men with 4 cores of GG1 than those with 3 or fewer cores GG1 or intermediate-risk prostate cancer is not surprising. When starting at a higher volume of cancer, one is likely to arrive at the arbitrary threshold (PSA, grade, volume) for intervention earlier. The most common triggers for treatment in this AS cohort were changes in Gleason grade or PSA or positive cores. It is important to consider that conversion to treatment (based on higher tumor volume or PSA) is not necessarily the biologic destiny of these cancers but likely an epiphenomenon related to the treating urologists’ understanding or concern over those changes. Does a change in positive cores with GG1 from 3 to 4 cores or an increase in PSA alone portend a poor prognosis? Does the conversion to treatment due to anxiety represent a missed opportunity for proper counseling to avoid unnecessary treatment?

This large cohort study confirms the safety of AS, as shown in the low rate of metastasis or death, including those who subsequently converted to treatment. The 33% rate of conversion to treatment (for any reasons) is not a failure of the AS strategy, but rather a success since two-thirds of patients were safely spared any treatment for over 7 years. Now, with the incorporation of prostate MRI or genomic tests, patients and urologists can feel more confident in the use of AS to safely avoid unnecessary treatment.

1. Cooley LF, Emeka AA, Meyers TJ, et al. Factors associated with time to conversion from active surveillance to treatment for prostate cancer in a multi-institutional cohort. 

Published online August 16, 2021. doi:10.1097/JU.0000000000001937

"This large cohort study confirms the safety of AS, as shown in the low rate of metastasis or death, including those who subsequently converted to treatment," writes Badar M. Mian, MD.

Badar M. Mian, MD

Articles

Unexpected increase in PSA testing after USPSTF recommendations

Transrectal vs transperineal biopsy: Comparable outcomes and QoL

Patient-reported HRQOL is maintained after cystectomy

Active surveillance for prostate cancer is generally safe, study results show