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

Badar M. Mian, MD

Radical cystectomy, along with systemic therapy, remains the recommended standard of care for patients with muscle-invasive bladder cancer. Often, patients requiring this complex surgery are older and have significant comorbidities that predispose a patient to a high rate of perioperative complications. Several interventions have been utilized to improve the outcomes following radical cystectomy. These include subspecialization, regionalization, early recovery protocols, and more recently, use of minimally invasive robotic surgery.

To determine the effect of robotic surgery on perioperative recovery and complications, Catto et al conducted a randomized controlled trial comparing completely intracorporeal robotic cystectomy with open surgery.

 The primary outcome measure was the number of days alive and out of the hospital within 90 days of surgery. Several other secondary outcomes were measured, including complication rate, quality of life, activity levels, and survival.

The investigators randomized 338 patients to either robotic radical cystectomy with intracorporeal reconstruction or open radical cystectomy. Of these, 317 patients underwent radical cystectomy and 305 were analyzed for primary outcome after either robotic radical cystectomy (n = 156) or open surgery (n = 149). Nearly one-third of patients received neoadjuvant chemotherapy and 89% received an ileal conduit. The mean age was 69 years (6% were 80+ years) and 79% were men.

The authors report that the median number of days alive and out of the hospital within 90 days of surgery for patients undergoing robotic cystectomy vs open surgery was 82 days and 80 days (

 = .01), respectively. The median length of hospital stay was 7 days for robotic cystectomy and 8 days for open surgery (

 = .05). Hospital readmission after discharge was required in 21.8% undergoing robotic cystectomy and 32.2% undergoing open cystectomy (difference, 10.4% [95% CI, 0.5%-20.3%]; 

 = .04). Cancer recurrence rates and all-cause mortality were similar between the groups.

Two-thirds (65.6%) of the patients had at least 1 complication within 12 weeks, including 63.4% in the robotic surgery group and 67.9% in the open surgery group. The robotic surgery group, compared with open surgery, had significantly less wound-related complications (5.6% vs 17.3%; difference, –11.72%) and thromboembolic complications (1.9% vs 8.3%; difference, –6.47%). Rates of other complications were essentially similar between groups.

General health-related quality of life (HRQOL) at 5 weeks was statistically significantly worse in the open surgery group, but the scores were similar between the groups at 12 weeks. Using a different HRQOL instrument, statistically significantly higher HRQOL was noted in the robotic surgery group at 5 and 12 weeks, but no difference was noted by 26 weeks. Overall, there was no significant difference in the activity level (as measured by daily step count) by week 5 and week 12.

This randomized controlled trial (RCT) has some important and distinct features when compared with previous studies. The current study focused on postoperative recovery, including complications and readmission using a completely intracorporeal technique. A previous RCT comparing robotic surgery (with open diversion) and open surgery had primarily focused on oncological outcomes, declaring the robotic approach as noninferior.

 The current study used an interesting primary end point (ie, number of days alive and out of hospital), which is a composite of postoperative length of stay, any readmissions, and deaths within 90 days. The investigators used 2 days as the minimum detectable difference for robotic surgery, as this difference was viewed by their health care purchasers to be of sufficient benefit to fund robotic surgery service in the British health care system. This difference of 2 days over a 3-month period may be too modest to mitigate the health care cost of robotic surgery in the United States.

Much of the benefit from robotic or other minimally invasive approaches is realized in the early post-operative period as evident from the early convalescence, increased mobility, and improved HRQOL in the first 5 weeks after surgery. However, the differences in HRQOL and activity level disappeared by 3 or 6 months after surgery. Although the overall complication rates were similar, the robotic surgery group had a lower risk of wound and thromboembolic complications, perhaps due to early and increased mobility following robotic cystectomy.

The investigators are to be commended for being able to conduct an RCT of 2 surgical approaches—a task that has been notoriously difficult to complete. This study demonstrated that robotic cystectomy with intracorporeal diversion was statistically superior by 2 days in terms of days alive and out of the hospital. As the authors point out, the clinical importance of these findings across various health systems and patient populations is uncertain.

Other studies have reported that proposed benefits of robotic surgery, such as smaller incisions, improved high-definition vision, decreased blood loss, and increased mobility, may not translate into improved functional recovery, HRQOL, or cancer control. Yet, several high-volume centers continue to promote the use of the robotic approach as the new standard of care. With the relatively modest and variable advantages of robotic cystectomy reported by this and previous RCTs, surgeons should continue to offer their best surgical technique (open or robotic) to patients in need of radical cystectomy.

1. Catto JWF, Khetrapal P, Ricciardi F, et al. Effect of robot-assisted radical cystectomy with intracorporeal urinary diversion vs open radical cystectomy on 90-day morbidity and mortality among patients with bladder cancer: a randomized clinical trial. 

.2022;327(21):2092-2103. doi:10.1001./jama.2022.7393

2. Parekh DJ, Reis IM, Castle EP, et al. Robot-assisted radical cystectomy versus open radical cystectomy in patients with bladder cancer (RAZOR): an open-label, randomised, phase 3, non-inferiority trial. 

2018;391(10139):2525-2536. doi:10.1016/S0140-6736(18)30996-6

Articles

Randomized controlled trial compares intracorporeal robotic technique with open surgery.

Robotic cystectomy is effective, but overall clinical impact is uncertain

Traditionally, radical prostatectomy (RP) for patients with high-risk prostate cancer was considered less effective than external beam radiation therapy (EBRT) combined with androgen deprivation therapy. Emerging data over the past decade have demonstrated that RP with adjuvant or salvage therapy can be as effective as EBRT combined with androgen deprivation therapy.

 the authors evaluated the roles of RP and EBRT in terms of the difference in cancer-specific mortality (CSM) for men with high-risk prostate cancer in the Surveillance, Epidemiology, and End Results (SEER) database. The authors hypothesized that there is no CSM difference between RP and EBRT.

It is important to understand the different definitions of high-risk prostate cancer. The National Comprehensive Cancer Network (NCCN) definition includes either Gleason scores (GS) of 8 to 10 (Grade Group 4-5) 

 prostate-specific antigen (PSA) level greater than 20 ng/mL 

 clinical stage of at least T3. They further subdivided the high-risk prostate cancer cohort based on the Johns Hopkins classification into Johns Hopkins high-risk (JH-HR) groups (cT3a 

 PSA>20 ng/mL) and very high-risk (JH-VHR) groups (cT3b-cT4 

≥5 positive biopsy cores with Grade Group 4).

Within the SEER database, CSM was defined as deaths attributable to prostate cancer as noted on the death certificates. Conversely, other cause mortality was defined as deaths attributable to causes other than prostate cancer. Within the SEER database (2010-2016), the authors identified all RP-treated or EBRT-treated patients. The primary outcome measure for this analysis was to determine whether any differences in CSM existed between RP and EBRT in the entire cohort of NCCN HR patients, and any survival differences, based on the treatment, existed within the JH-HR and JH-VHR subgroups.

Of the 24,407 NCCN patients with high-risk prostate cancer, 9823 (40%) underwent RP and 14,584 (60%) received EBRT. When divided into subgroups, 10,300 (42%) were classified as JH-HR and 14,107 (58%) were JH-VHR.

Of JH-HR patients, 4863 (47%) were treated with RP and 5437 (53%) with EBRT. Of the JH-VHR patients, 4960 (35%) were treated with RP and 9147 (65%) with EBRT. Patients receiving brachytherapy, alone or in combination, were excluded.

Among the main cohort, EBRT patients were older (median age, 71 vs 64 years), had higher PSA values (median, 13 vs 8 ng/mL), and had higher clinical T and N stages. Also, the 5-year other cause mortality rates were higher in the EBRT group compared with RP (12% vs 3.4%).

The authors utilized propensity score matching (PSM) to the entire cohort of NCCN high-risk patients to account for variation in baseline characteristics.PSM resulted in 2 equal groups of 7363 RP and 7363 EBRT patients, with no residual significant differences in age, PSA, biopsy GS, and clinical T and N stages. The median follow-up durations of patients without an event were 41 months and 35 months for RP and EBRT, respectively. The CSM rates at 5 years of follow-up were 2.3% (95% CI, 1.9-2.9) for RP and 4.1% (95% CI, 3.4-4.8) for EBRT (

<.01). This resulted in a multivariate competing-risk hazard ratio of 0.68 (95% CI, 0.54-0.86; 

<.001) in favor of RP. Further, the JH-VHR group was an independent predictor for higher CSM (HR, 4.2; 

After applying PSM to the JH-VHR cohort, 2 equally sized groups of 4020 RP and 4020 EBRT were identified, with no residual statistically significant differences in age, PSA, biopsy GS, or clinical T and N stages. The CSM rates at 5 years were 3.5% for RP and 6.0% for EBRT (

<.001), for a competing-risk multivariate hazard ratio of 0.58 (

Similarly, for the JH-HR cohort, matched groups of 3207 RP and 3207 EBRT were identified, without any residual statistically significant differences in age, PSA, biopsy GS, and clinical T and N stages. The CSM rates at 5 years of follow-up were 0.7% for RP and 1.2% for EBRT, with a statistically insignificant multivariate competing-risk hazard ratio of 0.7 (

High-risk prostate cancer requires discussion and planning for multimodality therapy, regardless of which primary therapy is used initially. In clinical practice, androgen deprivation therapy is used for virtually every patient receiving EBRT for high-risk prostate cancer. However, this information (ie, the percentage treated and the dose and duration of androgen deprivation therapy) is not available in this data set. Similarly, 50% or more of high-risk post-RP patients will require adjuvant or salvage (EBRT or androgen deprivation) therapy, but this information is also not available in the data set used for this analysis. Further, this population-based data set does not provide information regarding comorbidities and other factors that lead to the selection of one therapy over the other. PSM was used to account for the fact that the EBRT cohort was older and had higher PSA level and higher stage; however, it cannot account for all the unmeasured confounders. Despite several limitations, this type of analysis might be our best source of data regarding the comparative effectiveness of various treatment modalities for high-risk prostate cancer until the ongoing randomized controlled trials are completed.

Several important points can be gleaned from this analysis of large, population-based data set of patients with high-risk prostate cancer, which is further analyzed as JH-HR and JH-VHR cohorts. The JH subclassification into HR and VHR seems to be a robust prognostic variable for CSM. CSM was lower for patients treated with RP, compared with EBRT, in the entire NCCN cohort and in the subgroup of patients with JH-VHR prostate cancer, but not in the JH-HR subgroup. This may be because the event rate (ie, death) was quite low in the JH-HR prostate cancer group. It is interesting to note that in the JH-HR group, the 5-year CSM rate was only 0.7% for RP and 1.2% for EBRT. It’s very possible that the PSA screening-detected high-risk prostate cancer portends a more favorable outlook when compared with the pre-PSA era, regardless of the type of primary therapy utilized. These data can be useful when counseling patients regarding primary RP or EBRT and the risk of death following definitive treatment of high-risk prostate cancer.

1. Chierigo F, Wenzel M, Würnschimmel C, et al. Survival after radical prostatectomy versus radiation therapy in high-risk and very high-risk prostate cancer. 

2022;207(2):375-384. doi:10.1097/JU.0000000000002250

"It’s very possible that the PSA screening-detected high-risk prostate cancer portends a more favorable outlook when compared with the pre-PSA era, regardless of the type of primary therapy utilized," writes Badar M. Mian, MD.

RP appears more effective against high-risk prostate cancer

The advent of enhanced imaging and detection of localized prostate cancer through targeted biopsy has improved the feasibility and safety of targeted or focal therapy for men with prostate cancer. Once thought to be an option only suitable for men with low-risk prostate cancer, focal therapy is being used as a viable option for those with clinically significant prostate cancer, with the primary goal of avoiding or minimizing the treatment-related adverse effects associated with whole-gland treatment (radical prostatectomy or radiation therapy).

A recent article by Reddy et al reports updated results on patients with localized prostate cancer in the high-intensity focused ultrasound (HIFU) Evaluation and Assessment of Treatment (HEAT) registry from the United Kingdom over the past 15 years, where focal HIFU has been used as a standard alternative to whole-gland treatment.

A total of 1379 patients from 13 UK centers were reported in the HEAT registry between November 2005 and July 2020. Men with prostate cancer whose Gleason score was 6 to 9 and with a clinical stage up to T3bN0M0 were offered focal therapy using the Sonablate. Patients were classified as having D’Amico low-, intermediate-, or high-risk disease. Only patients with MRI-visible lesions, and without any high-volume (6 mm) Gleason score 6 or any-volume Gleason score 7 disease in the untreated gland, were considered suitable candidates for focal ablation.

The primary outcome was failure-free survival (FFS), defined as no evidence of cancer requiring whole-gland salvage treatment or third focal therapy treatment, any systemic treatment, development of metastases, or prostate cancer–specific death. Secondary outcomes included adverse events and complications classified by the Clavien-Dindo system, as well as other oncologic outcomes.

Follow-up included prostate-specific antigen (PSA) test and multiparametric MRI at variable intervals, as well as per protocol and for-cause repeat prostate biopsy. If clinically significant cancer (defined as Gleason score ≥ 3 + 4) was identified as occurring in field (residual disease) or out of field (de novo or progressive disease), patients were offered either repeat focal treatment or radical radiotherapy, or radical prostatectomy.

The median follow-up was 32 months for the entire cohort, and 82 months for the 325 (23%) patients with at least 5 years’ follow-up. The median age of patients was 66 years and median PSA level was 6.9 (4.9-9.4) ng/mL. Seventy-nine percent of patients (1093/1379) had grade group 2 or higher (19%, grade group 1; 78%, grade group 2).

The FFS at 7 years was 69%, and 7-year FFS for intermediate- and high-risk cancers was 68% and 65% (

 = .3), respectively. Significant differences in FFS were noted at 7 years between grade group 2 and 3 (

 = .05). Of the 609 patients who underwent repeat prostate biopsy, recurrent/residual cancer was reported in 403 (66%). Of these, 314 patients demonstrated residual/recurrent Gleason score 7 prostate cancer during their follow-up period.

Retreatment-free survival at 7 years was 43%; in other words, more than half of patients required some additional treatment. There was statistically significant difference in retreatment-free survival between D’Amico risk groups (

 < .0001). Overall, 132 patients underwent salvage whole-gland treatment or systemic treatment, including 53 salvage radical prostatectomy and 39 salvage radiotherapy. Salvage treatment-free survival at 7 years was 75%, with 3 patients developing metastases and 1 of whom subsequently died from prostate cancer.

Postoperative complications were noted in 83 of 1379 (6.0%) patients after focal therapy. The rate of complications in those with a Clavien-Dindo score greater than 2 was 0.5% (7/1379), and most complications were self-limiting, without hospital admission or intervention.

This study represents the largest cohort of partial-gland treatment for localized prostate cancer and is notable for utilizing MRI and transperineal biopsy for cancer diagnosis, patient selection, and treatment planning. Overall, 69% FFS was noted at 7 years after primary focal HIFU, with over 20% of patients requiring additional ablations. The study demonstrates the safety and feasibility of partial-gland ablation, along with acceptable cancer control, although any statements regarding oncological efficacy would be premature considering the median follow-up for the entire cohort was only 2.7 years.

Partial-gland treatment for prostate cancer has been studied for the past 15 to 20 years using various energy sources and ablative devices. Despite the early adoption of focal therapy in the United Kingdom, requiring 15 years to accumulate 1379 cases from 13 centers (about 7 cases/year/center) highlights the slow uptake of this modality for carefully selected patients only. Patient selection is further evident from the lack of differences in the outcomes between the intermediate- and high-risk cohorts, which seems to defy tumor biology, further suggesting the presence of favorable features in the high-risk cohort.

There are inherent differences in the definition of success following partial-gland or focal ablation and whole-gland treatment (surgery or radiation). For example, retreatment with another ablative procedure for tumor persistence or recurrence is not viewed as treatment failure, whereas any subsequent therapy after whole-gland treatment is considered failure of initial treatment. A microscopic positive margin or pg of detectable PSA is classified as residual disease after radical prostatectomy, whereas repeat biopsy showing obvious residual disease following focal ablation is viewed as an opportunity for further ablation without being classified as salvage treatment.

This, along with short follow-up, precludes oncologic efficacy comparison between focal ablative therapy and whole-gland treatment. If adequate cancer control can be achieved by focal or partial-gland treatment, then the favorable adverse event profile could make this a preferred option for a number of men with localized intermediate-risk (and possibly selected high-risk) prostate cancer. Until the ongoing randomized controlled trials with adequate follow-up can provide data on comparative effectiveness, physicians will have to rely on single-cohort studies demonstrating the feasibility and safety of focal treatment to guide patient counseling and clinical decision-making.

1. Reddy D, Peters M, Shah TT, van Son M, Tanaka MB, Huber PM, et al. Cancer control outcomes following focal therapy using high-intensity focused ultrasound in 1379 men with nonmetastatic prostate cancer: a multi-institute 15-year experience. 

2022;S0302-2838(22)00006-9. doi:10.1016/j.eururo.2022.01.005

"If adequate cancer control can be achieved by focal or partial-gland treatment, then the favorable adverse event profile could make this a preferred option for a number of men with localized intermediate-risk (and possibly selected high-risk) prostate cancer," writes Badar M. Mian, MD.

Findings support safety, feasibility of partial-gland treatment

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

"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.

Badar M. Mian, MD

Articles

Robotic cystectomy is effective, but overall clinical impact is uncertain

RP appears more effective against high-risk prostate cancer

Findings support safety, feasibility of partial-gland treatment

Unexpected increase in PSA testing after USPSTF recommendations