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

Badar M. Mian, MD

Badar M. Mian, MD, writes "While we await the results of several randomized clinical studies, this study provides useful data to guide contemporary clinical practice."

In the presence of metastatic renal cell carcinoma (mRCC), up-front removal of the tumor (ie, cytoreductive nephrectomy [CN]) along with the use of interferon and/or interleukins had been the standard of care for a couple of decades. The role of CN was challenged by the advent of more selective and effective systemic therapies for mRCC. The CARMENA trial (NCT00930033) demonstrated that use of sunitinib (Sutent) alone in patients with intermediate- and poor-risk mRCC was associated with similar overall survival (OS) compared with those who received up-front CN followed by sunitinib.

However, subgroup analyses that stratified patients for certain risk criteria indicated some patients could benefit from CN along with sunitinib. Since that trial, systemic therapy for mRCC has shifted from targeted agents (sunitinib) to immune checkpoint inhibitors (ICIs) as the preferred option at many centers. However, the role of CN in patients with mRCC treated with ICI therapy and the timing of CN are not well understood.

Bakouny et al addressed these questions using the International mRCC Database Consortium (IMDC), which includes patients with de novo mRCC who did not undergo nephrectomy and were treated with a first-line ICI or targeted therapy regimen.

 Each systemic therapy cohort (ICI and targeted) was further divided into subcohorts of patients receiving up-front CN or receiving systemic therapy without upfront CN. Patients had to have received systemic therapy after January 1, 2009. The primary outcome of interest was OS as calculated from the start of first-line systemic therapy until death from any cause.

The authors identified 4639 patients with mRCC who were eligible for this retrospective analysis. Of the 4202 patients receiving targeted therapy, 2326 (55%) underwent up-front CN, and of the 437 treated with ICI therapy, 234 (54%) underwent up-front CN. Sunitinib was used in majority of patients receiving targeted therapy, and the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) was most frequently utilized regimen in patients receiving ICI therapy. The median time between CN and starting targeted therapy or ICI therapy was 3.1 months and 2.5 months, respectively.

Patients receiving CN in both systemic cohorts had more favorable prognostic profiles than those who did not undergo CN. For patients undergoing CN, 72% and 60% of patients belonged to the intermediate-risk group in the targeted therapy and ICI therapy cohorts, respectively. Of those not undergoing CN, 47% and 46% had intermediate-risk features in the targeted therapy and ICI therapy cohorts, respectively. Older age; presence of bone, brain, or liver metastases; poor performance status; and IMDC poor-risk factors were associated with a lower likelihood of undergoing CN.

The median OS for patients in the ICI therapy group was 54 months for those receiving CN and 22 months for those not receiving CN. Similarly, the median OS for patients in the targeted therapy group undergoing CN vs patients not undergoing CN was 25 months and 13 months, respectively. The median follow-up in the targeted therapy and ICI therapy groups for surviving patients was 24 and 12 months, respectively.

Multivariable analysis demonstrated an OS benefit in favor of CN in both the ICI therapy (HR, 0.61; 

=.013) and the targeted therapy (HR, 0.72; 

<.001) cohorts. However, the extent of survival benefit associated with CN was not different between the ICI therapy and targeted therapy groups (interaction, 

=.6). Although there were substantial differences in baseline risk factors between the CN and no CN groups, sensitivity analysis using an inverse propensity of treatment weighting approach yielded similar results in both the targeted therapy (HR, 0.74) and the ICI therapy (HR, 0.66) groups.

The study results, using a large, prospectively maintained, multicenter database demonstrate that up-front CN was associated with a significant OS benefit regardless of the type of systemic therapy used. Since the advent of improved systemic therapies, there have been conflicting reports regarding the benefit of CN, with some studies questioning the need for up-front CN and others suggesting a potential benefit in properly selected patients. In the current study, younger patients who had fewer IMDC risk factors, no adverse metastases (bone, brain, or liver), and better performance status were more likely to be treated with up-front CN. The study results suggest that well-selected patients are best suited to realize the benefits from CN in the era of ICIs. The beneficial effects of CN may be a result of the immune-modulating effects of an up-front CN. It has been well-established that primary RCC is associated with the release of cytokines that inhibit T cells, thus blunting the systemic antitumor immune response. It is entirely conceivable that up-front CN may facilitate a more robust immune response in patients being treated with ICI therapy for mRCC.

The reason for the delay of 2.5 to 3 months before systemic therapy could be initiated also warrants further evaluation. With minimally invasive surgery and relatively favorable performance status, most patients should be able to initiate systemic therapy 1.5 months after surgery. It’s unclear whether this near doubling of time between surgery and systemic therapy has any detrimental effect on survival. The study results are subject to potential confounders including nonrandomized data and patient factors or symptoms that can affect the likelihood of receiving up-front CN (renal function, hematuria, pain, inferior vena caval thrombus, tumor extent). Furthermore, delayed nephrectomy after a period of initial systemic therapy in those not suitable for up-front CN also requires further discussion.

While we await the results of several randomized clinical studies, this study provides useful data to guide contemporary clinical practice. Up-front CN is associated with a survival benefit in selected patients with mRCC treated with either targeted therapy or ICI therapy. This is especially true for patients younger than 65 years without metastases to brain, bone, and liver and with good functional capacity.

1. Méjean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. 

2018;379:417-427. doi:10.1056/NEJMoa1803675

2. Bakouny Z, El Zarif T, Dudani S, et al. Upfront cytoreductive nephrectomy for metastatic renal cell carcinoma treated with immune checkpoint inhibitors or targeted therapy: an observational study from the International Metastatic Renal Cell Carcinoma Database Consortium. 

Published online October 19, 2022. doi:10.1016/j.eururo.2022.10.004

Articles

"Up-front CN is associated with a survival benefit in selected patients with mRCC treated with either targeted therapy or ICI therapy," writes Badar M. Mian, MD.

Nephrectomy shows benefit in mRCC managed with systemic therapy

The landscape of advanced prostate cancer treatment has changed dramatically over the past decade. Although novel oral hormonal drugs increase oncologic outcomes (eg, progression-free survival), they also increase financial toxicity for patients. The increase in insurance premium cost is further compounded by increasing out-of-pocket cost (OOPC) for patients because of increasing requirements for deductibles, co-payments, and coinsurance. The rising cost of care may disproportionately affect patients with cancer. Nearly two-thirds of patients with cancer report significant stress related to their medical bills.

To determine the OOPC for patients undergoing treatment for advanced prostate cancer, Joyce et al examined the administrative claims data for commercially insured adults from the OptumLabs Data Warehouse.

 The deidentified data include medical and pharmacy claims, enrollment records, and demographic data including age, race, and region. The authors identified men who received a diagnosis of advanced prostate cancer at various stages (recurrent, hormone-sensitive or castration-resistant, metastatic and nonmetastatic) between 2007 and 2019. Patients with less than 1 year of medical coverage were excluded, and a follow-up of 1 year was required to ensure patients would have met their OOPC.

The primary outcome of interest for this analysis was OOPC in the first year related to treatment with prostate cancer medications, including the sum of deductibles, co-payments, and coinsurance. Total OOPC included the OOPC for all medical and pharmacy claims during the first year of treatment. The type of treatment was divided into these groups: (1) standard androgen deprivation therapy (ADT) alone (including LHRH agonists and antagonists as well as surgical castration); (2) novel hormonal therapy (NHT): apalutamide (Erleada), darolutamide (Nubeqa), abiraterone acetate (Zytiga), and enzalutamide (Xtandi); and (3) nonandrogen systemic (NAS) agents: chemotherapy, sipuleucel-T (Provenge), and radium-223 (Xofigo). Medical or surgical castration was present in 98% and 80% of the NHT and NAS treatment groups, respectively.

For this analysis, there were 13,409 patients who had received ADT (10,926; 81%), NHT (832; 6.2%), and NAS therapy (1651; 12%). The average annual prostate cancer treatment–related OOPCs for the ADT, NHT, and NAS groups were $165, $4236, and $994, respectively. The use of NHT was associated with the highest annual total health care spending ($254,677), followed by NAS therapy ($52,825) and ADT ($778). There appeared to be bimodal distribution of OOPC in all 3 groups, suggesting a minority of patients accounted for the majority of OOPC. For example, in the NHT group, approximately 20% of patients accounted for 80% of the treatment-related OOPC, whereas a small proportion of patients incurred no OOPC.

In the multivariable analysis, after adjusting for baseline patient characteristics, treatment-related OOPC remained significantly higher for NHT, with predicted annual treatment-related OOPCs of $2731, $901, and $150 for NHT, NAS therapy, and ADT, respectively. The total OOPC was similarly higher for NHT and NAS treatments compared with that of DT. Certain patient characteristics were associated with higher treatment-related OOPC, including older age (65-74 years) and Black race. Conversely, lower treatment-related OOPC was noted in patients living in areas with higher household income, higher comorbidity scores, and better insurance coverage, whereas higher comorbidity index scores were associated with greater total OOPC. The data demonstrate that being treated for advanced prostate cancer, after adjusting for patient characteristics, was still 18 times more expensive than ADT ($2731 vs $150) for men with commercial insurance.

The study results provide valuable and actionable insight on the magnitude of OOPC for various treatment options and help identify patients who may be most in need of intervention to ameliorate financial toxicity. This study is among the few studies on the topic of OOPC incurred by patients because of contemporary advanced prostate cancer treatments. Previous study results have demonstrated that for patients with Medicare who do not receive low-income subsidies, the median OOPC during the first 6 months of abiraterone or enzalutamide treatment was $4498. As a result of the increasing financial burden, patients have reported skipping medication doses, foregoing prescription refills, or discontinuing treatments altogether. Other studies have reported Black patients with cancer were more likely to have cost-related nonadherence to medication than White patients.

When discussing health care economics and financial burden, one must recognize the countervailing forces at work. Most hospitals as well as oncology and urology practices, are involved in for-profit pharmaceutical ventures in some fashion. What we consider cost savings may be viewed by others as lost revenue. Strange as it once seemed, our clinics are littered with coupons from companies selling very expensive drugs. Whether these coupons and other pharmaceutical resources effectively reduce the OOPC burden (for those who need some relief) or just serve as window dressing for big pharmaceutical companies is open to debate.

How does a practicing urologist or oncologist help mitigate the financial burden of the ever-increasing OOPC for the patient? Should financial screening be a regular part of the clinical visits? Should a consultation with pharmacy representative or patient advocate be standard practice before initiating expensive therapies such as NHT? Who should be given this responsibility?

A discussion about financial burden of treatment, in addition to the discussion about cancer-related outcomes, prognosis and adverse effects, would pose a challenge to the clinical practice and workflow. But ultimately, it will be the treating physician’s responsibility to identify cost-effective alternatives and available resources to help mitigate the financial toxicity incurred from novel cancer therapies. These may include leveraging available financial support and low-income subsidies, using less expensive but effective alternatives, and/or modifying dosage and schedule based on published literature.

1. Joyce DD, Sharma V, Jiang DH, et al. Out-of-pocket cost burden associated with contemporary management of advanced prostate cancer among commercially insured patients. 

Published online September 12, 2022. doi:10.1097/JU.0000000000002856

"Ultimately, it will be the treating physician’s responsibility to identify cost-effective alternatives and available resources to help mitigate the financial toxicity incurred from novel cancer therapies," writes Badar M. Mian, MD.

Consider financial toxicity when recommending novel hormonal therapies for prostate cancer

The effect of 5-α-reductase inhibitors (5-ARIs) such as finasteride (Proscar) and dutasteride (Avodart) on prostate cancer–related outcomes has been hotly debated for almost 2 decades. The initial cause for debate arose from data from 2 clinical trials of 5-ARIs for chemoprevention of prostate cancer (PCPT and REDUCE [NCT00056407]), which showed a reduction in the risk of a prostate cancer diagnosis, but an increased incidence of high-risk prostate cancer. Further, observational studies have demonstrated conflicting results on the association between 5-ARI use and prostate cancer–specific mortality (PCSM).

In a recent population-based study, Björnebo et al investigated the association of treatment with 5-ARIs with PCSM in a large cohort of men receiving 5-ARIs for lower urinary tract symptoms (LUTS).

 This study from Stockholm, Sweden was conducted between January 1, 2007, and December 31, 2018, and included 429,977 men who had a prostate-specific antigen (PSA) test within the study period. Investigators linked multiple large registries including the Stockholm PSA and Biopsy Register, National Prostate Cancer Register of Sweden, Prescribed Drug Register, Swedish Cause of Death Register, and others. Only men without a previous prostate cancer diagnosis could enter the study. Men with prior transurethral resection of the prostate or treatment with a 5-ARI before their first PSA test were excluded. A minimum of 1.5 years between the start of 5-ARI treatment and first PSA test was required. A PSA level of 3 ng/mL or greater was considered elevated, and the PSA level was doubled if a 5-ARI had been used for at least 3 months.

Of the final cohort of 349,152 men, 26,190 were 5-ARI recipients with at least 2 filled prescriptions during follow-up. Median follow-up time was 8.2 years. The median exposure to 5-ARI was 4.5 years (interquartile range, 2.1-7.4). Men exposed to a 5-ARI during the study period were older, more likely to have had a previous negative biopsy, and had higher PSA levels than men not exposed to a 5-ARI. Prostate cancer was diagnosed in 1377 (0.4%) and 14,804 men (4.2%) with and without 5-ARI exposure, respectively. The exposed group also had a larger prostate volume, higher Gleason score, and higher primary tumor, lymph node, and metastases stage at diagnosis. A total of 35,767 patients (10.2%) died during follow-up, with 852 deaths attributed to prostate cancer.

Multivariable Cox regression demonstrated no difference in all-cause mortality for any duration of 5-ARI exposure (<2 years adjusted HR, 0.99; >8 years adjusted HR, 0.97). However, use of a 5-ARI was associated with a decrease in PCSM with longer exposure (<2.0 years adjusted HR, 0.89 vs >8 years adjusted HR, 0.44 [adjusted HR difference, 0.50]). Men treated with a 5-ARI had more PSA tests per year (median, 0.63 vs 0.33) and more biopsies per year (median, 0.22 vs 0.12) than the unexposed group. The time from elevated PSA levels to prostate biopsy was shorter in men treated with a 5-ARI than the unexposed group (median, 1.17 vs 1.20 years).

The study investigators found a decreased risk of dying of prostate cancer in men treated for LUTS with 5-ARI for more than 2 years compared with men not treated with a 5-ARI. These results suggest the safety of 5-ARI treatment and that the increased grade and stage of prostate cancer at diagnosis for men receiving 5-ARI treatment are not associated with increased PCSM.

Men receiving treatment with a 5-ARI had significantly higher diagnostic activity, with more PSA tests and prostate biopsies per year than nonrecipients of 5-ARI.

Data from previous studies on the use of 5-ARIs have shown a significantly lower diagnostic activity and prolonged time to prostate biopsy in those receiving treatment with a 5-ARI (median, 3.60 vs 1.40 years) in a cohort of men within the Veterans Affairs health care system.

 They also showed an increased PCSM that was associated with 5-ARI (adjusted HR, 1.39; 95% Cl, 1.27-1.52), which was likely related to inappropriate accounting for the effect of 5-ARI on PSA levels, with delays in diagnosis and treatment, resulting in worse PCSM. A possible explanation for the observed differences in the current study population may be that men receiving a 5-ARI had more frequent contact with urologists, with more frequent PSA tests and biopsies. The increased surveillance of men receiving treatment with 5-ARIs could explain the observed decrease in PCSM in this cohort.

It is important to consider the findings from various studies of 5-ARI effect on prostate cancer–related outcomes in light of the range of questions addressed by those studies such as incidence or detection rate, grade of cancer, and effect on PCSM and overall mortality. Similarly, the distinct features of the health care system and study population should be considered when comparing the results of those studies, as differences in clinical management and diagnostic activity may explain the disparate results.

The question remains whether the prostate cancer–related outcomes from the use of 5-ARIs are due to an effect on cancer biology or some other factors related to clinical practice. As the authors point out, it cannot be determined whether this is a causal relationship or a result of detection bias resulting from a more intensified diagnostic activity (more PSA tests, more biopsies, earlier biopsies) in the 5-ARI group. Could a similarly intensive diagnostic activity in the group without 5-ARI result in similar outcomes?

 with a 5-ARI is not the same as taking the drug for 

. Most studies on this subject include men receiving 5-ARI for treatment of LUTS. Whether the results of those studies can be extrapolated to a chemoprevention paradigm, in asymptomatic men who otherwise had no clinical reason to use a 5-ARI, remains unclear. Findings from most, but not all, observational studies suggest that despite the increased incidence of high-grade prostate cancer associated with 5-ARI usage, it is not associated with worse prostate cancer–related mortality. It is evident, however, that the safety of 5-ARIs as it relates to prostate cancer outcomes is contingent upon the clinician understanding its effect on PSA level and making appropriate adjustments to ensure timely deployment of diagnostic imaging and biopsy.

1. Björnebo L, Nordström T, Discacciati A, et al. Association of 5α-reductase inhibitors with prostate cancer mortality. 

2022;8(7):1019-1026. doi:10.1001/jamaoncol.2022.1501

2. Mian BM. What do recent studies tell us about finasteride and PCa? 

®. December 5, 2019. Accessed August 8, 2022. https://bit.ly/3Q8aRpx

"It is evident...that the safety of 5-ARIs as it relates to prostate cancer outcomes is contingent upon the clinician understanding its effect on PSA level and making appropriate adjustments to ensure timely deployment of diagnostic imaging and biopsy," writes Badar M. Mian, MD.

Do 5-ARIs protect against death from prostate cancer?

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

Randomized controlled trial compares intracorporeal robotic technique with open surgery.

Badar M. Mian, MD

Articles

Nephrectomy shows benefit in mRCC managed with systemic therapy

Consider financial toxicity when recommending novel hormonal therapies for prostate cancer

Do 5-ARIs protect against death from prostate cancer?

Robotic cystectomy is effective, but overall clinical impact is uncertain