For more than a generation, the notion of lumpectomy instead of radical mastectomy for breast cancer was met with scorn and treated as heresy. Now, it is the standard of care and has saved the physical QoL for many women. Prostate cancer (PCa), which is similar to breast cancer in many ways, has also been considered not amenable to focal therapy as a form of lumpectomy. This is because of the size of the prostate, its relative inaccessibility, the fact that PCa is often multifocal, and concerns that focal therapy may rule out some treatment options if the cancer recurs. However, with the recent FDA clearance of high-intensity focused ultrasound (HIFU) in prostate disease, this therapeutic option has become viable. HIFU has been used for decades in Europe with excellent oncologic control and acceptable AEs.

The potential for prostate lumpectomies expanded notably in June 2018, which is when the FDA cleared the Focal One HIFU device as the first medical apparatus designed specifically for focal treatment of the prostate, although earlier devices made this procedure possible. As with all technological advances, long-term studies and clinical data will ultimately determine whether Focal One distinguishes itself as a uniquely useful instrument. Nevertheless, its arrival is significant due to the degree of precision with which diseased prostate tissue can be ablated while sparing healthy tissue and thus reducing AEs.

The Focal One device provides precision capability to treat the prostate by integrating magnetic resonance and 3D biopsy data with real-time ultrasound imaging—a process known as fusion. This melding of advanced imagery and patient diagnostic data provides a detailed 3D view of the prostate on a large monitor in real time, enabling direct highintensity ultrasound waves to ablate the targeted area within the prostate.

Because this fusion of technologies allows for improved targeting of diseased tissue during treatment planning, the margins around the contours of that tissue can be drawn more concisely than the margin contours required by less-precise procedures used in the past, thus eliminating the need to remove larger volumes of prostate tissue. In addition, this advancement in focal ultrasound prostate tissue ablation enables clinicians to enact a protocol that respects the maxim “right patient, right treatment, right time,” because the focal HIFU therapy can be customized for each patient and for each clinical scenario.

Figure 1. German Study: Survival Rates for Patients With Localized PCa Treated With HIFU

During the procedure the device’s proximity to the rectal wall is constantly monitored for patient safety. The robotic HIFU device automatically readjusts itself and, if necessary, stops transmission of the high-frequency waves anytime they are too close to the rectal wall. This aids in avoiding rectal injury.

Future long-term studies are hoped to provide data needed to fully analyze the potential of focal HIFU therapy as an alternative to radiation and radical prostatectomy for treatment of localized PCa in the United States. European researchers have published positive peer-reviewed studies of the use of this technology for whole gland ablation.

Here is a brief review of 2 such studies: In 2013, the

published a German study of 704 patients treated with HIFU, in which co-investigators Stefan Thu&#776;roff and Christian Chaussy concluded that long-term follow-up with HIFU therapy demonstrated a high overall rate of cancerspecific survival (99%) and 10-year salvage treatment-free rates of 98% in low-risk, 72% in intermediate-risk, and 68% in high-risk patients. “Advances in HIFU technology and clinical practice, as well as the use of neoadjuvant transurethral prostate resection, allow the complete treatment of any size prostate without inducing metastasis,” the authors wrote.

The study assessed patients with primary localized PCa (T1-2, N0, M0, and prostate specific antigen [PSA] at first diagnosis <50 ng/mL) and follow-up longer than 15 months. Patients with previous long-term androgen deprivation therapy (ADT), locally advanced PCa, or any therapy influencing PSA were excluded from the study.

Among the study participants, 78.5% had intermediate- or high-risk disease. The mean follow-up was 5.3 years (range, 1.3-14). Metastasis-free survival was 95%. PSA nadir and Gleason score predicted biochemical failure, and AEs were moderate. The OS of the patient population was identical to current local Bavarian population survival statistics (

 Of the total patients, 38.4% were intermediate risk and 40% were high risk based on stratification tools of the 1990s and early 2000s. The study also concluded that the rate of low-risk patients being able to avoid salvage therapy was exceptionally high, based on long-term follow-up.

A second European study investigated HIFU-based whole-gland ablation of localized PCa in 1002 patients. This was led by Sebastien Crouzet in France, with results published by the European Association of Urology. Participants were patients treated from 1997 to 2009.

 The 10-year PCa-specific survival and metastasis-free survival rates were 97% and 94%, respectively.

Also, severe incontinence and bladder outlet obstruction decreased with refinement in the technology, from 6.4% and 34.9% to 3.1% and 5.9%, respectively. Limitations included that the study was a single-arm study without a comparison group. Researchers concluded that HIFU is a “potentially effective treatment” of localized PCa, with a low PCa-specific mortality rate and a high metastasis-free survival rate at 10 years, as well as acceptable morbidity. The 10-year OS rate and PCa-specific survival rate were 80% and 97%, respectively (

About two-thirds of the patients were determined to be intermediate or high risk during an era of frequent understaging.

In addition to this European research, the University of Miami Miller School of Medicine conducted a study of functional and oncologic outcomes resulting from HIFU for focal treatment of PCa. Preliminary results were presented at the Southeastern Section of the AUA conference in March 2018. Researchers at the University of Miami also introduced the FoR-UsA Registry (Focal Robotic Ultrasound Ablation Registry) in February, creating the first registry in the United States to specifically track baseline and long-term follow-up data on patients who have undergone focal therapy for prostate tissue ablation.

In Europe and in countries elsewhere, HIFU has been used to treat more than 50,000 patients. The accumulating data have established focal HIFU as a safe and effective therapy with statistically significant survival rates in the 3-to-5-year window. Further, the data from the 2 European studies mentioned here document positive outcomes at the 5-to-10-year follow-up points.

As these studies and other research show, focal HIFU is taking its place as a viable option among focal therapies for patients with localized PCa. Continued international research, US studies, and a US HIFU registry data collection are poised to bolster the case for making patients aware of this option.

Focal therapies are aimed at providing a middle ground for patients with localized PCa who wish to avoid the potential life-altering AEs that come with radical prostatectomy or radiation on the one hand or the stress of active surveillance on the other. Besides HIFU, laser ablation and cryotherapy also are a part of the tool set for achieving this goal.

Focal laser ablation (FLA) uses commercial laser fibers, generally 980-nm diode lasers. This method has been studied and used since it was determined to be a feasible alternate treatment approach by Lindner et al in 2009.4 FLA uses MRI guidance to treat regions of interest (ROIs) that are biopsy-confirmed areas of cancer. Thermal ablation of the cancer is then carried out, often under MRI thermometry control.

In the 2009 study, 12 men were treated with transrectal ultrasound fused with biopsy-proven MRI-determined ROIs. Target ablation was monitored with thermal sensors and contrast-enhanced ultrasound, and AEs, including the impact on voiding and erectile function, were evaluated in the aftermath.

The median MRI cancer volume was 0.25 cc (range, 0.1-0.99). Temperature probes were placed at the ablation zone boundary to ensure temperatures of ≥55

C were attained at the borders. Follow-up MRIs at 7 days revealed the median treatment lesion volume was 2.2 cc (range, 0.3-4.0), creating an ablated lesion that was an average of 12.25 times the tumor size. The overall median preand posttreatment MRI overlap was 53%, although better (83%) in the last 4 patients, demonstrating consistent imaging.

In the posttreatment follow-up, 10 core biopsies with 2 additional cores in the treatment zone revealed half of the patients to have completely negative biopsies; 2 of these patients had negative biopsies in the treatment zone but a positive low-volume core in the contralateral side. Four patients were treatment failures, with 3 having poor MRI overlap.

The authors concluded that image-guided focal photothermal ablation of low-risk and low-volume PCa is feasible, with minimal AEs; however, they said further studies would be required to demonstrate the efficacy of this treatment.

In a follow-up study, Lindner et al reported in 2010 on 4 men treated with FLA 7 days prior to radical prostatectomy.

 The study was designed to understand how well MRI represents true treatment effect and how effective FLA was in this group. The authors found that on “vital stain” pathologic evaluation, MRI-ablated volumes were 1.1 times greater than the pathology findings. They felt they had demonstrated that it was possible to fully ablate a specified volume in preoperatively chosen zones, leaving no viable cells. No mention was made of cancer cells at the borders of the treatment zone. Nonetheless, it does suggest the need for a safety zone around MRI-defined ROIs.

In 2015, Lepor et al reported on 25 men treated “in bore” (ie, in the MRI chamber) with FLA. They used a 600-μm laserdiffusing fiber with a 15-mm tip passed through a cooled catheter system, meant to keep fiber from overheating.

 These 25 patients had 28 ROIs treated, with 26 showing “no evidence of PCa” in the treatment zone.

Another in-bore study was reported in 2016 by Eggener and colleagues.7 In this phase II evaluation of MRI-guided FLA, at 3 months post treatment, 96% of the total 27 men had no cancer in the treatment zones on image-guided biopsies. A 15-watt fiber with reduced power was employed, and the treatment duration was 60 to 120 seconds at 6- to 15-watt bases on the intended size of the treatment zone. The target ablation temperature achieved was reported as a minimum of 60o C. The mean procedure duration was 197 minutes (range, 138-302), and the mean ablation time 320 seconds. The mean duration of treatment for the final 10 patients was 160 minutes. In 18 men, 1 MRI lesion with cancer confirmed by a biopsy was targeted, and 2 lesions were targeted in 9 patients. Follow-up biopsies at 1 year revealed cancer in 37% (10 men), including 11% (3 men) with cancer in the treatment zone.

In an effort to make FLA a bit more user friendly, Natarajan and Marks reported, in 2017, on 10 patients treated in the clinic under local anesthesia using MRI/ transrectal ultrasound fusion technology.8 For safety purposes, a temperature probe was near the rectal wall and in the ablation zone. The treatment involved a 15-watt laser fiber activated at 13.75 watts for a treatment time of 3 minutes (less if the rectal probe reached 42

C or the parallel probe reached 70o C). The patients tolerated the procedure well, with a maximum pain score of 5 reported during treatment. The mean treatment zone volume was 4.3 cc (range, 2.1-6.0) and the procedure took an average of 95 minutes (range, 71-105) to accomplish. At 6 months after treatment, fusion biopsies revealed only 3 patients were cancer free in the treatment zone. Of those deemed failures, 4 had Gleason score 7 disease present in the ablation area with maximum core length of 3 to 9 mm.

In these studies, QoL was generally well preserved. International Index of Erectile Function scores were unchanged or improved, and sexual function was unchanged or returned to baseline within 6 months. Most men were catheter-free at discharge post procedure, and all patients were catheter-free within 3 days post procedure. Issues such as potential hematuria, perineal ecchymosis, etc, were minimal.

Figure 2. French Study: Survival Rates for Patients With Localized Pca Treated With HIFU

All of these published studies of FLA support the concept of focal ablation for MRI-confirmed PCa. Nonetheless, they also reveal that oncologic control within the ablation zone can be haphazard, that issues with MRI definition of adequate treatment remain,

 and that treatment times can vary greatly, suggesting a steep learning curve. As MRI technology and localization of significant cancer improve and carefully conducted trials are carried out, the potential of this FLA therapy will become better defined.

The goal for focal or hemiablation cryosurgery in properly selected men is to reduce adverse consequences from more traditional therapy, such as urinary incontinence, stricture disease, bowl toxicity, and erectile dysfunction, while providing comparable cancer outcomes. All patients undergo a double freeze—thaw cycle during treatment with active thawing. Typically, 3 treatment probes are used along with 2 to 3 temperature probes to monitor treatment areas and the external sphincter. A urethral warming catheter is always utilized, and all focal patients typically are discharged on the same day. A suprapubic tube is not utilized, and most patients go home with a standard Foley catheter for 3 to 5 days. Patients have minimal discomfort and use of narcotics is rare. Monitoring is similar to that provided for radiation therapy, with PSAs every 3 months for a year and then every 6 months until the physician determines it is appropriate to stop. Repeat biopsies are not performed unless biochemical recurrence (BCR) is suspected based on the ASTRO definition (detectable or rising PSA value after surgery that is ≥0.2 ng/ml with a second confirmatory level ≥0.2 ng/ml).

Focal therapy, in general, started with cryotherapy/ cryosurgery. In 2007, Onik et al reported on the “male lumpectomy” using focal cryotherapy.

 Their protocol started in 2000 and reported on 93 men, 55 of whom had not suffered radio recurrent disease, with greater than 1 year of follow-up treated with focal cryoablation. Of these 55, 95% had a stable PSA. Twenty-nine had a biopsy at 1 year, and 26 were negative. The 3 remaining patients had a positive biopsy, and these were in untreated areas of the gland. Potency was preserved in 85%, and only 1 patient reported urinary incontinence, 2 pads daily. A year later, the investigators updated their reporting on 48 of the men; this group now had at least 2 years of follow-up. No local recurrences were found in the treated areas, nor was cancer found in the gland, and all biopsy findings were negative among the 26 patients with a stable PSA level who had undergone routine biopsy at 1 year. Ninety-four percent of the men had stable PSAs, with potency still in the 85% range, and none experienced incontinence.

One of the earliest reports on focal cryotherapy was from Bahn et al in 2006.

 In this study, 31 men with a mean age of 63 years underwent focal or hemiablation therapy. Follow-up for these patients was PSA monitoring every 3 to 6 months. Most significantly, patients underwent repeat prostate biopsies at 6 months, 12 months, 24 months, and 5 years. At a mean follow-up of 70 months, and according to the ASTRO definition, 92.8% of patients were still biochemically disease free and 96% had a negative biopsy rate. A potency rate of 88.9% was achieved: 48.1% of men not requiring any medical assistance for erections and 40.7% requiring oral pharmaceutical therapy for erections. There were no reports of stress urinary incontinence.

A follow-up study by Bahn in 2012 with 73 men showed encouraging outcomes as well.

 Complete follow-up was obtained in 70 patients, and all patients had repeat biopsies at 6 and 12 months and then yearly. Seventyfive percent of the patients had negative biopsies, and complete continence and potency was achieved in 100% and 86% of patients respectively.

Ward and Jones reported in 2011 on a large series of men from the COLD Registry, a national cryo online database with voluntary reporting from many urologists throughout the country.

 They found 1160 men managed with focal cryoablation. Most men (74%) had a Gleason score of ≤6, and 87% had stage ≤cT2b. Focal therapy increased every year from 1999 to 2007.

BCR at 2 years was approximately 24%, similar to the whole gland results. Biopsy was only performed for men with a rising PSA. Of the group, 163 (14.1%) were biopsied and 43 of these (26.3%) were positive. No data on whether the cancer was in the treated zone were provided. Morbidity was low, consistent with the other studies, although new-onset erectile dysfunction occurred in 42%. A big issue with this database is reliance on individual urologists providing all the necessary treatment and follow-up data, which, in general, has been haphazard in this registry.

Another focal study from Barqawi et al from 2014 demonstrated a negative biopsy in 81% of patients.

 Sixty-two patients were treated, and no patients experienced postoperative erectile dysfunction or stress urinary incontinence. These patients were diagnosed with 3D mapping biopsy using triplane transrectal ultrasonography.

Although all of these studies on early focal therapies— HIFU, cryo, and laser&mdash;are optimistic and generally enthusiastic, good long-term studies would be welcome. Unfortunately, in many respects, the “horse has already left the barn.” Patients want HIFU treatment, and practicing urologists are increasingly embracing it. As stated by Ward and Jones, “Although the prognosis for PCa is now very different from what it was 20 years ago, the aggressiveness of our treatment has not changed commensurately,” and furthermore “the concept of organ-sparing therapy went from improbable to plausible, and the explosion of its use…shows its appeal to the urologic community.”

A randomized multicenter control trial between these 3 modalities would be optimal, but it is most likely not feasible. Certainly, single-center studies of each option would be valuable and ongoing multicenter trials would be helpful. However, we believe a well-designed registry trial with defined pre— and post–focal therapy data that must be collected will be helpful. Failure will have to be well defined and dependence on the ASTRO definition of a BCR used in patients who have undergone radiation treatment will undoubtedly need to be replaced by either PSA kinetics, a single rise of greater than a “certain” percent, possibly PSA density, genomic profiling, or a combination of those. A biopsy requirement at 1 year, etc, will generally not be supported by urologists or patients unless required by laboratory or clinical data. We need to adapt to our current reality and move forward with the knowledge of where we are and what we can do. Focal therapy could become the male lumpectomy for appropriate men.

Thu&#776;roff S, Chaussy C. Evolution and outcomes of 3 MHz high intensity focused ultrasound therapy for localized prostate cancer during 15 years.

2013;190(2):702- 710. doi: 10.1016/j.juro.2013.02.010.

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Lindner U, Lawrentschuk N, Weersink RA, et al. Focal laser ablation for prostate cancer followed by radical prostatectomy: validation of focal therapy and imaging accuracy. 

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Lepor H, Llukani E, Sperling D, Fu&#776;tterer JJ. Complications, recovery, and early functional outcomes and oncologic control following in-bore focal laser ablation of prostate cancer. 

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Eggener SE, Yousuf A, Watson S, Wang S, Oto A. Phase II evaluation of magnetic resonance imaging guided focal laser ablation of prostate cancer.

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Natarajan S, Jones TA, Priester AM, et al. Focal laser ablation of prostate cancer: feasibility of magnetic resonance imaging-ultrasound fusion for guidance.

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Eggener SE, Yousuf A, Watson S, Wang S, Oto A. phase ii evaluation of magnetic resonance imaging guided focal laser ablation of prostate cancer.

Thompson IM, Valicenti RK, Albertsen P, et al. Adjuvant and salvage radiotherapy after prostatectomy: AUA/ASTRO Guideline. 

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Onik G, Vaughan D, Lotenfoe R, Dineen M, Brady J. “Male lumpectomy”: focal therapy for prostate cancer using cryoablation. 

2007;70(suppl 6):16-21. doi: 10.1016/j.urology.2007.06.001.

Bahn D, Silverman P, Lee F Sr, Badalament R, Bahn ED, Rewcastle JC. Focal prostate cryoablation: initial results show cancer control and potency preservation. 

2006;20(9):688-692 doi: 10.1089/end.2006.20.688.

Bahn D, de Castro Abreu AL, Gill IS, et al. Focal cryotherapy for clinically unilateral, lowintermediate risk prostate cancer in 73 men with a median follow-up of 3.7 years.

2012;62(1):55-63. doi: 10.1016/j.eururo.2012.03.006.

Ward JF, Jones JS. Focal cryotherapy for localized prostate cancer: a report from the national Cryo On-Line Database (COLD) Registry. 

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Articles

Historically, the management of localized prostate cancer has centered on removal or ablation of the entire gland with either extirpative surgery or radiation. However, the subsequent unacceptable adverse events profile can be devastating and life altering for many patients. 

Focal Therapy Evolves Into More Precise Treatment in Prostate Cancer

Since 2016, the FDA has approved 5 immune checkpoint inhibitors (ICIs) to treat urologic cancers. Although that is a good thing for patients, the rise of these agents means that the role of the urologist in cancer is changing, Noah M. Hahn, MD, said during the 2018 Large Urology Group Practice Association (LUGPA) Annual Meeting, held November 1-3 in Chicago, Illinois. Newer agents are changing traditional strategies for care, resulting in higher levels of collaboration.

Hahn, director of the medical oncology bladder program at Johns Hopkins School of Medicine, has been working closely with Howard I. Scher, MD, the D. Wayne Calloway Chair in Urologic Oncology at Memorial Sloan Kettering Cancer Center, over the past few years as systemic anticancer therapies have moved from the metastatic setting into earlier stages of urologic disease. “It’s a very exciting time right now in both spectrums: urology and oncology,” Hahn said. “We’re going to be seeing a lot more cross-discipline care.”

The KEYNOTE-045 trial was the first to show an overall survival (OS) advantage over chemotherapy for an ICI in advanced bladder cancer and helped to start this revolution, Hahn said. The trial was stopped early, in 2016, after meeting its primary endpoint of OS. Two-year follow-up data from the phase III trial showed sustained improvements in OS with pembrolizumab (Keytruda) over chemotherapy in pretreated patients with locally advanced or recurrent urothelial cancer.

The median OS was 10.3 months with pembrolizumab versus 7.4 months for chemotherapy (HR, 0.73; 95% CI, 0.59-0.91; 

 = .002), according to the initial results, published in the 

. The 12-month OS rate was 43.9% (95% CI, 37.8%-49.9%) in the pembrolizumab group versus 30.7% (95% CI, 25.0%-36.7%) in the chemotherapy group.

“What got immunotherapy approved in bladder cancer was the fact that this trial was the first trial to ever show an [OS] advantage versus chemotherapy in patients with advanced disease,” Hahn said. “We had never seen that despite the previous 30 years of trying with various chemotherapies and combinations.”

In KEYNOTE-045, patients with histologically or cytologically confirmed urothelial carcinoma who progressed after 1 to 2 lines of platinum-based chemotherapy were randomly assigned to 200 mg of pembrolizumab every 3 weeks (n = 270) or investigator’s choice of paclitaxel at 175 mg/m

, each administered every 3 weeks (n = 272).

As assessed by blinded central review, the overall response rate was 21.1% versus 11.4% in favor of the pembrolizumab arm (

 = .001). The median duration of response was not reached (range, 1.6-15.6 months) with pembrolizumab compared with 4.3 months (range, 1.4-15.4) with chemotherapy.

“What that trial showed was that immunotherapy with pembrolizumab resulted in about twice as many patients seeing their tumors shrink—about 20% compared with 10%,” Hahn said. “While that’s not a high percentage of patients, if you were in the group that responded, those responses tended to be durable.”

Figure: Early Stage Bladder Cancer is Less Challenging to Treat

The trial also provided supporting evidence that immunotherapy is generally better tolerated that chemotherapy, Hahn pointed out. In KEYNOTE-045, the incidence of treatment-related adverse events (TRAEs) was lower with pembrolizumab for any grade (60.9% vs 90.2%) and grade 3/5 (15.0% vs 49.4%). The discontinuation rate resulting from TRAEs was 5.6% in the pembrolizumab arm and 11% in the chemotherapy arm.

With the success of ICIs in metastatic disease—not just pembrolizumab, but also atezolizumab (Tecentriq), durvalumab (Imfinzi), and others&mdash;investigators have sought to determine if these agents can produce better outcomes in patients with earlier-stage bladder cancer, when the disease is less invasive (FIGURE). Several ongoing studies are exploring whether immunotherapy could be effective in patients with muscle invasive or nonmuscle invasive bladder cancer (MIBC/NMIBC).

Investigators are evaluating immunotherapy agents in the adjuvant setting in a pair of phase III trials: IMvigor010 (NCT02450331) is investigating atezolizumab versus observation in high-risk MIBC, and AMBASSADOR (NCT03244384) is investigating pembrolizumab versus observation in locally advanced bladder cancer. In addition, the phase II CheckMate 274 (NCT02632409) is investigating nivolumab (Opdivo) versus placebo in bladder or upper urinary tract cancer following surgery. Results from AMBASSADOR are expected in 2019. The other trials are expected to report in 2020.

Hahn sees much potential for success with early intervention using ICIs. “If we move to the nonmuscle invasive space, this is where I think things get really exciting,” he said. Data from the phase II KEYNOTE- 057 trial showed encouraging antitumor activity with pembrolizumab monotherapy in patients with high-risk NMIBC that is unresponsive to Bacillus Calmette-Guérin who refused or were ineligible for cystectomy. Findings from an interim analysis of the ongoing single-arm, open-label trial were presented at the European Society for Medical Oncology (ESMO) 2018 Congress.

At a median follow-up of 14.0 months, the rate of complete response (CR) in the first 103 patients enrolled with carcinoma in situ with or without papillary disease was 38.8% (95% CI, 29.4%-48.9%) at 3 months. Eighty percent of patients had a CR lasting 6 months. The median time to CR was 12.4 weeks (95% CI, 10.4-19.3). Twenty-nine (72.5%) responders had ongoing responses, and the median duration of CR had not been reached (range, 0-14.1 months).

“One of the questions that I think we’ll see addressed in follow-up presentations of these data is duration,” Hahn said. “These data are too early to give us insight into that, but they did give us a little bit of a hint of the durability of the CRs.” He noted that that the CR rate at 6 months based on these results would be about 31%, which falls short of the International Bladder Cancer Group’s guideline definition of a clinically meaningful 6-month CR rate for this patient population: 50%.

At this year’s ESMO Congress, Ronald de Wit, MD, PhD, group leader of the Experimental Systematic Therapy of Urogenital Cancers Program at Erasmus MC Cancer Institute, Rotterdam, The Netherlands, presented KEYNOTE-057 results for 130 patients who received 200 mg of pembrolizumab every 3 weeks. Treatment continued until recurrence of high-risk NMIBC. If NMIBC was present at any assessment, patients discontinued treatment and entered survival follow up. The primary endpoint was a CR, defined as absence of NMIBC.

The interim analysis used an enrollment cutoff to ensure adequate follow up for response evaluation. The database cutoff was July 18, 2018 and the enrollment cutoff was on April 1, 2018.

Most (96.1%) patients had at least 1 adverse event (AE). The rate of grade 3/5 AEs was 26.2% and the rate of grade 3/5 TRAEs was 12.6%. TRAEs in ≥2 patients included pruritus (10.7%), fatigue (9.7%), diarrhea (8.7%), hypothyroidism (5.8%), maculopapular rash (5.8%), arthralgia (4.9%), rash (4.9%), hyperthyroidism (3.9%), and nausea (3.9%). The most common grade 3/5 TRAEs were hyponatremia (2.9%) and arthralgia (1.9%). Immunerelated grade 3/5 TRAEs experienced by 1 patient each were adrenal insufficiency, colitis, hypophysitis, pruritus, rash, and type 1 diabetes.

Urology Practice Must Change to Accommodate Immunotherapy

Hahn noted that the incidence of grade 3/5 TRAEs in KEYNOTE-057 was similar to what had been previously observed in the metastatic setting. Of 3 deaths in the study, only 1, attributed to autoimmune colitis, was related to treatment. “That’s about what we see in all diseases,” Hahn said. “It’s about a 1% or less autoimmune-related potentially fatal event, and that’s something that has been consistent throughout.”

Immunotherapy is still a relatively new phenomenon in the urology world, but its success has been clear. Hahn noted that trial participants have been followed only for 3 to 4 years, but “are alive longer than we have ever seen before.”

However, when considering whether it is possible or practical to use immuno-oncology agents in early stages of disease, Hahn said practice concerns need to be kept in mind. Use of these agents will require a major education component for urologists generally and for oncologists who are unfamiliar with NMIBC. Further, urology practices will have to think about infusion center and toxicity management infrastructure, their relationships with practitioners in other specialties, and the in-house commitment to this treatment modality.

“How does your group feel about systemic therapy?” he said. “ It’s one thing to have a champion who wants to do it and is going to take on doing it for their patients, but who’s going to take the call on Friday at 4:30 PM. when you’re out on vacation? Those things need to be talked about.”

Bellmunt J, De Wit R, Vaughn DJ, et al; KEYNOTE-045 Investigators Pembrolizumab as second-line therapy for advanced urothelial carcinoma. 

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de Wit R, Kalkami GS, Uchio E, et al. Pembrolizumab for high-risk (HR) non—muscle invasive bladder cancer (NMIBC) unresponsive to bacillus calmette-guérin (BCG): phase 2 KEYNOTE-057 Trial. In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract 8640. academic.oup.com/annonc/article/29/suppl_8/ mdy283.073/5140263?searchresult=1.

Kamat AM, Sylvester RJ, Böhle A, et al. Definitions, end points, and clinical trial designs for non-muscle-invasive bladder cancer: recommendations from the International Bladder Cancer Group. 

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Newer immunotherapy agents are changing traditional strategies for care, resulting in higher levels of collaboration.

Immunotherapy Changes Early-Stage Urothelial Carcinoma Paradigm

The San Diego Count, California, weather and lifestyle may be ideal, but not the business conditions. Genesis Healthcare Partners, the region’s largest independent urology practice, is challenged by regulatory changes and the dominance of the regional managed care market, which has huge control of patient flow and payment structures. Even so, the urology practice has found ways to grow and improve care for its patients.

Some of the challenges in this market directly affect patients and their access to care, explained Edward Cohen, MD, CEO of Genesis. “A large number of patients are in managed care models. A patient could come in with a specific issue, and I have a doctor who can manage it, but they’re not in that particular managed care or independent physician association.” As a result, there can be a lot of work gaining prior authorizations and getting the approval to perform procedures.

The regulatory requirements are getting more intense, Cohen said. “In California, we recently started having to report and check the California database for every narcotic and every schedule 2 to 4 drug that we prescribe. California is known for its burdensome regulations, and that creates a struggle for everybody.” For medical practices in general, not just in California, requirements for documentation and the switch to electronic records systems has also been a challenge, he added.

In terms of payment, Cohen said the preferred provider organization market is much more limited than in other cities because many patients are in managed care groups. Further, there has been a broad shift of patients from commercial plans to managed care plans, which do not pay as much for services.

Genesis also faces challenges from Medicare, which has a negative impact on regional payment rates, Cohen said. An example was the geographical practice cost index (GPCI) coding system, which defined San Diego as a more rural area than it is, Cohen said. By contrast, the GPCI code for Orange County only 45 minutes north allows a 10% to 12% higher payment rate overall on the Medicare fee schedule.

“Independent private practice is a challenge in San Diego where the reimbursements are lower and the access to full-fare patients is more limited,” Cohen said. Additionally, Genesis finds it difficult to recruit new physicians because the region’s cost of living is high and payment rates are comparatively low, which results in noncompetitive income potential.

Some large cities have big players that control the commercial insurance markets. In such cases it can be easier for urology practices to negotiate with payers and demonstrate value, because dominant payers dealing with a large chunk of the urology market would be more willing to bargain, Cohen said. In San Diego, each private payer has no more than about 5% to 8% of the market. “With urology being a relatively small specialty with a small spend, it’s really hard to show and gain traction with insurance carriers,” he said.

Genesis was able to overcome some of these challenges by leveraging its size and by partnering with the University of California, San Diego. This allowed Genesis to participate in the university’s clinically integrated network wherein payment rates are more attractive. The network also helps Genesis address regulatory requirements and electronic medical records needs, while preserving its independence.

Genesis began as a member of the Large Urology Group Practice Association and formed its urology group in San Diego 9 years ago. It was able to unite 9 practicing groups, including a radiation oncology group, into 1 entity. The region is controlled by large healthcare institutions, including the university, Kaiser Permanente, Scripps Health, and Sharp Health- Care. “The county has been essentially divided across those lines, with patients in one system or another, and nobody really crossed systems,” Cohen said. As Genesis increased the size of its countywide footprint, it also became more relevant in the community.

The practice now treats patients with all genitourinary cancers; and because a radiation oncology center is now part of the Genesis system, physicians are able to provide radiation treatment in-house. They also have robotic surgery specialists, oncologists, and other specialists in urologic cancer care. “If we feel that [certain cancer cases] are too complicated, we lean on our partners at the university and send patients there to get treatment,” Cohen said. The practice performs genetic testing, MRI fusion biopsies, and confirmatory biopsies for patients who are on active surveillance.

For the past 5 years, Genesis has offered its Comprehensive Prostate Cancer Clinic, which is run by Paul E. Dato, MD, a urologist. “We attempt to handle all our patients with advanced prostate cancer in 1 area, because it’s hard for doctors to stay abreast of some clinical advances, and it’s hard to manage the costly drugs and make sure that we get reimbursed,” Cohen said. “We set up a single place where we can treat patients with advanced cancer. We have things set up so we can get authorization for the advanced drugs that are expensive, and patients are seeing the same group of nursing staff and physicians on a regular basis.”

Physicians who take the time needed for patients who have advanced prostate cancer, go over the options for treatment, and address what the patients can expect with those options. “Like any cancer center, it’s always evolving, and there’s no 1 treatment, so we use all the drugs that are available to us. It’s very individualized for the patient,” Cohen said.

Another aspect that is unique about the Genesis Comprehensive Prostate Cancer Clinic is that it has a database for managing all of its patients with prostate cancer. Within the administrative group, the clinic centrally monitors patients to see how their cancers are evolving and help make sure they get the best care possible. “For the urologist in the field, things may get overlooked—where the patient is in terms of their phase of cancer care. With the database, we can notify physicians of what needs to be done next,” Cohen said.

Genesis Healthcare Partners, the region’s largest independent urology practice, is challenged by regulatory changes and the dominance of the regional managed care market, which has huge control of patient flow and payment structures.

San Diego Urology Group Enjoys Growth in a Tough Market

Up to 30% of men with prostate cancer could meet criteria for genetic evaluation for hereditary disease. The hard part, Sanjeev Kaul, MD, said at the 2018 Large Urology Group Practice Association Conference, is separating the mutations that are relevant from those that are not.

“Just identifying a mutation on one of these genes doesn’t necessarily mean that mutation is clinically significant,” said Kaul, associate professor of urology with Oakland University and William Beaumont Hospital in Royal Oak, Michigan. “You can have mutations across the entire 

gene, but not all mutations are going to code for a protein, and not all coding mutations will actually affect the function of the gene.”

Moreover, there are benefits and drawbacks to testing. With those data, physicians can administer more accurate and effective treatment while avoiding potential hazards such as administering radiation to patients with mismatch repair (MMR) gene mutations. For example, radiation has been associated with increased risk for additional malignancies in patients with Lynch syndrome, which is caused by germline mutation in MMR genes.

Kaul noted that most germline gene mutations have 20% to 40% penetration among patients in general, compared with 90% for those with breast cancer; only 10% to 15% in prostate cancers are hereditary, so an actionable genetic mutation is not always present. In addition, genetic testing can be expensive and although federal law prevents payers from denying health coverage on the basis of test results, high-risk patients can be denied life insurance. Nonetheless, Kaul is a strong proponent of genetic evaluation, and there are clinical data to support his position.

Results from the GEM study published in 2017 provide crucial evidence of the importance of inherited mutations. “This was the first study run by a urology group that told us, ‘Yes, this is something that’s important,’” Kaul said.

Investigators recruited 200 men with a family history of hereditary cancer syndromes (HCSs), 62.5% of whom had prostate cancer. Participants were screened for the presence of 25 genes associated with cancer risk, including 

. Roughly 42.0% of men in the study had a personal or family history of cancer that met criteria for an HCS.

The overall mutation rate in the cohort was 5.5% (95% CI, 3.0%-9.9%), with a variations of unknown significance (VUS) rate of 35%. Most mutations were found in

 genes involved in DNA repair. The rate of mutations was highest in men with prostate cancer and a family history meeting strict criteria for any HCS (10.5%; 95% CI, 4.7%-23.4%).

“The prevalence of mutations varied broadly. In people with no prostate cancer, only 2.73% had a pathogenic or a malignant mutation,” Kaul said. “But in patients who had more aggressive cancer, Gleason [score of] 8 and above, or locally advanced cancer, the prevalence of these germline mutations was much higher; up to 8% to 10%.”

Previous data suggested that these mutations could play an important role in cancer risk. Findings presented at the American Urological Association 2016 Annual Meeting showed that African American men were more likely to have pathogenic and VUS mutations in 

compared with white men (7.3% vs 2.2%). Petrovics et al also observed a trend toward increased frequency of metastasis for men with these mutations compared with those without them (9.4% vs 2.4%). Patients with these mutations also had a significantly shorter time to metastasis (

In 2014, findings from the IMPACT study showed that, using a prostate-specific antigen (PSA) threshold of 3.0 ng/mL for detecting intermediate- and high-risk prostate cancer, the positive predictive value (PPV) of biopsy was 2.38% for

carriers versus 0.71% in age-matched controls (

mutation carriers was 48%, double what had been reported in previous population-screening studies.

In IMPACT, Bancroft et al recruited men aged 40 to 69 years with germline 

mutations and a control group of men negative for a pathogenic 

mutation that was known to be present in their families. The cohort included 791 BRCA1 carriers, 531

 controls (men who had a negative predictive genetic test for the 

All participants underwent PSA testing at enrollment, and those with PSA >3 ng/mL (n = 199) were offered prostate biopsy. Of the 162 men who underwent biopsy, 59 received a prostate cancer diagnosis. Eighteen were

controls. Sixty-six percent of cancers were intermediate or high risk.

mutated group and the positive predictive value of a biopsy in the BRCAmutated group,” Kaul added.

Clinical research consistently shows that patients with these germline mutations have poorer outcomes, Kaul said. Furthermore, the data have shown repeatedly that 

 are the most impactful genes in hereditary cancer. Patients with these mutations have a higher prevalence of disease, and their disease is more aggressive.

Other genes have been shown to have clinical significance. The presence of MMR genes and 

 is associated with higher risk for developing prostate cancer and a higher risk for more advanced disease at diagnosis. 

 is associated with a 9-times greater risk for hereditary or familial disease. 

, a target for poly (ADP-ribose) polymerase (PARP) inhibitors, is associated with an accelerated development of metastases and shorter disease-specific survival.

Men with a germline mutation also have a greater risk for additional cancers. Kaul said the presence of a 

mutation increases the risk for pancreatic cancer up to 36% compared with 0.5% in the general population. 

 increases the risk for melanoma up to 76% compared with 1.6% in the general population. Therefore, patients who are positive for genes associated with hereditary cancer risk require more rigorous surveillance.

“Screening for prostate cancer in this group of patients, especially if they [don’t appear to have cancer], should have a higher index of suspicion,” Kaul said. “Screen these patients more carefully than the general population.”

However, some of these mutations can be targets for treatment. PD-1 inhibitors target the MMR genes, and PARP inhibitors are proven effective in patients with 

 Androgen deprivation therapy has shown positive results for men with metastatic disease.

In 2017, the National Comprehensive Cancer Network added recommendations supporting family history and germline mutation testing to its prostate cancer guidelines. The guidelines were updated again this year to include testing for germline mutations in all patients with metastatic prostate cancer, as well as those with a Gleason score of 8 to 10, Gleason score of 4 + 3, and/or a PSA above 20. Patients with very low, low-, or favorable intermediate-risk disease should be tested if they have a strong family history of prostate cancer.

Kaul feels strongly that urologists should include testing for hereditary prostate cancer in regular clinical practice. The most important thing, he said, is capturing an accurate family history. He noted that 1 urology practice collected histories on 983 patients who visited the clinic over a 1-month period. The likelihood of a significant family history was 28%.

“These are just all-comers, not somebody specifically who comes to the office with a cancer,” he added. “Clearly, a significant family history is there, and you can get that in a significant proportion of your patients.”

Giri VN, Obeid E, Gross L, et al. Inherited mutations in men undergoing multigene panel testing for prostate cancer: emerging implications for personalized prostate cancer genetic evaluation [published online May 4, 2017]. 

Petrovics G, Ravindranath L, Chen Y, et al. Higher frequency of germline BRCA1 and BRCA2 mutations in African American prostate cancer. Presented at: 2016 American Urological Association Annual Meeting; May 6-10, 2016; San Diego, CA. Abstract MP39-18. jurology.com/article/S0022- 5347(16)00431-6/abstract.

Bancroft EK, Page EC, Castro E, et al; IMPACT Collaborators. Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: results from the initial screening round of the IMPACT study [erratum in Eur Urol. 2015;67(6):e126. doi: 10.1016/j.eururo.2014.12.001]. 

. 2014;66(3):489-99. doi: 10.1016/j.eururo.2014.01.003.

Up to 30% of men with prostate cancer could meet criteria for genetic evaluation for hereditary disease. The challenge is separating the mutations that are relevant from those that are not.

December 2018 | Oncology Live Urologists in Cancer Care®

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San Diego Urology Group Enjoys Growth in a Tough Market

Sifting for Relevance Among Germline Mutations in Prostate Cancer