Aa a specialty, urology has always been at the forefront of technology and innovation, improving outcomes and enhancing patient care. In the late 1980s and early 1990s, we were quick to operationalize and employ lithotripsy, which provided noninvasive treatment for our patients with stone disease and reduced the need for open surgery, long hospital stays, and weeks of recovery. Despite this, I do not believe that extracorporeal shock wave lithotripsy has received enough recognition as a significant medical breakthrough, especially considering how stone disease was managed prior to its introduction. During that period, we did not shun innovation, and neither do we now. We have led the charge for minimally invasive and medical therapy for benign prostatic hyperplasia (BPH).

The 21st century has brought us together in an era of vertical integration to deliver more efficient and less costly care for our patients. The ability to offer integrated services under the urology umbrella has led to new opportunities. A prime example is the development in many large groups across the United States of advanced prostate/therapeutic centers (and other centers of excellence) that allow us to provide a continuum of care for these challenging patients, who, for the most part, can now be appropriately and adequately treated within the practice where they started their journey years prior. By encouraging this type of subspecialization, those select providers—champions, if you will&mdash; gain a much better understanding of the disease state and can stay on top of the rapid developments and approvals that seem to arrive on a weekly basis. Again, the hope is better delivery and coordination of care in the quest for optimizing patient outcomes.

Calling Nashville, Tennessee, my home for the past 35 years, I am quite used to the mergers and consolidations that have dominated the hospital management services industry and the number of affiliated companies that support that market. Over the past 12 months, however, we have seen seismic horizontal mergers within the national healthcare industry. We now have a major retail pharmacy company merging with a payer (CVS Health with Aetna). Nonprofit hospital systems are collaborating with the government in the quest to distribute or manufacture generic drugs (Ascension, Intermountain Healthcare, SSM Health, Trinity Health, and the Department of Veterans Affairs). In December, a payer announced plans to buy one of the largest dialysis providers in the world (Optum, a subsidiary of UnitedHealth Group, will close the deal to buy DaVita Medical Group sometime in 2018). And over the past couple of months came the announcement that Amazon, Berkshire Hathaway, and JPMorgan Chase are partnering to form an independent healthcare company for their employees. Apple is expanding its offerings by purchasing start-ups to provide its customers with wearable/portable technology to monitor their health and potentially connect with healthcare systems. Lastly, in February, Roche Pharma, which had already purchased Genentech and invested heavily in consumer genetics testing company 23andMe, announced it would be buying Flatiron, clearly one of the leaders in data analytics for cancer care management.

Here is my burning question: Where are the physicians in all of this? In 2016, healthcare expenditure in the United States was $3.3 trillion—17.9% of the gross domestic product.

 Of that gargantuan number, which represents one-sixth of our total economy, only 20% is paid directly to providers.

However, the decisions that we make regarding care management—what prescriptions are written, whether and when to operate, where to admit, etc&mdash; have been estimated to be up to 90% of the healthcare dollar!

When one looks at the common denominator in the aforementioned mergers, all of these companies ingest and accumulate large tranches of data that they can then leverage. This data pool is the engine behind the predictive analytics and artificial intelligence that everyone is trying to develop. In all industries, collaboration and consolidation are inevitable. Outside the healthcare world, performance and outcomes are the norm, not the exception. As I see it, the opportunity that presents itself to us as urologists, especially in this new environment of value-based care, is that we are a small percentage of the dollar spent, but we are one of the most highly networked. The disease states that we manage, specifically prostate and bladder cancers, BPH, and overactive bladder, are associated with a significant annual cost in the United States. Standardization of care, tracking compliance, and outcome development are opportunities for us, like these major corporations, to aggregate our unique patient data—given our control of the healthcare dollar&mdash;and then leverage to our partners in industry, who desperately want this real-world data.

NHE fact sheet. Centers for Medicare & Medicaid Services website. cms.gov/research-statistics-data-and-systems/statistics-trends-and-reports/nationalhealthexpenddata/nhe-fact-sheet.html. Updated February 14, 2018. Accessed February 19, 2018.

Health expenditures. Centers for Disease Control and Prevention website. cdc.gov/nchs/fastats/health-expenditures.htm. Updated May 3, 2017. Accessed February 19, 2018.

Bloom E. How doctors are experimenting with cutting health-care costs. Atlantic. theatlantic.com/business/archive/2015/12/medical-savings-patients-doctors/422277/. Published December 30, 2015. Accessed February 19, 2018.

Articles

Raoul S. Concepcion, MD, FACS, discusses the current state of physicians the urology practice. 

Where Are the Physicians?

Since 2005, physician partners at Comprehensive Urologic Care (CUC) have been using a form of clampless surgery, which they developed at their practice, for partial nephrectomies. The robotic procedure reduces ischemia and represents a form of innovation that the partners say they strive for in their steadily growing practice in the northwestern Chicago, Illinois, suburbs.

“We have quite an extensive experience using robotic surgery, not only for treating malignant disease of the urinary system, but also some benign conditions,” said Richard Troy, MD, director of advanced prostate cancer and men’s health clinics at CUC. The partners have performed close to 2500 robotic procedures, he said.

Referred to as clampless zero-ischemia robotic partial nephrectomy, the novel technique for treating kidney cancer relies in part on radio-frequency ablation.

The advantage of this method is that it’s an effective way to remove kidney tumors without having to clamp the artery, so the kidneys remain perfused during the entire procedure. One of the problems of partial nephrectomy is that when the artery is clamped the surgeon has a limited amount of time before tissue damage occurs, according to David E. Goldrath, MD, MBA, president of CUC. Lack of perfusion causes ischemia, so there is little time to complete the resection and get the tumor samples evaluated by the pathology lab.

With the clampless method, the surgeons at CUC can keep the kidney perfused and send the tumor to pathology to make sure the margins are negative. The kidney can then be meticulously repaired without time constraints. “You don’t have to worry about ischemia time and loss of kidney tissue during the procedure,” Goldrath said.

CUC has 3 locations: the main office in Lake Barrington, another office in Elgin, and a third in Crystal Lake. Founded by Laurence Gott, MD, in 1978, the practice has grown without any mergers to a team of 53 support staff, and 7 physician partners. An eighth physician will join the team this summer.

The partners take pride in their expanding team of subspecialists who hail from programs across the country. “Every 4 or 5 years, we’ve added a new doctor. We’re always looking for new blood and new ideas,” Goldrath said, adding that the practice benefits from the diversity of perspectives.

CUC’s unique compensation system enables the physician partners to specialize, which Troy and Goldrath say increases productivity. Instead of managing patient caseloads, physicians are assigned tasks such as nephrectomies, diagnostics, and laparoscopic procedures and paid accordingly. Every procedure has an associated “economic unit,” similar to a relative value unit, to keep the team focused on productivity.

“We feel that whether we are reimbursed or not, this system is beneficial for the practice,” Goldrath said. “It’s a pretty fair way to go so that people can subspecialize, and if somebody’s better at something in the practice, we can refer a patient to them, which is better for the patient and better for the practice.”

The physician partners meet weekly to discuss strategy and things that are going on in the practice. “By doing this, we have to answer to ourselves, and we have to come through with ideas,” Goldrath said. “Some practices that don’t meet regularly tend to grow stagnant and fail to make changes effectively or solve problems efficiently.”

Troy and Goldrath like to think of the practice as a one-stop shop where patients can meet with physicians, have diagnostic procedures performed, and get the results all in 1 visit. Patients whose disease may have a genetic component, such as prostate cancer, are referred to genetic counselors. They also may be referred for DNA testing based on recurrent disease, biochemical failure, or a positive margin after radical prostatectomy. “We have patients who go on active surveillance, and genetic testing helps give us an idea of how aggressive the cancer is,” Goldrath said.

CUC sees patients whose cancer is at any stage, from newly diagnosed to widespread metastatic disease. The practice has also established an advanced prostate cancer clinic. “One trend we’ve seen in the last few years [involves] patients arriving who are further progressed in their disease state, with higher Gleason scores and advanced disease states,” Troy said. These men tend to prefer surgery, given the practice’s robotic specialty, but the physicians present all treatment options during a full and informed discussion with each patient.

An in-office pharmacy dispenses drugs for prostate cancer, such as enzalutamide (Xtandi), sipuleucel-T (Provenge), and abiraterone (Zytiga). CUC also offers in-office physical therapy for postoperative patients who have had prostatectomies or surgery for another type of cancer. “We typically see them before and after surgery, and that’s been a great boon for the patients,” Goldrath said. An on-site pathology lab keeps diagnostics and surgeries flowing efficiently.

The in-house bone health clinic provides androgen- deprivation therapy and focuses on maintaining bone health for patients with cancer. “We also do fall risk assessments for these patients and then make recommendations,” Troy said. “We [discuss] the importance of nutrition and exercise and the management of disease.”

Although CUC does not employ a medical oncologist, they work closely with practices that can give chemotherapy to patients who require it. A local radiation therapist provides radium-223 (Xofigo) when needed.

The practice has forged relationships with organizations in the Chicago area that provide palliative care and hospice services for patients who are nearing end of life. This ensures their patients always get the care they need, even if it means leaving CUC.

“We are concerned with not only taking care of the patient’s disease but also taking care of their social networks and emotional support. We want them to feel that they’re getting the best care they can possibly get,” Troy said.

Since 2005, physician partners at Comprehensive Urologic Care have been using a form of clampless surgery, which they developed at their practice, for partial nephrectomies.

Urology Practice Uses Robotic Surgery to Improve Outcomes

As ongoing research continues to deepen our understanding of prostate cancer biology and resistance mechanisms, our arsenal of therapeutic options for men with castration-resistant prostate cancer (CRPC) has steadily grown. Four general classes of therapeutic agents have emerged so far: cytotoxic chemotherapy (docetaxel [Taxotere] and cabazitaxel [Jevtana]), androgen receptor (AR)-pathway directed therapies (abiraterone [Zytiga], enzalutamide [Xtandi], and apalutamide [Erleada]), bone-targeted therapy (radium-223 [Xofigo]), and active cellular immunotherapy (sipuleucel-T [Provenge]). Each of the drugs in these classes has demonstrated significant clinical benefits in randomized phase III clinical trials in CRPC,

but the duration of response for each remains relatively shortlived and the survival benefits are moderate. There remains a great need for additional treatment options. Here we reexamine the case for platinum therapy.

Platinum agents have long been studied in metastatic CRPC (mCRPC), but in patient cohorts that are largely molecularly unselected (

). Trial experience with single-agent carboplatin,

 have generally yielded modest rates of prostatespecific antigen (PSA) decline, improvement in pain, and radiographic response.

Although platinum doublet combinations with a taxane,

 are usually associated with slightly higher rates of PSA decline, they are also associated with increased toxicity. Triplet combination regimens, such as paclitaxel/ estramustine/carboplatin

have been found to have significant clinical activity. In one study, docetaxel/estramustine/carboplatin was associated with a ≥50% decline in PSA in 95% of enrolled patients.

However, these studies were relatively small and these regimens have not been further developed. Of the 3 platinum drugs, cisplatin and oxaliplatin use is often limited by renal impairment and neuropathic toxicity. Carboplatin is generally well tolerated, but has a heavier footprint in terms of myelosuppressive effects.

Satraplatin, a fourth-generation oral platinum analogue, was tested in the randomized phase III SPARC study. A total of 950 men with chemotherapy- refractory mCRPC were enrolled and received either satraplatin plus prednisone or placebo plus prednisone. Although satraplatin was associated with a small, but significant, benefit in progression-free survival (11.1 vs 9.7 weeks; HR, 0.67; 95% CI, 0.57-0.77; 

 <.001), improvement in time to pain progression (66.1 vs 22.3 weeks; HR, 0.64; 95% CI, 0.51-0.79; 

 <.001), and PSA response (25.4% vs 12.4%;

<.001), there was no demonstrated difference in median overall survival (OS) compared with placebo (61.3 vs 61.4 weeks; HR, 0.98; 95% CI, 0.84-1.15; 

Although SPARC was ultimately a negative trial and further development of satraplatin stopped, the results again confirm that a subset of patients with mCRPC is responsive to platinum therapy, even as a single agent. Unfortunately, predictive markers to identify the cohort most likely to benefit from platinum therapy could not be developed from SPARC, as correlative and translational studies were not included in the study design.

Table. Platinum Agents Effective in Treating Subtypes of Prostate Cancer

Currently, outside of small cell carcinoma of the prostate, where platinum therapy is considered standard offering based on limited study findings

and an extrapolation of efficacy data in small cell lung cancer, platinum compounds have not been formally adopted into any professional practice guidelines. This is due to a lack of defined OS benefit in the general nonselected population with prostate cancer.

It could be argued that adoption of platinum drugs has also been poor due to inadequate characterization of the subtype of patients with CRPC who could benefit from platinum agents. Neuroendocrine prostate cancer (NEPC), a heterogeneous histology

 that most commonly transdifferentiates from preexisting adenocarcinoma as an adaptive response to long-term exposure to androgendeprivation therapy (ADT) and AR blockade,

 is classically considered to be responsive to platinumbased therapies. The response rates are as high as 70% in those with poorly differentiated histology.

Histologically, NEPC is archetypally characterized as the presence of small round blue neuroendocrine cells with a lack of AR expression. Phenotypically, NEPC frequently metastasizes to visceral organs, has disease burden out of proportion to serum PSA levels, and may express elevated serum neuroendocrine markers such as chromogranin A, synaptophysin, and neuron specific enolase. Clinically speaking, these findings are neither specific nor sensitive, so more definitive molecular characterization is needed to recognize this subgroup of patients who may be good candidates for platinum compounds.

Genomic instability has long been known to be a hallmark of cancer, leading to genomic heterogeneity that gives variable clinical courses and response to treatment. With recent advances in genomic profiling, changes to the cancer genome—both germline and somatic&mdash;have been better characterized.

Germline mutations that disrupt DNA damage repair, especially the process of homologous recombination, such as

have prognostic consequence. Various study results show them to be associated with increased risk of prostate cancer diagnosis at a younger age, higher histologic grade on diagnosis, more aggressive clinical course, and increased risk of cancer-specific mortality.

 It has also been suggested that homologous recombination is associated with relative insensitivity and worse outcomes with ADT.

The presence of germline mutations in DNA damage repair genes had previously been thought to be relatively low, with The Cancer Genome Atlas reporting a prevalence of 4.6% in men with localized prostate cancer.

 However, recent study results demonstrate a significantly higher proportion of men with mCRPC harboring these germline mutations, 11.8%, irrespective of family history of cancer.

 When considering both germline and somatic genomic alterations, the prevalence may be as high as 20% in mCRPC.

 Outside of specific mutations in the defined DNA damage repair pathway genes, a “

ness” genomic signature may exist for an even wider population of patients with mCRPC.

These genomic findings have therapeutic implications in that there has been evidence to suggest increased sensitivity to platinum therapy in ovarian

mutations. Platinum compounds exert their antineoplastic activity by forming covalent DNA adducts, causing double-stranded DNA breaks. Loss-of-function mutations or alterations to

 among other genes, all of which serve important roles in the repair process for double-stranded DNA breaks— including homologous repair, nonhomologous end joining, or altered DNA damage checkpoints&mdash;put the disease at a handicap in overcoming the effects of platinum agents.

Early evidence suggests that prostate cancers that harbor deficiencies in the DNA damage repair pathway are also associated with a higher likelihood of response to platinum agents and poly (ADP-ribose) polymerase (PARP) inhibitors.

In a retrospective analysis at Dana-Farber Cancer Institute of 141 men with CRPC who received at least 2 cycles of carboplatin/docetaxel chemotherapy, 75% (6/8) of men carrying deleterious 

variants experienced a >50% decline in PSA within 12 weeks of treatment initiation compared with 17% (23/133) in those who lacked the 

carriers had a >90% PSA decline versus 4.5% of noncarriers.

 Median OS from time of platinum therapy initiation was 18.9 months for carriers versus 9.5 months for noncarriers (

 = .03). Prospective studies are needed to fully realize the benefits of platinum compounds in molecularly selected patients (NCT02311764, NCT02598895).

Prostate Cancer Intensive Non-Cross Reactive Therapy for CRPC

Given the higher than expected prevalence of germline mutations and their prognostic and therapeutic implications, the question arises whether it would be appropriate to actively screen all men with mCRPC for these mutations. If so, what type of testing should be done? Would germline testing be sufficient by itself? Should somatic mutations be screened for as well? The prospect of obtaining metastatic biopsies on all patients with mCRPC, for the purpose of genomic testing, may prove to be a difficult task, especially as some lesions, such as osseous metastases, may not lend themselves to easy collection. Next-generation sequencing of circulating tumor cells or cell-free DNA analysis could play a role in identifying patients at higher likelihood of benefit with a platinum-based regimen.

In the absence of having genomic data to optimally guide treatment selection, is there still a place for the routine use of platinum therapy in the standard management of mCRPC? Emerging data suggest that prolonged therapeutic exposure to potent AR-pathway— targeting agents places selective pressures on the tumor, inducing adaptive changes and leading to the emergence of “treatment-induced lineage crisis,” characterized by poorly differentiated and aggressive prostate cancers, visceral and bulky metastasis, and low PSA production.

 Lineage crisis often occurs in the form of treatment-induced neuroendocrine differentiation or epithelial-to-mesenchymal transition. There may be a role for platinum-based agents in maintaining lineage plasticity and collateral sensitivity and preventing the onset of treatment-induced lineage crisis and therapeutic resistance.

Currently enrolling at the Mount Sinai Health System is the Prostate Cancer Intensive Non—Cross Reactive Therapy (PRINT) for CRPC trial (NCT02903160), a single-arm investigator-initiated phase II study aimed at evaluating the clinical benefits of treating an intrinsically heterogeneous tumor with a rapidly cycling, non–cross reactive regimen of FDA-approved prostate cancer therapeutic agents. While optimal timing and sequence of different drugs in mCRPC remains a topic of debate, the standard approach so far has been to treat with a single agent until resistance develops, at which point the patient is transitioned to a different agent. Inherent genetic instability will lead to substantial tumor heterogeneity

 along with varied amounts of genetic dysregulation and varied patterns of antineoplastic resistance.

This argues that a one-size-fits-all, sequential, single-agent approach will ultimately be met with limited success and subpopulations resilient to single-agent therapies will be identified, leading to a multidrug-refractory phenotype.

Our rapidly-cycling treatment regimen contains 3 consecutive treatment modules, each lasting 12 weeks:

By switching between non—cross reactive therapies, the selective pressure exerted by any single therapeutic agent’s intermittent use is limited, allowing resistance rates to stabilize or decrease in its absence. Additionally, the therapeutic agents are delivered as rationally designed combinations to achieve optimal therapeutic dosing and minimize overlapping adverse events. The rationale for inclusion of carboplatin in this regimen is 2-fold: to improve disease response and to help maintain lineage plasticity.

The primary endpoint of this study is time to disease progression following completion of the study regimen. If this novel treatment strategy significantly lengthens the time until disease progression, this trial would serve as proof-of-principle for future treatment regimen design in mCRPC. Additionally, as this regimen was designed to only include fully approved therapies, it would be immediately accessible to any treating oncologist.

Platinum compounds remain relevant in mCRPC. Going forward, next-generation sequencing will be needed to further develop and expand on the development of biomarkers to predict for platinum responsiveness and to better identify patients appropriate for prospective trials involving platinum-based regimens. A better understanding of whether biomarkers associated with platinum sensitivity and their association with response to PARP inhibitors, and vice versa, will be important. It’s also important to discover how these 2 classes of drugs with similar mechanisms of actions, but potentially different mechanisms of resistance, should interplay.

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Pomerantz MM, Spisák S, Jia L, et al. The association between germline BRCA2 variants and sensitivity to platinum-based chemotherapy among men with metastatic prostate cancer.

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Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. 

2015;373(18):1697-1708. doi: 10.1056/NEJMoa1506859.

Lord CJ, Ashworth A. BRCAness revisited. 

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Roubaud G, Liaw BC, Oh WK, Mulholland DJ. Strategies to avoid treatment-induced lineage crisis in advanced prostate cancer. 

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Cheng L, Bostwick DG, Li G, et al. Allelic imbalance in the clonal evolution of prostate carcinoma. 

Mitsiades N, Sung CC, Schultz N, et al. Distinct patterns of dysregulated expression of enzymes involved in androgen synthesis and metabolism in metastatic prostate cancer tumors. 

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Aparicio AM, Harzstark AL, Corn PG, et al. Platinum-based chemotherapy for variant castrate-resistant prostate cancer. 

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The arsenal of therapeutic options for men with castration-resistant prostate cancer has steadily grown as ongoing research uncovers more about prostate cancer biology and resistance mechanisms. 

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