Each year at the American Urological Association study led by Alan P. Lombard, PhD, of the University (AUA) Annual Meeting, there is always something new and exciting to discover. Not only does the meeting feature stellar research, engaging panel discussions, and informative lectures from experts in the field, but it also offers an opportunity for urologists from around the world to gather.

This international collaboration is essential as we move forward in deepening our understanding of genitourinary (GU) cancers and strategies for improving outcomes. Although the AUA is a US-based organization, its commitment to include researchers and experts from other nations is crucial in keeping urologists fully informed on best clinical practices.

 includes a report from the conference, “Benefit Confirmed for EBRT Plus ADT in Locally Advanced Prostate Cancer,” about research from Paul Sargos, MD, a radiotherapy oncologist at the Institut Bergonie&#769; in Bordeaux, France. Long-term study results indicate that the addition of external beam radiation therapy (EBRT) to androgen-deprivation therapy (ADT) reduced the risk of disease progression more than 70% compared with ADT alone among patients with locally advanced prostate cancer. These positive results could open urologists and their patients to a combination treatment strategy they may not have considered before and would improve survival for some patients.

Of course, research from American investigators was not lacking at this year’s AUA. In a fascinating of California Davis Medical Center, results indicated that inhibiting overexpression of the ABCB1 gene helps prevent resistance to docetaxel and cabazitaxel (Jevtana) in patients with castration-resistant prostate cancer (CRPC).

“Our previous work showed that increased expression of ABCB1 was largely responsible for mediating resistance to docetaxel. Thus, we sought to test whether this would alter cellular response to cabazitaxel,” Lombard and colleagues wrote in their abstract. The study concluded that inhibiting this gene with antiandrogen therapy, such as enzalutamide (Xtandi) and bicalutamide (Casodex), could increase the efficacy of taxane-based therapies in patients with CRPC.

This new information may eventually be a crucial piece to the puzzle for improving the treatment of patients with CRPC. If we can adjust treatment strategies, even re-sensitize cells to treatment with cabazitaxel, we could be that much closer to that elusive “cure” for CRPC.

These are just 2 studies that we highlight in this issue, and the advancements in treating GU cancers are only looking more positive as time goes on. If the field can retain its momentum, we will be able to improve outcomes and possibly cure these diseases.

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The American Urological Association Annual Meeting features stellar research, engaging panel discussions, and informative lectures from experts in the field, but it also offers an opportunity for urologists from around the world to gather.

Bringing AUA Advances Into the Clinic

The first of July ushers in a new batch of newly graduated physicians to begin the arduous journey of residency training in their chosen field, a process that began a full 2 years prior as third-year medical students. Thinking back, what are the determinants that influence this choice? For myself, and many others, it was an exposure very early in life to family members who were healthcare providers. I suspect that if a survey were to be administered across generations of physicians to explore these factors, there would be a litany of reasons, depending on the age of the respondent. One that goes underappreciated is how an individual was treated as a medical student by the resident physician(s) on a service. Did they take the time to teach? Did they show a passion and seem to really enjoy their specialty? And with that, did they encourage others to enter that same field?

Ultimately, the choice of specialty, with a few exceptions, comes down to the following: internal medicine, surgery, or pediatrics. Urology has always represented a true hybrid specialty. To succeed, one must possess both cognitive and technical skills as we tend to be a sign/symptom-driven field. The majority of us who go into urology truly enjoy the surgical side of medicine. I believe that many others would choose a surgical specialty, had they been given adequate exposure. We have also historically been on the vanguard of technology and quick to incorporate that into our clinical practice. Specifically, think lithotripsy, percutaneous procedures, and robotics to cite just a few examples. Due to our willingness to be early adopters, our patients spend fewer days in the hospital and have a quicker return to their preoperative functional status. We have improved patient care and quality of life, which should always be paramount as the cornerstone of our practice.

However, embracing technological advancement and minimally invasive procedures has resulted in a significant transformation of our beloved specialty over the past 10 to 15 years. If I had the ability to incorporate an audience response system into this column, it would be interesting to ask the following: Which of the following procedures have you personally performed over the past 10 years?

Open retroperitoneal lymph dissection for testicular cancer

Adrenalectomy through a supra 11th rib incision

Open ureterolithotomy via a Gibson incision

Open simple prostatectomy for benign disease

These and many other procedures are now relegated to textbooks for historical perspective. It has given way to an entirely new breed of urologic surgeons. It is not better or worse, just different.

The significant advances that take place in medicine occur almost daily. Take, for example, the management of hormone treatment-naïve, metastatic prostate cancer. What started as androgen deprivation therapy (ADT) alone, the mainstay of treatment for half a century in these patients, has moved to ADT and 6 cycles of docetaxel chemotherapy for high-volume disease

 to most recently, based on the updated STAMPEDE and LATTITUDE trials, ADT and abiraterone acetate.

Is this the new standard of care, as espoused by some? It is hard to determine at this point as all this has taken place over the short period of 2 years.

What is very clear to me, however, is that we are becoming less surgically inclined. Active surveillance for low-risk prostate cancer patients is appropriate. Newer agents used in an earlier setting may render the need for extirpative surgery obsolete, whether it be in prostate, bladder, or kidney cancers. Just as we have in the past incorporated newer surgical techniques and modifications, so must we be more adroit in our offering of nonsurgical therapeutics to take better care of our patients. We also must recognize our role as the thought leaders and maintain our leadership in managing these disease states, even if at times we are not standing at the operating room table with scalpel in hand. Being a Luddite in the field of medicine will only guarantee 1 outcome: obsolescence.

James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial.

. 2016;387(10024):1163-1177. doi: 10.1016/S0140-6736(15)01037-5.

Sweeney CJ, Chen YH, Carducci M. et al. Chemohormonal therapy in metastatic hormone- sensitive prostate cancer.

 2015;373(8):737-746. doi: 10.1056/ NEJMoa1503747.

Fizaxi K, Tran N, Fein LE, et al; the LATITUDE investigators. LATITUDE: A phase III double-blind, randomized trial of androgen deprivation therapy (ADT) with abiraterone acetate (AA) plus prednisone (P) or placebos (PBOs) in newly diagnosed high-risk metastatic hormone-naïve prostate cancer (mHNPC) patients (pts). 

2017;35 (suppl; abstr LBA3). abstracts.asco.org/199/AbstView_199_181729.html.

James ND, DeBono JS, Spears MR, et al. Adding abiraterone for men with high-risk prostate cancer (PCa) starting long-term androgen deprivation therapy (ADT): Survival results from STAMPEDE (NCT00268476).

 2017;35 (suppl; abstr LBA5003). abstracts.asco.org/199/AbstView_199_186716.html.

Raoul S. Concepcion, MD, FACS, shares his insight on the evolving role of the clinical urologist. 

The Metamorphosis of the Clinical Urologist

A first-ever collaboration between the American Urological Association (AUA) and other prominent urological groups has created a multidisciplinary set of guidelines on treating patients with nonmetastatic muscle-invasive bladder cancer (MIBC).

 These new guidelines provide a riskstratified clinical framework so that urologists and oncologists treating patients with MIBC can better diagnose, treat, and manage the disease.

The guideline statements included input from the AUA, ASCO, the Society of Urologic Oncology, the American Society for Radiation Oncology, and the president of the Bladder Cancer Advocacy Network, Diane Z. Quale. This first-of-its-kind collaboration offers clinicians evidence-based A, B, and C recommendations; clinical principle statements that all clinicians or urologists generally agree upon; and expert opinions that express the unanimous conclusions of the panelists.

Figure. Estimated New Genitourinary Cancer Cases and Deaths in the United States, 2017

There is a clinical need for improved management of patients with MIBC, as 79,030 new cases of bladder cancer and 16,870 deaths from the disease are predicted for 2017 in the United States (Figure).

 “Approximately 25% of newly diagnosed patients have muscle-invasive disease, and that rate hasn’t changed over the past 25 years. In addition, the overall prognosis of patients with muscle-invasive disease has not changed in the last 30 years and is primarily based on stage,” said Jeffrey M. Holzbeierlein, MD, who served as a panelist for formation of the guidelines. He is director of urologic oncology at the University of Kansas Medical Center, in his presentation of the guidelines.

The first series of guidelines includes statements regarding the need for staging evaluation during physical examination of patients under anesthesia. “The panel felt that this was an important component of identifying patients [whose tumors] might be resectable, and, of course, you would do this if you suspect MIBC at the time of [transurethral resection of bladder tumor (TURBT)]. Also, since there are a lot of comorbidities, this is a critical component to assess patients to determine what they might be candidates for in terms of treatment,” Holzbeierlein said.

Although imaging and lab evaluation are critical components of staging patients with MIBC, the panel did not recommend any specific imaging modalities. The panel, however, did agree that cross-section imaging of the abdomen and pelvis should be done with intravenous contrast, as well as recognized that there are no data to support any single imaging modality over another. The guidelines do not recommend PET scans, as the panel felt there was insufficient evidence to support their superiority over CT scans. They did note that PET imaging should be reserved for patients with abnormal chest, abdominal, or pelvic images that require further evaluation or in cases where a lymph node biopsy is not feasible.

Although chest imaging is somewhat controversial, the new guidelines recommend a chest CT scan if the patient has a history of smoking. “We do recognize that we are seeing increased amounts of variant histology, and when that is suspected, we recommended a review by a dedicated GU pathologist, as the definitive histology can change treatment in up to one-third of patients,” Holzbeierlein commented.

The guidelines recommend that patients receive an explanation of all treatment options that are available, including surgery, chemotherapy, and radiotherapy. “We recognize that not all clinicians have the ability to provide 3 different disciplines, but certainly 1 clinician can provide an explanation of the multidisciplinary approaches to treatment options that are available,” he said.

The implications of various treatments on quality of life should also be discussed with the patient, and this is expressed as a clinical principle in the guidelines.

The treatment guidelines strongly recommend neoadjuvant cisplatin-based chemotherapy prior to radical cystectomy based on 2 completed trials that showed improved survival in patients with MIBC using this treatment regimen.

 The panel recognized that there are currently no validated predictive factors or clinical characteristics that anticipate a patient’s response to neoadjuvant chemotherapy, but Holzbeierlein noted that there is an ongoing trial to determine these factors. He also said that the best regimen and duration for cisplatinbased chemotherapy have not yet been identified for patients with MIBC and that the decision regarding eligibility for cisplatin-based neoadjuvant chemotherapy should be based on comorbidities and performance status.

The panel did not recommend carboplatin-based chemotherapy in the guidelines. “In fact, if the patient is not eligible for cisplatin-based neoadjuvant chemotherapy, the panel recommends moving on directly to definitive locoregional therapy, such as radical cystectomy,” Holzbeierlein said. This conclusion is based on currently insufficient evidence for carboplatin as an effective neoadjuvant chemotherapy for patients with MIBC, as well as small, randomized studies in metastatic disease that suggest an inferior response.

Based on an expert opinion, the guidelines recommend moving from neoadjuvant chemotherapy to radical cystectomy as quickly as possible, between 4 and 8 weeks after the patient has completed and recovered from neoadjuvant chemotherapy. For patients who are eligible for cisplatin-based neoadjuvant chemotherapy but did not receive it and who have T3, T4, or node-positive disease, the guidelines recommend adjuvant cisplatinbased chemotherapy.

“There have never been any randomized, controlled trials that have shown a significant benefit, but the meta-analyses have suggested a benefit, and therefore we recommend this option,” Holzbeierlein commented.

The guidelines strongly recommend that clinicians offer radical cystectomy with bilateral pelvic lymphadenectomy for patients with resectable nonmetastatic MIBC. The guidelines also strongly recommend that in males, radical cystectomy include removal of the bladder, prostate, and seminal vesicles. In females, the removal of the bladder, uterus, fallopian tubes, ovaries, and anterior vaginal wall are recommended. “Of course, clinicians should discuss the consideration of sexual function preservation and organ preservation, such as the anterior vaginal wall, based on the patient’s specific disease characteristics,” Holzbeierlein said.

When urinary diversion is called for, it is a clinical principle that clinicians should have a discussion with the patient regarding all options, including ileal conduit, continent cutaneous, and orthotopic neobladder urinary diversions. Holzbeierlein said that although there was discussion about ways of identifying preoperatively whether a patient was a candidate for an orthotopic neobladder, the guidelines state, as a clinical principle, that clinicians verify a negative urethral margin at the time of the surgery.

For perioperative management, the panel’s opinion was that clinicians should optimize recovery from radical cystectomy by offering patients nutrition counseling or encouraging them to enroll in smoking cessation programs. The guidelines strongly recommend perioperative pharmacologic thromboembolic prophylaxis for patients undergoing radical cystectomy. This is because many of these patients have several risk factors associated with the development of a thrombosis.

The guidelines also strongly recommend mu-opioid antagonist therapy for bowel recovery after surgery. It was also stated that prior to leaving the hospital, patients should be educated regarding any type of urinary diversion that they have, ideally by an enterostomal therapist if the patient has an ileal conduit.

The guidelines recommend that clinicians perform a bilateral pelvic lymphadenectomy at the time of any surgery, with curative intent. “The extent of lymphadenectomy remains somewhat unknown at this time,” Holzbeierlein said. “We recommend at least removal of the external, internal, and obturator lymph nodes, and we would recommend that at least 12 lymph nodes would be removed, as this was felt to be a good surrogate for an adequate lymphadenectomy.”

It was stated as a clinical principle that doctors should discuss bladder preservation with all patients, and for patients with newly diagnosed, nonmetastatic MIBC who desire to retain their bladder or are unfit for radical cystectomy, clinicians should offer bladder preservation therapies.

In terms of bladder preservation strategies, “The panel’s preferred strategy is using a multimodal approach, which combines maximal TURBT, systemic chemotherapy, radiation therapy, and ongoing cystoscopy, to evaluate response and identify recurrences,” Holzbeierlein said. The guidelines recommend that prior to bladder preservation therapy, all patients undergo maximal debulking TURBT and an assessment for the presence of multifocal disease, such as carcinoma in situ. However, the guidelines do not recommend TURBT and partial cystectomy for patients who are surgical candidates, nor primary radiation therapy for this patient population.

For patients with MIBC who have chosen multimodal bladder preservation therapy, the guidelines strongly recommend that clinicians offer maximal transurethral resection of the bladder tumor, chemotherapy combined with external beam radiation therapy, and planned cystoscopic reevaluation. Further, the guidelines recommend that radiation-sensitizing chemotherapy regimens include cisplatin or fluorouracil and mitomycin C. Following bladder preservation therapy, they advise that clinicians perform regular surveillance with CT scans, cystoscopy, and urine cytology.

Notably, those who are biopsy-proven complete responders to bladder-preserving protocols remain at risk for invasive and noninvasive recurrences, as well as new tumors in the upper urinary tracts, although these recurrences may be successfully managed by prompt salvage therapy, according to Holzbeierlein. For patients who have unsuccessful bladder preserving treatment, cystectomy is strongly recommended for those who qualify. If patients have nonmuscle invasive recurrences, then they can undergo TURBT with intravesical therapies.

When it comes to patient surveillance and follow-up, the guidelines state that for all patients, clinicians should obtain chest and cross-sectional imaging of the abdomen and pelvis with CT or MRI at 6- to 12-month intervals for 2 to 3 years and continue annually. “We do recommend cross-sectional imaging and laboratory assessments every 3 to 6 months for 2 to 3 years after cystectomy or after bladder-preservation therapy and annually thereafter,” said Holzbeierlein. If a patient has urethral remnant, those patients should be monitored. Although the data do not support a survival advantage for urethral washes,

 the panel concluded that those may be considered an option.

Patient survivorship is also stressed in the guidelines. Clinicians should discuss with their patients how they are coping with their bladder cancer diagnosis and treatment. “For patients who have undergone cystectomy, we recommend participating in a cancer support group, as well as adoption of healthy lifestyles,” Holzbeierlein added.

“Variant histology is something that is an evolving topic within the MIBC guidelines and may require diversion from these guidelines,” Holzbeierlein commented. The guidelines recommend that for patients diagnosed with variant histology, clinicians consider diverging from standard evaluation and management for urothelial carcinoma.

According to Holzbeierlein, the most appropriate care and evaluation of variant histologies could be better understood as more are recognized over time. Thus, previous recommendations may not apply to a small, but significant, number of patients

Several other key areas deserve attention to improve care and outcomes for patients with MIBC. Enhanced detection of bladder cancer cells through imaging technologies or other means is necessary to identify patients with high-risk and advanced disease. Additionally, the growth and introduction of novel immunotherapies for treating bladder cancer has already shown much promise, with phase II and III trials demonstrating significant antitumor activity. According to Holzbeierlein, there is also a need to establish the roles of specific imaging and laboratory tests and their appropriate spacing. Future studies are needed to define patient-specific approaches to detection of MIBC, therapy, and optimal strategies for surveillance after definitive treatment.

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A first-ever collaboration between the American Urological Association and other prominent urological groups has created a multidisciplinary set of guidelines on treating patients with nonmetastatic muscle-invasive bladder cancer (MIBC).

August 2017 | Oncology Live Urologists in Cancer Care®

Bringing AUA Advances Into the Clinic

The Metamorphosis of the Clinical Urologist

First-of-Its-Kind Multidisciplinary Guidelines for MIBC Treatment