Welcome to another installment of Uranimals, our video series featuring urologists and their pets. From a dog duo to a group of animals living mountainside, check out our latest guests!

Uranimals: Episode 3

It has now been a decade when the urology world started to embrace the management of what was then labeled as “hormone resistant” prostate cancer.The flash point for this change was the approval of multiple agents that extended over-all survival and the delivery could be safely administered inside the walls of a urologic practice.However, many obstacles needed to be overcome in order to sway individuals and groups to adopt this non-surgical mentality, which many of us were not adequately trained nor exposed:

A basic understanding of the role of the androgen receptor and how it drives prostate cancer growth.

The heterogeneity of prostate cancer and the role of therapeutic layering.

Small rises in PSA in the setting of continuous ADT and castration levels of testosterone is a harbinger of disease progression.

With monotherapy, a survival benefit of > 4 months is significant.

For those that were early adopters and quick to overcome these hurdles in a vertically integrated setting, the benefits to both the patient and practice are significant:

On-going patient retention within the urology practice, given the nature and progression to what we now call castration resistant prostate cancer (CRPC).

Economic growth and revenue as a result of optimizing delivery of the multiple agents by the urologist.

Higher patient satisfaction, given the continued ability to be managed by his local urologist where more than likely he has been being closely followed for years for his disease.

Although this management approach to advancing prostate cancer is not applicable to all practices and providers, it has been proven to be a very successful model in certain markets.As we have stated repetitively, the urologist needs to be the gatekeeper of prostate cancer, starting at diagnosis and through the progression of disease that unfortunately many of our patients will have to endure.Our ability to manage and support the needs of our patients, beyond just offering surgical and therapeutic optimization, becomes critical.One area that we will all need to be more aware is the role of palliative care.In this edition, urologic colleague and UCC Editorial Board member Kristen Scarpato, MD, provides a very nice overview on how we need to embrace and incorporate palliative care for our oncologic patients, differentiating from what many of us, me included, had always thought to be hospice care.

And as we are all keenly aware, this leadership approach for disease management is being tested as we see more and more opportunities in the bladder cancer world, both non muscle invasive (NMIBC) and muscle invasive (MIBC).Our success in prostate cancer management can be directly attributed to:

Prior exposure to similar type agents (anti-androgens, androgen synthesis inhibitors, radiopharmaceuticals) and their side effect profiles.

Long standing history with the patient within the practice.

While the number of bladder cancer patients within a given practice is not to the same degree as prostate, NMIBC has always been 100% in the domain of the urologists. The explosion in the number of therapies in this particular disease segment, especially those that have been deemed BCG unresponsive, seems very reminiscent to that witnessed in the mCRPC space a decade ago. While some of the newer agents will be intravesical and therefore easy to deliver by many without changing workflow, the checkpoint inhibitors and immunotherapies present a different speed bump, given the nature of delivery and lack of significant prior experience with these types of targeted agents.The challenge for the urology community will be to similarly embrace and operationalize, just as we did for prostate cancer, these agents in order for us to provide the continuum of care that our patients wish to maintain with their urologist.

Articles

"The explosion in the number of therapies in this particular disease segment, especially those that have been deemed BCG unresponsive, seems very reminiscent to that witnessed in the mCRPC space a decade ago," writes Raoul S. Concepcion, MD, FACS.

The continuum of care in urologic oncology

discusses future research on Aquablation therapy following the presentation of the study, “Aquablation for benign prostatic hyperplasia in large prostates (80-150CC): 3-year results,” at the 2021 American Urological Association annual meeting. Zorn is an associate professor of urology at the University of Montreal, Canada.

Videos

“I think the key elements are that you should know about Aquablation if you are treating BPH in consideration for your patients and care, especially those who are looking for a more durable response and to maintain their ejaculation,” says Kevin Zorn, MD, FRCSC, FACS.

Aquablation therapy as a discussion point in patient counseling

Launer is a urology resident at Vanderbilt University Medical Center, Nashville, Tennessee.

Palliative care is patient-centered, coordinated care intended to decrease suffering and improve quality of life for patients with advanced disease. Palliative care may be offered to patients at end of life to ease distress-associated symptom burden and facilitate goals of care discussion or may be utilized for patients undergoing surgical or medical treatment with curative intent. Literature shows there is a significant unmet palliative care need in urologic oncology, and it is crucial that surgeons perceive palliative care as a management option in parallel with ongoing surgical care as opposed to an incompatible alternative; these specialties and concepts are not at odds with one another but are often intertwined and complementary. Palliative care has been shown to have myriad benefits for patients including improved quality of life and symptom management, as well as benefits for the health care system at large including decreased costs and health care utilization.

There are several important points when considering palliative care in urologic oncology. First, the scope of palliative care is broad, and many services directed toward prolonging and enhancing quality of life are included under the umbrella of palliative care. These services must be considered as part of the larger construct. For example, hospice care is reserved for the imminently dying patient with an expected survival of less than 6 months and refers specifically to end-of-life care. Unfortunately, there exists a misconception that hospice care and palliative care are the same when hospice care is merely a facet of palliative care. Similarly, palliative surgery aims to improve quality of life through procedural interventions, such as surgery to relieve malignant obstruction, but represents only an aspect of palliative care. Finally, palliative care can be delivered by a trained palliative care specialist via “specialty palliative care” or may be provided by health care professionals within their own medical or surgical subspecialty; in this case, urologic oncologists may provide “primary palliative care” directly to their own patients. Bolstering training for the latter may help fulfill the unmet palliative care need in urologic oncology.

Professional societies have published clear recommendations regarding palliative care: the American Society of Clinical Oncology recommends early palliative care initiation for patients with advanced malignancies concurrently undergoing active treatment.

 The National Comprehensive Cancer Network (NCCN) guidelines include multiple indications for palliative care involvement, ranging from moderate to severe distress related to cancer diagnosis, patient concerns about disease course, and advanced cancers associated with high morbidity and mortality.

 Although overall oncologic guidelines are clear, the integration of urologic malignancies and palliative care has been less emphatic. The term “palliative care” was present in the 2019 NCCN guidelines for penile, kidney, and testicular cancers but absent from guidelines for bladder and prostate cancer.

The American Urological Association (AUA) emphasized the role of palliative care in a recent white paper, providing a qualitative review of selected issues including optimizing outcomes in urologic surgery. The 2019 white paper highlighted the importance of palliative care following surgery with recommendations for delivering bad news, establishing goals of care, recognizing spiritual issues, and providing palliative and hospice care referrals.

 Similarly, this year the AUA Quality Improvement Summit acknowledged palliative care as a critical issue in patients with both advanced benign and malignant urologic diseases.

 This program educated participants on the current state of palliative care and helped define clinical scenarios when palliative care is needed. Furthermore, the program provided guidance on how to build a primary palliative care model within urology and perspectives on how best to increase the use of palliative care in urology.

Over 360,000 patients were diagnosed with urologic malignancy in the United States in 2020; in men, urologic malignancies account for 35% of all new cancer diagnoses and 18% of estimated deaths due to cancer.

 Patients with urologic malignancies experience a high symptom burden, especially in the end-of-life setting. Furthermore, each urologic malignancy carries a unique symptom burden, with diverse opportunities for palliation that may be delivered directly by urologists or through collaboration with multispecialty teams including palliative care specialists.

Patients with bladder cancer have high rates of morbidity and mortality, and repercussions on quality of life persist even after local disease treatment.

Advanced bladder cancer can cause ureteral/bladder outlet obstructions associated with poor quality of life, as well as metastatic burden and intractable hematuria.

 A 2019 review found that only 3.6% of 7303 Medicare patients receiving a diagnosis of muscle-invasive bladder cancer received a referral to palliative care, with patients more likely to receive palliative care if they were younger, female, or treated with radical cystectomy.

Men with prostate cancer, particularly those with advanced prostate cancer, can also benefit from incorporation of palliative care. Although prostate cancer is often minimally symptomatic at diagnosis, treatment with surgery or radiation can cause impotence and incontinence; later symptoms include bone pain and ureteral/bladder outlet obstruction.

 The Advanced Prostate Cancer (2020) AUA/American Society for Radiation Oncology/Society of Urologic Oncology guideline acknowledges the importance of multidisciplinary, holistic care, including palliative care, in the management of this complex patient population—particularly in the face of an ever-changing therapeutic landscape.

 Utilization of palliative care for patients with advanced prostate cancer has been shown to decrease both inpatient and intensive care admissions at the end of life; despite this, data also suggest that palliative care consultation for these patients is still too low.

Supportive care, including palliative care, is acknowledged as an important part of the treatment of patients suffering from advanced and metastatic renal cell carcinoma, which may spread to the lungs, bone, or brain. Patients face invasive surgeries as well as a risk of paraneoplastic syndrome–associated cachexia, fatigue, pain, and anemia.

 As therapies are being rapidly developed and improved, patients often experience increased longevity while being confronted with chronic treatment-related adverse effects, significantly impacting their quality of life.

The impact of palliative care on patients with urologic malignancies is relatively less well studied than other malignancies. This may be in part due to a lack of utilization. Palliative interventions, defined in the National Cancer Database (NCDB) as treatment directed toward alleviation of symptoms without attempt to diagnose, stage, or treat malignancy, are remarkably infrequent for patients with advanced urologic malignancy. Retrospective review of 76,016 NCDB-registered patients showed that 12.5% of patients diagnosed with stage IV bladder cancer received palliative interventions compared with 14.7% of patients with stage IV prostate cancer and 19.9% of patients with stage IV kidney cancer.18 Only 17.6% of patients with metastatic penile cancer received noncurative symptom management according to an NCDB review of patients with advanced penile cancer from 2004 to 2015; this rate fell to 7.11% in patients with locally advanced disease.

Outcomes of palliative care interventions in patients with urologic malignancy are even less readily available in the current literature. Results from the creation of an integrated urology-palliative care clinic showed increased clinician perception of quality of care as well as high rates of patient participation in hospice and advance planning discussions, as well as maintenance of health-related quality of life throughout the palliative process.

 From a broader surgical perspective, participants randomized to receive early palliative care during the immediate postoperative period after noncurative surgical intervention showed a nonsignificant reduction in symptom distress and pain intensity.

 The SCOPE trial (NCT03436290) is an ongoing randomized controlled trial evaluating physical and functional outcomes and quality of life of patients undergoing nonpalliative surgery randomized to receive either usual care or specialist palliative care consultation; the trial is set to complete enrollment in December 2021.

 When complete, to the authors’ knowledge, the SCOPE trial will be the first randomized trial to evaluate the role of palliative care for patients undergoing surgery with curative intent.

Barriers to palliative care exist at many levels, including patient misconceptions about the meaning of palliative care and limited access within health systems, but certainly physician factors play a role as well. Although a minority of clinicians may not recognize the true impact of advanced malignancies on patient quality of life, a lack of “buy-in” or awareness regarding the added value of comprehensive palliative care may also influence low utilization.

 Furthermore, some urologists may feel that a referral to palliative care represents “giving up” on their patient, or they may simply be uncomfortable introducing the topic. One option for increasing comfort with palliative care may be expanding the language we use to describe it—Sanford et al have compared utilizing the phrase “supportive care” instead of “palliative care” to the transition from “watchful waiting” to “active surveillance.”

 Indeed, Suwanabol et al characterized surgeon-specific determinants of palliative care and found that limited knowledge and comfort contribute to underuse.

 Etiology of this discomfort may stem from training patterns because structured palliative care curricula within surgical education has traditionally been lacking.

It is encouraging to see the urologic community acknowledging the importance of palliative care for our patients, particularly among patients with urologic malignancies. Urology-specific guidelines, white papers, quality improvement summits, and emerging data will undoubtedly inform the future landscape of urologic oncology. Although no target threshold for ideal utilization of palliative care within urologic oncology exists, data strongly indicate the improved care value associated with timely and appropriate utilization. We agree with NCCN Palliative Care Guidelines recommending “all health care professionals and trainees participate in the education that results in the acquisition of palliative care knowledge, skills, and attitudes.”

 Urologists need not be palliative care experts but must continue to consider palliative care, collaborate with palliative care specialists, and, when appropriate, provide primary palliative care within our own practices as we strive to deliver high-quality, patient-centered, cost-effective care.

 is an associate professor of urology at Vanderbilt University Medical Center, Nashville, Tennessee.

1. Bakitas MA, Tosteson TD, Li Z, et al. Early versus delayed initiation of concurrent palliative oncology care: patient outcomes in the ENABLE III randomized controlled trial. 

. 2015;33(13):1438-1445. doi:10.1200/JCO.2014.58.6362

2. Higginson IJ, Bausewein C, Reilly CC, et al. An integrated palliative and respiratory care service for patients with advanced disease and refractory breathlessness: a randomised controlled trial. 

. 2014;2(12):979-987. doi:10.1016/S2213-2600(14)70226-7

3. Bakitas M, Lyons KD, Hegel MT, et al. Effects of a palliative care intervention on clinical outcomes in patients with advanced cancer: the Project ENABLE II randomized controlled trial. 

. 2009;302(7):741-749. doi:10.1001/jama.2009.1198

4. Ferrell BR, Temel JS, Temin S, et al. Integration of palliative care into standard oncology care: American Society of Clinical Oncology clinical practice guideline update. 

. 2017;35(1):96-112. doi:10.1200/JCO.2016.70.1474

5. NCCN. Clinical Practice Guidelines in Oncology. Palliative care, version 2.2021. Accessed November 6, 2021. https://www.nccn.org/professionals/physician_gls/pdf/palliative.pdf

6. Mo L, Urbauer DL, Bruera E, Hui D. Recommendations for palliative and hospice care in NCCN guidelines for treatment of cancer. 

. 2021;26(1):77-83. doi:10.1002/ONCO.13515

7. Smith A, Anders M, Auffenberg G, et al. Optimizing outcomes in urologic surgery: postoperative. American Urological Association. 2018. Accessed Nov. 9, 2021. https://www.auanet.org/guidelines/guidelines/optimizing-outcomes-in-urologic-surgery-postoperative

8. AUA 2021 Quality Improvement Summit. American Urological Association. Accessed Nov 9, 2021. https://www.auanet.org/practice-resources/patient-safety-and-quality-of-care/2021-quality-improvement-summit

9. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. 

. 2020;70(1):7-30. doi:10.3322/caac.21590

10. Benner C, Greenberg M, Shepard N, Meng MV, Rabow MW. The natural history of symptoms and distress in patients and families following cystectomy for treatment of muscle invasive bladder cancer. 

. 2014;191(4):937-942. doi:10.1016/j.juro.2013.10.101

11. Smith AB, Jaeger B, Pinheiro LC, et al. Impact of bladder cancer on health‐related quality of life. 

. 2018;121(4):549-557. doi:10.1111/bju.14047

12. Hugar LA, Lopa SH, Yabes JG, et al. Palliative care use amongst patients with bladder cancer. 

. 2019;123(6):968-975. doi:10.1111/bju.14708

13. Ok JH, Meyers FJ, Evans CP. Medical and surgical palliative care of patients with urological malignancies. 

. 2005;174(4 Pt 1):1177-1182. doi:10.1097/01.ju.0000173077.84274.01

14. Lowrance W, Breau R, Chou R, et al. Advanced prostate cancer: AUA/ASTRO/SUO guideline. American Urological Association.https://www.auanet.org/guidelines/guidelines/advanced-prostate-cancer

15. Dinan MA, Curtis LH, Setoguchi S, Cheung WY. Advanced imaging and hospice use in end-of-life cancer care. 

. 2018;26(10):3619-3625. doi:10.1007/s00520-018-4223-0

16. Bergman J, Saigal CS, Lorenz KA, et al; Urologic Diseases in America Project. Hospice use and high-intensity care in men dying of prostate cancer. 

. 2011;171(3):204-210. doi:10.1001/archinternmed.2010.394

17. de Groot S, Redekop WK, Versteegh MM, et al. Health-related quality of life and its determinants in patients with metastatic renal cell carcinoma. 

. 2018;27(1):115-124. doi:10.1007/s11136-017-1704-4

18. Lec PM, Lenis AT, Brisbane W, et al. Trends in palliative care interventions among patients with advanced bladder, prostate, or kidney cancer: a retrospective cohort study. 

2020;38(11):854.e1-854.e9. doi:10.1016/j.urolonc.2020.04.029

19. Davaro FM, Weinstein D, Siddiqui SA, Hamilton ZA. A lack of palliative therapy use in patients with advanced penile cancer. 

. 2021;36(2):98-104. doi:10.1177/0825859720946887

20. Bergman J, Ballon-Landa E, Lorenz KA, et al. Community-partnered collaboration to build an integrated palliative care clinic: the view from urology. 

. 2016;33(2):164-170. doi:10.1177/1049909114555156

21. Huen K, Huang C, Liu H, et al. Outcomes of an integrated urology-palliative care clinic for patients with advanced urological cancers: maintenance of quality of life and satisfaction and high rate of hospice utilization through end of life. 

. 2019;36(9):801-806. doi:10.1177/1049909119833663

22. Wallen GR, Baker K, Stolar M, et al. Palliative care outcomes in surgical oncology patients with advanced malignancies: a mixed methods approach. 

. 2012;21(3):405-415. doi:10.1007/s11136-011-0065-7

23. Shinall MC Jr, Hoskins A, Hawkins AT, et al. A randomized trial of a specialist palliative care intervention for patients undergoing surgery for cancer: rationale and design of the Surgery for Cancer with Option of Palliative Care Expert (SCOPE) Trial. 

. 2019;20(1):713. doi:10.1186/s13063-019-3754-0

24. Sanford MT, Greene KL, Carroll PR. The argument for palliative care in prostate cancer. 

. 2013;2(4):278-280. doi:10.3978/j.issn.2223-4683.2013.09.13

25. Suwanabol PA, Reichstein AC, Suzer-Gurtekin ZT, et al. Surgeons' perceived barriers to palliative and end-of-life care: a mixed methods study of a surgical society. 

. 2018;21(6):780-788. doi:10.1089/jpm.2017.0470

26. Wancata LM, Hinshaw DB, Suwanabol PA. Palliative care and surgical training: are we being trained to be unprepared? 

. 2017;265(1):32-33. doi:10.1097/SLA.0000000000001779

Benefits include improved quality of life and symptom management.

Considerations for palliative care in urologic oncology

The field of urology is a specialty that has always been dominated by men, but what does the gender gap look like now?

, discussed how the gender gap in urology has evolved over time. In addition, she stressed the importance of women in this field as the population of female urologic patients continues to grow. Miles-Thomas is the President of Urology of Virginia, PLLC, Virginia Beach.

Please discuss strategies for recruiting female urologists to your practice.

The first strategy is to actually have female urologists in your practice. I think it's difficult. This is still really a male-dominated field; however, the patient population is well mixed. There's men and women that are patients, and a lot of female patients are asking and requesting female urologists. So, I think the need is there and from our standpoint, the communication needs to be there. We understand that you may not just do female urology. You may do oncology, you may want to treat stones, but we have people who are asking for you in particular. And so, if someone understands that they're valued and they're needed, then I think it’s more than likely that they'd want to join you.

Please discuss retention strategies for keeping female urologists in your practice.

We have female urologists in our practice; we currently have 4. And the number 1 thing for retention is to listen. The experience for a female in urology is different than a male in urology. There's a lot of microaggressions. There [are] a lot of inappropriate comments and conduct that happen. Also in the operating room, as surgeons, there's a certain personality type, and it's really accepted a lot more as a male to say or do certain things [that would get you] written up if you're a female. It's blatant; it's there. The number 1 thing that we do to maintain our female urologists is to listen. To listen to what happened, and to make sure there wasn't a disparity between others in the practice.

Where is the field of urology at in terms of the gender gap in the percentage of male/female practicing urologists and what can be done to continue to close that gap?

Percentagewise, it's about 10% now, which is much improved from when I came out. And what's happening to close that gap? Well, I think we've recognized that it's important to have a better mix of people who are providing the care. First, in medical school, there's a lot more women who are being exposed to urology. And then, I think, in residency, a lot of the classes now are at least 50% women. When you bring women into a group, just the same as any other field, the more diverse the field, the better answers you get, the stronger the program is going to be. And so, I think it's a pipeline. You start maybe even in high school. [For] med school, you have to have exposure. [For] residency, you have exposure, and you also have exposure to faculty—people who can mentor you and explain [why] this is how it is and how to help change things. Once you are faculty and you’re recruiting, [it’s important] to be available for the real questions.

Can you describe the gender pay gap in urology and what can be done to address it?

It depends on how you're paid and the structure of the compensation model. So, if you're truly paid for, let's say, [relative value units, (RVUs)] versus collections, there are some disease states that women have more than men that don't reimburse as well. And so, one of the strategies is to make sure that there's a better mix of that patient population, and that it's not just all shifted to maybe the female urologist to see that certain type of disease state. And that will really help, too.

If you were addressing female doctors choosing a specialty, what would you say to them as to why they should specialize in urology?

I think urology is just a great field. It's a great field because it's diverse. Not in so much as who's providing the service, but the different disease states that we can treat. So, you could be a urologist who only functions in the office and never goes to the OR. You can do 80% of what you do in the office. Or you can be someone who does large, major cases in the hospital. You can treat men, you can treat women, you can be a pediatric urologist just to treat children. So, I think urology is a special field. Between the medical and the surgical interventions, and then diversity of the patient population, there are so many options. I think more women should go into urology.

"This is still really a male-dominated field; however, the patient population is well mixed. There's men and women that are patients, and a lot of female patients are requesting female urologists," said Jennifer Miles-Thomas, MD. 

Dr. Jennifer Miles-Thomas addresses the gender gap in urology

 discusses the takeaways and further research of 2 studies he presented at the 2021 International Continence Society Meeting: “The Optilume urethral drug coated balloon for recurrent anterior urethral strictures: 3-year results from the ROBUST I Study,” and “A randomized controlled trial evaluating the Optilume urethral drug coated balloon vs endoscopic management for treatment of recurrent anterior urethral strictures.” Chee is a reconstructive urological surgeon at Murac Health, East Melbourne, Australia.

“New things are being developed and, I believe, at the moment showing great initiative and resolve,” says Justin Chee, MD.

Dr. Chee on novel Optilume device for patients with recurrent anterior urethral stricture

Yasin is a genitourinary oncology fellow at Vanderbilt University Medical Center, Nashville, Tennessee.

Davis is an associate professor of medicine and urology and vice president for Cancer Care Network and Strategy at Vanderbilt University Medical Center, Nashville, Tennessee.

Bladder cancer is a prevalent and burdensome cancer, with nearly 83,000 new diagnoses expected in 2021.1 Approximately 75% of patients present with localized, non–muscle-invasive bladder cancer (NMIBC).

 The current standard of care for intermediate- and high-risk NMIBC is resection of all visible disease followed by induction intravesical treatment with bacillus Calmette-Guérin (BCG), and then maintenance therapy for up to 3 years.

 Prospective data have supported the first-line use of BCG for more than 20 years.

High-risk NMIBC is a resource-intensive entity, with a clinical hallmark being frequent recurrences and risk of progression, resulting in a substantial therapy burden for patients.

 Although intravesical treatment BCG has long been the standard of care for NMIBC, BCG failure occurs in 30% to 50% of patients, with limited salvage options. At present, only 2 agents currently have FDA approval for use in BCG-unresponsive disease: valrubicin and pembrolizumab (Keytruda), both of which have response rates of 50% or less.

When faced with this challenging clinical scenario, it is important to understand salient definitions surrounding BCG failure, as differing criteria over time can make interpretation of study data and recommendations difficult. In 2018, the FDA set forth formal definitions of post-BCG high-risk NMIBC.

Importantly, “adequate” BCG in the context of these definitions means receipt of at least 5 to 6 doses at induction and 2 to 3 doses of maintenance, or at least 5 to 6 BCG treatments at initial induction and 2 to 6 instillations on a second induction course.10 For patients meeting these criteria, additional courses of BCG are unlikely to induce remission. For the purposes of the remainder of this review, our focus will be on salvage intravesical, surgical, and systemic immunotherapy options for BCG-unresponsive NMIBC.

Intravesical options for BCG-unresponsive NMIBC

 Valrubicin is the onlychemotherapeutic agent currently approved for intravesical therapy in patients with BCG-unresponsive carcinoma in situ (CIS), based upon an 18% complete response (CR) rate in a study of 230 BCG-unresponsive NMIBC patients undergoing 6 or 9 weeks of valrubicin.

 Disease-free survival (DFS) was merely 4% at 2 years in this trial.

 The FDA label specifically indicates use in patients “for whom immediate cystectomy would be associated with unacceptable morbidity or mortality.”

 This relatively narrow indication as well as the poor overall long-term performance as salvage therapy has resulted in limited adoption of valrubicin in contemporary management.

Gemcitabine, given by intravesical route, is an off-label chemotherapy utilized in the setting of BCG-unresponsive disease. In a study by Dalbagni et al, CR was 50% at 6 months, although 12-month DFS was only 21%.

 Similarly, a randomized trial by Di Lorenzo and colleagues compared additional BCG induction vs intravesical gemcitabine instillation in 80 patients with BCG-unresponsive disease, utilizing a 6-week induction course and 3 weekly maintenance instillations at 3, 6, and 12 months for both treatment arms. Recurrence-free survival (RFS) was greater in the gemcitabine group at 2 years than in the repeat BCG group (19% vs 3%). Importantly, 33% and 37% of patients in the gemcitabine and BCG groups, respectively, had disease progression requiring radical cystectomy (RC).

 Although no trial has identified an optimal format for therapy, gemcitabine dosing and frequency is extrapolated from the experience with BCG and is typically instilled on the same schedule as BCG, with 6 induction courses and maintenance.

Docetaxel and paclitaxel are also off-label chemotherapy options with at least moderate evidence for salvage intravesical use in BCG-unresponsive disease. In a small phase 1 trial of docetaxel in 18 patients with BCG-unresponsive disease, a 22% CR was observed at a median follow-up of 43 months, with 56% of patients initially having no visible disease on initial cystoscopy or biopsy after treatment.

Unfortunately, longer-term follow-up demonstrated an overall treatment failure rate of 61% requiring additional interventions (including RC), with median DFS of 13.3 months.

Likewise, intravesical paclitaxel was evaluated in a small phase 1 trial of 16 patients with BCG-unresponsive CIS; the CR rate was 60% at 8-week evaluation. Long-term results with use of paclitaxel are uncertain.

Given the results of single-agent gemcitabine and docetaxel in the previously discussed trials, the combination was investigated as salvage treatment for patients who were unfit or unwilling to undergo RC for BCG-unresponsive NMIBC. A 2019 retrospective analysis by Steinberg and colleagues reported on 276 patients who received combination intravesical gemcitabine and docetaxel therapy for BCG-unresponsive disease, including recurrent high-grade (HG) T1 disease with or without CIS. RFS rates at 1 and 2 years were 60% and 46%, respectively, with 15.6% of patients progressing to RC at a median time of 11.3 months from induction.

Surgical options for BCG-unresponsive NMIBC

In 2021, RC remains a guideline-recommended standard of care first-line option for patients with high-risk, BCG-unresponsive NMIBC, and it improves survival.

There are many compelling studies demonstrating the adverse oncologic risks of delayed surgical management in BCG-unresponsive NMIBC.

 Specifically, in patients with BCG-unresponsive HG T1 disease, cancer-specific and overall survival were inferior in patients who underwent delayed (>2 years) vs early RC.

 Likewise, Bianco et al demonstrated that for patients with pT1 disease, with or without CIS, treated with RC, 27% were up-staged on surgical pathology to muscle-invasive bladder cancer (MIBC), including 12% with nodal disease.

The use of RC for T1 recurrent disease after BCG treatment has a decreased 5-year cumulative incidence of death compared with patients treated with re-resection and more BCG.

 Finally, patients with initial high-risk NMIBC who progress to MIBC and undergo RC have been found to have a worse prognosis than patients with de novo MIBC, demonstrating the danger of delaying timely intervention in this population.

 Thus, considering timely management with RC after reaching a state of BCG-unresponsiveness is a key decision point for patients with high-risk NMIBC. Nevertheless, one must acknowledge the continued challenges surrounding patient selection for RC in populations with increasingly complicated medical comorbidities. Furthermore, the long-term quality-of-life and lifestyle impacts of RC and urinary diversion remain a barrier for many patients.

Despite a long-standing indication for platinum-based chemotherapy treatment in the first-line setting for advanced bladder cancer, there is currently no role for systemic chemotherapy in the management of BCG-unresponsive NMIBC. Recently, immunotherapy checkpoint inhibitors have led to improved outcomes in advanced bladder cancer when compared to the use of second-line chemotherapy regimens following receipt of a platinum-based regimen. Additionally, the use of immunotherapy is appropriate in the first-line setting for those who are deemed platinum-ineligible or who have PD-L1 expression. There are 5 PD-1/PD-L1 inhibitors approved for use in advanced bladder cancer; however, not all patients achieve or maintain benefit from these treatments. The idea of possible success of systemic immunotherapy in BCG-unresponsive NMIBC has roots in the biology of NMIBC. HG bladder cancer has one of the highest tumor mutational burdens, which is known to be a feature of tumors more likely to respond to checkpoint inhibition. Additionally, BCG, an immunomodulating agent, has been the backbone of treatment for HG NMIBC for more than 45 years.

Multiple studies have explored the use of immunotherapy in NMIBC. KEYNOTE-057 (NCT02625961) was a single-arm phase 2 trial involving 103 patients with BCG-refractory NMIBC who were not candidates for, or refused, RC. Patients received pembrolizumab 200 mg intravenously (IV) 3 times a week for 24 months or until disease progression. Assessment for response occurred after 3 months. A total of 38.8% (95% CI, 29.4%-48.9%) achieved CR, and 80.2% maintained CR for longer than 6 months. There was no progression to muscle-invasive or metastatic disease at the time of analysis. No new safety signals arose; 18.4% had immune-related adverse events (AEs), and 1 treatment-related death from colitis occurred.

The results of KEYNOTE-057 led to FDA approval for pembrolizumab in BCG-unresponsive, high-risk NMIBC.

Similarly, SWOG 1605 (NCT02844816) evaluated atezolizumab (Tecentriq) 1200 mg IV 3 times a week for 1 year in a single-arm, phase 2 study of patients with BCG-unresponsive high-risk NMIBC who were unfit for, or declined, RC. The primary outcome was pathologic CR (pCR) rate at 6 months by mandatory biopsy. Results for a subset of 75 patients with CIS, with or without concomitant Ta or T1 disease, were presented at the virtual American Society of Clinical Oncology 2020 Annual Meeting. The pCR rate at 3 months was 41.1% (95% CI, 29.7%-53.2%) and 26% (95% CI, 16.5%-37.6%) at 6 months. No new safety signals were noted, with 12.3% of patients experiencing at least a grade 3 AE; there was 1 immune-related death from myasthenia gravis.

PD-L1 expression in the tumor microenvironment may lead to attenuated response to BCG. KEYNOTE-676 (NCT03711032) is a phase 3 randomized study evaluating the efficacy and safety of BCG with or without pembrolizumab in patients with relapsed or refractory high-risk NMIBC following standard BCG therapy. The primary end point is CR rate in patients with CIS.

Multiple other trials are underway to investigate various agents in BCG-unresponsive bladder cancer. Below are highlighted several important studies that are either underway or have reported preliminary results.

The Hoosier Cancer Research Network is currently conducting a multiarm, multistage, multicenter phase 1/2 study (ADAPT BLADDER) investigating the efficacy and safety of IV durvalumab plus BCG with or without external beam radiation therapy in BCG-unresponsive NMIBC. After the recommended phase 2 dose is identified, the primary end point for the phase 2 expansion will be progression-free survival at 6 months. Recruitment is ongoing and preliminary results are expected by September 2022.

Nadofaragene firadenovec is a recombinant adenovirus delivering human interferon-α cDNA into bladder epithelium along with Syn3, a polyamide surfactant that enhances the viral transduction of the urothelium; this results in local interferon-α production, which in turn produces tumor regression.

Based on success of preclinical studies and a phase 1 trial on intravesical formulation of this agent, a phase 3 trial was conducted to further examine efficacy in CIS (with or without a HG Ta or T1 tumor).

 In total, 55 (53.4%) of 103 patients with CIS (with or without a HG Ta or T1 tumor) who were included for efficacy analysis had response within 3 months of the first dose, and this response was maintained in 25 (45.5%) of 55 patients at 12 months. Micturition urgency was the most common AE and there were no treatment-related deaths.

CG0070 is an oncolytic immunotherapy using an adenovirus engineered to preferentially replicate in, and destroy, RB pathway defective cells using the E2F-1 promoter element to limit virus replication and expression of the immunomodulatory transgene granulocyte-macrophage colony-stimulating factor.

 Preclinical and phase 1 studies on intravesical CG0070 showed both safety and efficacy in NMIBC.

Packiam and others conducted a phase 2, open-label, single-arm study to evaluate its efficacy; 45 patients who had received at least 2 prior courses of intravesical therapy for CIS, with at least 1 being a course of BCG, were evaluated, and CR at 6 months was 47% (95% CI, 32%-62%).

N-803 is an interleukin-15–based immunostimulatory protein complex that activates and proliferates natural killer cells and CD8+ T cells.

 A recent study of 80 patients with BCG-unresponsive CIS who were treated with N803 plus BCG showed 72% CR; 59% remained in CR at 12 months and median duration of CR was 19.2 months (range, 7.6-26.4). The combination was safe and well tolerated with only 9 patients experiencing an AE higher than grade 3.

A significant increase in the number of effective treatments for advanced bladder cancer have been developed in recent years. Although the treatment landscape of NMIBC has simultaneously been evolving, only pembrolizumab has gained FDA approval in BCG-unresponsive disease. As understanding of the mechanism for BCG resistance, and the variability of post-BCG disease states, has increased, multiple investigational agents have been developed and are being studied. The paucity of accepted and effective therapeutics in the BCG-unresponsive setting highlights the necessity for clinical trial participation to answer clinical questions and expand the spectrum of effective treatments in this population.

 is a clinical instructor and Society of Urologic Oncology fellow, 

 is a genitourinary oncology fellow, and 

 is an associate professor of medicine and urology and vice president for Cancer Care Network and Strategy at Vanderbilt University Medical Center, Nashville, Tennessee.

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. 

2. Chang SS, Boorjian SA, Chou R, et al. Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline. American Urological Association. 2020. Accessed November 6, 2021. https://www.auanet.org/guidelines/bladder-cancer-non-muscle-invasive-guideline

3. NCCN. Clinical Practice Guidelines in Oncology. Bladder cancer, version 6.2020. Accessed November 6, 2021. 

https://www.nccn.org/professionals/physician_gls/default.aspx#bladder.pdf

4. Palou J, Laguna P, Millán-Rodríguez F, Hall RR, Salvador-Bayarri J, Vicente-Rodríguez J. Control group and maintenance treatment with bacillus Calmette-Guerin for carcinoma in situ and/or high-grade bladder tumors. 

5. Lamm DL, Blumenstein BA, Crissman JD, et al. Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. 

6. Sylvester RJ, van der Meijden APM, Lamm DL. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. 

 2002;168(5):1964-1970. doi:10.1097/01.ju.0000034450.80198.1c

7. Saluja M, Gilling P. Intravesical bacillus Calmette-Guérin instillation in non–muscle-invasive bladder cancer: a review. 

8. Dinney CP, Greenberg RE, Steinberg GD. Intravesical valrubicin in patients with bladder carcinoma in situ and contraindication to or failure after Bacillus Calmette-Guérin. 

 2013;31(8):1635-1642. doi:10.1016/j.urolonc.2012.04.010

9. Balar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab (pembro) for the treatment of patients with Bacillus Calmette–Guérin (BCG) unresponsive, high-risk (HR) non–muscle-invasive bladder cancer (NMIBC): over two years follow-up of KEYNOTE-057. 

2020;38(suppl 15):abstr 5041. doi:10.1200/JCO.2020.38.15_suppl.5041

10. BCG-unresponsive nonmuscle invasive bladder cancer: developing drugs and biologics for treatment guidance for industry. FDA. February 2018. Accessed November 6, 2021. 

https://www.fda.gov/media/101468/download

11. Steinberg G, Bahnson R, Brosman S, Middleton R, Wajsman Z, Wehle M. Efficacy and safety of valrubicin for the treatment of Bacillus Calmette-Guerin refractory carcinoma in situ of the bladder. The Valrubicin Study Group. 

12. Valstar. Prescribing information. Endo; 2011. Accessed October 26, 2021. 

https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020892s013lbl.pdf

13. Dalbagni G, Russo P, Bochner B, et al. Phase II trial of intravesical gemcitabine in bacille Calmette-Guérin–refractory transitional cell carcinoma of the bladder. 

 2006;24(18):2729-2734. doi:10.1200/JCO.2005.05.2720

14. Di Lorenzo G, Perdonà S, Damiano R, et al. Gemcitabine versus bacille Calmette-Guérin after initial bacille Calmette-Guérin failure in non–muscle-invasive bladder cancer: a multicenter prospective randomized trial. 

 2010;116(8):1893-1900. doi:10.1002/cncr.24914

15. McKiernan JM, Masson P, Murphy AM, et al. Phase I trial of intravesical docetaxel in the management of superficial bladder cancer refractory to standard intravesical therapy. 

 2006;24(19):3075-3080. doi:10.1200/JCO.2005.03.1161

16. Laudano MA, Barlow LJ, Murphy AM, et al. Long-term clinical outcomes of a phase I trial of intravesical docetaxel in the management of non–muscle-invasive bladder cancer refractory to standard intravesical therapy. 

. 2010;75(1):134-137. doi:10.1016/j.urology.2009.06.112

17. Bassi PF, Volpe A, D’Agostino D, et al. Paclitaxel-hyaluronic acid for intravesical therapy of bacillus Calmette-Guérin refractory carcinoma in situ of the bladder: results of a phase I study. 

2011;185(2):445-449. doi:10.1016/j.juro.2010.09.073

18. Steinberg RL, Thomas LJ, Brooks N, et al. Multi-institution evaluation of sequential gemcitabine and docetaxel as rescue therapy for nonmuscle invasive bladder cancer. 

2020;203(5):902-909. doi:10.1097/JU.0000000000000688

19. Herr HW, Sogani PC. Does early cystectomy improve the survival of patients with high risk superficial bladder tumors? 

20. Lerner SP, Tangen CM, Sucharew H, Wood D, Crawford ED. Failure to achieve a complete response to induction BCG therapy is associated with increased risk of disease worsening and death in patients with high risk non-muscle invasive bladder cancer. 

Multiple investigational agents have been developed and are being studied.

Dr. Ziegelmann on novel injection for patients with Peyronie's disease

Expert Forum on Bladder Cancer: Nadofaragene Firadenovec for BCG-unresponsive NMIBC

Dr. Koontz gives an overview of ASTRO discussion on new RTOG-0815 data