Bladder cancer is the sixth most commonly diagnosed cancer in the United States and is responsible for nearly 18,000 deaths per year in this country.

 Of the estimated 81,000 new cases of bladder cancer in 2020, 75% will be diagnosed as non–muscle–invasive bladder cancer (NMIBC).

 These cancers, by definition, are confined to the mucosa or subepithelial layer of the bladder and spare the muscularis propria.

Accurate staging of carcinoma in situ, Ta, and T1 cancers is of the upmost importance because the treatment of NMIBC is drastically different from that of muscle-invasive disease. Emphasizing the challenges associated with precise diagnosis and surveillance of NMIBC, national guideline organizations such as the American Urological Association,

 and the National Comprehensive Cancer Network

 have incorporated blue light cystoscopy (BLC) with hexaminolevulinate (HAL) into the recommendations for endoscopic detection of bladder cancer and bladder cancer recurrence. This article reviews the mechanism of action of HAL, familiarizes the reader with the body of evidence supporting its use, and provides a real-world workflow for incorporation of BLC into clinical practice.

HAL mechanism of action, indications, and efficacy

Under the trade name Cysview, HAL is FDA approved for the detection of bladder cancer, including carcinoma in situ, in patients with a known history of bladder cancer and also in patients undergoing cystoscopic evaluation for the suspicion of bladder cancer.

 In the cytoplasm of bladder cancer cells, HAL becomes incorporated into the heme biosynthetic pathway and is converted into coporphyrinogen. Coporphyrinogen is transported into mitochondria where it is further metabolized into photoactive porphyrins.

Photoactive porphyrins accumulate in the mitochondria, and in sufficient concentrations, fluoresce when exposed to 360- to 450-nm wavelengths of light—hence the moniker 

 In practice, this manifests as well-defined focal areas of pink mucosa where bladder cancer is likely present surrounded by a field of blue-appearing tissue where unaffected bladder exists.

The efficacy of BLC to increase detection of bladder cancer and reduce recurrence was established in 2018 through a phase 3, multicenter, prospective, randomized clinical trial.

 A total of 304 patients were instilled with HAL prior to undergoing a routine white-light cystoscopy. To ensure proper diligence of the white-light component of the exam, the patients were then randomized to either continue with a subsequent blue light component or were discontinued from the study.

In total, 103 patients from the blue light cohort of the trial went on to undergo a transurethral resection of bladder tumor for a suspicion of bladder cancer recurrence. In total, 63 patients (20% of the entire trial population) were diagnosed with bladder cancer recurrence that was detected only on the blue light component of the exam (

 <.001). Twenty-six patients (8.5%) were found to have carcinoma in situ, and of these, 9 (34%) were detected only with BLC (

BLC has also been shown to be well tolerated in the surveillance setting. In the phase 3 trial, Patient-Reported Outcomes Measurement Information System questionnaires evaluating anxiety, pain, and whether the procedure was felt to be worthwhile were administered.

 According to those surveyed, patients who underwent BLC had reduced anxiety without any significant increase in reported pain levels. Ninety-four percent of patients who underwent BLC reported that the procedure was worthwhile and would do it again. More than 90% of surveyed patients responded that they would recommend BLC to others.

Citing these data, guideline panels from the American Urological Association and the Society of Urologic Oncology have strengthened their recommendations that BLC “should” be offered, if available, in patients with NMIBC “to increase detection and decrease recurrence.”

 The National Comprehensive Cancer Network includes the use of BLC as an option.

 An expert panel consensus statement for BLC in the United States is also available supporting its use.

How I incorporate BLC into clinical practice

Performing cystoscopy with the aid of BLC can be easily incorporated into existing clinical practice both in the academic and the community setting. However, there is no escaping that the procedure takes longer than a traditional white-light cystoscopy. Adherence to a few simple principles will ensure that the existing workflow of the urologist’s clinic continues uninterrupted and that the procedure quickly becomes time efficient 

First, patients must arrive early. In my practice, the patient’s “appointment time” is actually the “scope time.” In order for my clinic staff to adequately intake the patient, instill their bladder with HAL, and provide the necessary dwell time, the patient must arrive 1 to 1.5 hours before their scope time. All patients are notified during their routine appointment reminder of both their arrival time and the expected scope time so that they are aware of the difference.

Second, the clinic staff should perform all intake and preparation responsibilities before and after scope time with minimal involvement of the urologist. This step requires that at least 1 member of the care team understand how to constitute the HAL for instillation, be skilled with in-and-out catheterization, and be adept at scope cleaning/equipment turnover. In my practice, these duties are assigned to a single medical assistant, although many practices will utilize registered nurses or nonphysician providers for this responsibility.

A high-functioning assistant trained in this exercise is essential for ensuring that the urologist continues to see nonprocedural patients during the 1 to 1.5 hours that the patient with BLC is in preparation or turnover. 

 demonstrates our procedure suite ready for BLC.

Third, keep the clinic rooms open and continuing to turn over. My patients with BLC occupy a consultation room only during instillation, and they are excused back into the waiting room during the 40-minute dwell period. This strategy keeps the encounter areas open and allows my staff to room patients who are not undergoing BLC during the dwell time. A restroom is adjacent to the waiting area in the event that the patient cannot tolerate holding the solution for the entire dwell time. The assistant then brings the patient to the procedure suite after the appropriate dwell time and positions them on the table with all drapes applied before declaring the patient ready for BLC.

If the urologist has the ability to biopsy and fulgurate lesions in the office, then preparing every patient for a potential biopsy from the outset is my fourth principle. We instill 10 to 15 mL of 1% lidocaine solution at the same time as the HAL and ensure the proper grounding pad is applied during positioning. 

demonstrates the necessary instillation components we apply to every patient. Early anticipation of lesion detection in this manner ensures that the urologist is ready to biopsy immediately upon identifying a lesion, can treat the entire area once the tissue has been sampled, and avoids unnecessary delays or scope reinsertions.

As with any procedure, developing a routine for the cystoscopy that can be easily replicated will save time and increase efficiency. Perform a complete white-light cystoscopy first. Identify any suspicious areas and note them. Retroflex the scope to visualize the anterior bladder neck as the last step of the white-light component, and with the scope in retroflexion, switch to BLC and perform the BLC in reverse order.

This strategy allows for a single retroflexion of the scope and avoids repeating the more uncomfortable portions of the exam. Biopsy and fulguration, if necessary, are performed only after completing comprehensive white- and blue-light components.

When a biopsy is performed, I use flexible biopsy forceps and a monopolar current set at 20 watts for fulguration and hemostasis. I engage the blue light before the biopsy to delineate the entire area needed for treatment. The cautery device can be used to demarcate this area, if desired. The blue light is then engaged again after the biopsy and fulguration to ensure that all fluorescing tissue has been treated. The entire duration of scope time, including time allotted for biopsy and fulguration, rarely exceeds the time necessary for a routine return office visit.

Having adhered to these principles, the urologist and staff should be able to perform at least 4 BLCs in a half day, all of which can be seamlessly interwoven with other nonprocedure appointments. With a motivated care team and dedication to optimizing this process over time, BLC will become a rewarding procedure that is easily replicable and results in improved outcomes for your patients with NMIBC.

Daniel C. Parker, MD, is an assistant professor of urology at The University of Oklahoma College of Medicine, Oklahoma City, Oklahoma.

1. Howlader N, Noone A, Krapcho M, et al. SEER Cancer Statistics Review (CSR) 1975-2017. National Cancer Institute. https://seer.cancer.gov/csr/1975_2017/

2. Babjuk M, Burger M, Compérat EM, et al. European Association of Urology Guidelines on Non-muscle-invasive bladder cancer (TaT1 and carcinoma in situ) - 2019 update. 

3. Chang SS, Bochner BH, Chou R, et al. Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO guideline. 

4. Flaig TW, Spiess PE, Agarwal N, et al. Bladder Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology. 

5. Hexaminolevulinate. Prescribing information. FDA; 2010:1-11. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022555s000lbl.pdf. Accessed May 21, 2020.

6. Witjes JA, Redorta JP, Jacqmin D, et al. Hexaminolevulinate-guided fluorescence cystoscopy in the diagnosis and follow-up of patients with non-muscle-invasive bladder cancer: review of the evidence and recommendations. 

7. Daneshmand S, Patel S, Lotan Y, et al. Efficacy and safety of blue light flexible cystoscopy with hexaminolevulinate in the surveillance of bladder cancer: a phase III, comparative, multicenter study. 

8. Smith AB, Daneshmand S, Patel S, et al. Patient-reported outcomes of blue-light flexible cystoscopy with hexaminolevulinate in the surveillance of bladder cancer: results from a prospective multicentre study. 

9. Lotan Y, Bivalacqua TJ, Downs T, et al. Blue light flexible cystoscopy with hexaminolevulinate in non-muscle-invasive bladder cancer: review of the clinical evidence and consensus statement on optimal use in the USA - update 2018. Vol 16. Nature Publishing Group 2019;377-386.

Articles

BLC with hexaminolevulinate can be an easily replicable procedure
in patients with non–muscle-invasive bladder cancer.

How to perform office-based blue light cystoscopy

The use of immune checkpoint inhibitors (CPIs) has transformed cancer care in the last decade, but prostate cancer has not yet joined the immunotherapy revolution despite many clinical trials. Most recently, the IMbassador 250 study of atezolizumab (Tecentriq) added to enzalutamide (Xtandi) (NCT03016312) showed no benefit to adding atezolizumab.

Although it is clear that most patients with prostate cancer do not benefit from the currently available CPIs, it is nevertheless apparent that certain molecular subtypes of metastatic castrate-resistant prostate cancer (mCRPC) that can benefit from immunotherapy can be identified by genomic testing. We have many good new treatments for prostate cancer, but metastatic disease remains incurable and will be the cause of death for most patients. They will die from prostate cancer, not just with it. As long as that remains true, interest in immunotherapy for prostate cancer will remain high.

Although the ideal answer to this interest is to enroll patients in clinical trials, there are still scenarios in which nontrial treatment is the best available option. What follows is our approach to CPIs in patients with advanced prostate cancer.

Biologic differences in gene expression profiling and the presence of germline and somatic mutations exist in men with prostate cancer. National Comprehensive Cancer Network guidelines now recommend germline testing for all men with high-risk, very high-risk, or metastatic prostate cancer. We also conduct somatic (tumor) testing of all patients with metastatic disease and retesting whenever progression develops on a line of systemic therapy.

The adoption of genomic profiling with next-generation sequencing (NGS) has proven that there is significant diversity of mutational patterns in the tumors of men with metastatic prostate cancer.

 Genetic testing can identify patients who would benefit from PARP inhibitors such as olaparib (Lynparza) and rucaparib (Rubraca), and it can also identify patients whose tumors are more likely to respond to CPIs. These subtypes have a common characteristic of having mutations associated with DNA repair defects

 and include deficient mismatch repair genes (dMMR)/microsatellite instability-high (MSI-H), overexpression of PD-1 T-cell receptor and its ligand (PD-L1), high tumor mutational burden (TMB), and tumors with 

Although CPIs are less toxic for the average patient than chemotherapy, they are not benign and carry a small but real risk of treatment-related mortality and a 10% to 20% risk of hospitalization across many studies. They are also expensive therapies that have to be given intravenously (IV). However, we believe in being thoughtful about when and to whom we recommend CPIs 

 and limit them to patients whose genomics suggest a meaningful chance of response.

Subtypes of prostate cancer responsive to CPIs

Tumors that lack the dMMR mechanism are hypermutated compared with tumors without such MMR defects, and the neoantigens from these additionalmutations are more immunogenic. The use of NGS is encouraged to look for dMMR/MSI-H in all patients with advanced prostate cancer. Pembrolizumab (Keytruda) received a blanket FDA approval for patients with dMMR/MSI-H prostate cancer that progressed on prior treatments.

 An initial study in mCRPC showed clinical response in a patient with dMMR/MSI-H, treated with combination pembrolizumab and enzalutamide, suggesting that a high neoantigen load could predict responses to CPIs.

In a subsequent case series focusing on mCRPC, a minority of 3.1% (32 patients) had dMMR/MSI-H PC. Among the 11 patients who received PD-1/PD-L1 therapy, 55% had a decline in prostate-specific antigen (PSA), and 45% achieved a durable clinical benefit for as long as 19 months.

The open-label basket phase 1b KEYNOTE-028 trial studied pembrolizumab 10 mg/kg IV every 2 weeks for 24 months. It included 245 patients with mCRPC; 35 (14%) were positive for PD-L1. Among the 23 of 35 patients who were positive for PD-L1 who received pembrolizumab, the overall response rate (ORR) was 17%, with stable disease in 35%, progressive disease in 39%, median duration of response of 13.5 months, and median overall survival of 8 months. These findings were confirmed by KEYNOTE-199, a phase 2 trial using pembrolizumab 200 mg IV every 3 weeks for 21 cycles in 539 patients with docetaxel-refractory mCRPC.8 This study showed a PD-L1 overexpression of 32% in mCRPC and 8% in primary prostate cancer.

 In the PD-L1-positive cohort including 133 patients, there was an ORR of 7%, a median duration of response (mDOR) of 16.8 months, a complete response (CR) in 2 patients, and a median overall survival of 9.5 months.

Of note, studies exploring PD-1/PD-L1 expression in prostate cancer use different techniques and thresholds, which result in highly variable frequencies of positivity. In summary, these combined results suggest that up to 32% of advanced prostate cancers may use the PD-L1 pathway to escape immune system detection. Patients with mCRPC and the PD-L1 subtype have a small but meaningful and sometimes durable benefit from single-agent pembrolizumab.

 Patients with mCRPC seem to have a higher TMB compared with patients earlier in the disease course.

 In general, the tumors with higher TMB correlate with dMMR. A preliminary report from the CHECKMATE 650 trial (NCT029855957) using combination ipilimumab (Yervoy) and nivolumab (Opdivo) had better outcomes in patients with high TMB compared with low TMB (TMB cutoff not reported). Results showed an ORR of 58% in both chemotherapy-naive (60% vs 0%) and after taxane based-chemotherapy (50% vs 0%).

 is a tumor suppressor protein involved in genomic stability.

 Preclinical studies have suggested that biallelic 

 mutations are associated with higher neoantigens, tumor-infiltrating lymphocytes, and higher sensitivity to CPIs.

 An initial retrospective study demonstrated CPI sensitivity in 8 patients receiving PD-1 inhibitors as fourth- to sixth-line treatment. These heavily pretreated patients had a 38% PSA decline of more than 50% and a median PFS of 6.6 months.

 These results were corroborated in a retrospective study with 46 patients with 

 mutations (34 biallelic mutations). In a cohort of 5 patients treated with a PD-1 inhibitor, 40% achieved a PSA response.

Finally, a larger retrospective multicenter study included 60 patients with prostate cancer who had somatic loss-of-function 

 mutations. Nine patients were treated with a PD-1 inhibitor (5 with pembrolizumab, 4 with nivolumab) as 4th- to 6th-line treatment, with 33% having a PSA response and median PFS of 5.4 months.

 An ongoing prospective clinical trial (NCT03570619) is examining the predictive role of CDK12 as a biomarker for the use of CPI in prostate cancer.

 Selected POLE and POLD mutations can generate tumors associated with very high TMB without MSI-H. These mutations have been found in about 2% of prostate cancers.17 A case report has been described in an exceptional responder to pembrolizumab with a documented POLE V411L mutation.

 Similarly, a patient with a POLD1 D402N, MSH2 mutation, and high TMB has been reported with a good clinical response to pembrolizumab.

In our practice, we actively sort patients onto different treatment paths based on the genetic signature of their tumors. A small but meaningful percentage of patients will have genetic aberrations that predict responsiveness to CPIs, and the results for those lucky patients can be dramatic. We try to enroll patients on immunotherapy trials as much as possible. These trials often involve combinations of existing drugs but may also involve entirely new drugs that will be more effective for mCRPC.

We recently reported results from a phase 1 study of PT-112 in patients with a median of 6.5 lines of prior therapy. In this trial, 10 patients treated with PT-112 had a median overall survival of 15.1 months. We have also combined PT-112 with avelumab (Bavencio), with accrual to that study ongoing.

There are many possibilities yet to explore, and we need to find a way to expand immunotherapy to all patients with mCRPC. In the meantime, NGS can identify the patients who are most likely to respond to CPIs while also identifying patients who carry an inherited cancer susceptibility gene and patients who will benefit from PARP inhibitors.

is a hematology/oncology fellow at Mayo Clinic, Phoenix, Arizona, and 

is an associate professor of medicine at Mayo Clinic, Phoenix, Arizona.

1. Chung JH, Dewal N, Sokol E, Mathew P, Whitehead R, Millis SZ, et al. Prospective comprehensive genomic profiling of primary and metastatic prostate tumors. 

2. Hansen AR, Massard C, Ott PA, et al. Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study. A

3. Campbell BB, Light N, Fabrizio D, Zatzman M, Fuligni F, de Borja R, et al. Comprehensive analysis of hypermutation in human cancer. 

4. Fay AP, Antonarakis ES. Blocking the PD-1/PD-L1 axis in advanced prostate cancer: are we moving in the right direction? 

5. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency.

6. Graff JN, Alumkal JJ, Drake CG, Thomas GV, Redmond WL, Farhad M, et al. Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. 

7. Abida W, Cheng ML, Armenia J, Middha S, Autio KA, Vargas HA, et al. Analysis of the prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade. 

8. Antonarakis ES, Piulats JM, Gross-Goupil M, Goh J, Ojamaa K, Hoimes CJ, et al. Pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer: multicohort, open-label phase II KEYNOTE-199 study. 

9. Ryan MJ, Bose R. Genomic alteration burden in advanced prostate cancer and therapeutic implications. 

10. Sharma P, Pachynski RK, Narayan V, Flechon A, Gravis G, Galsky MD, et al. Initial results from a phase II study of nivolumab (NIVO) plus ipilimumab (IPI) for the treatment of metastatic castration-resistant prostate cancer (mCRPC; CheckMate 650). 

11. Antonarakis ES. Cyclin-dependent kinase 12, immunity, and prostate Cancer. 

12. Wu YM, Cieślik M, Lonigro RJ, Vats P, Reimers MA, Cao X, et al. Inactivation of CDK12 delineates a distinct immunogenic class of advanced prostate cancer. 

13. Barrero M, Rediti M, Crespo M, Dolling D, Rescigno P, Messina C, et al. Tumor-infiltrating lymphocytes in biallelic-CDK12 mutated prostate cancer. 

14. Antonarakis ES, Isaacsson Velho P, Agarwal N. CDK12-altered prostate cancer: clinical features and therapeutic outcomes to standard systemic therapies, PARP inhibitors, and PD1 inhibitors. Paper presented at: European Society of Medical Oncology Annual Meeting; September 29, 2019; Barcelona, Spain. Accessed May 27, 2020. https://oncologypro.esmo.org/meeting-resources/esmo-2019-congress/CDK12-altered-prostate-cancer-Clinical-features-and-therapeutic-outcomes-to-standard-systemic-therapies-PARP-inhibitors-and-PD1-inhibitors

15. Reimers MA, Yip SM, Zhang L, Cieslik M, Dhawan M, Montgomery B, et al. Clinical Outcomes in Cyclin-dependent Kinase 12 Mutant Advanced Prostate Cancer. 

16. Antonarakis ES, Velho PI, Fu W, Wang H, Agarwal N, Santos VS, et al. CDK12-altered prostate cancer: clinical features and therapeutic outcomes to standard systemic therapies, poly (ADP-ribose) polymerase inhibitors, and PD-1 inhibitors. 

17. Wang F, Zhao Q, Wang YN, Jin Y, He MM, Liu ZX, et al. Evaluation of POLE and POLD1 mutations as biomarkers for immunotherapy outcomes across multiple cancer types. 

18. Lee L, Ali S, Genega E, Reed D, Sokol E, Mathew P. Aggressive-variant microsatellite-stable POLE mutant prostate cancer with high mutation burden and durable response to immune checkpoint inhibitor therapy. 

19. Guedes LB, Antonarakis ES, Schweizer MT, Mirkheshti N, Almutairi F, Park JC, et al. MSH2 loss in primary prostate cancer. 

20. Bryce AH, Costello BA, Infante JR, Ames TD, Jimeno J, Karp DD. PT-112 in advanced metastatic castrate-resistant prostate cancer (mCRPC), as monotherapy or in combination with PD-L1 inhibitor avelumab: findings from two phase I studies. Poster presented at: 2020 Genitourinary Cancers Symposium; February 13, 2020; Chicago, IL. 

 2020;(supplement 6), abstract 83. Accessed May 27, 2020. doi:10.1200/JCO.2020.38.6_suppl.83

Next-generation sequencing identifies subtypes that may benefit from immune checkpoint inhibitors.

How to approach immune checkpoint inhibitor therapy in prostate cancer

Combination therapies have become the standard of care in the treatment of patients with metastatic renal cell carcinoma (RCC). Scientific discoveries culminating in Nobel Prizes that were sequentially awarded in physiology or medicine in 2018 and 2019 have dramatically changed the RCC treatment paradigm from monotherapies to combinations. The 2018 Nobel Prize presented to James Allison, PhD, and Tasuku Honjo, MD, PhD, was awarded for identifying key proteins that act as brakes on the immune system. These discoveries led to the development of immune checkpoint inhibitors (ICIs) (atezolizumab [Tecentriq], avelumab [Bavencio], ipilimumab [Yervoy], nivolumab [Opdivo], and pembrolizumab [Keytruda]).

The 2019 Nobel Prize presented to William Kaelin, MD, Sir Peter Ratcliffe, FRS, and Gregg Semenza, MD, PhD, was awarded for elucidating how cells sense and adapt to low oxygen levels by regulating blood vessel growth. These discoveries led to the development of antiangiogenic therapies (axitinib [Inlyta], bevacizumab [Avastin], cabozantinib [Cabometyx], lenvatinib [Lenvima], pazopanib [Votrient], sorafenib [Nexavar], and sunitinib [Sutent]).

When evaluating clinical studies and ultimately choosing a first-line therapy, it is important to assess: patient prognostic category, efficacy, mechanism of action, safety, and route/schedule of administration. Prognostic scoring systems integrate independent prognostic factors of survival in patients affected by metastatic RCC. The International Metastatic Renal Cell Carcinoma Database Consortium Criteria uses standard laboratory values and clinical assessment to apply risk stratification to categorize patients into favorable-, intermediate-, and poor-risk groups.

 Prognostic factors include less than 1 year from the time of diagnosis to systemic therapy, performance status (<80% Karnofsky Performance Status Scale), hemoglobin below the lower limit of normal (normal lower limit, 12 g/dL), calcium above the upper limit of normal (normal range, 8.5-10.2 mg/dL), neutrophils above the upper limit of normal (normal range, 2.0-7.0 x 109/L), and platelet counts above the upper limit of normal (normal, 150,000-400,000). Favorable-risk groups have no prognostic factors, intermediate-risk groups have 1 or 2 prognostic factors, and poor-risk groups have 3 to 6 prognostic factors.

Prior to 2018, sunitinib antiangiogenic monotherapy was considered the standard of care for first-line treatment of patients with RCC, but durable responses were rare. Cytokine therapies had durable complete responses (CRs) but were limited by their toxicities and were largely reserved for healthy patients.

From 2018 to 2019, 3 combinations (ipilimumab + nivolumab, pembrolizumab + axitinib, avelumab + axitinib) were approved by the FDA for demonstrating improved overall survival in phase 3 trials when compared with sunitinib monotherapy 

, with improved CRs. The CHECKMATE 214 trial studied the combination of ipilimumab (inhibits cytotoxic T-lymphocyte–associated protein-4) with nivolumab (inhibits PD-1) to restore patients’ immune surveillance mechanisms to target RCC.

 On the other hand, the KEYNOTE-426 and JAVELIN Renal 101 trials studied the combinations of axitinib (inhibits angiogenesis) with pembrolizumab (inhibits PD-1) and axitinib with avelumab (inhibits PD-L1), respectively to simultaneously restore patients’ immune surveillance mechanisms and target angiogenesis.

 In all 3 studies, at least 80% of the patients had a prior nephrectomy. As a group, the objective response rates, which include complete and partial responses, range from 39% to 59%.

Historically, single-agent sunitinib had CRs of 1%, whereas the combination regimens range from 3% to 10% with the highest CR rate observed in the CHECKMATE 214 trial further supporting the role of harnessing the immune system to produce durable responses. However, with the higher CR rate, CHECKMATE 214 also had a higher incidence of treatment discontinuation at 22%. Based on the National Comprehensive Cancer Network Guidelines (version 2.2020), ipilimumab + nivolumab and axitinib + pembrolizumab are preferred category 1 recommendations per the International Metastatic Renal Cell Carcinoma Database Consortium for patients with intermediate- or poor-risk disease with clear cell histology.

 Axitinib + pembrolizumab is recommended for favorable-risk patients with clear cell histology.

Although biomarkers such as PD-L1 immunohistochemistry were evaluated in the 3 studies, there is no FDA label requirement for a predictive marker to prescribe any of the 3 combinations. Emerging first-line therapies that are undergoing FDA review include the combination of cabozantinib with nivolumab.

As part of a multidisciplinary team for the treatment of RCC, it is important to consider that each combination has unique adverse event (AE) profiles depending on their mechanism of action. As a class, antiangiogenic small molecules have been associated with hypertension, diarrhea, palmar-plantar erythrodysesthesia, and hypothyroidism. Management typically includes titration of antihypertensives, antidiarrheals (loperamide or diphenoxylate), topical creams (lidocaine, moisturizing exfoliants), and thyroid replacement therapy, respectively. Depending on the half-life of the small molecules and liver metabolism, these antiangiogenic therapies may also impair wound healing and interact with other drugs that are processed through the cytochrome P450 system.

In contrast, immune checkpoint therapies have been associated with autoimmune phenomena or inflammation of the lungs, intestines, skin, liver, and heart requiring inpatient admission for administration of high-dose steroids and may require weeks of a prolonged steroid taper. The increased immune activity related to T-cell activation/proliferation, increased complement-mediated inflammation, and increased cytokine production may affect any healthy tissue. The rate of high-dose steroid administration for ipilimumab + nivolumab was 35%, and for avelumab + axitinib, 11%.

These immune-related AEs typically manifest between 2 to 9 weeks for cytotoxic T-lymphocyte associated protein-4 and 5 to 10 weeks for PD-1/PD-L1 therapies. Allergic-type infusion reactions can occur with monoclonal antibodies and can be managed with premedications. The AEs of immune checkpoint therapies require early identification because they self-propagate, whereas the small-molecule AEs typically resolve after discontinuation. To manage AEs, ICIs are usually held completely, as opposed to the small molecules, which are dose adjusted.

Given the increasing number of biological drug choices, it can be challenging to recall the names or mechanisms of action. In general, cancer drugs that end with the suffix “nib” refer to small molecules and typically have oral administration routes. The suffix “mab” refers to monoclonal antibodies, which are typically administered intravenously (IV). Consistent with using the suffixes as a guide, the ipilimumab + nivolumab ICI combination is administered every 3 weeks IV for 4 cycles and then patients can be transitioned to nivolumab monotherapy IV every 4 weeks. In contrast, axitinib is administered twice a day orally in combination with either pembrolizumab IV every 3 weeks or avelumab IV every 2 weeks.

The discoveries from 2 Nobel Prize groups have advanced the field to combination therapies of ICIs from cytokine-based immunotherapies that were difficult to administer or antiangiogenic inhibitors that lacked durable responses. By targeting multiple pathways in a tumor and its microenvironment, these combination therapies have improved CRs. Future trials are focused on finding new mechanisms to restore the immune system surveillance after prior immune checkpoint failure and targeting transcription factors involved in angiogenesis.

is associate professor in the Division of Hematology/Oncology at Mayo Clinic Arizona, Phoenix.

1. Heng DY, Xie W, Regan MM, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. 

 2009;27:5794-5799. doi:10.1200/JCO.2008.21.4809

2. M Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. 

. 2018;378:1277-1290. doi:10.1056/NEJMoa1712126

3. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. 

. 2019;380:1116-1127, doi:10.1056/NEJMoa1816714

4. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. 

. 2019;380:1103-1115. doi:10.1056/NEJMoa1816047

5. Motzer RJ, Jonasch E, Michaelson MD, et al. NCCN guidelines insights: kidney cancer, version 2.2020. 

 2019. 17:1278-1285, doi:10.6004/jnccn.2019.0054

Combination therapy is the first-line standard for metastatic renal cell carcinoma.

How to choose systemic therapy for metastatic RCC

The coronavirus disease 2019 (COVID-19) pandemic has dramatically transformed health care delivery around the globe. In several months, nearly every component of health care 

has been altered as the medical community faces the challenge of continuing to deliver quality care while mitigating risk of the severe acute respiratory syndrome coronavirus 2.

Cancer care has a unique challenge given the need to continue to provide effective treatment while balancing the risk of COVID-19 in a vulnerable patient population. Individuals with cancer are particularly susceptible to the negative consequences of COVID-191-4 given frequent touch points with the health system, immunosuppressive effects of treatments, and the underlying malignancy itself, which can potentially impact viral transmission and pathogenesis. Additionally, patients may be older and have contributing comorbidities that can amplify the risk of COVID-19–related complications.

During this unprecedented time, oncology teams have been propelled to develop new operational models for care delivery. One of the most immediate and dramatic alterations has been the widespread adoption of telehealth services. Although the technology is not new, barriers to implementation have historically included ingrained culture and reimbursement challenges. Telehealth services have facilitated the recommendation for physical distancing to curtail the spread of the virus. As we implement telehealth services, it is critical to establish early best practices for integration of translator services, conducting informed consent, and incorporating support for individuals with fewer resources.

While we are catapulted into this innovative technology age, caution must be taken to continue to protect the interface between patients and clinicians that serves as the core of the practice of medicine. Preserving the art of doctoring, as established by Sir William Osler, will safeguard against the dilution of clinical skills and burnout.

Additional measures have been invariably implemented across oncology practices with the goal of mitigating risk while continuing to provide essential care for patients. These approaches include screening procedures to identify and triage persons with presumptive COVID-19 disease, restrictive visitor policy to decrease foot traffic throughout medical facilities, and use of personal protective equipment (although this has been limited by insufficient supply in many settings).

Additionally, screening with polymerase chain reaction testing of asymptomatic patients, particularly those undergoing a procedure, having surgery, or receiving infusional treatment and also screening of asymptomatic health care workers is being performed as availability of testing increases. Rapid point-of-care tests to accelerate clinical decision-making and decrease burden on centralized laboratories are critically needed, especially as patients continue to receive oncologic care.

The COVID-19 pandemic presents a unique set of challenges for clinicians caring for individuals with genitourinary malignancies. Clinicians have responded to the pandemic by adapting patient care to minimize COVID-19 exposure risk and preserve health care resources. Current preliminary guidelines for disease management are based on expert opinion and indirect scientific evidence given lack of robust data to guide clinical decision-making.5 Factors influencing treatment recommendations include (1) goals of therapy (curative, palliative, or supportive intent), (2) disease context (neoadjuvant, adjuvant, recurrent, or metastatic), (3) mode of treatment delivery (oral, injection, infusion), and (4) toxicity profile associated with therapy (myelosuppression, pulmonary toxicity, risk of hospitalization, and others).

As the pandemic evolves and our understanding of factors that impact risk expand, recommendations will adapt to optimize treatments for patients with genitourinary malignancies. Given the unprecedented context of the COVID-19 pandemic, the long-term consequences of alterations in care, particularly regarding cancer-related outcomes, remain unknown.

Management of genitourinary malignancies requires a highly integrated and multidisciplinary approach. It is critical that readiness measures and risk mitigation strategies continue to include multidisciplinary discussions. Continued virtual tumor boards incorporating urology, medical oncology, radiation oncology, pathology, and radiology can enhance clinical decision-making and individualize care for patients in the context of institutional policies. Additionally, developing management recommendations based on local and regional pandemic severity will be critical to ensure the best outcomes for patients.

An essential component of urologic oncology is facilitating advanced care planning and providing end-of-life care for patients with terminal malignancies. Developing a proactive and coordinated approach with other members of the care team, including palliative care and social work, will be necessary for medico-ethical decision-making based on patient wishes and preferences. Preserving compassion and avoiding care disparities at the end of life has never been more important.

Access to clinical trials is a core component of the care of patients with genitourinary malignancies. Although clinical trials may provide opportunities for patients, involvement will likely be on a case-by-case basis, depending on a multitude of factors. The FDA has outlined considerations to ensure the safety of trial participants, maintain compliance with good clinical practice, and minimize the risks of trial integrity.6 Health systems have fully focused on responding to the crisis, in parallel to clinical research efforts, but basic and translational research has been substantially scaled down.

It is still too early to determine the long-term impact of the pandemic on future research. However, it is becoming increasingly evident that scientists need to adapt and develop new ways to continue to innovate.

As a field that is largely driven by evidence-based medicine, the oncology community needs better data to inform clinical decisions and guide clinical practice recommendations. Working together to share best practices will be critical as we recover from the pandemic. Additionally, granular longitudinal data will be needed to develop guidelines to protect patients and the community. The COVID-19 and Cancer Consortium developed as a grassroots initiative with the mission to rapidly collect and disseminate information about cancer and COVID-19 (www.ccc19.org). The COVID-19 and Cancer Consortium registry collects information from patients who test positive for severe acute respiratory syndrome coronavirus 2 (or those who are presumed positive for COVID-19) with all cancer types. Other multi-institutional registries established by the American Society of Clinical Oncology, American Society of Hematology, and National Cancer Institute are also established with a unified mission to help the oncology community learn more about patterns of presentation of COVID-19 in patients with cancer, COVID-19 transmission and complications, and impact of COVID-19 on cancer care delivery and outcomes.

As the medical system looks ahead to the recovery phases of the COVID-19 pandemic, it is likely that new strategies will need to be implemented to ensure the continued safety of patients and health care workers. As practicing clinicians, it is essential that we continue to meet the needs of our patients and deliver safe, high-quality care.

is assistant professor of medicine at the Moores Cancer Center at the University of California San Diego, La Jolla, California.

1. Zhang L, Zhu F, Xie L, et al. Clinical characteristics of COVID-19-infected cancer patients: a retrospective case study in three hospitals within Wuhan, China. 

. 2020. Mar 26;S0923-7534(20)36383-3. doi: 10.1016/j.annonc.2020.03.296 Online ahead of print.

2. Mehta V, Goel S, Kabarriti R, et al. Case fatality rate of cancer patients with COVID-19 in a New York hospital system. 

. 2020. May 1;CD-20-0516.doi: 10.1158/2159-8290.CD-20-0516 Online ahead of print.

3. Liang W, Guan W, Chen R, et al. Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China. 

. 2020;21(3):335-337. doi: 10.1016/S1470-2045(20)30096-6

4. Dai M, Liu D, Liu M, et al. Patients with cancer appear more vulnerable to SARS-COV-2: a multicenter study during the COVID-19 outbreak. 

. 2020 Apr 28.doi: 10.1158/2159-8290.CD-20-0422 Online ahead of print.

5. Wallis CJD, Novara G, Marandino L, et al. Risks from deferring treatment for genitourinary cancers: a collaborative review to aid triage and management during the COVID-19 pandemic. 

. 2020. May 3;S0302-2838(20)30331-6. doi: 10.1016/j.eururo.2020.04.063 Online ahead of print.

6. FDA guidance on conduct of clinical trials of medical products during COVID-19 public health emergency. US Food and Drug Administration. March 2020. Accessed May 19, 2020. 

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/fda-guidance-conduct-clinical-trials-medical-products-during-covid-19-public-health-emergency.

Patients with cancer are particularly susceptible to negative consequences of COVID-19.

GU oncologist's perspective: pandemic poses unique challenges in vulnerable patients

There is an old saying, or some say curse, often attributed to the Chinese, which projects, “May you live in interesting times.” If that is the case, we are certainly living out that curse! 

The outbreak of the coronavirus disease 2019 (COVID-19) has been chronicled well enough. What is now emerging are the details of how everyone dealt with it. For reasons outside the scope of this article, the state in which I practice, Louisiana, had among the highest rates of infection in the world.

As urologic oncologists, each of us had different challenges, varying by location, practice type, and patient load. These tasks involved deciding which cases to place on hold; how to modify our resource utilization; whether to send patients elsewhere; whether we would provide any interim “place-holder” measures for their disease; and, perhaps the biggest, most time-consuming—discussing all of this with our patients.

In Louisiana, the governor used an executive order early to rein in the spread of COVID-19 and “flatten the curve.” The first such order limited surgery to severe urgencies and emergencies. In our practice, we made the decision that bladder tumors and prostates must continue to be biopsied; how else would we know if there is a cancer and just how aggressive it would be? Patients with testis masses, muscle-invasive urothelial carcinoma, and high-risk prostate cancer continued to go straight to the operating room (OR) or receive standard treatment.

This first executive order immediately changed the world for us, likely forever. We rapidly adopted telemedicine for the majority of patients, while postoperative patients and new, potentially high-risk patients, were still seen in the office.

The reaction of patients was mixed. Some were angry that we would not see them in the office, whereas others were thankful. Many patients embraced telemedicine (even seen by some as a personal treat to be able to welcome their doctor into their home); others refused to cooperate until things returned to “normal.” The 1 consistent theme among patients was concern that their cancer would progress to a point where control was not possible. The amount of time it took to refocus education and anxieties was significant.

Just as we started to get a handle on this situation, the governor issued a new order, and regulations became even tighter. Now, only patients with an immediate life-threatening condition could utilize hospital resources. During this second phase, almost all cancer surgery stopped. Patients with testis masses proceeded to the OR, but biopsies and resections were not performed.

Patients with muscle-invasive bladder cancers were allowed to undergo cystectomy, but this introduced a new dilemma: How prudent was it to take this patient to the hospital and potentially utilize resources urgently needed for the patients with COVID-19?

For example, I had a patient I will call Stan. Stan had high-grade muscle-invasive urothelial carcinoma and a negative metastatic survey. He completed neoadjuvant chemotherapy in the beginning of March. He was already a high risk for surgery, however, with an ejection fraction of 38%. He also had severe chronic obstructive pulmonary disease. None of this is considered abnormal for a patient with bladder cancer.

What was abnormal however, was the thought process of resource rationing. During my 25 years in practice, we found the cancer, followed appropriate protocols, and when it was time, took the patient to the OR. Never before had I asked, “Will there be an available ICU bed when he needs it?”

That was just the half of it, though. In evaluating whether or not to proceed with Stan, just as every other patient during these times, we also had to consider the possibility of his becoming infected with COVID-19 while in the hospital. If infected, with his comorbidities, would his risk exceed the oncologic risk? Eventually, after consulting with all involved, Stan’s surgery was delayed until the COVID-19 wave reversed. To complete this particular happy ending, in the second week of May, Stan had an uneventful cystoprostatectomy and ileal conduit. His pathology was TxN0.

Although Stan’s success is worth celebrating, it is not time to pat ourselves on the back. We have no way of knowing whether a wave of worse cancer is coming. How significant is the delay of treatment going to be nationally or worldwide? There are two sides to this question. First, of our patients with known disease, what is the impact of the treatment delay? Hopefully minimal. Hospitals across the country are pledging extended hours to catch up on the backlog of cases. I believe, given the natural course of urologic disease, that this population will demonstrate a minimal effect.

One positive may come of this. In my practice, I am seeing a sudden increase in the acceptance of active surveillance as a treatment alternative.

The second, more concerning half of the question: what about the patients who have had their initial diagnosis delayed by the COVID-19 crisis? With regard to prostate cancer alone, we are already dealing with the fallout from the United States Preventive Services Task Force decree with a noted increase in presentation of patients with a higher stage and grade. What of the men who had their initial diagnosis delayed? It stands to reason that this population will grow because of COVID-19. Men being men, the window of willingness to be screened may be closed for a while.

The same could be true of other urologic malignancies, although with worse consequences. In the next few years, we may see a significant increase in delayed presentation of all malignancies.

In Louisiana, we are open again. We are in catch-up mode. Let us pray we do not have the second COVID-19 wave that some have forecast. The lessons learned here are twofold: We, as a urologic community, need to prepare for the next pandemic or whatever worldwide disaster interrupts patient care as pervasively as COVID-19 has. More immediately however, we need the organizations that speak the loudest for our specialty to get the word out to our patients: do not allow COVID-19 to make you a statistic. Delay your care no more. Do not let another year go by until you have that annual digital rectal exam and prostate-specific antigen screening.

For the patient who had hematuria and their office visit was canceled by COVID-19, do not wait until you see blood again. As for the testis nodule that may have become less acute and more “comfortable,” it is not normal; go to the doctor.

The urologist in cancer care is a resilient and vigilant clinician. I believe we and our patients made it through this. Like Clint Eastwood’s character in 

, we improvised, we adapted, and we overcame.

is a urologist at Regional Urology in Shreveport, Louisiana.

Urologists and patients show resilience, but we must be better prepared in the future, says urologist R. Jonathan Henderson, MD.

UCC June 2020

How to perform office-based blue light cystoscopy

How to approach immune checkpoint inhibitor therapy in prostate cancer

How to choose systemic therapy for metastatic RCC

GU oncologist's perspective: pandemic poses unique challenges in vulnerable patients

Urologist's Perspective: COVID-19 provides tough decisions—and valuable lessons