Abstract
Purpose of Review
BCG is the gold standard agent used in high-risk non-muscle-invasive bladder cancer (NMIBC) that is amenable to bladder sparing management. However, recent BCG shortages appear to be a chronic problem. There are limited effective intravesical options in lieu of BCG or in patients in whom BCG is not effective. This review aims to highlight emerging bladder sparing therapies and trials for NMIBC.
Recent Findings
Patients with high-risk NMIBC who do not respond to BCG are at increased risk for progression and death from bladder cancer. There are a variety of clinical trials exploring different therapeutic approaches including checkpoint inhibition, novel chemotherapy and drug delivery, viral and gene therapy, vaccines, and targeted therapy.
Summary
In the era of limited supply of BCG, there is a need for both effective first-line alternatives as and options for patients who do not respond to BCG. Fortunately, there are a variety of active trials and mechanisms exploring these areas aggressively.
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Introduction
There are an estimated 549,393 new cases of bladder cancer diagnosed per year worldwide, with an estimated 81,190 new diagnoses in the USA in 2019 [1, 2]. Non-muscle-invasive bladder cancer (NMIBC) accounts for approximately 75% of bladder cancer diagnoses [3]. NMIBC is a heterogenous category including both low- and high-grade disease, and tumor stages of carcinoma in situ (CIS), papillary tumor (Ta), and tumor invasive to the lamina propria (T1) [4]. Disease progression and mortality have wide variability across tumor grade, stage, and other risk factors, which has been the attention of publications that attempt to risk stratify disease [5, 6].
The initial management of NMIBC is well documented in guidelines including those put forth by the American Urology Association (AUA), European Association of Urology (EAU), and National Comprehensive Cancer Network (NCCN) [7,8,9]. The first step in management is local tumor staging by performing a high-quality transurethral resection of bladder tumor (TURBT) [7,8,9]. TURBT is a critically important procedure as it yields staging, therapeutic, and prognostic benefits [10].
In patients with high-risk NMIBC (CIS, high-grade Ta, or high-grade T1 bladder cancer), the two aims of management are to limit bladder cancer–specific morbidity and mortality, and to maintain quality of life (QOL). In addition, the key component in managing high-risk NMIBC is to intervene before the patient progresses to muscle-invasive disease. Progression to muscle-invasive bladder cancer (MIBC) during management of NMIBC has been shown to raise the risk of disease-specific mortality [11].
Intravesical bacillus Calmette-Guérin (BCG) is utilized in the adjuvant setting following TURBT for intermediate and high-risk NMIBC to improve disease-specific mortality and allow for bladder preservation, with response noted in approximately 50% of patients [12,13,14]. At this time, multiple daughter strains have been obtained during the process of serial passages that include Tice, Connaught, and Tokyo [15].
There are several contemporary problems with the use of BCG. First, recurrence rates for patients who receive BCG range as high as 80%, and up to 45% of patients, can develop MIBC within 5 years [16]. For patients who progress or harbor persistent high-risk disease, there are no definitive intravesical salvage therapies. The only FDA-approved salvage therapy for patients who fail BCG is valrubicin, with a 2-year efficacy of only 8% [17, 18]. Recently, the availability of BCG, particularly in the USA, has become a major issue requiring physicians to ration and in some cases, use alternative medications [19••, 20]. The three predominant strains all have unique impediments to availability; Sanofi announced shortages of the Connaught strain since 2012 with permanent closure of production in 2017, Merck announced shortages of the Tice strain in 2014 with diminishing supplies over time, and the Tokyo strain is not approved for use in the USA [19••].
Given the aforementioned needs, there has been a resurgence of interest in novel intravesical therapies [21]. This review will outline currently accruing and yet to be published clinical trials for various NMIBC disease states. Each section will be organized as follows: background information, previously published data, and ongoing or unpublished clinical trials for the spectrum of BCG-Naïve, BCG-exposed, and BCG-unresponsive NMIBC (Table 1).
Definitions for BCG-Exposure and Unresponsiveness
Risk groups for NMIBC have large amounts of variability and portend specific management options and prognosis. The receipt of BCG can also be used to classify patients. Patients with high-risk NMIBC who have not yet received BCG are BCG-naïve. BCG-unresponsive is a definition that refers to those the highest risk of progression after receipt of adequate BCG: (1) no response to BCG treatment and with new or recurrent high-grade Ta/T1 or CIS, (2) recurrence at or around 6 months after BCG initiation, or (3) relapse within 6 months of last BCG treatment despite an initial complete response [22]. In our manuscript, we will refer to patients who are not strictly BCG-naïve or BCG-unresponsive as “BCG-exposed.”
In order to contextualize historic trials, it is important to understand the classic terminology “BCG failure,” or NMIBC which recurs or progresses within 6 months of BCG therapy [23], and other various subgroups including BCG-refractory, failure to achieve disease-free status by 6 months after induction BCG with maintenance or re-treatment; BCG-persistent, recurrent or persistent lower stage/grade tumor at 3 months with complete response at 6 months; BCG-relapsing, recurrence of disease by 6 months after disease-free status was achieved; and BCG intolerant, disease recurrence after an inadequate treatment course was applied due to serious adverse effects or symptomatic intolerance [24].
Given the unmet need for effective bladder sparing treatments, the FDA has set a threshold for NMIBC trials, particularly for BCG-unresponsive disease, which includes both the allowance of open-label and non-randomized trial design, and an informal criteria of early complete response rate of 50% with a long-term complete response rate of about 30% at 1 year [22, 25].
BCG-Augmented Immunotherapy
There are trials evaluating immunomodulators that can potentially augment the innate immune response activity of BCG. IFN was studied in monotherapy trials in the 1990s that demonstrated durable complete response rates between 8 and 22% [26, 27]. IFN was subsequently studied in combination trials with BCG and showed up to 45% durable complete response rates in select NMIBC populations [28, 29]. Mycobacterial cell wall nucleic acid complex (MCNA) is originally derived from emulsified Mycobacterial cell walls, and contains both cell wall and DNA [30]. MCNA was shown to have 2-year complete response rates between 19 and 46% across patients with a range of prior BCG-exposures [31, 32]. This agent was ultimately denied FDA approval in 2016 [33].
A more recent BCG-augmenting agent is ALT-803, which is an IL-15 super-agonist with both immune and adaptive immune response stimulation. The IL-15 cytokine is a predominantly a natural killer (NK) cell agonist although it also stimulates effector T cells. There is currently a Phase Ib/II randomized trial comparing ALT-803 with BCG versus BCG alone in patients with high-risk BCG-naïve NMIBC (NCT02138734). There is also a single-arm Phase II trial assessing ALT-803 with BCG in the BCG-unresponsive setting (NCT03022825; QUILT-3.032). Preliminary data from these trials are promising, and a trial of ALT-803 alone seems warranted.
VPM1002BC is a genetically modified strain of BCG (Mycobacterium bovis) with insertion of a gene from Listeria (listeriolysin), with the aim of increased immune response. Phase I results confirmed safety, and a Phase I/II study of 39 patients with prior BCG-exposure is underway (NCT02371447).
Checkpoint Inhibition
Checkpoint inhibition has shown success in the metastatic setting for bladder cancer, as well as recent promise in the non-metastatic MIBC setting [34]. There has been a surge of interest in using checkpoint inhibitors earlier in the disease course for NMIBC. There are currently trials assessing pembrolizumab, durvalumab, atezolizumab, avelumab, and nivolumab across a variety of NMIBC disease risk states and BCG-exposure settings.
Pembrolizumab (MK-3475) is a programmed cell death protein 1 (PD-1) inhibitor that is investigated as a single agent in a phase II trial for high-risk T1 NMIBC (NCT03504163), as well as in a large randomized combination trial with BCG for patients with persistent disease following an induction course of BCG, aiming to enroll 550 patients (NCT03711032; KEYNOTE-676). This agent is typically administered via intravenous transfusion, but intravesical pembrolizumab is being explored in both a single-arm trial (NCT02808143) and a randomized marker lesion trial versus intravenous pembrolizumab (NCT03167151). There are important practice pattern implications in the ability of checkpoint inhibitors to be delivered via intravesical route. KEYNOTE-057 is a trial assessing pembrolizumab for patients with BCG-unresponsive NMIBC, and aims to enroll 260 patients. Interim results from this study demonstrated 3-month complete response of 38%, with approximately 50% durability of response at 12 months, although formal 12-month complete response data is pending [35•].
Durvalumab is a PD-L1 inhibitor that is being assessed in the large POTOMAC study, a three-arm Phase III trial aiming to accrue 975 BCG-naïve high-risk patients comparing durvalumab with induction BCG alone, durvalumab with induction and maintenance BCG, and induction and maintenance BCG alone. Durvalumab is also being assessed in patients with BCG-unresponsive bladder cancer in combination with radiation and BCG in the ADAPT-BLADDER trial, as well as in combination with vicinium (oportuzumab monatox) (NCT03258593).
Atezolizumab is a PD-L1 inhibitor that is being evaluated in several studies. The ALBAN trial is a Phase III trial assessing 614 BCG-naïve patients comparing a year of BCG alone versus Atezolizumab with BCG. There is also a Phase II trial of 202 BCG-unresponsive patients that will assess 6-month complete response and 18-month event-free survival after 1 year of atezolizumab (NCT02844816). Avelumab is a PD-L1 inhibitor being assessed for patients with BCG-unresponsive disease in a combination trial with 60-–66-Gy radiation (NCT03950362) and with BCG (NCT03892642). Nivolumab is a PD-1 inhibitor that is evaluated in the CheckMate 9UT trial which is a Phase II study aiming to accrue 436 patients with BCG-unresponsive NMIBC. Another agent evaluated in this trial is BMS-986205, which inhibits indoleamine 2,3-dioxygenase 1 (IDO1). Four arms of this trial compare nivolumab alone, nivolumab with BCG, nivolumab with BMS-986205, and BMS-896205 with BCG.
Chemotherapy
Intravesical chemotherapy for BCG-naïve patients, including thiotepa, adriamycin, and mitomycin c have been used and studied in the past [36]. Mitomycin C is currently utilized as a first-line treatment if BCG is not available, although studies have generally shown higher risk of recurrence with mitomycin C [37, 38]. Salvage intravesical chemotherapy for patients with prior BCG-exposure has also been investigated and shown suboptimal results [21, 39]. Gemcitabine is relatively well studied, demonstrating 21% 2-year complete response in the Phase II SWOG S0353 trial [40].
Mitomycin C with or without BCG is currently being studied, predominately in patients with BCG-naïve disease. The largest of such trials is a randomized Phase III trial that aims to accrue 500 patients with high-risk NMIBC to either 1 year of BCG or 1 year of BCG with mitomycin C (NCT02948543). The trial expects to complete in December 2020 and has a primary endpoint of disease-free survival. Another Phase III trial is accruing patients with high-risk BCG-refractory NMIBC and compares Nanoxel®M, a nanoparticle formulation of docetaxel, versus mitomycin C (NCT02982395).
Apaziquone is a synthetic alkylating agent that has been assessed in both the BCG-naïve and BCG-unresponsive settings, although predominantly as an immediate post-operative intravesical chemotherapy agent following TURBT [41, 42]. There are two large Phase III trials planned for this agent. The first is the CONQUER trial that is assessing the impact of immediate post-operative instillation of apaziquone versus placebo following TURBT of low- to intermediate-risk NMIBC. The second is a multi-arm randomized trial comparing one dose of apaziquone versus two doses of apaziquone versus placebo following TURBT (NCT02563561). However, it should be noted that the FDA has previously rejected this apaziquone as an immediate post-operative intravesical chemotherapy agent following TURBT after analysis of over 2800 trial patients failed to show benefit of the agent.
Combination of chemotherapy agents has been previously assessed, the most well studied of which is sequential intravesical gemcitabine and docetaxel [43,44,45]. This regimen has been shown to confer approximately 30–40% disease-free survival at 2 years [43, 45]. A small study assessed gemcitabine and mitomycin C with promising results in 10 BCG-refractory patients [46]. A Phase I trial is current aiming to accrue 19 patients with BCG-unresponsive NMIBC and receive intravesical cabazitaxel, gemcitabine, and cisplatin (CGC) (NCT02202772).
Novel Chemotherapy Drug Delivery
The goal of novel intravesical delivery systems is to improve the absorption of intravesical chemotherapies relative to traditional intravesical drug instillation techniques. The simplest of these techniques is to change the penetration characteristics of the chemotherapeutic agent. Paclitaxel has been modified as conjugated paclitaxel-hyaluronic acid and assessed in a Phase I study of 16 patients, showing promising early results [47]. Another formulation of paclitaxel is nanoparticle albumin-bound (nab-)paclitaxel, which was assessed in a Phase II study and showed 36% complete response at 1 year [48]. The NanoDoce trial is a unique Phase I/II study that evaluates the safety and efficacy of both intravesical instillation and peritumoral injection of NanoDoce, which is a submicron particle docetaxel suspension (NCT03636256).
TC-3 hydrogel is drug delivery vehicle for mitomycin C. TC-3 mixed with mitomycin C is instilled in a liquid state into the bladder, where it solidifies and forms a drug reservoir inside the bladder, and dissolves over time with urinary contact. There have been a series of completed but unpublished studies of mitomycin C in TC-3 Gel for patients prior to TURBT, and after TURBT of both NMIBC and MIBC (NCT01803295, NCT02307487, NCT02891460, NCT01648010). The largest of these trials was a Phase II trial that accrued 80 patients with instillation prior to TURBT (NCT01803295). A similar hydrogel system is UGN-102, which is currently accruing to a Phase II trial.
The GemRIS system is modified from the previously studied Lidocaine Releasing Intravesical System (LiRIS) for interstitial cystitis that deploys into a “pretzel” shape in the bladder after cystoscopic placement and allows for slow release of intravesical gemcitabine. This is currently being evaluated in BCG-naïve patients in a Phase Ib study (NCT02720367).
Thermo-chemotherapy is based on the concept of suboptimal bladder wall penetration from traditional intravesical chemotherapy instillation techniques. Addition of heat may allow for increased drug penetration, which has been tested for Mitomycin C administered at 42 °C [49]. This study demonstrated up to 61% response rates. A current single-arm trial is utilizing the Synergo system to deliver mitomycin C in patients with BCG-unresponsive NMIBC. The COMBAT-BRS® system is another mitomycin C hyperthermic delivery system that has demonstrated efficacy and is currently being evaluated in European trials [50]. Finally, electromotive therapy is being studied in a high-risk BCG-naïve population (NCT03664869).
Viral and Gene Therapy
The use of oncolytic viruses to deliver genes facilitating cell destruction was first explored with the vaccinia virus, a derivative of the smallpox vaccine [51]. There is currently an ongoing trial studying use of an attenuated measles virus (MV-NIS) in patients with who are undergoing urothelial carcinoma but are ineligible or do not desire neoadjuvant chemotherapy (NCT03171493). There are currently three trials actively assessing oncolytic viral agents for NMIBC.
CG0070 is a replication selective serotype-5 oncolytic adenovirus that functions by preferential replication in RB pathway defective cells. The adenovirus inserts a gene that results in production of GM-CSF, and cell killing occurs both by direct cytotoxicity and immune mediated killing. A Phase I study showed that clinical response was increased in patients with RB pathway defective compared with wild-type RB patients (58% versus 20%) [52]. The Phase II BONDII study demonstrated an interim overall 47% complete response rate at 6 months in 45 patients with BCG-unresponsive NMIBC [53]. The primary outcome of 18-month complete response in the full 67 patient cohort was presented at the 2018 AUA, showing 21% complete response, but these results have not been formally published (NCT02365818).
INSTILADRIN (nanofaragene firadenovec) is a replication-deficient adenovirus-based gene transfer vector that encodes for IFNα-2b. Syn3 is a novel surfactant that improves adenoviral transduction into tumor cells. Phase I results of 17 patients with BCG-unresponsive NMIBC showed no dose-limiting toxicity, evidence of clinical response, and elevated urinary IFNα levels [18]. A Phase II study randomized 43 patients to two doses of INSTILADRIN and showed that 35% of patients were free of high-grade disease at 12 months [54]. Results are awaited from a single-arm Phase III study of 150 patients with BCG-unresponsive NMIBC that completed accrual in June 2018 (NCT02773849).
BC-819 (inodiftagene vixteplasmid) is a tumor-selective recombinant double-stranded DNA plasmid resulting in production of the bacterial diphtheria toxin. Tumor selectivity is secondary to use of the H19 gene which is upregulated in bladder tumors. Results from an early trial in patients with intermediate-risk NMIBC and prior BCG-exposure demonstrated promising complete response rates [55]. This is currently being investigated in a Phase II study of patients with BCG-unresponsive NMIBC (NCT03719300).
Finally, intravesical Coxsackievirus A21 (CVA21) showed promising clinical activity in ta study of 15 patients who were administered the oncolytic adenovirus and underwent radical cystectomy (CAVATEK trial), and a larger trial of this agent is currently being designed [56].
Vaccines
Vaccine therapy is appealing because vaccines can theoretically confer lifelong cancer immunity. Vaccines are being evaluated in numerous trials. One vaccine therapy that was recently reported includes injections of a subunit cancer vaccine (recMAGE-A3 protein+AS15) alone or in two combinations of intravesical BCG-instillations, and demonstrated increased serum vaccine–specific T cells without significant increase in adverse events versus BCG alone [53].
SWOG S1602 is a study that predominantly compares strains of BCG, but also has an intradermal priming component with BCG vaccination. This is a large Phase III study aiming to accrue 969 patients with BCG-naïve high-risk NMIBC and compares intravesical TICE BCG, intravesical Tokyo-172 BCG, and intravesical Tokyo-172 BCG with intradermal priming with BCG (NCT03091660). The trial is important since it will simultaneously evaluate for potential use of the Tokyo strain as well as evaluate the efficacy of intradermal priming.
HS-410 (Vesigenurtacel-L) is an intradermal vaccine comprised of a cancer cell line with increased expression of bladder tumor antigens that was transfected with a heat shock protein (hsp90B1) and neoantigen (gp96-Ig). Preliminary data suggests no significant difference in recurrences for HS-410 versus placebo, although increased immune response to tumor-associated peptides was observed in patients exposed to the vaccine (NCT02010203) [57].
PANVAC is a recombinant poxviral vector vaccine that contains genes for human CEA, MUC-1, and T cell co-stimulatory molecules (B7, ICAM, LFA-3). CEA is a cell surface glycoprotein and MUC-1 is a glycosylated transmembrane protein that are overexpressed in > 75% of bladder tumors. Preliminary results for 16 patients showed that the vaccine resulted in increased immunologic response, although the final results of the Phase II study in patients with high-grade NMIBC exposed to prior BCG are still pending (NCT02015104).
Two active vaccine trials for BCG-naïve disease are investigating Ty21a, a component of the typhoid vaccine, in 25 patients (NCT03421236) and RUTIVAC-1 in 40 patients (NCT03191578).
Targeted Therapy/Toxins/Photodynamic Therapy
There has been a surge of trials for targeted therapies and toxins. In patients with BCG-naïve NMIBC, a variety of agents are being explored, including rapamycin (NCT02753309), tamoxifen (NCT02197897), metformin (NCT03379909), pemagitinib, an FGFR 1, 2, 3 inhibitor (NCT03914794), sunitinib (NCT00794950), and lenalidomide (NCT01373294). A Phase II study was performed and published for imiquimod (TMX-101), a TLR-7 agonist that is typically used for skin malignancies, showing that the agent was safe and well tolerated in 12 patients with CIS with and without BCG-exposure [58]. Other currently pending Phase I trials for patients with history of BCG-exposure include APL-1202, a methionine aminopeptidase II inhibitor (NCT03672240), and BGJ398, an oral FGFR kinase inhibitor (NCT02657486).
A Phase I/II trial of ABI-009, an albumin-bound rapamycin nanoparticle agent (Nab-rapamycin), is currently ongoing for BCG-unresponsive patients (NCT02009332). One of the most heavily studied targeted therapies for BCG-unresponsive NMIBC is vicinium (oportuzumab monatox, VB4-845). This agent is a recombinant fusion protein with an antiEpCAM antibody linked to the Pseudomonas exotoxin. The desired mechanism is selective internalization by tumor cells and subsequent cell death. A phase II study demonstrated excellent tolerability but low complete response [59]. There is a current Phase III trial assessing 134 patients with BCG-unresponsive NMIBC that reported interim results of 42% complete response at 3 months (NCT02449239). Another intriguing trial is evaluating combination of this agent with the immune checkpoint inhibitor durvalumab in patients with BCG-unresponsive disease (NCT03258593).
Photodynamic therapy has been assessed in several older studies of both 5-aminolevulinic acid and hexaminolevulinic acid [60, 61]. These agents are precursors of protoporphyrin that are preferentially absorbed by tumor cells, and targets for subsequent cytotoxic radiation to a specific wavelength of light. More recently, a Phase Ib study of TLD-1433, another photodynamic compound, was completed (NCT03053635), and a Phase II study aiming to accrue 125 BCG-unresponsive patients is ongoing (NCT03945162).
Radiation
Radiation alone for NMIBC has not been associated with promising results [62]. However, there is renewed interest in combining radiation with other therapies, to cause synergistic effect. There are several ongoing trials combining radiation with chemotherapy or with checkpoint inhibition. The Phase II RTOG 0926 trial combines radiation with fluorouracil and mitomycin C following thorough transurethral resection, and aims to accrue 37 patients with high-grade BCG-ineligible or BCG-refractory NMIBC. The trial aims to evaluate 3-year cystectomy free survival as its primary endpoint. The ADAPT-BLADDER trial is a multi-arm multi-stage study that assesses combinations of durvalumab, BCG, and 18-Gy external beam radiation to the bladder, and aims to accrue 186 patients. Finally, there is a trial evaluating the combination of Avelumab and 60-–66-Gy radiation (NCT03950362).
Discussion
NMIBC is a heterogenous condition that is currently the focus of over 50 active and registered clinical trials. This clinical trial landscape has previously been limited by heterogeneous disease states and inclusion criteria, accrual issues, and inconsistent endpoints [63••]. In 2016 a consensus statement addressed some of these problems and posited consistent guidelines in trial design [63••]. Given the explosion of studies in this space, it is important to have a comprehensive understanding of currently available trials. Our review focused on high-risk NMIBC, but there are important developments being made for low-risk disease as well.
It is becoming increasingly apparent that the decreased availability of BCG will be a chronic problem for urologists, and thus, novel agents for high-risk BCG-naïve disease are needed. It is encouraging to see new trials, particularly with checkpoint inhibitors, moving into this space. In the meantime, the SWOG S1602 trial is very important since it will potentially allow for an additional BCG strain (Tokyo) to be utilized in the USA. While awaiting these data, many institutions are using reduced dose BCG with shortened maintenance regiments, as recommended by a recent Society of Urologic Oncology advisory. In lieu of BCG, chemotherapy is used either as a single agent or combination regimens.
Regarding patients with prior BCG-exposure of BCG-unresponsive NMIBC, using standardized inclusion criteria and the BCG-unresponsive designation will improve interpretation of results from trials in this setting. Checkpoint inhibition in isolation or in combination with other agents offers a possibility for higher response rates than previously seen. It will be important to assess predictive biomarkers and correlative studies to facilitate targeted use of these agents with proper patient selection. A final critically important principle is that radical cystectomy should be used aggressively in patients with BCG-unresponsive disease who are fit and agreeable to surgery, as well as in patients who are not responding to salvage treatments.
Conclusion
Intravesical BCG remains the mainstay of management of intermediate and high-risk NMIBC. However, BCG shortages that appear to be permanent are speeding up the development of novel agents in this setting. Furthermore, for patients in whom BCG is not effective, there is myriad of new trials assessing promising salvage therapies.
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Vignesh T. Packiam received honorarium from Cold Genesys.
Ryan P. Werntz has no disclosures.
Gary D. Steinberg is a scientific advisor/consultant for the following companies: Heat Biologics, Cold Genesys, Photo-Cure, Merck, Roche/Genentech, CiClomed, Taris Biomedical, MDxHealth, Fidia Farmaceuticals, Urogen, Ferring, Aduro, Boston Scientific, BMS, Astra Zeneca, Pfizer, Janssen, Epivax Oncology, Natera, FKD, EnGene Bio, SesenBio. He is a member of the Clinical Trial Protocol Committee for the following companies: Merck, BMS, Janssen, Cold Genesys. He has equity stock/options for Epivax Oncology and Urogen.
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Packiam, V.T., Werntz, R.P. & Steinberg, G.D. Current Clinical Trials in Non-muscle-Invasive Bladder Cancer: Heightened Need in an Era of Chronic BCG Shortage. Curr Urol Rep 20, 84 (2019). https://doi.org/10.1007/s11934-019-0952-y
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DOI: https://doi.org/10.1007/s11934-019-0952-y