The third annual Bladder Cancer Academy was held in St. Louis, Missouri, between February 28 and March 2, 2019. The meeting was organized by MedReviews and LUGPA, and included urology residents and fellows, LUGPA members, medical oncology and radiation oncology fellows, and faculty from leading academic centers. The purpose was to discuss the future of advanced genitourinary oncologic care, emphasizing the interaction between faculty and participants with moderated question-and-answer sessions and didactic sessions complemented by case-based discussions.
Bladder cancer (BC) is one of the most common genitourinary malignancies, and despite well-established risk factors such as age, smoking, and family history, strategies for early detection are lacking. The current gold standard remains urine cytology with cystoscopic examination.1 The former has low sensitivity for low-grade tumors, is often inconclusive, and does not come as a point of care (POC) test.1 Cystoscopy is invasive with the potential to miss carcinoma in situ (CIS).2 Biomarkers have the potential to aid in diagnosis, surveillance, staging, prognosis, and, possibly, therapeutic guidance. Over 30 urine biomarkers exist; however, only a fraction of these are approved by the US Food and Drug Administration (FDA). The most commonly used markers are NMP22® BladderChek® Test (Abbott, Lake Bluff, IL), BTA stat® Test (Polymedco, Cortlandt Manor, NY), UroVysion® FISH (Abbott), ImmunoCyt™ (DiagnoCure Inc., Quebec, Canada), and, more recently, CxBladder™ (Pacific Edge Diagnostics USA, Hummelstown, PA). Although there is increased efficacy with higher grade and stage, most of the markers are plagued by relatively low sensitivity rates. As such, the American Urological Association (AUA) does not endorse biomarkers as a replacement for cystoscopy, but rather to assess response to intravesical Bacillus Calmette-Guerin (BCG) and adjudicate equivocal cytology.2
NMP22 is available as a POC test as well as a quantitative ELISA. Nuclear matrix proteins involved in mitosis mechanisms are identified, with a sensitivity and specificity of 73% and 80%, respectively.3 Similarly, BTA stat is also POC or quantitative test, and identifies a basement membrane protein more prevalent in BC. Overall sensitivity and specificity are 71% and 73%, respectively; however, both of these protein-based tests have high false-positive (FP) rates in the setting of inflammation of varying etiology, resulting in lower specificity than urine cytology.4 UroVysion FISH identifies altered copy numbers in chromosomes 3, 7, and 17 and loss of 9p21 locus. Problems include poor sensitivity for low-grade cancers, increased costs, and need for skilled cytophathologists. ImmunoCyt identifies three cell-surface glycoproteins present in BC. The test has a higher sensitivity but lower specificity than FISH, both ~78%; however, it does not come as POC and requires 500 cells for diagnosis.4 Cytology, currently the gold standard, is an imperfect test with poor sensitivity. In a prospective trial comparing blue and white light cystoscopy for BC surveillance, 0 of the 13 patients that recurred had positive cytology.5
Due to the imperfect nature of the tests, newer ones have been brought to market. CxBladder is a urine-based test measuring gene expression of five signature biomarkers for BC and importantly includes a biomarker for inflammation in order to reduce FPs. It is used in the setting of hematuria to either detect (rule in) disease with a specificity of 85% to 94% or triage (rule out) disease with a negative predictive value (NPV) of 98.5%.6
Atypical cytology is a diagnostic challenge; however, prospective studies show that FISH reflex testing has a strong positive predictive value (PPV) for high-grade (HG) tumors in this setting.7 Additionally, the use of FISH may help identify BCG response, with a positive result 3 to 5 times and 5 to 13 times more likely to recur and progress, respectively.8
Several urinary biomarkers with promising early results are currently under investigation with assays for DNA methylation, FGF 3 receptors, serine-threonine kinase, and human telomerase, including an at-home testing kit called Bladder CARE™ (Pangea® Laboratory, Costa Mesa, CA). Future roles include predictors of upstaging at repeat resection, recurrence after cystectomy, resistance and response to chemotherapy, and a predictor of those who may be suited for salvage therapy sooner. Decipher Bladder™ (GenomeDX, San Diego, CA) is a genomic test that may improve patient outcomes by identifying those with basal tumors who may benefit most from neoadjuvant chemotherapy (NAC) prior to cystectomy.9 A prospective study repurposed CA 125, CA 19-9, and CEA for bladder cancer, demonstrating that persistently elevated levels following NAC were predictive of a poor prognosis after cystectomy for muscle-invasive bladder cancer (MIBC).10 With so many biomarkers available and under investigation, a roadmap for use will take more time and study. Identifying patients at highest risk for disease progression and NAC benefit will improve survival and, likely, quality of life (QOL).
Transurethral resection of bladder tumor (TURBT) is the first step in the management of BC and can be diagnostic, prognostic, and therapeutic; therefore, the quality of resection is important. For T1 cases, residual tumor can be found about 50% of the time on repeat resection and upstaging to T2 disease can be as often as 10%.11 Bladder mapping and the use of multiple different degree lenses ensure a thorough inspection of the urethra, bladder, and bladder neck. A quality TURBT assesses multiple prognostic factors such as number of tumors, size, descriptive characteristics, and clinical stage, and should include a bimanual examination, muscle visualization, evaluation of perforation, and a separate deep specimen if the tumor appears invasive. Multiple optical imaging technologies both new and old aid in identification such as blue light cystoscopy (BLC), narrow band imaging (NBI), confocal laser endomicroscopy (CLE), and optical coherence tomography (OTC). BLC is performed with the aid of hexaminolevulinic acid, an optical imaging agent with photoactive porphyrines that accumulate preferentially in neoplastic cells. Hexaminolevulinic acid requires instillation 60 minutes prior to cystoscopy for optimal visualization and a specialized camera; however, an adapter has been developed for use with most endoscopes. Additionally, a flexible scope is available for BLC for in-office use. In comparison with white light cystoscopy, BLC detected 32% more CIS (P < 0.0001) and 43% of tumors identified by BLC were high grade with no significant difference in FP results.12 BLC has also been shown to significantly reduce the rate of progression in meta-analysis.13
NBI uses two wavelengths absorbed by hemoglobin, allowing more vascularized tumors to be discriminated from benign urothelium with 12% more tumors identified versus white light.14 CLE offers real-time microscopy using a fiber-optic imaging probe through a standard endoscope with images like conventional histopathology. Due to its limited field of view, it cannot survey the whole bladder and has been investigated as an adjunct to BLC to reduce FP rates. Additional technologies, such as OCT, use infrared light, providing spatial resolution close to the cellular level and allow real-time staging with cross-sectional imaging with high sensitivity and specificity.15 Per AUA/ Society for Urologic Oncology (SUO) guidelines BLC should be offered and NBI may be considered with non–muscle invasive bladder cancer (NMIBC) at the time of TURBT if available to increase detection and decrease recurrence.2
Guidelines note the necessity of risk stratification for NMIBC as it directs therapeutic decisions. About 15% of NMIBC is high-risk (T1, TaHG, CIS), potentially life-threatening disease, with recurrence and progression as high as 80% and 50%, respectively. Intravesical therapy with BCG for 3 years is the mainstay of treatment after TURBT, reduces recurrence and progression, and has demonstrated superiority to mitomycin C.2 However, during efficacy studies only 20% of patients completed the full 3-year course due toxicity, with no difference in toxicity with 1/3 dose; however, there is less efficacy in high-risk disease.16 Identifying which patients warrant early cystectomy is a clinical imperative, and a balance between risking progression and possibly death versus the morbidity and overtreatment with surgery is key. BCG failure poses a major dilemma for clinicians as valrubicin is the only approved second-line agent, showing poor complete response (CR) rates of 18% and 10% at 6 and 12 months, respectively.17
In 2014, the FDA defined BCG-unresponsive patients as those who failed two prior courses of at least 5 of 6 induction installations and at least 2 of 3 maintenance installations, those with persistent HG disease at 6 months or CIS within 12 months of a disease-free state, and persistence or progression to T1 after induction BCG.18 More than 18 trials are currently exploring efficacy in BCG-unresponsive disease using immunotherapy, vaccines, cytotoxic therapy, chemotherapy, or gene therapy. Notable examples are vicinium, a single-protein drug fused with bacterial endotoxin, which showed CR of 37% at 3 months and 14% at 12 months in phase III testing. Intravesical gemcitabine and docetaxel had a recurrence-free survival (RFS) of 54% and CR of 21% at 12 months.19 Additionally, intravesical CG0070, an oncocytic adenovirus that targets BC cells, had a CR of 47% at 6 months in high-risk, BCG unresponsive NMIBC with low overall toxicity.20
Importantly, not all T1 HG disease is the same and adverse clinical features such as concurrent CIS, lymphovascular invasion (LVI), prostatic urethral involvement, and variant histology should make immediate cystectomy a consideration. Further testing and new approaches to predictive tools, and treatment of BCG-unresponsive or poor-risk NMIBC is a high priority for urologists to help avoid the morbidity of cystectomy.
Radical cystectomy (RC) with pelvic lymph node dissection (LND) has been considered standard of care for MIBC. More recently, both the AUA and National Comprehensive Cancer Network (NCCN) guidelines have included bladder-sparing, tri-modal therapy (TMT) in appropriately selected patients, including those with no hydronephrosis, no CIS or aberrant histology, an absence of LVI, and no T3 disease.21 In keeping with modern oncologic practice, organ preservation hopes to mitigate surgical morbidity and its effect on QOL for those who are too sick or refuse to undergo cystectomy. Notably, TMT has never been compared with RC in a prospective randomly controlled trial (RCT) due mostly to accrual issues, as patients often do not want to be randomized, and comparative data on QOL is lacking.
Organ-sparing therapy must begin with complete TURBT, with the goal of rendering the patient pT0. Complete TURBT demonstrated improved overall survival (OS), disease-specific survival (DSS), and significantly less salvage cystectomy when compared with a visually incomplete TURBT.22 Additionally, In a phase III RCT, chemoradiation was shown to be superior to radiotherapy alone for OS and DSS.23 Therefore, the guideline recommends TMT with maximal TURBT, systemic chemotherapy with radiosensitizing agents such as cisplatin, gemcitabine, or 5-FU with mitomycin, followed by radiation therapy and ongoing cystoscopic evaluation.
Salvage cystectomy should be recommended for those with recurrent disease or partial response.21 Long-term outcomes of TMT show 5- and 10-year DSS and DSS of 66% and 59%, with 5- and 10-year OS of 57% and 39%, which are comparable to RC. Clinical T2 disease had a significantly better response than cT3-T4a disease (83% vs 63%; P < 0.001), and hydronephrosis (HR 1.51; P < 0.02) and the presence of CIS (HR 1.56; P < 0.002) were predictors of worse OS, highlighting the fact that patient selection is paramount.24 Cystectomy rates in those age 70 years and older are about 50% and decrease with age, thus an organ-sparing approach dovetails with data demonstrating a clear unmet need in this population.25
On other fronts, hypofracationated radiotherapy with capecitabine was tested in patients too sick for cystectomy or TMT due to its recognized tolerability for pelvic malignancies. Of 11 patients, CR was seen in 64% with OS of 81% and 61% at 1 and 2 years, respectively, with a low toxicity profile.26 Building on prior successes of TMT and immunotherapy, a phase II trial with pembrolizumab (a PD-1 inhibitor to be subsequent discussed) along with gemcitabine and maximal TURBT is currently accruing. TMT is a viable option for correctly selected patients with MIBC. With the ongoing advances in immunotherapy and predictive biomarkers, and considering the well-known morbidity of RC, organ-sparing therapy is likely to continue to gain ground.
Platinum-based chemotherapy is standard of care for patients with metastatic bladder cancer (mBC) with poor survival data of 15 and 9 months with cisplatin and second-line carboplatin, respectively.27 Over the past 30 years there has been little advancement in mBC; however, immunotherapy has ushered in a paradigm shift with an explosion of new drugs available in this space. These checkpoint inhibitors (CPI) include antibodies targeting both programmed cell death 1 and programmed death-ligand (PD-1/PDL-1), as well as other targets.
In 2014, atezolizumab was granted “breakthrough” status by the FDA based on promising preliminary trial results with subsequent approval of nivolumab, durvalumab, avelumab, and pembrolizumab.28 The PD-1 inhibitor pembrolizumab (KEYNOTE 045) demonstrated improved OS (10.3 vs 4.7 months; HR 0.73) versus second- and third-line chemotherapy with 2-year survival of 26.9% versus 14.3% regardless of PD-L1 status.29 Similar improvements were seen with other PD-1/PDL-1 inhibitors, although notably OS with atezolizumab (IMvigor2010) was not improved with PD-L1–positive staining, but expression of PD-L1 did function as a positive prognostic biomarker.30
As first-line therapy, atezolizumab demonstrated median OS of 15.9 months, objective response rate (ORR) of 23.5% with a CR of 9%.31 In the first-line setting, pembrolizumab (KEYNOTE 052) had effective antitumor activity (ORR 29%, CR 7%) with acceptable tolerability in elderly, sick patients with poor prognostic factors unable tolerate platinum-based therapy.32 In both trials, first-line effect was only seen in tumors with high PD-L1 expression, thus the FDA has restricting its use to cisplatin-ineligible patients with PD-L1 positive tumors. Building upon these data, recent phase II trials show meaningful pathological CR rates in both atezolizumab and pembrolizumab as NAC treating MIBC prior to cystectomy for PD-L1–positive, cisplatin-ineligible patients.
Looking forward, other immune-targeting drugs such as iplimumab (a monoclonal antibody targeting CTLA-4) and NKTR-214 (a pro-drug that increases tumor-infiltrating lymphocytes) are being used to potentiate PD-1/PDL-1 inhibitors in both the neoadjuvant and adjuvant settings for various stages of BC. These trials are sure to contribute to the continuing sea change created by immunotherapy for urothelial cancer.
PD-1 pathway inhibitors have revolutionized BC; however, only a subset of patients respond to these therapies. Cytotoxic medications still have a role to play, with newer drugs and unique targets currently being tested for non-responders.
Enfortumab vedotin (EV) is an antibody-drug conjugate that targets nectin-4 a transmembrane adhesion molecule highly expressed in urothelial cancers. Phase I testing presented at ASCO 2018 showed an ORR of 41% with effect in both CPI-treated and -naive patients. The median duration of response was 5.75 months and it was generally well tolerated with dose limiting issues due to neuropathy and rash. Ongoing phase II/III studies are planned.33 Similarly, IMMU-132 (sacituzumab govitecan) previously used in triple-negative breast cancer, targets Trop-2, which is highly overexpressed in multiple solid tumors including urothelial cancer. Confirmed ORR was 34% and the median OS of 16.1 months in a small study compares favorably to other second-line UC trials with a phase II study is currently underway. Adverse events (AEs) were primarily neutropenia and diarrhea without any treatment-related deaths.34
In phase II testing, erdafinitib, a pan-FGFR targeting molecule, demonstrated a 40% ORR in chemorefractory mBC with confirmed FGFR expression.35 Rogaratinib and pemigatinib, two other FGFR-targeting molecules had ORR of 24% and 25%, respectively, in patients with similar genetics and a favourable safety profile.36,37
Metastatic renal cell carcinoma (mRCC) is well known to have high mortality rates ranging from 8% to 43% depending upon prognostic factors.38 For two decades the mainstay of first- and second-line therapy has been VEGF inhibitors (bevacizumab) with IFN-a, mTOR inhibitors (everolimus, temsirolimus), and tyrosine kinase inhibitors (TKI) such as sunitinib. Recently, however, as with BC, immunotherapy has altered the landscape and outcomes.
Beginning in 2017, multiple first-line setting trials were published beginning with the CheckMate 214 trail testing combined immunotherapy with nivolumab (NIVO) and ipimumab (IPI) versus sunitinib in mRCC treatment-naive patients. Intermediate- and poor-risk patients had an ORR of 42% with immunotherapy versus 27% with sunitinib (P < 0.001), and, importantly, a CR of 9% versus 1% with a better response in tumors that expressed PD-L1. Notably, AEs were significant with 60% of the NIVO/IPI group requiring corticosteroids during treatment. Conversely, sunitinib outperformed NIVO/IPI in favorable-risk patients in both ORR and progression-free survival (PFS), suggesting these tumors may be driven more by angiogenesis than PD-L1 expression.39 As a result, NIVO/IPI was approved for first-line therapy in intermediate- and poor-risk patients.
The IMmotion151 trial compared bevacizumab and atezolizumab (an anti-PD-L1 drug) with sunitinib alone, with improved PFS and a HR of 0.74 in the immunotherapy arm in patients with PD-L1 positivity by investigator review. The ORR was 43% versus 35%, again favoring immunotherapy with duration of response not yet reached. OS survival data has not yet matured but will likely shed important light on this combination therapy in the first-line setting.40
Progressing chronologically, the JAVELIN Renal 101 is the first study to test a CPI (avelumab) with a TKI (axitinib) versus TKI alone (sunitinib). PFS was 13.8 versus 7.2 months in the combination therapy arm, and, impressively, the ORR was twice as good with combination therapy than a single agent (55.2% vs 25.5%) with final data for OS yet to mature. Axitinib is highly selective with less hepatic toxicity than sunitinib, and AEs were similar in both arms of treatment.41 Similarly, in data presented at ASCO 2019, pembrolizumab plus axitinib demonstrated a dramatic ORR of 59.3% versus 35.7% with sunitinib alone in newly diagnosed clear-cell mRCC patients, with similar response amongst subgroups. Duration of response was longer with combination therapy, with a median not yet reached versus 15.2 months with sunitinib with comparable toxicity profiles.42
Despite these newer therapies, VEGF-TKIs still play a role. Cabozantinib, a small molecule inhibitor of the tyrosine kinases, c-Met, VEGFR2, and AXL, was approved for first-line therapy by the FDA with improved PFS versus sunitinib. With continued understanding of the molecular heterogeneity of mRCC and multiple new combination therapy trials underway, the armamentarium of targeted treatment will continue to expand, as will the role of immunotherapy to help improve OS of this deadly disease.
Kidney cancer death rates are falling considering the robust expansion of drugs and research for systemic therapy, and despite a paucity of recent advancements in surgery. AUA guidelines for localized RCC management focus on proper patient selection and counselling when deciding upon surgical approach, genetic screening, active surveillance, and expected outcomes. 43
Per guidelines, a detailed history and physical along with chronic kidney disease (CKD) staging and cross-sectional imaging with CT or MRI are necessary.43 Patients should understand that preoperative modalities cannot predict tumor biology (benign vs malignant, indolent vs aggressive) and genetic counseling should be offered in select patients. Notably, partial nephrectomy (PN) and radical nephrectomy (RN) have shown equal efficacy for oncologic control, and despite a slight advantage for RN with perioperative complications, the nephron-sparing benefits of PN make it the surgery of choice when feasible.43 Tumor ablations (TA) appears non-inferior for masses <3 cm, although repeat ablation is often needed. Active surveillance (AS) is favored in elderly patients, or in those who wish to avoid surgery with slow growing masses <2 cm.43 In clinical practice, the Fox Chase experience was highly successful using AS, with a cancer-specific mortality of 1.2% making this a viable option for those with small renal masses.44
With regards to surgical management in advanced RCC, the AUA recommends LND for “clinically concerning” nodes for staging purposes; however, studies have yet to confirm a survival benefit for LND in RCC.43 Due to the S-TRAC trial, adjuvant chemotherapy has been included as an option in the NCCN guidelines following surgery for locally advanced clear-cell RCC, with improvement in disease-free survival but not OS. Cytoreductive nephrectomy (CN) has shown efficacy with over 40 years of application and has shown improved survival in patients with clear-cell disease and good performance status. The much-publicized CAREMAN trial demonstrated that OS with sunitinib is non-inferior to combination CN and sunitinib in patients with intermediate- and poor-risk mRCC.45 The trail has been criticized for incomplete accrual, selection of patients with increased metastatic burden, patient crossover, and lack of generalizability. Currently, no level one evidence exists for CN; however, it remains an option for advanced RCC per NCCN guidelines. Although the rate of CN has been falling since 2004, this new evidence may bring closer scrutiny on practical considerations regarding which patients are eligible and who may see a benefit from this chosen therapy.