Bladder Cancer Academy 2018 Selected Summaries

Bladder CanCer aCademy Bladder Cancer Academy 2018 Selected Summaries Nermarie Velázquez, MD Department of Urology, NYU Langone Health Medical Center, New York, NY [Rev Urol. 2018;20(1):31–37 doi: 10.3909/riu02001BCA] ® © 2018 MedReviews , LLC KEY WORDS Urinary biomarkers • Transurethral resection of a bladder tumor (TURBT) • Intravesical chemotherapy • Trimodal therapy (TMT) • Immunotherapy • Renal masses T he second annual Bladder Cancer Academy was held in St. Louis, Missouri, between March 1-3, 2018. The meeting, organized by MedReviews and LUGPA, brought together urology residents and fellows, LUGPA members, medical oncology and radiation oncology fellows, and faculty from leading academic centers to discuss the future of advanced genitourinary oncologic care. The program emphasized the interaction between faculty and program participants with moderated Q&A sessions and included multiple didactic sessions complemented by case-based discussions. Bladder Cancer Biomarkers: New and Old Presented by Michael S. Cookson, MD Cystoscopy supplemented by cytology is the current standard of practice in bladder cancer (BC) detection and surveillance. Urinary biomarkers have emerging roles in diagnosis, surveillance, and staging of BC. More than 30 biomarkers have been reported yet far fewer have obtained US Food and Drug Administration (FDA) approval.1 Issues of low specificity have dogged the adoption of biomarkers for screening purposes as they have relatively high false-positive (FP) rates—mostly from hematuria or infection cross-contamination. Among the most commonly used today are BTA®, NMP22®, UroVysion® FISH, and ImmunoCyt™. BTA comes in both a point of care (POC) and a send-out ELISA test. Both assays have sensitivities between 62% and 68%, dependent on tumor grade, stage, and size; have a specificity around 73.6%; and suffer from FP results due to hematuria, infection, and prior Bacillus Calmette-Guerin (BCG) treatment. NMP22® is also available in POC or as a quantitative ELISA test with sensitivity of 67%, specificity of 75%, and similar issues with FP results due to hematuria, stones, infection, and recent instrumentation.2 UroVysion® FISH detects alteration in chromosomes 3,7,17 and loss of 9p21 locus. As this test is based on cytology, it requires trained personnel and special equipment. It does not come as a POC and has better outcomes for high-grade tumors and can detect occult carcinoma in situ (CIS).3 ImmunoCyt™ looks at three monoclonal antibodies associated with urothelial carcinoma Vol. 20 No. 1 • 2018 • Reviews in Urology • 31 4170018_07_RiU2001BCA_V1_rev01.indd 31 4/23/18 5:14 PM Bladder Cancer Academy 2018 Summaries continued cells. It enjoys a sensitivity of 81% with specificity of 75% and again has FP results due to infection, stones, and benign prostatic hyperplasia (BPH). An additional hindrance to this test is that it requires trained personnel, does not come as POC, and requires 500 cells to make a diagnosis.4 Given the known limitations of these tests, new and emerging urine markers have been developed. Among them, AssureMDx looks at DNA methylation of three genes with a sensitivity of 93%, specificity of 83%, and negative predictive value (NPV) of 99.6%. In small prospective studies, reduction of diagnostic cystoscopy by 82% has been demonstrated. Currently, it is ongoing large validation studies in North America. Alternatively, Cx-Bladder measures the gene expression of five biomarkers via mRNA with a sensitivity of 93% and specificity of 85%. It seems to perform quite well when compared with cytology or NMP22 and includes a biomarker that is a mediator for inflammation to reduce FP results. Cx-Bladder Monitor is an effective rule-out test given its high sensitivity and high NPV of 97%. Meanwhile, the older FISH technology has found new use in the arbitration of atypical cytology with significant cost reduction to the system.5 FISH can also be used post BCG treatments to predict recurrence as well as progression during treatment because it has been shown that a positive FISH 6 weeks after initiating BCG treatment leads to a three- to fivefold increased likelihood of recurrence and 5- to 13-fold likelihood of disease progression.6 Urinary biomarkers are now being used to assist in the management of patients with nonmuscle-invasive bladder cancer (NMIBC). Currently, their best use lies as adjuncts to surveillance to reduce patients’ need for invasive cystoscopy, reflex testing for atypical cytology, and in monitoring response to intravesical BCG. AUA guidelines promote urinary biomarkers to assess response to intravesical BCG and adjudicate equivocal cytology, whereas NCCN guidelines allow for use of biomarkers in monitoring of recurrence only. Quality Indicators and Enhanced Imaging in Cystoscopy and TURBT Presented by Michael S. Cookson, MD Improvements in the quality of our transurethral resection of a bladder tumor (TURBTs) can help reduce recurrence and decrease cost. Up to 50% of patients with high-grade (HG) Ta have persistent tumor at re-resection.7 Signs of a quality TURBT are documentation of tumor mapping (location, number of tumors), degree of resection (completeness), description of the mass, and presence of muscle in the specimen. To aid in this endeavor, better visualization of tumors is key and thus Cysview™ (hexaminolevulinate) blue light cystoscopy (BLC) and narrow band imaging (NBI) cystoscopy have been developed. NBI filters white light into narrow bands primarily of blue and green spectrum that are highly absorbed by hemoglobin, thus allowing highlighting highly vascular structures. This has been used in several other cancers and can be used both via a flexible or rigid scope for both bladder and upper tract disease. Improved detection and decreased recurrence rates have been shown in small studies.8 During BLC with Cysview there is selective accumulation of protoporphyrin IX in neoplastic cells due to their high mitotic rate. When this is illuminated with blue light, it produces red fluorescence. This technique requires specialized scopes as well as an extra catheterization step to instill the hexaminolevulinate. In meta-analysis, BLC detected significantly more tumors (14.7% more Ta, and 40.8% more CIS; P # 0.001), recurrence rates were significantly lower (34.5% vs 45.4%; P 5 0.006),9 and even reduced progression rates were shown. Further areas of ongoing research include the safety and efficacy of repeat BLC, its comparison to white light for surveillance, as well as its use after BCG. Enhanced cystoscopy techniques are currently endorsed by European guidelines as well as the AUA/SUO. Intravesical Therapy for High-risk Disease Presented by Colin P. Dinney, MD Therapy for NMIBC aims to prevent recurrence, delay progression, minimize morbidity and expense, and identify refractory or progressive disease before it becomes metastatic. A well-performed TURBT ensuring complete resection of all visible tumor is critical. Re-TUR for all T1 and most HG tumors should also be performed in accordance with AUA/EAU/ICUD guidelines. Furthermore, single perioperative instillation of intravesical chemotherapy reduces recurrences particularly in single low-grade tumors, although it remains underused. High-risk (HR) bladder cancer is comprised of any T1, Ta HG, and CIS. This distinction is important as they have an 80% recurrence rate and up to 50% progression rate, which is life threatening. Maintenance BCG for HR disease can reduce recurrence; and when patients undergo a 3-year maintenance protocol as demonstrated by SWOG 850710 and EORTC 3091111 decreases metastasis and mortality. 32 • Vol. 20 No. 1 • 2018 • Reviews in Urology 4170018_07_RiU2001BCA_V1_rev01.indd 32 4/23/18 5:14 PM Bladder Cancer Academy 2018 Summaries SWOG 8507 also demonstrated that early (3 months) BCG failure can be salvaged with a second round of induction in 64% of patients and should be offered. In these studies, only 20% of patients underwent the complete 3-year treatment due to toxicity. No significant difference in toxicity has been demonstrated between full dose and one-third dose but there is less efficacy in the lower dose.12 Some patients, however, do benefit from early cystectomy and identifying them is key. These include early BCG failures, T1 disease with unreliable staging due to location (anterior wall or dome), multifocal T1, or residual T1 found on re-TUR, patients with adverse histology (CIS, lymphovascular invasion, or variant histology), prostate stromal or ductal involvement, and those with sessile tumors. Additionally, patients with $2 HR features have demonstrated improved survival with neoadjuvant chemotherapy prior to radical cystectomy.13 New approaches for NMIBC should be a priority as there are still no good predictors of response to intravesical BCG. Intravesical Therapy: When Bacillus Calmette-Guerin Fails Presented by Noah M. Hahn, MD BCG has been used for bladder cancer since it was repurposed by Dr. Alvaro Morales in the 1970s. Many terms for describing a patient’s BCG status have been used. Former terminology of BCG naïve, intolerant, failure, or refractory led to challenges in understanding study data as they often included variable populations of Ta, T1, and CIS. Established post-BCG intravesical therapy for those deemed failed or refractory included BCG 1 interferon a, and intravesical gemcitabine, valrubicin, or gemcitabine 1 docetaxel. However, given the low cure rates and conflicting data, the FDA intervened in 2012-2014, creating new terminology for BCG unresponsive patients and allowing use of a single-armed trials for approval consideration in this population.14 BCG unresponsive patients are those who have failed two prior courses of at least 5 of 6 induction installations and at least 2 of 3 maintenance installations (minimum 5 1 2), those with persistent T1 at initial cystoscopy after induction, those who relapsed within 6 months of last BCG exposure during maintenance, or those with prostatic urethra involvement. Since establishing this new roadmap for drug development many compounds have come to trial. Nanoparticle albumin bound paclitaxel, which is coated to make it more soluble, has a more durable complete response rate of 30% to 35% up to 12 months. Oportuzumab monatox—a drug which targets Ep-CAM—has a compete response rate of 44% with good results up to 12 months and is currently undergoing phase 3 trials.15 CG0070 utilizes a modified adenovirus to enter tumor cells, replicate, lyse them, and present their antigens to surrounding immune cells to engage them in tumor fighting activity. This has shown a complete response rate of 50% at 6 months with good patient tolerability.16 Intravesical rAd IFN/Syn3, also an adenovirus vector that accentuates the local immune response, has a complete response rate 44% initially and 35% at 12 months and is undergoing phase 3 trials.17 Finally, intravesical BC-819, a modified diphtheria bacterial plasmid, causes local cytotoxic effects on cancer cells and is undergoing phase 3 trials in BCG unresponsive as well as BCGrelapsing NMIBC. These ongoing pivotal trials represent the future in treatment of NMIBC and will need urologist support to further their progress. Bladder-sparing Strategies Presented by Jason A. Efstathiou, MD, MPhil Organ preservation is commonplace in contemporary oncology and there has been a paradigm shift into multimodal therapy for invasive cancers. This is of importance in muscle invasive bladder cancer (MIBC) as radical cystectomy (RC) is life altering. Trimodal therapy (TMT) is now supported by multiple guidelines including NCCN 2016. Currently we have two standard chemoradiation (CRT) methods of bladder preservation: maximal TURBT followed by split course CRT versus single course CRT. In both models, salvage cystectomy is recommended for those with only partial response on cystoscopy. Two important aspects needed for successful TMT are complete TURBT and concurrent chemotherapy with radiosensitizing drugs such as cisplatin, paclitaxel, 5-FU, mytomicin C, or gemcitabine. Long-term results of TMT are excellent and comparable to those of RC with improving CR over time, now nearing 85%.18 Disease-specific survival (DSS) at 10 years 60% with overall survival (OS) in the 29% to 39% range (comparable to RC 27-32%).18 This is true even for histologic variants as shown on meta-analysis. It should be noted that the DSS at 10 years drops from 60% to 50% when TURBT is incomplete. Cystectomy is already not being performed in 50% of patients who need it, particularly if older than 70.19 Thus there is a huge unmet need and this gap can be filled with TMT. Salvage RC are performed in 15% of patients in most recent cohorts of TMT.18 These are generally performed Vol. 20 No. 1 • 2018 • Reviews in Urology • 33 4170018_07_RiU2001BCA_V1_rev01.indd 33 4/23/18 5:14 PM Bladder Cancer Academy 2018 Summaries continued with similar morbidity and mortality to primary RCs. The toxicity of TMT is acceptable and quality of life (QoL) is at least as good if not slightly better for patients who preserve their bladder. Among the areas of improved QoL are markedly better sexual function, less concerns about appearance, less life interference from cancer or its treatment reported by patients, and better-informed decision making. Finally, superficial recurrences can be managed conservatively with re-TURBT and BCG in those with a complete response to TMT.20 TMT is now being considered for recurrent T1 bladder cancer and is undergoing phase 2 trials (RTOG0926). Predictive biomarkers such as MRE11A and p53 can help us elucidate patients who will benefit from TMT versus RC and are the key to future patient selection. Neoadjuvant and Adjuvant Chemotherapy in Bladder Cancer Presented by Matthew Galsky, MD Despite advances, there remains a high risk of recurrence after radical cystectomy (RC), even when disease appeared to be organ confined. This likely reflects our limitations identifying micrometastases and not true recurrences. SWOG 8710 demonstrated a real though modest survival benefit of neoadjuvant chemotherapy (NAC) for patients with T1-T2No BC.21 The MRC trial looked at NAC with local therapy (either CRT or RC) and also demonstrated survival benefit when the data was allowed to mature to 10 years.22 The downside to NAC lies in its side-effect profile, with 35% of patients experiencing grade 3 and 4 toxicity. There was concern that patients with cT2 disease would not benefit from NAC, but studies have shown that neither tumor stage nor patient age influences response to treatment.21 NAC was also shown to be beneficial whether pathological complete response (CR) is reached at the time of cystectomy. The role for adjuvant chemotherapy (AC) remains less clear. Three contemporary trials were attempted in patients with pT2-4 and node positive disease; however, they all closed early due to poor accrual. From the limited data that can be gleaned from them, they did suggest a benefit to AC. NAC has been improved using granulocyte colony stimulating factor as supportive care for patients undergoing chemotherapy. Additionally, shorter regiments with more condensed doses seem to work better in particular when given more frequently as they kill more cells. Current guidelines recommend NAC over AC whenever possible; in particular, dose-dense methotrexate 1 vinblastine 1 adriamycin 1 cisplatin (DD-MVAC) has been shown to be superior to MVAC. Substitution for patients ineligible for DD-MVAC can be done with gemcitabine 1 cisplatin but patients should never receive carboplatin as it has worse results. Despite the benefit that has been shown for NAC its use remains low, only given in 20% of cases.23 This reflects the average age for diagnosis of BC in the United States, which is 73. Biomarkers, either predictive or prognostic, may help us determine which patients would benefit the most from our therapies. DDR alterations can be used as predictive biomarkers of cisplatin-based NAC benefit whereas RNA biomarkers that reflect cell of origin can help us classify responders. These are not quite ready for clinical implementation but reflect potential future avenues. Immunotherapy of Advanced Bladder Cancer: The Next Frontier Presented by Jonathan E. Rosenberg, MD Immunotherapy has changed the treatment paradigm for advanced bladder cancer (BC). Today we can exploit multiple immune checkpoints for anti-cancer effects. The PD-1 to PDL-1 pathway is used to prevent autoimmunity by normal and tumor cells; inhibitors thus allow the immune system to recognize and attack cancer cells. Before 2016 median survival for patients with locally advanced or metastatic BC on cisplatin-based combination therapy was 15 months, worse for those on carboplatin (9 months).24 Then in 2016-2017, five immune checkpoint inhibitors of the PD-1/PDL-1 pathway were approved: atezolizumab, nivolumab, durvalumab, avelumab, and pembrolizumab. As second-line therapy for locally advanced and metastatic urothelial carcinoma (UC), pembrolizumab has demonstrated improved median OS of 10.3 months versus 7.4 months for chemotherapy, with ORR 21% and CR 7%.25 Similar results have been shown with the other PD-1/PDL-1 inhibitors. They performed better than second- and third-line chemotherapy regiments. Of note, when looking specifically at PDL-1 positive population, atezolizumab did not improve OS when compared with chemotherapy. What was noted was that PDL-1 staining functioned as a positive prognostic biomarker of better outcomes for patients in both the chemotherapy and immunotherapy arm.26 Now in their use as first-line therapy as well; the IMVigor 210 (atezolizumab) trial demonstrated median OS of 15.9 months, ORR of 23.5% including a CR of 9%.27 34 • Vol. 20 No. 1 • 2018 • Reviews in Urology 4170018_07_RiU2001BCA_V1_rev01.indd 34 4/23/18 5:14 PM Bladder Cancer Academy 2018 Summaries Meanwhile, Keynote 052 (pembrolizumab) trial demonstrated an ORR of 29% with 7% CR; median OS still has not been reached.28 These studies were done in cisplatin-ineligible patients, with Keynote 52 having a sicker cohort of patients with poorer performance status. Novel immune-immune combinations are also being evaluated and hold significant promise. There are multiple ongoing large trials that will change the treatment paradigm looking at the use of antiPD1/PDL1 for metastatic urothelial carcinoma without having received prior therapy as well as for nodepositive MIBC after RC. Managing Small Renal Masses Presented by Robert G. Uzzo, MD, FACS As the incidence of small renal masses increased with the dissemination of cross-abdominal imaging, the management options have expanded to include excision, ablation, or observation. Active surveillance (AS) is now an accepted option, with recognized very low oncologic risk for patients with masses ,2 cm and is included in the 2016 AUA guidelines.29 Additionally, today the role of radical nephrectomy (RN) is limited as we have recognized the benefits of nephron-sparing surgery (NSS) and that a negative surgical margin, regardless of how big, provides the same oncologic results. Thus, surgical management today usually takes the form of partial nephrectomy (PN). Furthermore, ablation of tumors (TA) ,3 cm appears to be non-inferior to surgical resection of these masses for selected patients, although with an increased likelihood of tumor persistence requiring a second ablation. Appropriate and thorough counseling of patients today is of great importance. Discussion should include patient-specific risk assessment that can be accomplished with published nomograms (w w w.cancernomograms.com), morbidities of treatment, risk of progressive chronic kidney disease (CKD), and best assessment of tumor biology from limited preoperative modalities. Contemporary trends in management demonstrate that we are performing more PN with a steady rate of AS despite its demonstrated safety in properly selected patients.30 Perhaps this reflects the uncertainty that still exists regarding which patients will have indolent disease and which will progress, at times quite quickly. Although renal tumor biopsies can help fill some of the gaps, with excellent positive predictive value (PPV) of 99.6%, they are not always reliable and a negative biopsy is not necessarily a useful tool.31 The AUA does not have a strict recommendation for when to biopsy; however, good strategies may include performing them in those going into AS, prior to TA, or where these is a suspicion for lymphoma or metastasis from other sources. We must continue to work on biomarkers that can help us risk stratify our patients to appropriately tailor their treatment and remain in the forefront of the management of renal masses. Advanced Kidney Cancer Management: Targeted Therapies Presented by Anil Kapoor, MD, FRCSC Metastatic RCC (mRCC) remains a deadly disease. Depending on a patients IMDC criteria risk stratification their predicted survival ranges from 8 to 43 months.32 Front-line therapy for advanced or mRCC includes bevacizumab (a VEGF inhibitor) with interferon a and TKIs such as pazopanib or sunitnib. These TKIs are generally better tolerated than prior therapies, particularly with altered dosing schedules. Available clinical trial and international database data suggests equivalence between these two agents. Newer TKIs, like cabozantinib, have demonstrated better clinical results when compared against sunitnib in patients with advanced RCC with intermediate or poor prognosis designation in phase II trials.33 It remains to be seen if this holds on phase III trials, as well as whether a change in the sunitnib dosing schedule will affect these results. A potential role for immunotherapies as firstline treatment with nivolumab, pembrolizumab, pidilizumab, avelumab, or atezolizumab is also being explored. Checkmate 214 evaluated nivolumab 1 ipilimumab for treatment-naïve advanced or mRCC with improvements seen in ORR and OS as compared with sunitnib.34 Based on this early success, further studies are underway combining these checkpoint inhibitors with TKIs. Where they will lie in the treatment algorithm remains to be seen. Second-line therapy options vary depending on the original treatment used but include axitinib, lenvatinib 1 everolimus, nivolumab, and cabozantinib. In the METEOR trial, cabozantinib was compared with everolimus with benefit in ORR, PFS, and OS, especially in patients with bony and visceral metastasis. Cabozantinib has the highest ORR and PFS when compared against everolimus and axitinib in patient who had previously received sunitnib as first-line trwatment. Nivolumab has also demonstrated OS benefit when compared with everolimus.35 Finally, for high-risk patients, adjuvant sunitnib may delay Vol. 20 No. 1 • 2018 • Reviews in Urology • 35 4170018_07_RiU2001BCA_V1_rev01.indd 35 4/23/18 5:14 PM Bladder Cancer Academy 2018 Summaries continued progression by about a year when added to local excision as per the S-TRAC trial. Other trials are ongoing to test the efficacy of nivolumab in this space. Systemic Therapies for Renal Cell Carcinoma: Combinations Beyond Single Agent PD-1 Presented by Hans Hammers, MD, PhD As with bladder cancer, PD1/ PDL1 inhibitors are the backbone of immune modulators for RCC. Despite advances in PD1 therapy, as monotherapy this is not enough to improve PFS, thus they have been combined with VEGF/TKI therapies. Checkmate 214 explored ipilimumab 1 nivolumab, a CTLA4 and PDL1 inhibitor combination, in a cohort primarily comprised of intermediate- and poor-risk patients. Results demonstrated an ORR of 42% versus sunitnib (ORR 27%), with a CR of 9% versus 1%, respectively. Duration of response for sunitnib was 18 months and has not been reached yet for the ipilimumab 1 nivolumab combination but is .20 months. Furthermore, for PDL11 patients the response was even greater with an ORR of 58% and a CR of 16%.34 Toxicity for these agents mostly consisted of diarrhea/colitis, hepatitis, and rash. Steroids were required to manage inflammatory responses in 50% of patients and does not seem to affect response to therapy. IMMotion 151 evaluated sunitnib versus atezolizumab 1 bevacizumab, a PDL1 and VEGF inhibitor combination, and data just presented at ASCO 2018 demonstrated an ORR of 35% versus 43% and a CR of 4% versus 9%, respectively. This combination did not show an OS benefit but is one of the best tolerated. Other combinations in trial now include indoleamine-dioxygenase (IDO) inhibitors as well interleukin (IL) and PDL1 inhibitor combinations. It is important to evaluate these for long-term response as we know that PD1 monotherapy cannot stave off progression forever,36 though the ipilimumab 1 nivolumab combination seems to have stabilization at around 10% cure rate. The Future of Genitourinary Cancers and Beyond Presented by Arjun V. Balar, MD Multiple questions surround what the standard therapies for both bladder and renal cancer will be in 5 years. Checkpoint blockade for bladder cancer is firmly established treatment but it may not be enough as a single agent. Combinations such as CTLA/PDL1 may improve durability of response at the cost of worsened toxicity.37 This is perhaps indicated in patients who are PDL1 negative and have worsened prognosis. Platinum-based chemotherapy and immunotherapy combinations are expected to improve ORR and PFS and should be used in those patients who have a high burden of disease with a small window to initiate chemotherapy before metastasis. In the world of advanced RCC treatment, PD1s have been well tolerated and consistent; however, with few if any complete responses. CTLA/PD1 combination show promise and may be approved for IMDC intermediate/poor risk RCC, perhaps with broadened use in the future. Meanwhile, VEGF-Ab/PDL1 combinations may be more tolerable with good results limited to the PDL1 1 population. Finally, it seems VEGFR/PD1 may be the combination with the most promise; with a reported 60% to 70% ORR in phase I studies.38 We will have to await the results of further studies before determining the best modality in advanced RCC but the multiple combinations discussed throughout this meeting hold promise in the management of these complex patients. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. Urine tumor markers in bladder cancer diagnosis: overview of urine tumor markers, genetic aberrations in bladder cancer, fluorescence in situ hybridization. Medscape website. https://emedicine.medscape.com/ article/1953022-overview. Accessed March 18, 2018. Shariat SF, Karam JA, Lotan Y, et al. Critical evaluation of urinary markers for bladder cancer detection and monitoring. Rev Urol. 2008;10:120-135. Villicana P, Whiting B, Goodison S, et al. Urine-based assays for the detection of bladder cancer. Biomark Med. 2009;3:265-274. Fradet Y, Lockhard C. Performance characteristics of a new monoclonal antibody test for bladder cancer: ImmunoCyt™. Can J Urol. 1997;4:400-405. Gayed BA, Seideman C, Lotan Y. Cost-effectiveness of fluorescence in situ hybridization in patients with atypical cytology for the detection of urothelial carcinoma. J Urol. 2013;190:1181-1186. Kamat AM, Dickstein RJ, Messetti F, et al. Use of fluorescence in situ hybridization to predict response to Bacillus Calmette-Guérin therapy for bladder cancer: results of a prospective trial. J Urol. 2012;187:862-867. Chang SS, Boorjian SA, Chou R, et al. Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO Guideline. J Urol. 2016;196:1021-1029. Naselli A, Introini C, Timossi L, et al. A randomized prospective trial to assess the impact of transurethral resection in narrow band imaging modality on non– muscle-invasive bladder cancer recurrence. Eur Urol. 2012;61:908-913. Burger M, Grossman HB, Droller M, et al. Photodynamic diagnosis of non–muscle-invasive bladder cancer with hexaminolevulinate cystoscopy: a metaanalysis of detection and recurrence based on raw data. Eur Urol. 2013;64:846-854. Lamm DL, Blumenstein BA, Crissman JD et al. Maintenance Bacillus Calmette-Guerin immunotherapy for recurrent Ta, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol. 2000;163:1124-1129. Sylvester RJ, Brausi MA, Kirkels WJ, et al. Long-term efficacy results of EORTC Genito-Urinary Group Randomized Phase 3 Study 30911 comparing intravesical instillations of epirubicin, Bacillus CalmetteGuérin, and Bacillus Calmette-Guérin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol. 2010;57:766-773. Oddens J, Brausi M, Sylvester R, et al. Final results of an EORTC-GU Cancers Group randomized study of maintenance Bacillus Calmette-Guérin in intermediate- and high-risk Ta, T1 papillary carcinoma of the urinary bladder: one-third dose versus full dose and 1 year versus 3 years of maintenance. Eur Urol. 2013;63:462-472. Metcalfe MJ, Ferguson JE, Li R, et al. Impact of highrisk features and effect of neoadjuvant chemotherapy in urothelial cancer patients with invasion into the lamina propria on transurethral resection in the absence of deep muscle invasion. Eur Urol Focus. 2017 Jul 13. pii: S2405-4569(17)30155-4. Lerner SP, Dinney C, Kamat A, et al. Clarification of bladder cancer disease states following treatment 36 • Vol. 20 No. 1 • 2018 • Reviews in Urology 4170018_07_RiU2001BCA_V1_rev01.indd 36 4/23/18 5:14 PM Bladder Cancer Academy 2018 Summaries 15. 16. 17. 18. 19. 20. 21. 22. of patients with intravesical BCG. Bladder Cancer. 2015;1: 29-30. Kowalski M, Guindon J, Brazas L, et al. A phase ii study of oportuzumab monatox: an immunotoxin therapy for patients with noninvasive urothelial carcinoma in situ previously treated with Bacillus Calmette-Guérin. J Urol. 2012;188:1712-1718. Packiam VT, Lamm DL, Barocas DA, et al. An open label, single-arm, phase II multicenter study of the safety and efficacy of CG0070 oncolytic vector regimen in patients with BCG-unresponsive non-muscleinvasive bladder cancer: interim results. Urol Oncol. 2017 Jul 26. pii: S1078-1439(17)30350-2. Shore ND, Boorjian SA, Canter DJ, et al. Intravesical rAd–IFNα/Syn3 for patients with high-grade, Bacillus Calmette-Guerin–refractory or relapsed non–muscleinvasive bladder cancer: a phase ii randomized study. J Clin Oncol. 2017;35:3410-3416. Giacalone NJ, Shipley WU, Clayman RH, et al. Longterm outcomes after bladder-preserving tri-modality therapy for patients with muscle-invasive bladder cancer: an updated analysis of the Massachusetts General Hospital experience. Eur Urol. 2017;71: 952-960. Gray PJ, Fedewa SA, Shipley WU, et al. Receipt of aggressive therapies for muscle-invasive bladder cancer: results from the National Cancer Data Base. J Clin Oncol. 2012;30:272. Sanchez A, Wszolek MF, Clayman RH, et al. MP26-12 Incidence and management of non-muscle invasive bladder cancer recurrences after complete response to combined-modality organ-preserving therapy for muscle-invasive bladder cancer. J Urol. 2015;193:e298. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003;349:859-866. International Collaboration of Trialists, Medical Research Council Advanced Bladder Cancer Working Party (now the National Cancer Research Institute 23. 24. 25. 26. 27. 28. 29. Bladder Cancer Clinical Studies Group), European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group, et al. International phase iii trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol. 2011;29:2171-2177. Reardon ZD, Patel SG, Zaid HB, et al. Trends in the use of perioperative chemotherapy for localized and locally advanced muscle-invasive bladder cancer: a sign of changing tides. Eur Urol. 2015;67:165-170. Bellmunt J, von der Maase H, Mead GM, et al. 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