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International Journal of Urology (2018) 25, 134--140

doi: 10.1111/iju.13495

Review Article

Can bladder preservation therapy come to the center stage? Teruo Inamoto,1 Naokazu Ibuki,1 Kazumasa Komura,1 Hiroshi Juri,2 Kiyohito Yamamoto,2 Kazuhiro Yamamoto,2 Kazutoshi Fujita,3 Norio Nonomura,3 Yoshifumi Narumi2 and Haruhito Azuma1 1 Department of Urology, 2Department of Radiology, Osaka Medical College, Takatsuki, and 3Department of Urology, Osaka University, Suita, Osaka, Japan

Abbreviations & Acronyms 5-FU = 5-fluorouracil BCG = bacillus Calmette– Guerin BOAI = balloon-occluded arterial infusion CIS = carcinoma in situ CR = complete response CRT = conformal radiation therapy CSS = cancer-specific survival EBRT = extra beam radiation therapy HR = hazard ratio MIBC = muscle-invasive bladder cancer NMIBC = non-muscleinvasive bladder cancer OMC = Osaka Medical College OS = overall survival PDD = photodynamic diagnosis QOL = quality of life RC = radical cystectomy RCT = randomized controlled trial TMT = trimodal therapy TURBT = transurethral resection of bladder tumor UBC = urothelial carcinoma of the bladder Correspondence: Teruo Inamoto M.D., Ph.D., Department of Urology, Osaka Medical College, 2-7 Daigakucho, Takatsuki, Osaka 5698686, Japan. Email: [email protected] Received 6 September 2017; accepted 23 October 2017. Online publication 23 November 2017

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Abstract: Decision-making in urological cancer care requires a multidisciplinary approach for refinement, but its impact on urothelial carcinoma of the bladder has not been fully addressed for the past three decades, except for the latest immunological checkpoint inhibitor approved by the U.S. Food and Drug Administration for metastatic muscle-invasive bladder cancer that is resistant to platinum-based chemotherapy. For the time being, radical cystectomy is the gold standard of curative therapy for muscleinvasive bladder cancer. Trimodal therapy that combines chemotherapy for the purpose of radiation sensitization, external beam radiotherapy and transurethral resection of bladder tumor has emerged as a potential alternative treatment option that preserves the bladder. In lack of randomized studies for bladder preservation therapy compared with surgery, the principles of management of urothelial carcinoma of the bladder have evolved in recent times, with an emphasis on bladder preservation. A number of bladder preservation techniques are available to the surgeon; however, appropriately selected patients with muscle-invasive bladder cancer should be offered the opportunity to discuss various treatment options, including organ-sparing trimodal therapy. The aim of the present study was to compare the primary outcomes of the available treatment methods and identify the sources of variance among studies. A review of various bladder preservation techniques in vogue for the management of urothelial carcinoma of the bladder is discussed.

Key words: bladder preservation, muscle-invasive bladder cancer, prognosis.

Introduction So far, the treatment for MIBC includes RC, either alone or in combination with systemic chemotherapy. The past four decades have not seen important technological advances in the treatment of bladder cancer, especially for advanced disease. Since the discovery of the combination regimen of methotrexate, vinblastine, doxorubicin and cisplatin in 1985 for the treatment of muscle-invasive disease, it is not going too far to state any major breakthrough agents have not been approved by the U.S. Food and Drug Administration until recently.1 Immunological checkpoint inhibitors targeting the programmed death 1/programmed deathligand 1 and cytotoxic T-lymphocyte-associated protein 4 pathways have been proven to possess powerful antitumor activity, durable safety profiles by the treatment and long-term responses in clinical trials.2 Atezolizumab, avelumab, durvalumab, nivolumab and pembrolizumab are programmed death 1/programmed death-ligand 1 pathway blocking agents under clinical investigation that might redefine the standard of curative therapy for UBC.2 For example, atezolizumab, approved in May 2016, and nivolumab, approved in February 2017, are both the first U.S. Food and Drug Administration-approved immunological checkpoint inhibitors in UBC for platinum-based chemotherapy-resistant disease based on phase II data. On 16 March 2017, results from the phase III KEYNOTE-045 trial showed that patient OS was significantly longer in patients treated with pembrolizumab than those treated with the conventional second-line chemotherapy.2–4 Despite these major advancements of therapy in metastatic UBC that failed after platinum-based chemotherapeutics, until recently no therapeutic options beyond cystectomy had entered the daily clinical routine and none of the tested therapeutic options, except for RC, had been approved for the treatment of MIBC. When © 2017 The Japanese Urological Association

Contemporary review of bladder preservation therapy for muscle invasive bladder cancer

physicians decide to treat MIBC patients, RC with extended resection of the retroperitoneal lymph node will be offered as a standard of care. Although patients need suggests that cancer control is not the only goal, as QOL is an important issue as well, potentially to be a treatment risk. Patients might be subjected before therapy to selection of a specific treatment approach, and hence patients are prepared for the advantages and disadvantages related to each curative therapy, leading to a selection bias. This fact has allowed the focus to shift to “bladder preservation” as a potential major treatment for MIBC. Bladder preservation includes monotherapy (radiation only, chemotherapy only or resection only), whereas TMT includes all of these. For now TMT seems to be the most widely used combination method for bladder preservation. Maintenance of QOL and minimizing adverse effects is now considered an important therapeutic goal irrespective of the stage of disease and the choice of treatment modality.

Principles of bladder preservation The clinical success of bladder preservation modality depends on achieving a balance between effective locoregional tumor control and functional maintain. Also, many clinical questions present. For example, in patients with MIBC who did not undergo RC, the correct chemotherapy regimens are still under investigation, that, when administered concurrently with conventional or intensified radiotherapy, are superior to other regimens on clinical outcomes, such as response rate, survival rate and bladder preservation rate. The principles of bladder preservation consist of four categories.

Tumor assessment Accurate assessment for individualized treatment including bladder preservation therapy depends on initial diagnostic accuracy. The correct assessment of bladder cancer extent – both mucosal spread plus three-dimensional tumor load – rather than relying on the conventional T-stage system is the bottom line. For the bladder preservation technique, clinical T stage, but not the pathological T stage, are used as the disease stage.5–7 The drawbacks of the current T-staging system has to be discussed for the preservation therapy. Koga et al. propose that patients proven to be non-CR after induction CRT in bladder-sparing approaches be grouped into different risk groups for death based on conventional pathology of cystectomy specimens.8 In patients who underwent radical surgery, pT3–4a (HR 8.3 vs pT0–2, P < 0.001) and pN+ (HR 3.0 vs pN0, P = 0.037) were found to be independent risk variables among other factors including pT stage, lymph node yield at surgery, pN stage and lymphovascular invasion.8 Patients proven to be non-CR were grouped by the risk factors into low- (pT0–2pN0, 5-year CSS rate 85%) and highrisk (pT3–4a or pN+, 5-year CSS rate 20%) groups.8

Local tumor control Regular checkups with close inspection is imperative. The bladder urothelium is not well visualized with routine imaging studies, including computed tomography scanning and © 2017 The Japanese Urological Association

magnetic resonance therapy. The mainstay of diagnosis and follow up of bladder neoplasia as of now is conventional cystoscopy. The poor detection rate for positive regions in cystoscopy with bladder preservation techniques can make fine detection of residual tumor or recurrent cancer difficult. For, example fluorescence endoscopy, often referred to as PDD, with intravesical/oral application of photosensitizing agents, has been established to enhance the fine detection of tumor.9 There is growing evidence that PDD using 5-aminolaevulinic acid, hexyl-aminolaevulinic acid ester or hypericin enhances the detection of bladder cancer.9 As one of a tertiary bladder preservation medical centers in Japan, we have been using 5aminolaevulinic acid PDD for the detection of complex UBC cases including CIS or NMIBC in a patient who underwent bladder preservation therapy.10 A total of 147 resected specimens from 25 patients included in the analysis, 45 of 92 PDD-positive specimens were proven to be UBC and 51 of 55 PDD-negative specimens were proven to be negative.10 The sensitivity of TURBT followed with PDD was 91.8% (45/49), and the specificity was 52.0% (51/98). The sensitivity : specificity was 89.5% (17/19):47.6% (30/63) in 12 2nd-TUR patients, 90.5% (19/21):61.1% (11/18) in seven MIBC patients and 95.0% (19/20):48.5% (16/33) in eight failed BCG cases.10

Presence of concomitant CIS or high-risk NMIBC The presence of CIS or high-risk NMIBC is the confounding factor for making the right tumor assessment difficult. Nakai et al. investigated the role of maintaining BCG instillation for the intermediate-/high-risk NMIBC receiving aggressive complete TURBT.11 Recurrence-/progression-free survival did not improve in the maintenance cohort when compared with the non-maintenance cohort.11 It is difficult to completely eradicate the recurrence of high-risk NMIBC, even by maintenance BCG instillation combined with complete TURBT, and a significant number of high-risk NMIBC are flat tumors similar to CIS. Perhaps, regardless of abnormal cystoscopic appearance, all NMIBC patients with positive cytology could be possible candidates for additional random biopsies. The detection rate relies on cystoscopy accuracy by white light.12 Aside from potential tumor risks and behavior, white-light cystoscopy shortcomings include differentiation from inflammation with malignancy, lower detection for flat lesions and fine tumor delineation so as to enable complete resection.12 Liu et al. analyzed the additive impact of novel technology including fluorescence cystoscopy/photodynamic diagnosis, narrow band imaging, confocal laser endomicroscopy and optical coherence tomography beyond conventional white-light cystoscopy, and evaluated their maturity to change the clinical course after the scope, and found data on photodynamic diagnosis are best, although the clinical effectiveness of these technologies is yet to be proven.12 In most of the studies of TMT, recurrence of NMIBC or CIS, but not MIBC, is managed by TURBT followed by BCG instillation. Nevertheless, these NMIBC/CIS recurrences are at risk of upstaging to MIBC, requiring delayed cystectomy. Routine checkups with 135

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urine cytology help equip physicians for the detection of NMIBC/CIS recurrence.

Drug response Response to chemotherapy is one of the important factors for predicting the success of the clinical response of preservation therapy, because chemotherapy is the key component of the multimodal bladder preservation regimen. In bladder preservation methods, mainly consisting of TURBT and CRT to MIBC, patients who clinically accomplish CR to induction CRT achieve a favorable outcome and QOL with a functioning bladder, whereas those with persistent aggressive tumors have poor prognosis despite salvage RC, and risk factors to predict cancer death among the non-responders remain to be clarified.8 Zarger et al. have investigated the relationship of patient survival and pathological response after gemcitabine and cisplatin neoadjuvant chemotherapy in a large multicenter cohort study, with a focus on the difference between the absence of residual viable tumor and the presence of residual NMIBC (pTa, pTis, pT1).13 The mean estimated OS for patients with pT0 and NMIBC were 186.7 months (median 241.1, 95% CI 145.9–227.6) and 138 months (median 187.4, 95% CI 118.2–157.8), respectively. These were statistically significantly longer than the mean estimated OS of 84.4 months (median 48, 95% CI 66.9–101.9) observed in patients with pT2N0 or higher (P < 0.001), suggesting that patients with residual NMIBC disease after neoadjuvant chemotherapy have survival outcomes comparable with those free of residual viable cancer.13 Hafeez et al. evaluated survival advantage provided by neoadjuvant cisplatin-based chemotherapy to help physicians to select patients for bladder preservation and identify those that will have better outcomes with radiotherapy.14 In 89 patients for whom response was assessed, 88% showed response; 60% achieved CR; 83% responders had radiotherapy; and 4.5% opted for total cystectomy.14 Of the 11 patients (12%) in the poor response cohort, 10 underwent cystectomy.14 Median survival in the CR cohort was 90 months (95% CI 64.7–115.9) compared with 16 months (95% CI 5.4–27.4, P < 0.001) in non-responders.14 On Cox multivariate analysis, CR status in response to treatment was associated with progression-free survival, OS and DSS. After a median follow up of 39 months, 14 (16%) required salvage total cystectomy (eight for residual NMIBC, five for MIBC recurrence, one for EBRT-induced toxicity).14

Complications and QOL Perhaps TMT could be regarded as one of the aggressive therapies, which are usually defined as any open surgery or radiotherapy with a total radiation dose of ≥50 Gy. For TMT, chemoradiation is delivered to patients. The concept of organ preservation in the subset of patients who respond well to TMT is attractive, given that the agents are well characterdefined, tolerated and easy to apply. Safety and tolerability thus need to be critically examined for TMT, as such therapy has the potential to fill a treatment gap in patients with MIBC. Usually tolerability with only mild neutropenia, 136

anemia and thrombocytopenia (grade 1 or 2) are seen in patients that undergo TMT. Turgeon et al. found the TMT was well tolerated, and there was no grade 4 gastrointestinal or genitourinary toxicity.15 Of all patients, 8.2% experienced grade 2 hematuria relatively at late period of treatment, and similarly 8.2% experienced dysuria, which required urethral dilatation.15 In the RTOG 95-06 trial, grade 3 toxicity was 6% genitourinary, 18% hematological and 15% gastrointestinal.16 Usually, grade 3 or higher late toxicity is minimal for TMT.17,18 In most reports, there are a limited number of treatment toxicity-associated deaths.17,18 In the RTOG 95-06 trial, grade 4 toxicity was 3% genitourinary, 3% hematological and 3% gastrointestinal.16 In a contemporary systematic review focusing on TMT, the rate of the acute grade 3–4 toxicity ranges from 10% to 36%,19 perhaps this is because of the heterogeneous treatment modalities that provide data on long-term acute or late toxicity. For now, direct comparison and prospective data for QOL assessment in TMT with RC are lacking (Table 1). Also, we are unable to carry out the direct QOL comparison with TMT and RC, as patients treated by TMT have their functioning bladder after the treatment, on the other hand, patients underwent cystectomy lose their bladder. TMT has been initially challenged as a palliative therapy for those who does not fit for surgical management, otherwise who refused cystectomy. For the TMT patents who might be annoyed by dysuria, bothersomeness (QOL index) from the International Prostate Symptom Score and the questionnaire from the King’s Health Questionnaire is applied, whereas RC patients require a totally different QOL domain assessment. Zietman et al. investigated the QOL of TMT patients.20 Bladder compliance was decreased in 3.7% of patients who underwent TMT.20 A total of 48 patients who completed the QOL assessment proved to have high global health-related QOL, but 20% of these had bowel dysfunction.20

Table 1 Pros and cons of TMT and RC TMT

RC (reference)

QOL Superior28,44,45 Comparable46,47 Inferior48–50 Impossible to draw conclusion51 Survival Superior to comparable (possibly, no RCT present)28,30,31,40 Comparable19,30,47,52–59 Inferior50,60,61 Impossible to draw conclusion51 Toxicity Comparable62 Inferior50 Impossible to draw conclusion51 Cost Costly48 Impossible to draw conclusion51

Standard of care

Gold standard

Cost-effective

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Contemporary review of bladder preservation therapy for muscle invasive bladder cancer

Modality of preservation Solo preservation therapy in comparison with RC Depending on the stage at presentation, the primary management strategies for patients with MIBC consist of surgery and/or chemotherapy. The cure rates for stage II cancers treated with surgery alone are high. A key challenge in the management of MIBC is that the majority of patients have locally advanced disease (stages III–IV) at first presentation. There is a continuum between early-stage and advanced-stage tumors, and the latter is usually associated with less differentiation and aneuploidy, with common sites of metastasis including locoregional nodes, lung, bone and so forth.21 From the low survival rates achieved with RC, there is evidence that MIBC, possibly from the outset, is a systemic disease.21 The limitations of local therapy are well documented. A local cancer control rate of 30% with radiation treatment, and 50–70% with radical cystectomy, and improvement in cure rate seen with the use of preoperative radiation is limited.21 Over the past decades, since the initial reports of the effectiveness of cisplatin in the treatment of metastatic UBC, there has been a steady flow of chemotherapeutics, singly and in combination, which are potent in the treatment of UBC.21 Although response rates and CR rates have increased by the combination, this has not translated into survival advantage in advanced UBC of >16 months.21 Although RC, with continent diversion or ileal neobladder construction in selected patients, remains the standard of care in the USA and other countries for muscle-invasive UBC, several institutions have challenged therapeutic strategies aiming at bladder preservation.21 Initial approaches with the aim of bladder preservation consisted of radiotherapy, chemotherapy or complete TURBT as monotherapy for solitary tumors. Only a small proportion of carefully selected patients can be treated by complete TURBT alone, or by partial cystectomy alone.22 Solsona et al. investigated the feasibility of complete TURBT in selected patients with MIBC with a minimal follow up of 15 years, and investigated the clinical impact of patient age on survival, concluding complete TURBT is a reliable therapeutic for patients with MIBC if negative biopsies of the tumor bed are assured.23 By single-therapy bladder preservation, CSS was 81.9%, 79.5% and 76.7%, and progressionfree survival was 75.5%, 64.9% and 57.8% at 5, 10 and 15 years, respectively.23 Patient age had a negative impact on OS on univariate (HR 0.842, P = 0.049) and multivariate analyses (HR 1.062, P = 0.000).23 Although consent is that single mode of treatment is not potent enough to accomplish cure with preserved bladder. Even in the latest series, with the potential use of refined operative technologies, radiotherapy or TURBT alone offers inferior cancer control compared with RC. Supit et al. followed 150 patients with T2–T4a, N0, M0 UBC treated with RC, TURBT or radiotherapy.24 The actual 5-year OS for all patients was 50% for RC, 22.7% for radiotherapy and just 8.3% for TURBT, suggesting RC is the only reliable single therapy among all (log–rank P = 0.029).24 For T2 disease, the 5-year OS was 62.5% for RC, 31.2% for radiotherapy and 8.3% for TURBT (log–rank © 2017 The Japanese Urological Association

P = 0.017).24 Given these, most of the researchers gave up applying monotherapy aiming at bladder preservation. Similarly, systemic chemotherapy as monotherapy is inadequate and cannot be recommended.

Multimodal preservation therapy As in 1995 any multimodality therapeutic regimen had not yet been shown to be optimal with regard to local cancer control and minimizing toxicity, monotherapy for bladder preservation was thought not to be desirable as a routine approach.22 By combining each of these, better results are achieved with accelerated fractionation, neoadjuvant chemotherapy or concomitant radiochemotherapy.25 In particular, with the latter, the rate of CR (70%) is 30% higher as compared with radiotherapy alone or transurethral resection of bladder and chemotherapy.25 Over the past three decades, the premier bladder preservation center, Massachusetts General Hospital and the Radiation Therapy Oncology Group, have investigated patients with MIBC utilizing the TMT method: complete TURBT followed by EBRT with concurrent radiosensitizing chemotherapeutics and, subsequently, adjuvant chemotherapy.7,16,26 Thus, for the so-called TMT, chemotherapeutics have been basically used in two distinctive phases as radiosensitizers, given concurrently with radiation treatment and as adjuvant treatment, recognizing that favorable patient survival will be established by the treatment for micrometastases.7,16,21,26 In our group, the double BOAI of chemotherapeutics (cisplatin/gemcitabine) has been utilized for the purpose of bladder preservation in patients with MIBC.27,28 BOAI delivers an extremely high concentration of chemotherapeutics to the diseased site without systemic toxicities, along with concurrent radiation (OMC regimen) in patients with locally advanced UBC. The OMC regimen can be deemed as a curative alternative therapy to RC. Hence, any TN0M0 patients are candidates for the OMC regimen. Patients with positive nodes are outliers for this therapy, but a limited number of patients with positive pelvic nodes do experience a preferable clinical course after the OMC regimen, possibly suggesting the role of BOAI to lymph nodes. Our collaborators at interventional radiology compared double- versus single-balloon methods by software-assisted hemodynamic evaluation of pelvic flow during chemoperfusion of pelvic arteries.29 The OMC regimen uses double BOAI through a four-lumen double-balloon catheter, which was originally developed at OMC, Takatsuki, Osaka, Japan.29 The proximal balloon is located at the internal iliac artery, upstream of the bifurcation of the superior gluteal artery (Fig. 1).29 The distal balloon is located at the origin of the superior gluteal artery to isolate the anterior trunk of the internal iliac artery, which lies upstream of the target bladder arteries between the balloons.29 Double BOAI allows for accumulation of a higher concentration of chemotherapeutics at the disease site without flow to unrelated tissues than conventional single BOAI, which uses a single-balloon catheter elsewhere (Fig. 2).29 In our protocol, patients underwent complete resection of the tumor as far as possible followed by induction CRT (40 Gy with cisplatin), and the clinical response was evaluated. Our OMC bladder preservation 137

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Fig. 1 We use double balloon catheters that are introduced into both superior gluteal arteries via contralateral femoral artery access.

protocol consists of CRT by one course of gemcitabine and cisplatin therapy combined with a planned method to a total of 60 Gy, as 50 Gy (in 25 fractions) for the whole pelvis and 10 Gy (5 fractions) for local irradiation to the bladder. Patients receive the BOAI treatment (100, 200 or 300 mg cisplatin as defined by renal function) 4–5 weeks after the transurethral resection of their bladder tumors. For the purpose of complete resection of the tumor, we literally eradicate the whole mass of the tumor. If the tumors are present beside the ureteral orifice to hide it, the tumors accompanied with the intramural ureter are resected with the cutting mode, and use of the coagulation mode is limited in case ureteral stricture is evident. Active bleeding during the procedure can be managed by precise pinpoint hemostasis using the cutting mode. In the absence of level 1 evidence, a recent study compared the outcomes between patients treated with 56 RC or 56 TMT by using a propensity score-matched cohort analysis that adjusted for sex, age, T stage, node status, Eastern

Fig. 2 Side holes between the distal and proximal balloons are placed at the origin of each bladder artery. Administration of chemotherapeutics intraarterially instead of intravenously, and higher local peak plasma drug concentration results in higher tumor concentrations of the drug.

Cooperative Oncology Group status, Charlson Comorbidity score, treatment date, CIS presence and hydronephrosis status.30 The 5-year CSS rate was 73.2% in the RC cohort and 76.6% in the TMT cohort, respectively (P = 0.49), with salvage cystectomy being carried out in six (10.7%) of 56 patients who received TMT, concluding that TMT yielded a survival benefit comparable with those of propensity-matched patients who underwent RC.30 So far, TMT has been tested in prospective trials from single institutions or cooperative groups (Table 2). CR rates ranged from 40% to 87%, and OS rates ranged from 23% to 77% (Table 2). This level 2 evidence suggests that the outcomes with chemoradiation therapy are better than those with radiotherapy therapy alone,

Table 2 Prospective trials on bladder preservation therapy for MIBC Reported year

Cohort size (n)

Mokarim et al. Fellin et al.32 Retz et al.33 Hussain et al.34 Eapen et al.35 Danesi et al.36 Kragelj et al.37 Gogna et al.38 Caffo et al.39 Lagrange et al.40 Choudhury et al.41 James et al.42

1997 1997 2000 2004 2004 2004 2005 2006 2011 2011 2011 2012

35 56 53 41 185 77 84 113 26 53 50 182

Tunio et al.43

2012

230

Investigator 31

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Intervention Intra-arterial cisplatin and doxorubicin plus EBRT Methotrexate, cisplatin and vinblastine plus EBRT Cisplatin and epirubicin plus EBRT Mitomycin C and 5-FU plus EBRT Intra-arterial cisplatin plus EBRT Cisplatin and 5-FU plus EBRT Vinablastine plus EBRT Cisplatin plus EBRT Cisplatin and gemcitabine plus EBRT Cisplatin and 5-FU plus EBRT Gemcitabine plus EBRT Cisplatin and mitomycin C plus EBRT (whole-bladder radiotherapy or modified-volume radiotherapy) Cisplatin plus EBRT

Overall survival (%)

Study design

77 59 23 36 48 58 42 50 70 44 65 48

Prospective Prospective Prospective Prospective Prospective Prospective Prospective Prospective Prospective Prospective Prospective Prospective

52

Prospective phase III

phase phase phase phase phase phase phase phase phase phase phase phase

Target disease I–II II I–II I–II I–II I–II II II I–II II II III

Clinical Clinical Clinical Clinical Clinical Clinical Clinical Clinical Clinical Clinical Clinical Clinical

T2–4 N T2–4 N T2–4 N /+ T2–4 T2–4 N /+ T2–4 T2–4 T2–4 ≥T2 N T2–4 N T2–4 N0 T2–4 N

Clinical T2–4

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Contemporary review of bladder preservation therapy for muscle invasive bladder cancer

realizing that the combination of multiple modalities might play a role in these findings. There are no available randomized prospective trials that compare RC and TMT. Level 1 evidence is necessary to give patients with MIBC definitive answers on the possibility of choosing the most appropriate individual treatment.

Conclusions Accumulating reports show the superiority of TMT over RC. In contrast, a considerable number of reports show inferior cancer control of TMT compared with RC, because patients in the bladder preservation group received a preservation therapy with palliative intent that probably increased morbidity and side-effects, and compromised the potential advantages of TMT. Because TMT requires validation, radiotherapy should remain the standard of care for patients with this disease. However, organ preservation with TMT may be a reasonable alternative in certain patients.

Acknowledgment Mr Niinobe Shigefumi (Osaka Medical College Biomedical Computation Center) attributed to the artwork design.

Conflict of interest None declared.

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