Treatment Options and Outcomes in Nonmetastatic Muscle Invasive Bladder Cancer

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Review

Treatment Options and Outcomes in Nonmetastatic Muscle Invasive Bladder Cancer Rashed Ghandour

,1 Nirmish Singla,1 and Yair Lotan1,*

Muscle-invasive bladder cancer (MIBC) represents 25% of newly diagnosed bladder cancer. MIBC is aggressive and requires timely management. The current standard of care is neoadjuvant chemotherapy followed by radical cystectomy, an approach that could result in significant morbidities. Modifications in the chemotherapy regimens, as well as in perioperative care and surgical approach, have resulted in better overall toxicity profile and faster recovery. However, bladder-preservation in carefully selected patients can lead to acceptable oncological outcomes and better quality of life. Optimization of bladderpreservation protocols and proper identification of patients who tolerate and respond to various treatment modalities will significantly impact patient survival in the coming future.

Highlights Neoadjuvant chemotherapy followed by radical cystectomy continues to be the standard of care in muscle-invasive bladder cancer, and adjuvant chemotherapy is not supported to date by high-level evidence Lymph node dissection has an established benefit, but the optimal extent is not yet determined Robotic cystectomy is associated with longer operative times, less blood loss, and faster recovery; however, it results in similar complication rates.

Epidemiology and General Background The estimated incidence of bladder cancer in the United States in 2019 is 80 470 new cases, with 17 670 deaths, roughly three-quarters of whom are males [1]. Approximately 25% of bladder cancer patients present with muscle-invasive or metastatic disease and require aggressive therapy [2]. This rate has been stable in fact from 2004 to 2014 in the Surveillance, Epidemiology, and End Results (SEER)i registry, and the main predictor of outcomes has been the stage of disease and the treatment strategy used [3]. The recommended standard of care treatment for nonmetastatic muscle-invasive bladder cancer (MIBC; see Glossary) is radical cystectomy (RC) with neoadjuvant platinum-based chemotherapy if tolerable, while bladder-preserving strategies are accepted alternatives in nonsurgical candidates and in those who desire to retain their bladders [4–6]. The American Urological Association, American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Urologic Oncology (AUA/ASCO/ ASTRO/SUO)ii joint guidelines state that patients with newly diagnosed nonmetastatic MIBC who desire to retain their bladder, and for those with significant comorbidities for whom RC is not a treatment option, clinicians should offer bladder preserving therapy when clinically appropriate [4] (Figure 1). The overall survival (OS) of MIBC clinically confined to the bladder was reported in the National Cancer Database (NCDB)iii according to treatment modality. Patients treated with RC had a median OS of 48 months compared with 28 months for those treated with chemo-radiation, and 5 months when not treated, as shown in Figure 2 [7]. Importantly, most patients did not receive definitive therapy and when controlling for multiple covariates, the OS for cystectomy was similar to that for chemo-radiation. This highlights the importance of attempting curative therapy in patients with MIBC who have no evidence of metastatic disease. Stratified by pathologic stage obtained at cystectomy, the overall disease-specific survival (DSS) of patients with organ confined, node-negative disease over 5 and 10 years was 60%–85%, compared with 426

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Enhanced recovery protocols are being adopted and result in faster recovery, less minor complications, and earlier discharge; however, this results in similar long-term and major complication rates. Bladder-preserving strategies are acceptable options for medically unfit patients; however, equivalent results to radical cystectomy are seen in highlyselected patients with strict follow-up and prompt salvage therapy for recurrence or incomplete response.

1

Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9110, USA

*Correspondence: [email protected] (Y. Lotan).

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50% in node-negative extravesical disease, and a long-term recurrence-free survival (RFS) of 30% in node-positive after lymphadenectomy [8]. Although American Joint Committee on Cancer stage was found to be the strongest predictor of OS and cancer-specific survival in a large SEER and Texas Cancer Registryiv linked data [9], the effect of therapeutic modality cannot be overlooked. In this review, we will focus on nonmetastatic MIBC, the available guidelines and advances in the field, and the associated oncological outcomes.

Treatments of Nonmetastatic MIBC This review is focusing on nonmetastatic MIBC. The initial evaluation of any patient who has MIBC based on transurethral resection of bladder tumor (TURBT) requires a complete evaluation to establish if the disease is metastatic or not. The recommended evaluation based on the AUA/ ASCO/ASTRO/SUO joint guidelines include full history and physical exam, and staging including chest imaging and cross-sectional imaging with intravenous contrast of the abdomen and pelvis [4]. Patients with nonmetastatic MIBC should be offered curative treatment options (Figure 1). Unfortunately, understaging is common in patients with MIBC and patients have nodal involvement and micrometastatic disease more than 25% of the time, which is why many of the treatments involve systemic and not just local therapies [10]. Patients should be counselled about the complications and subsequent quality of life following each treatment modality. Shared decision making is key to engage patients in a multidisciplinary approach that takes into consideration the patient biological age, comorbidities, and nutritional status [4,5]. RC and Pelvic Lymph Node Dissection While the National Comprehensive Cancer Network (NCCN)v guidelines lists RC as one of the treatment options for nonmetastatic MIBC [6], there is a general consensus supported by historical and recent data as well as the updated European Association of Urology (EAU)vi guidelines and the joint AUA/ASCO/ASTRO/SUO guidelines that RC is the mainstay treatment and the standard of care curative treatment in patients with MIBC when surgery can be tolerated [4,5]. The guidelines mentioned above specify that salvage RC should be part of the alternative therapies algorithms in case of failure. The standard extirpative RC includes removal of the bladder, in addition to the prostate and seminal vesicles in males, and uterus, fallopian tubes, ovaries, and anterior vaginal wall in females. Performing RC promptly within 3 months from diagnosis is an accepted principle supported by the EAU guidelines as a measure to improve oncological outcomes [5,11,12]. However, several reports challenged this concept, with the time from diagnosis examined as both a continuous and dichotomous variable [13–15]. Most of these studies did not include at all or included a very small subset of patients who received neoadjuvant of adjuvant chemotherapy (AC), which could be confounding variables when survival is examined. However, in general it seems reasonable to proceed as soon as feasible to reduce the chance of progression of disease. Nerve-sparing RC is mentioned in the EAU and AUA/ASCO/ASTRO/SUO guidelines as an option to consider and discuss with male patients with organ-confined disease and cancer-free bladder neck and prostatic urethra [4,5]. Oncological outcomes did not differ when patients were carefully chosen. The mentioned types of sexual-preserving techniques resulted in significantly better sexual outcomes compared with RC (P b 0.05). Because of the moderate quality of evidence, the conclusion is that when such modalities are offered, patients must be carefully selected, counselled, and closely followed [5]. Functional outcomes are also of importance in women undergoing RC, and preservation of the neurovascular bundle, vagina, uterus, or variations of

Glossary Adjuvant chemotherapy (AC): administered within 3 months after surgery based on adverse pathological findings in the surgical specimen. Cancer-specific survival: percentage of people who did not die from cancer. Carcinoma in situ (CIS): malignant changes limited to mucosal layers without invasion of basement membrane; feature of aggressive disease in bladder cancer. Combined positive score (CPS): described measure of expression of PD-L1 in tumor cells. Disease-specific survival (DSS): percentage of people who did not die from disease, interchangeable with cancer-specific survival in cancer. Enhanced recovery after surgery (ERAS): standardized protocol of perioperative care for a specific surgery. Hazard ratio (HR): measure of comparison of survival among two interventions. Lymph node dissection (LND): surgical removal of lymph nodes in the landing zone according to established templates. Lymphovascular invasion (LVI): pathological finding that confers higher risk of spread of cancer. Metastasis-free survival: percentage of people who continue to live without metastasis of their cancer. Muscle-invasive bladder cancer (MIBC): invasion of the muscle layer leading to worse outcome; requires immediate aggressive therapy. Neoadjuvant chemotherapy (NAC): administered prior to surgery to improve cancer control and survival. Non-muscle invasive bladder cancer (NMIBC): cancer that has not invaded the muscularis propria layer and can be in most cases treated with conservative measures. Overall survival (OS): percentage of people still alive at a certain time in the study. PD-1: programmed cell death protein 1, present on the surface of T cells, that serves to suppress the immune system response to cancer cells. Progression-free survival (PFS): percentage of people who are still alive without progressing locally to higher stage or spreading distantly. Radiation therapy (RT): radiation to an organ with cancer to treat and control cancer.

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described techniques have been reported, and an unpublished meta-analysis shows acceptable oncological outcomes; however, the quality of the data was limited, with only 318 patients included [5]. Pelvic lymph node dissection (LND) is an integral part of the procedure with a high level of evidence [4,5]. Several meta-analyses of retrospective reports examined the impact of LND and its extent on oncological outcomes. Bruins et al. concluded that LND resulted in at least one better oncological outcome than no lymphadenectomy across all included studies and that an extended/superextended LND was superior to limited/standard LND [16]. No difference in outcome between extended and superextended LND could be proven. These results were reproduced by another meta-analysis by Bi et al. [17]. The anatomic boundaries of superextended LND are defined as the following: the origin of the inferior mesenteric artery proximally, the genitofemoral nerves laterally, the circumflex iliac vein distally, the internal iliac vessels posteriorly, with the obturator fossa presciatic and presacral lymph nodes overlying the sacral promontory [18]. Extended LND is bound by the aortic bifurcation proximally, while the standard LND is bound by the bifurcation of the common iliac vessels. A recent randomized controlled trial

Radical cystectomy (RC): surgical removal of the bladder to prevent spread of cancer. Transurethral resection of bladder tumor (TURBT): endoscopic resection of bladder tumor done by accessing the bladder through the urethra; can be diagnostic and therapeutic. Trimodality therapy (TMT): consists of maximal resection of bladder tumor followed by simultaneous chemotherapy with radiation therapy.

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Figure 1. Treatment Algorithm for Muscle Invasive Bladder Cancer. This algorithm illustrates the stepwise evaluation of patients with muscle-invasive bladder cancer, followed by the decision-making based on patient preference and eligibility for radical cystectomy (RC) and neoadjuvant cisplatin-based chemotherapy. The initial therapies are then followed by assessment of response or relapse. For example, adverse pathological findings following RC might necessitate adjuvant chemotherapy or even potentially adjuvant checkpoint inhibitor therapy. Conversely, for patients undergoing a bladder-sparing protocol, close surveillance is essential to prompt salvage RC for those patients with incomplete response or relapse. Single modality bladder preservation protocols are not considered curative approaches. Abbreviations: CT, Computed tomography; CXR, chest x-ray; H & P, history and physical exam; MRI, magnetic resonance imaging; NAC, neoadjuvant chemotherapy; RC, radical cystectomy; RT, radiation therapy; TMT, trimodality therapy; TUR, transurethral resection.

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Figure 2. Overall Survival of Muscle-Invasive Bladder Cancer According to Treatment Choice. Data from the National Cancer Database, which represents roughly 70% of cancer patients in the United States, Kaplan-Meier curves representing survival of 36 469 patients with nonmetastatic muscle-invasive bladder cancer between 1998 and 2010. Abbreviations: Agg, Aggressive (defined as radical cystectomy or chemo-radiation); CI, confidence interval; Cyst, radical cystectomy; C/R, chemo-radiation; Non, non-aggressive (defined as otherwise palliative measures); OS, overall survival. Reproduced, with permission, from [7].

(RCT) from Germany that randomized 401 patients to receive limited versus extended LND failed to demonstrate statistically significant differences in RFS, DSS, or OS. Of note, 14% of patients had pathological non-muscle invasive bladder cancer (NMIBC) on RC specimen, and 44% pT3–T4. The 5-year RFS was 64.6% versus 59.2% (P = 0.36), 5-year DSS was 75.9% versus 64.5% (P = 0.1), and 5-year OS was 58.9% versus 49.7% (P = 0.12) for the extended and limited LND groups, respectively. In addition, all curves separated well during the initial 5 years of follow-up, and median RFS and DSS were not reached during the study period. The authors concluded that larger studies could overcome these limitations of underpowered groups [19]. A Southwest Oncology Group (SWOG)vii trial that has completed enrollment will provide further information on the value of extended LND (NCT01224665)viii. The current guideline recommendations are to remove, at a minimum, the external and internal iliac and obturator lymph nodes (standard lymphadenectomy) (Figure 3). This can be curative in up to 30%–40% of patients with lymph node involvement [20]. Neoadjuvant Chemotherapy Prior to RC The addition of combination neoadjuvant chemotherapy (NAC) to RC has been demonstrated over the last two decades to improve oncological outcomes, and this multimodal approach became the standard of care treatment of nonmetastatic MIBC [4–6]. The first level I evidence to prove the significant benefit following the administration of neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) regimen was the RCT by Grossman et al. in 2003 (S8710), randomizing 307 patients to receive RC alone or following NAC. The group treated with NAC and RC achieved a complete pathologic response on surgical specimen in 38%, compared with 15% only in the RC alone group (P b 0.001). The median survival was 77 months versus 46 months in the respective groups, while the 5-year OS improved from 43% to 57% with the addition of NAC (P = 0.06). Interestingly, patients with pT0 on RC specimen had comparable survival regardless of the use of NAC, and the 5-year survival of those patients from both arms was 85%, revealing the favorable prognostic relevance of absent tumor on pathologic examination after RC [21]. A

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Figure 3. Anatomic Templates of Lymph Node Dissection during Radical Cystectomy. Standard lymph node dissection (LND) includes the external iliac (1), internal iliac (2), and obturator nodes (3), and extends from the bifurcation of the common iliac (4) arteries proximally to the pelvic floor distally, bound laterally by the genitofemoral nerve. In addition, the extended LND includes the common iliac (4) and the presacral (5) nodes. Superextended LND further extends to the take-off of the internal mesenteric artery (6) and includes paracaval, interaortocaval, and para-aortic nodes surrounding the inferior vena cava (IVC) and aorta (Ao), posteriorly reaching the pelvis and rectum. Abbreviations: UB, Urinary bladder.

meta-analysis and a long-term follow-up of an international Phase III trial showed that cisplatinbased NAC improves survival by an absolute 5%–6% [22,23]. However, the benefit of NAC varies by the regimen used and, as noted above, was higher in S8710 when optimal MVAC was used. Cisplatin is known to have major toxicities, such as nephrotoxicity, neurotoxicity, and hearing loss, and can result in cardiac dysfunction and, accordingly, 30%–50% in the metastatic setting are deemed ineligible to receive this drug [24]. Unfortunately, despite level 1 evidence supporting use of NAC and guideline recommendations, rates of utilization are approximately 20%–30% in the US [25]. Carboplatin, a second-generation platinum compound, is an alternative to cisplatin in the metastatic setting, however, with a small effect of cisplatin in the NAC setting and a potentially significant delay of RC, particularly in patients with platinum-resistant tumors, the AUA/ASCO/ASTRO/ SUO guidelines strongly recommend against the use of carboplatin-based NAC prior to RC [4]. Alternative cisplatin-based regimens have been used since then. Gemcitabine in combination with cisplatin was shown to lead to comparable complete (pT0) and partial responses (≤pT1) in a retrospective single-center report of 178 patients and a simultaneous pooled analysis of 164 patients [26,27]. In a non-inferiority RCT of 405 patients that showed a similar OS and response rate in the locally advanced or metastatic setting, the toxicity profile favored the gemcitabine/ 430

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cisplatin (GC) regimen, with lower grade 3–4 anemia, neutropenic fever or sepsis, and mucositis [28]. This data was later supported by larger NAC series [29], leading to the wide acceptance and use of the GC regimens in the neoadjuvant setting prior to RC for nonmetastatic MIBC. Accelerated or dose-dense (dd) MVAC was later introduced to overcome the toxicity of the standard MVAC regimen. This regimen is characterized by an accelerated schedule over 6 weeks rather than the standard 12-week MVAC regimen, lower dose of methotrexate, and G-CSF support with pegfilgrastim [30,31]. In both NAC and metastatic settings, ddMVAC regimen was shown to have similar oncological outcomes with a more tolerable toxicity profile [30–34]. In fact, a recent multi-institutional retrospective study examined 319 cT3-4N0 patients who received ddMVAC (100) or GC (219) prior to RC, and concluded that ddMVAC resulted in better pT0 rates (28% versus 14.6%, P = 0.005), better partial responses (41% versus 30%, P = 0.07), and a better mean survival (7 years versus 4.2 years, P = 0.001). The median time from the start of NAC regimen to RC was 12 weeks for ddMVAC versus 17 weeks for GC (P b 0.001) [35]. Although propensity score analysis of hazard ratios (HR) after adjustment for baseline covariates was performed and the survival difference remained significant, it is hard to interpret the results of this report because of the major limitations in the study design. A recent Phase II study evaluated the use of three cycles of pembrolizumab for neoadjuvant therapy in 50 patients regardless of their cisplatin eligibility. The study found that 21 patients were pT0 [42%; 95% confidence interval (CI), 28.2% to 56.8%] and 27 patients (54%) had bpT2. pT0 rates were 54.3% and 13.3% in patients with PD-L1 combined positive score (CPS) ≥ 10% and CPS b 10%, respectively. Future studies will be needed to determine if checkpoint inhibitors will be useful treatments in all patients undergoing NAC or, at a minimum, in patients who are platinum-ineligible [36]. Similarly, other checkpoint inhibitor protocols, such as atezolizumab monotherapy and pembrolizumab in combination with GC, are studied in the neoadjuvant setting prior to RC with promising preliminary results (NCT02451423ix; NCT02690558x). AC following RC Patients who did not receive NAC yet have adverse pathologic features after cystectomy, such as extravesical disease (pT3–4) or nodal metastasis, have the option to get AC in the guidelines (level 2A in NCCN and grade C in EAU and AUA/ASCO/ASTRO/SUO guidelines) [4–6]. The evidence for AC is derived from meta-analyses and large observational studies, where 23%–30% risk reduction for death was observed [37–39]. Improved disease-free survival (DFS) was observed (HR = 0.66, P = 0.014) with an even greater benefit in patients with nodal metastasis [37]. In a recent European Organization for Research and Treatment of Cancerxi trial, 284 patients of the planned 660 patients were randomized to receive immediate AC with four cycles of GC or MVAC compared with six cycles of chemotherapy at relapse. Progression-free survival (PFS) was improved with immediate AC compared with deferred treatment (HR = 0.54, P b 0.0001), however OS was not different [40]. No RCT compared NAC in all patients with AC reserved to higher-risk patients, and with better evidence in favor in the NAC strategy, AC is reserved for patients who did not receive preoperative chemotherapy. An ongoing Phase III trial compares adjuvant pembrolizumab with observation following RC in patients with locally advanced MIBC (AMBASSADOR trial). Pembrolizumab is infused intravenously every 3 weeks for 18 cycles in the absence of disease progression or major toxicity. The primary outcomes are OS and DSS, while subgroup analyses will be undergone for patients with PD-L1 positive and negative statuses (NCT03244384)xii. Another Phase III multicenter study (IMvigor010) is evaluating the efficacy and safety of adjuvant atezolizumab compared with observation in urothelial MIBC patients who are at high risk for recurrence after cystectomy

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(NCT02450331)xiii. Similarly, adjuvant nivolumab compared with placebo following cystectomy in high-risk MIBC patients is studied in an RCT (CheckMate 274). The target enrollment for this trial is 640 patients, and co-primary endpoints are DFS in all randomized patients as well as those with PD-L1 ≥ 1% expression (NCT02632409)xiv. Complications of RC RC is a major surgery with significant postoperative morbidity. The early morbidity (within 3 months) and 30-day mortality in a single-center experience in nearly 1054 patients from 1971 to 1997 was 28% and 3%, respectively [41]. A more contemporary registry of 50 000 patients from the Nationwide Inpatient Sample showed a stable rate of in-hospital complications of 28% in the years 2001 and 2008 and mortality of 2.3%–2.4% [42]. Evaluation of the National Surgical Quality Improvement Programxv identified 1094 patients who underwent RC from 2006 to 2011, and the overall rate of complications was 31.1%, while transfusions, prolonged length of hospitalization, readmission, and mortality occurred in 34.4%, 25.9%, 20.2%, and 2.7%, respectively. While sepsis occurred in 14% of patients, urinary tract infections (UTI) and wound infections occurred in 10% each, and pulmonary, thromboembolic, renal, and cardiac complications occurred in 6.5%, 5.9%, 4.1%, and 1.4%, respectively [43]. Higher body mass index and smoking were independently associated with higher complication rates [43–45]. Similarly, prolonged operative time beyond 4 hours was associated with a nearly twofold increase in UTI, wound infection, and sepsis, while transfusion was associated with a 30% increase in wound infection and sepsis (all P b 0.05) [46]. No increase in perioperative complication rates were observed when NAC was administered prior to RC [47]. The long-term complications are related primarily to the use of bowel in urinary diversion. The properties of the bowel mucosal lining result in reabsorption of urine with subsequent metabolic imbalances, such as acidosis with subsequent nephrolithiasis and potential osteoporosis, which is seen more frequently in continent diversions [48]. The use of distal ileum can increase problems with malabsorption of vitamins such as B12 and cholelithiasis [48]. Bowel obstruction is another long-term complication of RC. The observed rate of intestinal obstruction in a series of 4199 patients was 2.8% following a RC and rose to 10% following a palliative RC. The rate was higher for colonic diversion (6.2%) than for ileal conduit (2.9%) and ileal neobladder (1.6%) [49]. Robotic RC Robotic approaches were developed for RC in an attempt to reduce the morbidity of open surgery. A non-inferiority RCT of 302 patients treated with open or robotic RC found that the robotic approach was associated with less blood loss, lower rate of transfusion, and shorter length of stay but with longer operative times [50]. The study found nearly identical PFS at 2 years of 71.6% in the former compared with 72.3% in the latter. The overall rates of postoperative adverse events were similar with 69% and 67%, while grade III–IV complications occurred in 19% in both groups, and perioperative mortality in 3% in both groups; all subgroups had comparable complication rates [50]. Similar to this, a large multi-institutional analysis of 1887 patients and a prior systematic review that found robotic RC to be associated with less blood loss and lower rates of transfusions, shorter length of stay, yet longer operative times [50–52]. All the above studies showed similar 30- and 90-day complication rates, readmissions, reoperations, and mortality. There still remain questions on whether the short-term benefits of the robotic approach justify the added cost and learning curve associated with this technique. Enhanced Recovery after Surgery In an aim to improve surgical outcomes and standardize the perioperative management, the enhanced recovery after surgery (ERAS) pathways were adopted in several centers in the 432

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last two decades, and their results were published and analyzed collectively in a meta-analysis in 2016 [53]. The ERAS pathways involve collaboration between surgical, anesthesia, and nursing teams, and focus on optimizing preoperative, intraoperative, and postoperative care. Preoperative modifications include improving nutrition prior to surgery and minimizing bowel preparation. Intraoperative recommendations include judicious intravenous hydration during surgery, shortacting anesthetic agents, epidural anesthesia/analgesia, and maintenance of normothermia [54]. Postoperative recommendations include use of alvimopan, early postoperative enteral feeding, early mobilization, and self-care encouragement [55]. The expected outcomes from this protocol would be a shorter time to bowel recovery, reduced length of hospital stay, reduced overall complications rates, and reduced rates of readmission, however reported effects of ERAS pathways in RC have been conflicting [53]. The pooled analysis of 13 comparative studies of a mixture of prospective and retrospective RC studies, with a total of 801 ERAS participants and 692 controls, examined the above outcomes. Time-to-bowel activity was shorter by 1.1 days (P = 0.003) and length of stay was shorted by 5.4 days (P = 0.001) in the ERAS group. Overall complications were reduced from 51.5% in standard care group to 39.6% in the ERAS group (P = 0.017), however most of the benefits were in Clavien-Dindo low grade (I or II) complications, while 90-day mortality did not differ. The 90-day readmission rates were comparable, while a stratified analysis of 30-day readmission rates favored ERAS by 2.5-fold risk reduction (P = 0.015) [53]. A recent RCT from China randomized 289 patients who underwent RC and ileal conduit urinary diversion to an ERAS arm (n = 144) and a conventional arm (n = 145). Similar to the metaanalysis mentioned above, the ERAS group had improved recovery of bowel activity measured as bowel movements (median 88 versus 100 hours, P = 0.01), fluid diet tolerance (median 68 versus 96 hours, P b 0.001), and shorter time to regular diet tolerance (125 versus 168 hours, P = 0.004). Time to flatus and length of stay were similar, and median time to ambulation was 64 hours in the ERAS group, 8 hours less than the conventional RC group, although ERAS in other centers consists of day 1 ambulation [56]. Another RCT examined the effect of oral alvimopan, a peripherally acting μ opioid antagonist, and demonstrated a quicker time to first tolerance of solid diet and first bowel movement (5.5 versus 6.8 days; HR = 1.8; P b 0.0001), shorter length of stay (mean 7.4 versus 10.1 days; P = 0.005), and lower rate of postoperative ileus (8.4% versus 29.1%; P b 0.001) [57]. Bladder-Preserving Strategies Trimodal Therapy The guidelines reserve bladder-preserving strategies for patients who are medically unfit to undergo a major surgery such as RC and to those adamant to keep their bladders. In those patients, multimodality treatment is strongly favored over single modalities such as TURBT alone, radiation therapy (RT) alone, or chemotherapy alone [4–6]. Although no RCTs have been performed to compare RC with trimodality therapy (TMT), there is evidence that carefully selected patients with proper follow-up and timely salvage RC, in the case of failure, achieve comparable results with those known for upfront RC [58]. TMT consists of an aggressive but safe TURBT of the tumor, followed by concurrent chemotherapy and RT. Chemotherapy is meant as a radiosensitizer and options include cisplatin as the most active singe agent [59,60], mitomycin C (MMC)/5-fluorouracil (5-FU) [61], gemcitabine [62], and other agents such as carbogen-nicotinamide and panitumumab [63,64]. Radiation regimens differed across studies, but the current radiation protocol widely accepted includes external-beam RT to the bladder and limited pelvic lymph nodes up to 40 Gy, with a boost to the whole bladder to 54 Gy, and a further boost to the tumor bed to a total dose of 64-65 Gy

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[58,65]. Immune checkpoint inhibitors are also being used in the realm of TMT. An ongoing joint SWOG/NRGxvi Phase III trial is randomizing patients with localized MIBC who are not eligible for RC to undergo concurrent chemo-radiotherapy with or without atezolizumab. In this trial, atezolizumab is infused intravenously every 3 weeks, starting day 1 of chemotherapy, for a total of 6 months in the absence of disease progression or major toxicity. The primary endpoint is 2-year DFS, while control rate, OS, treatment-related adverse events and quality of life are all secondary outcomes (NCT03775265)xvii. Patient Selection Selection criteria for TMT are key to the improved survival of patients, as MIBC represents a heterogenous group of tumors. Several historical reports about predictors of poor response to RT, and hence to TMT, with subsequent poor survival, have been published [66,67]. Carcinoma in situ (CIS), incomplete resection, locally advanced disease (cT4), ureteral obstruction, and hydronephrosis were all implicated in poorer response to RT and TMT. Hydronephrosis and diffuse multifocal disease patients are generally excluded from TMT studies because of the accepted negative effect on response rates, while maximal TURBT, when compared with incomplete TURBT, was shown to considerably improve complete response and bladder preservation from 57% to 79% and from 22% to 42%, respectively [58,67]. Good pretreatment bladder function should be taken into consideration prior to proceeding to TMT [6]. In addition, variables that are predictive of more aggressive disease in RC series, such as higher grade of the tumor, lymphovascular invasion (LVI), and lymph node involvement, were also associated with worse outcomes following TMT [58]. Finally, only 10%–15% of medically operable patients might be good candidates for bladder preservation [68], and patient compliance and motivation might be key in identifying early recurrences in order to consider salvage therapy. In fact, a currently enrolling Phase II trial is examining the oncological effect of risk-adapted approach after accelerated MVAC and maximal TURBT, where bladder preservation through surveillance, intravesical therapies, or chemo-radiation are allowed for select cases based on clinical stage and mutation status (NCT02710734)xviii. Another ongoing Phase II trial from the National Cancer Institute is enrolling patients with DNA damage repair mutations on the pretreatment TURBT tumor, where patients receive ddGC as NAC and then are reassessed. Patients with residual disease bcT1 undergo bladder sparing, while those with higher stage residual tumor undergo RC or chemo-radiation (NCT03609216)xix. Salvage RC Salvage treatment, in particular RC, is the standard procedure for MIBC patients who are medically fit for major surgery and who do not respond to or subsequently fail TMT. Initial complete responders have recurrent bladder tumors at a rate of 24%–43% and have muscle-invasive disease in 11%–18% [58]. Noninvasive recurrences could be managed with local measures such as TURBT and intravesical therapy, however, NMIBC relapse could be a predictor of later invasive recurrences [69]. RC with pelvic LND is strongly recommended for residual or recurrent MIBC and, in fact, adopting this approach is part of the reason why TMT series achieved relatively high survival rates [4,5]. Oncological Outcomes of TMT The response and survival following TMT are related to the general medical condition of the patient and the tolerability of surgery under general anesthesia [58,70]. OS ranges from 30% to 42% after 4 years of follow-up [58]. In medically operable patients, the mean overall response rate is 73%, the 5-year DSS ranged from 50% to 82%, and the 5-year OS rates were 48% to 60% if prompt salvage cystectomy was performed in patients without complete response to TMT, which occurred at a rate of 25%–30% [58]. It is difficult to compare these rates to those 434

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following NAC and RC, particularly since RC patients are generally higher risk with permissively worse pathological and clinical features. While it is difficult to compare outcomes across different studies, a study from MD Anderson included 199 patients with designated low-risk MIBC based on T2 stage, and lack of hydronephrosis, LVI, or variant histologies, who underwent RC without NAC and showed that the 5-year DSS survival in this category exceeded 80% [71]. An RCT comparing RC and RT is lacking and will be the only way to answer this question regarding a preferred approach to treating MIBC. Complications TMT seems to be well tolerated, with acute toxicity experienced by 10%–36% and up to 80%– 90% completing the entire course of the treatment. Toxicities were mainly hematologic, gastroenterologic, and genitourinary, in addition to neuropathy when cisplatin was used [58]. An RCT comparing RT with or without 5-FU and MMC found no increase in the rate of major toxicity or decrease in rates of completion of RT [72]. In addition, salvage RC following conventionally fractionated RT in contemporary series showed no significant differences in major complication rates and perioperative mortality compared with primary RC [73], although early salvage RC had higher cardiovascular and hematologic complications (37% versus 15%, P = 0.02), while delayed salvage RC had higher tissue healing complications (35% versus 12%, P = 0.05) [74]. Late grade 3 urinary toxicities occurred in 3%–8% of cases, namely urgency, nocturia, and dysuria, and required cystectomy for distressing symptoms in 0%–2%. Quality of life was suggested to be better in the bladder preservation pathway, with better overall sexual function [58]. Alternative Approaches in Treatment of MIBC When bladder preservation is elected, clinicians should strongly recommend a multimodal approach as opposed to TURBT followed by surveillance, partial cystectomy, RT, or chemotherapy as single modalities [4,5]. Hence, while these modalities have been described, they are rarely performed with a curative intent and instead are reserved for palliative purposes in patients who cannot tolerate more intensive therapies or refuse other treatment. Maximal TURBT Alone Maximal TURBT has been reported, and might be an option in tumors smaller than 2 cm that minimally invade the muscle, in the absence of CIS, palpable mass, and hydronephrosis [6]. These patients should receive intravesical therapy and be followed aggressively with cystoscopies and cytology, and prompt decision should be done at relapse according to the stage of the tumor [6]. In a report on the long-term follow-up of 133 patients who had MIBC with a negative biopsy of the tumor bed, with no residual tumor, hydronephrosis, or metastatic disease, the DSS was 82%, 80%, and 77% while PFS with preserved bladder was 76%, 65%, and 58% at 5, 10, and 15 years [75]. There is not enough evidence however to validate the findings of this study and patients should be discouraged to consider this a curative approach. Partial Cystectomy Partial cystectomy is a less morbid procedure when compared with RC since urinary diversion is not necessary in avoiding potential bowel complications. The AUA/ASCO/ASTRO/SUO guidelines recommend against partial cystectomy in medically fit patients willing to undergo RC [4]. However, when such patients are carefully selected, partial cystectomy can be an acceptable option. A SEER matched analysis showed that RC and partial cystectomy offered comparable DSS and OS [76]. In 2012 the Mayo Clinic group published their cohort analysis of 86 patients who underwent partial cystectomy matched to 167 patients who underwent RC. The analysis

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showed a similar 10-year metastasis-free survival (66% for partial versus 61% for RC, P = 0.63) and DSS (63% versus 58%, P = 0.67) [77]. No prospective randomized trial has been performed to compare RC with partial cystectomy and hence no real conclusion could be made about the suitability of partial cystectomy as an option with curative intent, especially if coupled to NAC.

Outstanding Questions

RT Alone RT as a monotherapy is no longer an accepted option in nonmetastatic MIBC in the curative setting [4,5]. While the initial response could be reasonable, the 10-year DSS and OS in a study were as low as 35% and 19%, respectively [78]. Furthermore, in a Cochranexx analysis, RT alone was shown to be inferior to RC in MIBC, with a mean OS at 3 and 5 years of 45% and 36% for surgery, and 28% and 20% for RT alone, respectively [79]. Similarly, RT alone was inferior to RT with radiosensitizing chemotherapy in a multicenter Phase 3 trial of 360 patients. DFS was significantly better in the chemo-radiation arm with a median follow-up of 70 months (HR = 0.68, P = 0.03), while the advantage in OS was not statistically significant (HR = 0.82, P = 0.16) [61].

Can we predict response to neoadjuvant platinum-based chemotherapy and how will this impact use of neoadjuvant therapies?

NAC Alone This approach is limited to patients who achieve clinically complete response following NAC with an intent to proceed to RC, however elect against surgery based on this complete response. While it is known that complete response to chemotherapy is a major predictor of better survival at cystectomy, it is not known whether this response is durable when bladder is retained. The common experience of Memorial Sloan Kettering and Columbia University with 148 patients showed a 5-year DSS, OS, cystectomy-free survival, and RFS of 90%, 86%, 76%, and 64%, respectively. Only 11% recurred with muscle-invasive disease and only 4 of the 26 patients who underwent salvage RC died of bladder cancer [80]. While this study shows that this practice can be acceptable in a very carefully selected and compliant patient population, chemotherapy should not be advocated as monotherapy in the treatment of localized MIBC, since most patients have residual disease and recur if the bladder is left intact [5].

Concluding Remarks MIBC is an aggressive disease but can be cured, especially in patients with organ-confined disease, when prompt treatment is provided. The standard of care treatment for nonmetastatic MIBC in patients who can tolerate these treatments is cisplatin-based NAC followed by RC. A considerable proportion of patients are not cisplatin eligible or are medically unfit to tolerate a major surgery and these pose a significant challenge. However, a proportion of patients have platinum-resistant tumors and these might progress while receiving chemotherapy as RC is being delayed. To date, urologists and oncologists are not able to identify that category of patients with cisplatin-resistant tumors in order to proceed directly to RC but molecular markers are being evaluated for this goal (see Outstanding Questions). There are no validated markers yet but identification of a gene signature that could predict response to cisplatin therapy could significantly direct the management plan and impact survival of MIBC patients. Furthermore, while immune checkpoint inhibitors such as the PD-1 inhibitor pembrolizumab are being studied in the neoadjuvant setting as an alternative in cisplatin-ineligible patients, with promising results, immunotherapy could also have a role in patients with cisplatinresistant tumors. More research is needed in this field, and future genetic signatures could also help predict the response and its durability following other therapies, such as RT alone, chemotherapy alone, and TMT. Disclaimer Statement None of the authors has a conflict of interest related to writing and publishing this manuscript.

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Can we improve staging of muscleinvasive bladder cancer to identify nonorgan confined disease and will this improve management decisions and outcomes?

Will advancements in urinary and tissue tumor markers allow for prediction of response to various therapies? Will there be an established role for immunotherapy and immune checkpoint inhibitors in the neoadjuvant setting in cisplatin-ineligible patients? Will proper prediction of adequate response to radiation therapy as part of trimodality therapy allow for more utilization of this treatment strategy? Are we going to be able to predict durable response as part of the assessment of response to bladder-preserving strategies? Will novel radiosensitizers under study improve response rates to radiation therapy as part of trimodality therapy? What will be the role of adjuvant therapies in patients undergoing cystectomy who are found to have non-organ confined disease?

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Resources i

https://seer.cancer.gov/

ii

www.auanet.org/

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www.facs.org/quality-programs/cancer/ncdb

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www.dshs.texas.gov/tcr/

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www.nccn.org/professionals/physician_gls/

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https://uroweb.org/guidelines/

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www.swog.org/

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https://clinicaltrials.gov/ct2/show/NCT01224665

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https://clinicaltrials.gov/ct2/show/NCT02451423

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https://clinicaltrials.gov/ct2/show/NCT02690558

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www.eortc.org/

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https://clinicaltrials.gov/ct2/show/NCT03244384

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https://clinicaltrials.gov/ct2/show/NCT02450331

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https://clinicaltrials.gov/ct2/show/NCT02632409

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www.facs.org/quality-programs/acs-nsqip

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www.nrgoncology.org/

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https://clinicaltrials.gov/ct2/show/NCT03775265

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