Therapy For Muscle-invasive Bladder Cancer Research Articles

Refining neoadjuvant therapy clinical trial design for muscle-invasive bladder cancer before cystectomy: a joint US Food and Drug Administration and Bladder Cancer Advocacy Network workshop.

The success of the use of novel therapies in the treatment of advanced urothelial carcinoma has contributed to growing interest in evaluating these therapies at earlier stages of the disease. However, trials evaluating these therapies in the neoadjuvant setting must have clearly defined study elements and appropriately selected end points to ensure the applicability of the trial and enable interpretation of the study results. To advance the development of rational trial design, a public workshop jointly sponsored by the US Food and Drug Administration and the Bladder Cancer Advocacy Network convened in August 2019. Clinicians, clinical trialists, radiologists, biostatisticians, patients, advocates and other stakeholders discussed key elements and end points when designing trials of neoadjuvant therapy for muscle-invasive bladder cancer (MIBC), identifying opportunities to refine eligibility, design and end points for neoadjuvant trials in MIBC. Although pathological complete response (pCR) is already being used as a co-primary end point, both individual-level and trial-level surrogacy for time-to-event end points, such as event-free survival or overall survival, remain incompletely characterized in MIBC. Additionally, use of pCR is limited by heterogeneity in pathological evaluation and the fact that the magnitude of pCR improvement that might translate into a meaningful clinical benefit remains unclear. Given existing knowledge gaps, capture of highly granular patient-related, tumour-related and treatment-related characteristics in the current generation of neoadjuvant MIBC trials will be critical to informing the design of future trials.

703P Camrelizumab in combination with gemcitabine plus cisplatin as neoadjuvant therapy for muscle-invasive bladder cancer

Chemotherapy combined with immunotherapy before radical cystectomy (RC) is anticipated to improve survival of muscle-invasive bladder cancer (MIBC) patients(pts). We investigated the efficacy and safety of camrelizumab in combination with gemcitabine plus cisplatin (GC) as neoadjuvant therapy in MIBC pts.

Retrospective evaluation of planning margins for patients undergoing radical radiation therapy treatment for bladder cancer using volumetric modulated arc therapy and cone beam computed tomography.

IntroductionCurrent contouring guidelines for curative radiation therapy for muscle‐invasive bladder cancer (MIBC) recommend margins of 1.5–2.0 cm, applied to the clinical target volume (CTV). This study assessed whether the use of volumetric modulated arc therapy (VMAT), cone beam computed tomography (CBCT) and strict bladder preparation allowed for a reduced planning target volume (PTV) expansion, resulting in lower doses to surrounding organs at risk (OARs).MethodsDaily CBCT images for 12 patients (382 scans total) were retrospectively reviewed against four potential PTV margins created on and exported with the reference CT scan. To form the PTVs, three isotropic expansions of 0.5, 1.0 and 1.5 cm were applied to the CTV, as well as an anisotropic expansion of 1.5 cm superiorly and 1.0 cm in all other dimensions. Following treatment completion, the CBCTs were visually assessed to determine the margins encapsulating the bladder. For retrospective planning purposes, the 1.0‐cm and anisotropic margins were compared with the previously recommended margins to determine differences in OAR doses.ResultsThe 0.5‐, 1.0‐ and 1.5‐cm isotropic margins (IM) and the anisotropic margin (ANIM) covered the CTV in 46.1, 96.8, 100 and 100% of CBCTs retrospectively. Doses to OARs were significantly lower for the reduced margin plans for the small bowel, rectum and sigmoid.ConclusionBladder planning target volumes may be safely reduced. We endorse a PTV margin of 1.0cm anteriorly, posteriorly and inferiorly with 1.0–1.5 cm superiorly for radical whole bladder cases using strict bladder preparation, VMAT and pretreatment CBCTs.

Patterns and predictors of treatment in muscle-invasive bladder cancer (MIBC): A real-world study.

e16531 Background: Among the approaches to curative-intent therapy for MIBC, neoadjuvant cisplatin-based chemotherapy (NAC) is recognized as the gold standard. The combined modality approach of concurrent chemo-radiation is also considered a standard of care. Despite guidelines recommending multidisciplinary care, studies have shown a low adoption rate of multidisciplinary approaches for MIBC. This study aimed to describe the treatment patterns for MIBC pts using real world data. Methods: Following the appropriate IRB approvals, investigators followed a common protocol under the auspices of the Rapid Case Ascertainment at the Yale Cancer Center. Manual chart review was performed on MIBC pts diagnosed in Connecticut from 2004 –2015 and treated at investigator-affiliated hospitals. Information on medical history, comorbidity, and treatment types were recorded. This data set was linked to the Surveillance, Epidemiology, and End Results (SEER) database for demographic information. The descriptive and logistic regression were used to analyze treatment patterns and predicators in each treatment lines: surgery alone, chemotherapy alone, radiation alone and standard care (NAC followed by surgery; surgery followed by adjuvant chemotherapy and concurrent chemo-radiation). Results: The number of adult MIBC pts in the cohort was 1,198. Among them, 290 (24.2%) received surgery as the only treatment; 117 (9.8%) received chemotherapy only; 100 (8.3%) received concurrent chemo-radiation; 96 (8.0%) received NAC followed by surgery. Besides age ( OR: 0.546, 95% CI: 0.289-0.986), when comparing female to male patients on the likelihood of receiving NAC to the alternative treatment types (radiation or surgery), female pts were less likely to receive NAC than males (OR: 0.421, 95% CI: 0.184-0.930). Conclusions: Regardless of demographics, the overall adoption rate of standard care was low, consisting of 236 pts (19.7%) of the population. From the logistic regression results, age was consistently shown as a predictor for receiving NAC over the alternative treatment types, and sex was identified as another strong predictor. Older and female patients were less likely to receive NAC than younger males.[Table: see text]

Ultrasound-Mediated Gemcitabine Delivery Reduces the Normal-Tissue Toxicity of Chemoradiation Therapy in a Muscle-Invasive Bladder Cancer Model

PurposeChemoradiation therapy is the standard of care in muscle-invasive bladder cancer (MIBC). Although agents such as gemcitabine can enhance tumor radiosensitivity, their side effects can limit patient eligibility and treatment efficacy. This study investigates ultrasound and microbubbles for targeting gemcitabine delivery to reduce normal-tissue toxicity in a murine orthotopic MIBC model.Materials and MethodsCD1-nude mice were injected orthotopically with RT112 bladder tumor cells. Conventional chemoradiation involved injecting gemcitabine (10 mg/kg) before 6 Gy targeted irradiation of the bladder area using the Small Animal Radiation Research Platform (SARRP). Ultrasound-mediated gemcitabine delivery (10 mg/kg gemcitabine) involved either coadministration of microbubbles with gemcitabine or conjugating gemcitabine onto microbubbles followed by exposure to ultrasound (1.1 MHz center frequency, 1 MPa peak negative pressure, 1% duty cycle, and 0.5 Hz pulse repetition frequency) before SARRP irradiation. The effect of ultrasound and microbubbles alone was also tested. Tumor volumes were measured by 3D ultrasound imaging. Acute normal-tissue toxicity from 12 Gy to the lower bowel area was assessed using an intestinal crypt assay in mice culled 3.75 days posttreatment.ResultsA significant delay in tumor growth was observed with conventional chemoradiation therapy and both microbubble groups (P < .05 compared with the radiation-only group). Transient weight loss was seen in the microbubble groups, which resolved within 10 days posttreatment. A positive correlation was found between weight loss on day 3 posttreatment and tumor growth delay (P < .05; R2 = 0.76). In contrast with conventional chemoradiation therapy, ultrasound-mediated drug delivery methods did not exacerbate the acute intestinal toxicity using the crypt assay.ConclusionsUltrasound and microbubbles offer a promising new approach for improving chemoradiation therapy for muscle-invasive bladder cancer, maintaining a delay in tumor growth but with reduced acute intestinal toxicity compared with conventional chemoradiation therapy.

Phase II trial of escalating doses of neoadjuvant atezolizumab for patients with non-metastatic urothelial carcinoma ineligible for cisplatin-based neoadjuvant chemotherapy.

442 Background: For patients (pts) with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based chemotherapy (cisplatin), the standard of care option is radical cystectomy (RC) alone. This prospective clinical trial investigated the safety and efficacy of escalating doses of atezolizumab (ATZ) as neoadjuvant therapy prior to RC in pts with non-metastatic urothelial cancer. Methods: This single-arm, single institution, phase II trial investigated the administration of one (n = 6), two (n = 5) or three (n = 9) cycles of ATZ (1200 mg IV given every 3 weeks) in pts with MIBC who are either ineligible for or refused cisplatin prior to RC. Key inclusion criteria were urothelial carcinoma of the bladder (T2-T4a,N0-1,M0) and inability to receive cisplatin-based treatment (eGFR &lt; 60 mL/min, G≥2 neuropathy/hearing loss, pt decision). Pts with high-risk disease ( &gt; pT2 or LN+) at the time of RC were eligible to receive adjuvant ATZ for up to 16 total cycles. Primary efficacy endpoint was pathologic complete response (pCR; pT0N0). Important secondary endpoints were safety of treatment, rates of pathologic downstaging and biomarker assessments in serial tissue samples. Pts were followed for up to 2 years following RC. Results: Among 20 pts with MIBC, median age was 69 (range 61-81) and 75% were male. Most commonly pts were cisplatin-ineligible due to low GFR (35%), hearing loss (25%) or neuropathy (10%); remainder refused cisplatin (30%). At trial enrollment, pT2, pT3, and pT4 was present in 80%, 15%, and 5% of pts and 10% had enlarged pelvic lymph nodes ( &gt; 10 mm) on scans. All pts completed intended treatment cycles and all had RC within the defined timeframe ( &gt; 3 weeks from last and &lt; 12 weeks from first treatment). pCR at RC was 10% (2/20 pts), and was observed in pts receiving 1 and 2 cycles of ATZ. Pathologic downstaging (≤pT1N0) was achieved in 25% (5/20 pts) and observed across all three dose levels. Adjuvant ATZ was given to 8 pts. TRAEs of any grade during perioperative period occurred in 75% and G3 TRAEs in 10% (diarrhea, fecal incontinence). There were no G4 or G5 events. Median follow-up from the time of RC was 21.4 months at the time of data cutoff in 10/2020. Among evaluable pts, 1-year RFS and OS were 71% and 94% while 2-year RFS and OS were 64% and 75%. Conclusions: This prospective trial supports the safety and efficacy of ATZ as neoadjuvant therapy in MIBC. Although pCR and rates of downstaging were lower than what was previously reported in comparable neoadjuvant trials of checkpoint inhibitors in MIBC, pCRs in this trial were seen even in pts receiving only 1-2 doses of ATZ. Many pts had a durable recurrence-free period and all 4 evaluable pts who had pathologic downstaging were alive and disease free at 2 years post RC. Translational and biomarker work from this study is also being pursued. Clinical trial information: NCT02451423.

Staging 18F-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Changes Treatment Recommendation in Invasive Bladder Cancer

Given the high risk of systemic relapse following initial therapy for muscle-invasive bladder cancer (MIBC), improved pretreatment staging is needed. We evaluated the incremental value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) after standard conventional staging, in the largest cohort of MIBC patients to date. This is a retrospective analysis of 711 consecutive patients with invasive urothelial bladder cancer who underwent staging contrast-enhanced CT (chest and abdomen) and FDG-PET/CT in a tertiary referral center between 2011 and 2020. We recorded the clinical stage before and after FDG-PET/CT and treatment recommendation based on the stage before and after FDG-PET/CT. Clinical stage changed after FDG-PET/CT in 184/711 (26%) patients. Consequently, the recommended treatment strategy based on imaging changed in 127/711 (18%) patients. In 65/711 (9.1%) patients, potential curative treatment changed to palliative treatment because of the detection of distant metastases by FDG-PET/CT. Fifty (7.0%) patients were selected for neoadjuvant/induction chemotherapy based on FDG-PET/CT. Moreover, FDG-PET/CT detected lesions suspicious for second primary tumors in 15%; a second primary malignancy was confirmed in 28/711 (3.9%), leading to treatment change in ten (1.4%) patients. Contrarily 57/711 (8.1%) had false positive secondary findings. In conclusion, FDG-PET/CT provides important incremental staging information, which potentially influences clinical management in 18% of MIBC patients, but leads to false positive results as well. Patient summaryIn this report, we investigated the impact of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) scanning on treatment of bladder cancer patients. We found that FDG-PET/CT potentially influences the treatment of almost one-fifth of patients. We therefore suggest performing FDG-PET/CT as part of bladder cancer staging.

Diagnostic performance of contrast-enhanced dynamic and diffusion-weighted MR imaging in the assessment of tumor response to neoadjuvant therapy in muscle-invasive bladder cancer.

To evaluate the diagnostic performance of DCE MRI and DWI in the assessment of pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC). This prospective study included 90 patients with MIBC who finished NAC. Two radiologists independently assessed MRI for the determination of semi-quantitative parameters (wash-in rate and wash-out rate) and apparent diffusion coefficient (ADC) value. The correlation between pCR and wash-in rate, wash-out rate, ADC value were analyzed. The area under the ROC curve (AUC) was used to evaluate the diagnostic performance for detecting pCR. Inter-reader agreement was assessed using the ICC statistics. On cystectomy specimens, pCR was confirmed in (43.3%, 39/90). pCR is negatively correlated with wash-out rate (r = - 0.701, p = 0.01) and ADC value (r = - 0.621, p = 0.01). ADC value is positively correlated with wash-out rate (r = 0.631, p = 0.001). The diagnostic accuracy of ADC value (cut-off value: 0.911 × 10-3mm2/s) and wash-out rate (cut-off value: 0.677 min-1) in the identification of pCR was (92% for reader 1, 91% for reader 2), and (90% for reader 1, 88% for reader 2), respectively. The sensitivity, specificity for predicting pCR using ADC value + washout rate cut off values were 95.4%, 97.7% for reader 1, and 96%, 97% for reader 2, respectively. AUC was 0.981 for reader 1, 0.971 for reader 2. The overall reproducibility of the mean ADC value and wash out rate was excellent (ICC = 0.83-0.90). The ICC values for the mean ADC value, washout rate was 0.89 (95% CI 0.84-0.89) and 0.87 (95% CI 0.86-0.91), respectively. Semi-quantitative parameter (wash-out) derived from DCE-MRI and ADC has the potential to assess the tumor's complete pathologic response. The two parameters using together can offer the best possibility to identify complete response to NAC in MIBC.

The Significance of Neutrophil-to-Lymphocyte Ratio and Combined Chemoradiotherapy in Patients Undergoing Bladder Preservation Therapy for Muscle-Invasive Bladder Cancer.

BackgroundBladder-sparing treatment has been developed with the aim of preserving bladder function. However, considerable controversy remains regarding the effectiveness of organ preservation strategies. Accordingly, we investigated factors influencing the prognosis of muscle-invasive bladder cancer (MIBC) patients who received bladder-sparing treatment.Materials and MethodsIn the study, we retrospectively reviewed 193 patients who were newly diagnosed with MIBC and received bladder-sparing treatment from 2006 to 2013 in our hospital.ResultsThe 5-year overall survival, progression-free survival (PFS) and bladder-preservation survival rates after diagnosis were 64.7%, 52.1%, and 64%, respectively. The presence of hydronephrosis, advanced stage and not achieving complete response were associated with a marked reduction in PFS. Treatment with an adequate dose of combined chemoradiotherapy (CCRT) (chemotherapy ≥2 cycles combined with radiotherapy dose ≥56Gy) significantly improved the complete response (CR), 5-year bladder-preservation survival, and PFS rates, particularly for patients with good performance status. The 5-year bladder-preservation survival rates for CR and non-CR patients were 75%, and 21%, respectively. Furthermore, higher pre-treatment neutrophil-to-lymphocyte ratio (NLR) (≥3) and lower hemoglobin (≤12) were significantly associated with lower CR rate, increased risk of loco-regional recurrence and reduced bladder-preservation survival rate. Multivariable Cox regression analysis based on different co-variables showed that pretreatment NLR was an independent prognostic factor for PFS when MIBC patients were stratified by clinical stage and the doses of CCRT.ConclusionIn MIBC patients with bladder-sparing treatment, adequate doses of CCRT and low NLR were found to be correlated with better PFS. We suggest the use of NLR as a clinical biomarker for the prognosis of MIBC and guidance of treatment decisions.

Radical Cystectomy Versus Bladder-Sparing Trimodal Therapy in Muscle-Invasive Bladder Cancer

Radical Cystectomy Versus Bladder-Sparing Trimodal Therapy in Muscle-Invasive Bladder Cancer

Refining assessment of response to radiation-based therapy for muscle-invasive bladder cancer: Is post-treatment tumor bed biopsy always necessary?

IntroductionRadiation-based therapy (RT) has emerged as a suitable alternative to radical cystectomy (RC) and pelvic lymph node dissection for muscle-invasive bladder cancer (MIBC) patients. Routine biopsy after RT to rule out residual disease remains inconsistent across guidelines. Our objective was to review the significance of a bladder biopsy in terms of assessment of response post-RT and its potential impact on survival. Patients and methodsThis was a single-center retrospective study on patients with MIBC (cT2-4aN0-2M0) treated with curative intent RT. A total of 169 patients with primary urothelial carcinoma were analyzed. Patients’ demographic, clinical and pathological variables, imaging, cystoscopy, urine cytology, and biopsy reports after RT were collected and compiled. Whenever urine cytology was positive or cystoscopy showed any malignant-appearing lesion, the first assessment post-RT was considered suspicious for residual disease. A descriptive population analysis was reported. Cox regression multivariable analysis was performed to identify independent variables associated with survival outcomes. ResultsMedian age was 75 years (interquartile range 66–82) and clinical staging was cT2 in 152 (90%) patients. Cytology and cystoscopy were normal in 140 (83%) after RT. Of patients with a control biopsy, residual MIBC was present in 3 (5%) and non-MIBC in another 6 (11%). On the contrary, a for-cause biopsy due to a suspicious assessment post-RT did not yield residual cancer in 45% of patients. Multivariable analysis showed that age (hazard ratio [HR] 1.04, P< 0.001), lymphovascular invasion (HR 1.68, P = 0.03) and a suspicious assessment after RT (HR 3.21; P< 0.001) were significantly associated with worse OS. This study was limited by its retrospective design. ConclusionsA routine biopsy after RT may be warranted to assess treatment response. This might be particularly important for patients who may benefit from early surgical intervention for residual MIBC. Further prospective studies are needed to confirm our findings.

Mutational Landscape and Genetic Determinants of Response to Trimodality Therapy in Muscle-Invasive Bladder Cancer

Mutational Landscape and Genetic Determinants of Response to Trimodality Therapy in Muscle-Invasive Bladder Cancer

Towards Evidence Based Practice: The American Radium Society (ARS) and American College of Radiology (ACR) Appropriate Use Guidelines on Radiation Therapy for Muscle-Invasive Bladder Cancer

Definitive radiotherapy (RT), with or without concurrent chemotherapy, is an alternative to radical cystectomy for patients with localized, muscle-invasive bladder cancer (MIBC) who are either not surgical candidates or prefer organ preservation. There is a paucity of high-quality, prospective data to guide patient selection and management. We aim to synthesize a consensus guideline regarding the appropriate use of radiotherapy based upon a systematic review of the available literature. We performed a Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) literature review using the PubMed and Europe PMC databases. Articles published before and up to 3/18/2019 were included in the systematic review. Search parameters were prospectively recorded and sequentially refined for relevance of article titles. Studies were included for full manuscript review after screening of the abstracts. Based upon findings of the literature review, critical management topics were identified and reformulated into consensus questions. An expert panel was assembled to address key areas of both consensus and controversy. A total of 761 articles were screened, of which 60 were published between 1975 to 2019 and included for full review. Of these, there were seven well-designed studies, 20 good quality studies, 27 quality studies with design limitations, and six references not suited as primary evidence. While early studies included node-positive MIBC, contemporary trials mostly exclude this population from definitive radiotherapy treatments. Adjuvant radiotherapy after cystectomy was not included due to lack of high-quality data or clinical utilization. An expert panel consisting of 14 radiation oncologists, one medical oncologist, and one urologist from 14 institutions was assembled. We identified four clinical variants of MIBC: surgically fit patients who wish to pursue organ preservation; patients surgically unfit for cystectomy; patients medically unfit for cisplatin-based chemotherapy; and borderline cystectomy candidates based on age with unilateral hydronephrosis and normal renal function. After synthesis of the evidence, we identified key areas of controversy, including use of definitive radiotherapy for patients with negative prognostic factors (e.g. hydronephrosis, multi-focal disease, extensive CIS), appropriate radiotherapy dose, fractionation, fields and technique when used, and chemotherapy sequencing and choice of agent. A systematic review of the literature was performed to assess the evidence for radiotherapy for patients with localized MIBC. Overall, there is a paucity of level-one evidence to guide clinical practice. Studies vary significantly with regards to patient selection, chemotherapy utilization, and radiotherapy technique. A consensus guideline on the appropriateness of RT for MIBC may aid practicing oncologists in bridging the gap between data and clinical practice.

CD40 Agonist Restores the Antitumor Efficacy of Anti-PD1 Therapy in Muscle-Invasive Bladder Cancer in an IFN I/II-Mediated Manner.

Bladder cancer is one of the most common malignancies and has poor prognosis for patients with locally advanced, muscle-invasive, disease despite the efficacy of immune checkpoint blockade. To develop more effective immunotherapy strategies, we studied a genetic mouse model carrying deletion of Tp53 and Pten in the bladder, which recapitulates bladder cancer tumorigenesis and gene expression patterns found in patients. We discovered that tumor cells became more malignant and the tumor immune microenvironment evolved from an inflammatory to an immunosuppressive state. Accordingly, treatment with anti-PD1 was ineffective, but resistance to anti-PD1 therapy was overcome by combination with a CD40 agonist (anti-CD40), leading to strong antitumor immune responses. Mechanistically, this combination led to CD8+ T-cell recruitment from draining lymph nodes. CD8+ T cells induced an IFNγ-dependent repolarization toward M1-like/IFNβ-producing macrophages. CD8+ T cells, macrophages, IFN I, and IFN II were all necessary for tumor control, as demonstrated in vivo by the administration of blocking antibodies. Our results identify essential cross-talk between innate and adaptive immunity to control tumor development in a model representative of anti-PD1-resistant human bladder cancer and provide scientific rationale to target CD40 in combination with blocking antibodies, such as anti-PD1/PD-L1, for muscle-invasive bladder cancer.

Abstract IA24: Predictive biomarkers of response to neoadjuvant therapy

Abstract The addition of cisplatin-based neoadjuvant chemotherapy prior to radical cystectomy provides a modest overall survival benefit for patients with muscle-invasive bladder cancer (MIBC). Moreover, the extent of pathologic response at cystectomy correlates with survival, and patients who achieve a complete pathologic response following neoadjuvant chemotherapy have significantly improved survival compared to patients with residual MIBC. Clinical features alone are unable to predict which patients will respond to neoadjuvant chemotherapy, and there is an urgent clinical need to identify genomic biomarkers to guide neoadjuvant therapy for MIBC. The Cancer Genome Atlas (TCGA) and related efforts have defined the genomic landscape of MIBC and have identified recurrent genomic alterations including mutations, chromosomal translocations, and copy number alterations. Additionally, gene expression profiling has defined molecular subtypes of MIBC that have distinct clinical and genomic features. These genomic data are being harnessed to understand the association among genomic features, response to neoadjuvant therapy, and clinical outcomes. Alterations in DNA damage and repair (DDR) genes have emerged as a biomarker of response to neoadjuvant cisplatin-based chemotherapy in several studies. Loss-of-function mutations in the nucleotide excision repair gene ERCC2 as well as in related DDR genes including ATM, FANCC, and RB1 have been associated with complete pathologic response to cisplatin-based chemotherapy and improved survival in MIBC patients receiving cisplatin-based chemotherapy. Functional studies have confirmed that many of the clinically identified DDR gene mutations confer loss of DNA repair capacity and drive cisplatin sensitivity in preclinical bladder systems. These data have informed the design of several ongoing biomarker-driven clinical trials that seek to identify a subset of patients with DDR-altered tumors who may be cured with cisplatin-based chemotherapy alone. In addition to driving response to DNA damaging-based chemotherapy, DDR gene alterations have also recently been associated with improved response to immune checkpoint inhibition in patients with metastatic urothelial cancer. The mechanism underlying this association remains incompletely understood; however, DDR pathway alterations can lead to increased tumor mutational burden and neoantigen load, which have each been associated with improved response to anti-PD1/PD-L1 agents. Immune checkpoint inhibitors have transformed the management of metastatic bladder cancer, and these agents are now being investigated in numerous clinical trials for patients with localized bladder cancer. However, only a subset of patients benefit from anti-PD1/PD-L1 therapy; therefore, identifying reliable predictive biomarkers of immunotherapy response in bladder cancer remains a critical need. Gene expression-based analyses have defined molecular subtypes that exhibit distinct clinical properties and therapeutic vulnerabilities. Tumors with basal-like gene expression properties appear to respond more robustly to neoadjuvant chemotherapy than luminal-like tumors. However, the specific genetic/epigenetic drivers of chemotherapy response among basal tumors are incompletely understood. Recently, gene expression subtypes were also found to correlate with response to immune checkpoint inhibition, including robust responses among a small but unique subset of patients with a neuronal tumor subtype. It is likely that applying similar genomic approaches to additional cohorts may provide further insights into the genomic drivers of therapeutic response and resistance to neoadjuvant therapies. Citation Format: Kent W. Mouw. Predictive biomarkers of response to neoadjuvant therapy [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr IA24.

Canadian experience of neoadjuvant chemotherapy on bladder recurrences in patients managed with trimodal therapy for muscle-invasive bladder cancer.

Bladder preservation with trimodal therapy (TMT) has emerged as a feasible alternative to radical cystectomy in patients with muscle-invasive bladder cancer. Neoadjuvant chemotherapy (NAC) was proven to cause pathological downstaging. For this reason, we evaluated whether receipt of NAC decreases local bladder recurrences in TMT patients. We retrospectively analyzed our TMT database for all patients treated between 2003 and 2017. Patients were treated with maximal transurethral resection of bladder tumor (TURBT) followed by chemotherapy/radiotherapy with or without NAC. Baseline demographic and tumor characteristics were recorded. Rates of local and systemic recurrence were analyzed per receipt of NAC. Overall recurrence-free survival (RFS) and bladder (b)RFS were analyzed using the Kaplan-Meier method and Cox proportional hazards modelling. Median age and followup periods were 72 years and 3.6 years, respectively. Fifty-four patients had NAC and concurrent chemoradiation (NAC-TMT) vs. 70 patients who had concurrent chemoradiation only (TMT). Carcinoma in situ (CIS) was present in 31% of the patients in NAC-TMT group compared to 24% in TMT group (p=0.40). After treatment, 24 (44%) and 31 (44%) patients in NAC-TMT and TMT groups, respectively, had bladder tumor recurrence. Overall RFS at three years was 46% and 50% in NAC-TMT and TMT groups, respectively (p=0.70). BRFS at three years was 55% and 69% in NAC-TMT and TMT groups, respectively (p=0.27). Multivariable analyses found that the presence of concomitant CIS (hazard ratio [HR] 2.13; 95% confidence interval CI 1.06-4.27; p=0.0036) was the primary factor associated with local bladder recurrence. Receipt of NAC does not obviate the risk of bladder recurrence post-TMT. Patients with CIS should be monitored especially closely for local recurrence.

Bladder preservation therapy in muscle-invasive bladder cancer: Current evidence and future perspectives

: Radical cystectomy has been widely accepted as the standard treatment in muscle-invasive bladder cancer. However, removal of the bladder requires urinary diversions and substantially impairs patients’ quality of life. Radical cystectomy is also associated with a significant risk of perioperative complications and mortality. Bladder preservation therapy has been explored as a potential alternative to overcome such limitations of radical cystectomy, and a growing body of evidence suggests that bladder preservation therapy could become the primary treatment strategy in muscle-invasive bladder cancer patients. This review aims to provide an overview of the current practices, efficacy, limitations, and future perspectives on bladder preservation therapy. The trimodality protocol of bladder preservation therapy consists of maximal transurethral resection of the bladder tumor followed by radiotherapy with concurrent chemotherapy (chemoradiotherapy). Prospective studies demonstrated that the 5-year overall survival rates are comparable in both bladder preservation therapy and radical cystectomy (50–70%), suggesting that the two treatment paradigms have similar long-term outcomes. Major limitations of bladder preservation therapy include a significant risk of recurrence and insufficient survival outcomes, particularly in chemoradiotherapy non-responders. In addition, prediction of chemoradiotherapy response remains challenging even when clinical manifestations include large tumor size, advanced T stage, multifocality, concomitant carcinoma in situ, and hydronephrosis. Recently, different molecular biomarkers have been identified that could help select optimal muscle-invasive bladder cancer patients for bladder preservation therapy. A personalized treatment plan and further refinements of bladder preservation protocols are expected to improve treatment outcomes. For instance, consolidative partial cystectomy and pelvic lymph node dissection could be used as an adjunct in chemoradiation-based bladder preservation therapy to lower the recurrence rate of muscle-invasive bladder cancer. Additionally, several clinical trials are ongoing to explore whether synergistic anti-tumor activity, achieved by a combination of immune checkpoint inhibitors and chemoradiation-based bladder preservation therapy, could achieve beneficial results in muscle-invasive bladder cancer patients.

Trimodality Therapy for Muscle-Invasive Bladder Cancer: Concurrent Chemotherapy is Not Enough.

Trimodality Therapy for Muscle-Invasive Bladder Cancer: Concurrent Chemotherapy is Not Enough.

Impact of Molecular Subtyping and Immune Infiltration on Pathological Response and Outcome Following Neoadjuvant Pembrolizumab in Muscle-invasive Bladder Cancer

BackgroundThe PURE-01 study (NCT02736266) evaluated the use of pembrolizumab before radical cystectomy (RC) in muscle-invasive bladder cancer (MIBC). ObjectiveTo evaluate the ability of molecular signatures to predict the pathological complete response (CR: ypT0N0) and progression-free survival (PFS) after pembrolizumab and RC. Design, setting, and participantsWe analyzed the expression data from patients with T2–4aN0M0 MIBC enrolled in the PURE-01 study (N=84) and from patients of a retrospective multicenter cohort treated with cisplatin-based neoadjuvant chemotherapy (NAC; N=140). InterventionNeoadjuvant pembrolizumab or NAC and RC. Outcome measurements and statistical analysisImmune signatures and molecular subtyping (The Cancer Genome Atlas, consensus model, and genomic subtyping classifier [GSC]) were evaluated in relation to CR and PFS. Multivariable logistic regression analyses for CR were used, adjusting for gender and clinical T stage. Results and limitationsThe Immune190 signature was significant for CR on multivariable logistic regression analyses (p= 0.02) in PURE-01, but not in the NAC cohort (p= 0.7). Hallmark signatures for interferon gamma (IFNγ; p= 0.004) and IFNα response (p= 0.006) were also associated with CR for PURE-01, but not for NAC (IFNγ: p= 0.9 and IFNα: p= 0.8). In PURE-01, 93% of patients with the highest Immune190 scores (>1st quartile) had 2-yr PFS versus 79% of those with lower scores; no difference was observed in NAC patients, as well as for the other hallmarks in both groups. The neuroendocrine-like subtype had the worst 2-yr PFS in all three subtyping models (33%) and the GSC claudin-low subtype had the best, with no recurrences in 2 yr. Basal subtypes (across classifications) with higher Immune190 scores showed 100% 2-yr PFS after pembrolizumab therapy (p = 0.04, compared with basal-Immune190 low). Statistical analyses are limited by the small number of events and short follow-up. ConclusionsHigher RNA-based immune signature scores were significantly associated with CR and numerically improved PFS outcomes after pembrolizumab, but not after NAC. These data emphasize that RNA profiling is a potential tool for personalizing neoadjuvant therapy selection. Patient summaryWe used gene expression profiling to evaluate the association between immune gene expression and response to neoadjuvant immunotherapy, compared with standard chemotherapy, in patients with muscle-invasive bladder cancer (MIBC). We found a significant association between immune gene expression and response to pembrolizumab, but not chemotherapy. We conclude that gene expression profiling has the potential to guide personalized neoadjuvant therapy in MIBC.

Outcomes and Profiles of Older Patients Receiving Definitive Radiation Therapy for Muscle-Invasive Bladder Cancer at a Tertiary Medical Center

PurposeOur purpose was to evaluate the outcomes and profiles of older patients with muscle-invasive bladder cancer (MIBC) treated with definitive radiation therapy (RT) with or without chemotherapy (CHT) at a tertiary medical center. Methods and MaterialsA retrospective study was conducted for older patients with MIBC who were ≥70 years old and underwent RT with or without CHT between 2000 and 2016. Overall survival (OS) was estimated using the Kaplan-Meier method. Disease-specific survival (DSS), cumulative incidence of progression, patterns of recurrence, and toxicities were examined. Univariate analyses were performed to identify variables associated with OS, DSS, and cumulative incidence of progression, using the Cox proportional hazards model. ResultsA total of 84 patients underwent definitive RT with or without CHT. Of these, only 29% were deemed medically fit to undergo radical cystectomy, and the remainder were medically unfit or had surgically unresectable disease. Median age was 81 years. Sixty-one percent, 29%, and 11% had clinical stage II, III, and IV disease, respectively. Eighty-six percent had maximal transurethral resection of bladder tumor before RT. Seventy-three percent received CHT with RT, and 27% had RT alone. Median follow-up was 5.7 years. Median OS was 1.9 years. OS was 42% and 25%, and DSS was 64% and 54% at 3 and 5 years, respectively. On univariate analysis, medical fitness to undergo radical cystectomy, receipt of CHT, lower T stage, and maximal transurethral resection of bladder tumor were associated with better OS; lower T stage was associated with better DSS. The cumulative incidence of progression was 44% and 49% at 3 and 5 years, respectively. Late grade 3 genitourinary and gastrointestinal toxicity were 15% and 4%, respectively. None had grade 4 or 5 toxicity. ConclusionsOlder patients with MIBC referred for RT were often medically unfit or had a surgically unresectable tumor. In these medically compromised patients, definitive RT with or without CHT was well tolerated and yielded encouraging treatment outcomes.