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Upper tract urothelial cancer (UTUC) is a rare cancer of the urothelium, comprising only a fraction of cases as compared to urothelial tumors of the bladder. As a result, systemic treatment approaches in bladder cancer are often applied to patients with UTUC. Given the anatomical location of these tumors, the age, the comorbid conditions of these patients with UTUC, and the need for radical nephroureterectomy for treatment, most patients have substantial impairment of renal reserve. There is growing evidence for the benefit of perioperative chemotherapy in this disease. Patients with UTUC have high rates of microsatellite instability and fibroblast growth factor receptor 3 mutations as compared to their bladder counterparts presenting unique, important subsets in UTUC. Immune checkpoint inhibitors targeting the programmed death receptor 1 and ligand have provided a new second-line treatment option for patients with UTUC and appear particularly well suited for patients with microsatellite instability. More work in understanding the molecular gene signatures and its relationship to response to chemotherapy, immunotherapy, and targeted therapy is needed to continually optimize care for patients with all stages of disease. Advances in UTUC are possible, when one accounts for the unique clinical and biological features of this disease. [ABSTRACT FROM AUTHOR]

Small cell (SC) urothelial cancer (UC) is a rare aggressive subtype with limited treatments and scarce knowledge about its biology. It frequently (60-70%) co-exists with different histologic forms, mainly urothelial carcinoma (UC), in the largest described series. Yet, it is currently unknown whether co-existent histologic components are found in metastatic SCUC tumors.;Given the presence of targeted therapies in UC, understanding the contribution of these mixed morphologies may help improve treatment strategies. In this study, we aimed to describe the morphologies of metastatic SCUC biopsies from localized disease (LD) to metastatic disease (MD). Data was extracted from a historical cohort of 409 patients with SCUC treated at MDACC between 1985 and 2020. Out of 124 patients who developed metastases after treatment for localized disease, 61 had a metastatic site biopsy. We assessed morphology in specimens reviewed by MDACC pathologists at three timepoints in patient trajectory: at LD or at transurethral resection (TUR), at definitive surgery (when available), and at MD. In morphological annotation, 'predominant SCUC' was defined as >50% of SC components in a biospecimen while 'minority SCUC' refers to less than 50% of SC. Patients were mostly male (52/61, 85.2%) and Caucasian (57/61, 93.4%), with a median age of 68.3 years [ICR: 60.3-70]. Fourty one (41/61, 67.2%) patients had a smoking history. At definitive treatment, 51/61 (83.6%) had radical or partial cystectomy, 30/61 (49.2%) received neoadjuvant chemotherapy and 16/61 (26.2%) received adjuvant treatment. The morphologies seen at TUR were 'SCUC only' in 13/61 patients (21.3%), 'predominant SCUC' in 30/61;(49.2%) and 'minority SCUC' in 18/61;(29.5%). In mixed tumors at TUR, UC was the most frequent co-existent morphology in 37/48 (77.1%). At surgery, 10/13 (76.9%) of patients with;'SCUC only' at TUR had other non-SC morphologies. At MD, most biopsies reflected 'SCUC only'; final distribution at MD was 'SCUC only' in 38/61 (62.3%), followed by 'predominant SCUC' in 11/61 (18%) and 'non-SCUC' in 12/61 (19.7%).;At;MD, most 'predominant SCUC' morphologies at TUR (21/30, 70%) had 'SCUC only', most 'SCUC only' (11/13,;84.6%) stayed the same, while;'minority SCUC' did not follow a specific pattern.;These shifts in SC predominance between LD and MD might reflect;the effect of chemotherapy;and limitations in tumor sampling when comparing tissues between TUR, resection and metastasis. In patients with 'SCUC only' prior to receiving neoadjuvant chemotherapy, around 77% were found to have non-SC components at the time of surgery. Yet, upon development of MD, most biopsies demonstrate 'SCUC only' morphology. This likely represents the more rapid proliferation and early metastatic potential observed with SCUC. Understanding the impact of various co-existent histological subtypes may help us understand whether targeted therapies play a role in the management of this disease. The challenges include the inability to assess tumor heterogeneity of SCUC in biospecimens at LD and MD. [ABSTRACT FROM AUTHOR]

Introduction: Muscle-invasive bladder cancer (BC) often occurs in patients with competing mortality risks, while also being associated with the highest rate of second primary nonurothelial cancers (SNUC) of all solid malignancies. We investigated the incidence, risk factors, and timing of SNUC as a competing mortality risk factor in patients with BC who were treated with curative intent radical cystectomy (RC).Methods: We performed a retrospective cohort study assessing patients who underwent RC for cT2-4 N0M0 BC from January 1, 2005 to December 31, 2018 at a single, high volume tertiary care referral center. The Fine-Gray multivariable regression model was used to evaluate predictive factors for SNUC. Cumulative incidence of mortality (CIM) was estimated with modified Kaplan-Meier analysis.Results: The median follow-up time for the 693 patients who underwent RC was 3.7 years (interquartile range [IQR] 1.9-5.9 years). SNUC developed in 85 (12.3%) patients at a median 3.0 years post-RC (IQR 1.2-5.5 years). On multivariable analysis, the only significant predictor for developing SNUC was freedom from BC recurrence or metastasis (HR 1.54, 95% CI 1.12-1.76, P = 0.019). The most common SNUCs were primary lung cancer (24, 3.2% of cohort) and colon cancer (9, 1.3% of cohort). BC surveillance imaging diagnosed SNUC in 35/52 (67.3%) patients with solid-organ visceral primaries. The overall mortality rate for any SNUC was 38.8%, with the 3 most lethal cancer types being pancreatic, lung, and colon (62.5%, 54.2%, and 44.4% mortality, respectively). The incidence of SNUC uniformly increased postoperatively, with a cumulative incidence of 22.1% (95% CI, 16.8-27.9%) at 12-years post-RC. 163 patients (23.5%) died from BC, 33 patients (4.8%) died from SNUC, and 94 patients (13.6%) died from other causes. While the CIM for BC plateaued around 5-years post-RC at 24%, the incidence of other-cause mortality uniformly rose throughout the postoperative period. By post-RC year 9 there was no significant difference in CIM between BC (CIM 27.2%, 95% CI, 23.5-31.1%) and other-causes (CIM 20.0%, 95% CI, 15.8-24.6%).Conclusions: The cumulative incidence of SNUC at 12-years post-RC was 22%, with the majority identified on BC surveillance imaging. While BC mortality plateaued around 5-years post-RC, mortality related to SNUC or other causes rose steadily in the postoperative period. These data have clinical significance with regards to patient counseling, survivorship and oncologic surveillance in the highly comorbid muscle-invasive BC population. [ABSTRACT FROM AUTHOR]

Purpose: Renal function dictates sequencing and eligibility for definitive therapy in upper tract urothelial carcinoma. We investigated longitudinal glomerular filtration rate (GFR) changes after neoadjuvant chemotherapy (NAC) and nephroureterectomy (RNU).Materials and Methods: Patients treated with ≥3 cycles of chemotherapy prior to RNU for UTUC from 2000 to 2019 were included. GFR was calculated by CKD-Epi before chemotherapy, before RNU, 1 to 3 months, and 12 months post-RNU. Pathologic stage and overall survival were compared in those with stable GFR (+/-10% of baseline) to the rest of the cohort.Results: One hundred and fifty-two patients received ≥3 cycles of NAC, with 121 (79%) receiving at least 1 cycle of cisplatin. Renal function dropped by mean of 22.3 ml/min/1.73 m2 from the beginning of chemotherapy to 1-year post-surgery. In patients receiving cisplatin, a mean decline of 26.2 ml/min/1.73 m2 was observed vs. 8.8 ml/min/1.73 m2 without cisplatin-based NAC (P < 0.01). GFR after RNU was unchanged between 3 and 12 months postoperatively. At 1 to 3 months after RNU, 19% of patients had GFR<30 ml/min/1.73m2. Improvement in GFR during NAC was associated with invasive final pathologic stage (P = 0.018) and worse overall survival (P = 0.049).Conclusions: In patients managed with NAC prior to RNU, renal function stabilizes at 1 to 3 months post-operatively and remains clinically similar for cisplatin or non-cisplatin-based therapy. Improvement in GFR during NAC was associated with higher pathologic stage and poorer survival, especially in those receiving non-cisplatin-based therapy, an observation that requires further investigation. [ABSTRACT FROM AUTHOR]

Objective: Tumor shrinkage of at least 10% after presurgical targeted molecular therapy (TMT) in renal cell carcinoma (RCC) patients has been associated with better overall survival (OS) outcomes. We characterized primary and metastatic tumor diameter response and OS in patients with metastatic clear cell RCC (ccRCC) who received preoperative TMT, immunotherapy, or both followed by deferred cytoreductive nephrectomy (dCN).Materials and Methods: Patients with metastatic ccRCC (n = 198) who underwent preoperative therapy and dCN from 2005 to 2019 were identified retrospectively. Longest primary and metastatic tumor diameters were calculated using cross-sectional images obtained before systemic therapy and dCN using the Response Evaluation Criteria in Solid Tumors. Patients were stratified by tumor shrinkage of at least 10% in the primary and/or metastatic tumors after systemic therapy. The Kaplan-Meier method was used to estimate OS, and Cox proportional hazards models were used to assess the association of patient characteristics with OS.Results: In total, 31.31% of patients had only metastatic tumor shrinkage (MTS) ≥ 10%, 8.08% had only primary tumor shrinkage (PTS) ≥ 10%, 32.32% had PTS and MTS ≥ 10%, and 28.28% had PTS/MTS < 10%. The median OS, number of patients with tumor shrinkage ≥ 10%, and International Metastatic Database Consortium (IMDC) scores were similar among the 3 systemic therapy groups (all P ≥ 0.80). Patients with MTS ≥ 10%, PTS ≥ 10%, and PTS/MTS ≥ 10% had significantly longer median OS compared to patients with PTS/MTS < 10% (P < 0.01). Patients with intermediate-risk IMDC scores had significantly longer median OS compared to patients in the poor-risk group. After adjusting for preoperative therapy and IMDC risk group, MTS ≥ 10%, PTS ≥ 10%, and PTS/MTS ≥ 10% were associated with better OS outcomes (HR 0.48 95% CI 0.32-0.73, P < 0.001; HR 0.48, 95% CI 0.23-0.98, P = 0.04; HR 0.44, 95% CI 0.29-0.67, P < 0.001, respectively).Conclusions: Intermediate risk score and shrinkage of at least 10% in the primary tumor, metastases, or both were associated with better OS outcomes in patients with metastatic ccRCC who underwent dCN independent of the type of preoperative systemic therapy. [ABSTRACT FROM AUTHOR]

Purpose: The presence of sarcomatoid features and/or lymph node-positive disease may be associated with a worse prognosis in chromophobe renal cell carcinoma (ChRCC). We sought to better characterize patients' long-term outcomes with these features compared with those without these features.Materials and Methods: We identified 300 patients treated for sporadic, unilateral, nonmetastatic ChRCC between 1993 and 2019. Clinical and pathologic features were summarized, and cancer-specific survival (CSS) and recurrence-free survival (RFS) were analyzed using Kaplan-Meier plots. Cox regression analysis was performed to determine factors associated with recurrence. Patients with sarcomatoid features and/or nodal disease were grouped as high-risk in a secondary analysis.Results: The median age was 60 years, 43.7% were female, 29.3% had pT3/T4 disease, 3.3% had sarcomatoid features, and 4% had pathologic N1 disease. Sixteen patients were categorized as high-risk based on the presence of sarcomatoid features (n = 4), pathologic N1 disease (n = 6), or both (n = 6). There were 22 recurrences; the recurrence rate in the low-risk group was 4.9% and 50% in the high-risk group. 10-year RFS was 91.4% in the low-risk group and 34.4% in the high-risk group (P < 0.001). 10-year CSS was 96.4% in the low-risk group and 54.3% in the high-risk group (P < 0.001). In multivariable analysis, sarcomatoid features (HR 5.5, CI 1.5-20.2, P = 0.01) and pN1 disease (HR 16.5, CI 5.3-51.4, P < 0.0001) were independently associated with RFS.Conclusions: The presence of sarcomatoid features and/or lymph node-positive disease portends a poor prognosis in ChRCC. Further studies evaluating the impact of novel therapeutic agents in these patients are warranted. [ABSTRACT FROM AUTHOR]

Introduction: Metastatic renal cell carcinoma with sarcomatoid dedifferentiation (sRCC) is associated with poor survival outcomes. We aimed to analyze the efficacy and safety of immune checkpoint inhibitors (ICI) in patients with sRCC comparing clear-cell (sccRCC) to non-clear cell epithelial histology (snccRCC).Methods: We performed retrospective analysis of sRCC patients who received ICI at MD Anderson Cancer Center (n = 48, 41 with ccRCC and 7 with nccRCC) to determine the overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Additionally, we performed a prespecified multivariable Cox regression comparing survival outcomes between sccRCC and snccRCC.Results: The ORR for the entire cohort was 35.4% (95% confidence interval [CI]: 23.4%, 49.6%), including 8 (16.7%) patients (95% CI: 8.7%, 29.6%) who achieved a complete remission. The disease control rate was 52% (95% CI: 38.3%, 65.5%). In patients with sccRCC, the ORR was 39% (95% CI: 25.7%, 54.3%) and disease control rate 58.5% (43.4%, 72.2%). Among 7 snccRCC patients, only one (14.3%) achieved an objective partial response. At a median follow-up of 51.1 months, the median PFS was 4.9 months (95% CI: 2.7, 16.3) and the median OS was 28.4 months (95% CI: 15.8, NA) for the entire cohort. For patients with sccRCC, the median PFS was 8.9 months, with median OS of 30.1 months, compared with median PFS of 2.3 months (HR 0.25 [95% CI: 0.08, 0.78]; P= 0.0145) and median OS of 6.7 months (HR 0.13 [95% CI 0.04, 0.44]; P=0.0009) for patients with snccRCC.Conclusion: ICIs appear to be effective in sccRCC while the treatment of snccRCC remains challenging. [ABSTRACT FROM AUTHOR]

Modern advances in systemic and localized therapies for patients with renal cell carcinoma (RCC) have significantly improved patients' outcomes. If disease progression occurs after initial treatment, clinicians often have multiple options for a first salvage therapy. Because salvage and initial treatments both may affect overall survival time, and they may interact in unanticipated ways, there is a growing need to determine sequences of initial therapy and first salvage therapy that maximize overall survival while maintaining quality of life. The complexity of this problem grows if a second salvage therapy must be chosen for patients with treatment-resistant disease or a second progression occurs following first salvage. On November 9, 2023, a think tank was convened during the International Kidney Cancer Symposium (IKCS) North America to discuss challenges in accounting for postprogression therapies when estimating overall survival (OS) time based on randomized controlled trial (RCT) data. The present manuscript summarizes the topics discussed, with the aim to encourage adoption of statistical methods that account for salvage therapy effects to obtain scientifically valid OS estimation. We highlight limitations of traditional methods for estimating OS that account for initial treatments while ignoring salvage therapy effects and discuss advantages of applying more sophisticated statistical methods for estimation and trial design. These include identifying multistage treatment strategies, correcting for confounding due to salvage therapy effects, and conducting Sequentially Multiple Assignment Randomized Trials (SMARTs) to obtain unbiased comparisons between multistage strategies. We emphasize the critical role of patient input in trial design, and the potential for information technology (IT) advances to support complex trial designs and real-time data analyses. By addressing these challenges, future RCTs can better inform clinical decision-making and improve patient outcomes in RCC., Competing Interests: Declaration of competing interest Pavlos Msaouel reports honoraria for scientific advisory board membership for Mirati Therapeutics, Bristol Myers Squibb, and Exelixis; consulting fees from Axiom Healthcare; nonbranded educational programs supported by Exelixis, Pfizer, and DAVA Oncology; leadership or fiduciary roles as a Medical Steering Committee member for the Kidney Cancer Association and a Kidney Cancer Scientific Advisory Board member for KCCure; and research funding from Takeda, Bristol Myers Squibb, Mirati Therapeutics, Regeneron Pharmaceuticals, and Gateway for Cancer Research. Eric A. Singer reports honoraria for data safety monitoring board membership for Aura Biosciences and leadership or fiduciary roles as a Medical Steering Committee member for the Kidney Cancer Association. Kathryn E Beckermann received funding to the institution for preclinical awards including BMS-IASLC-LCFA, Pionyr, Arsenal Bio, and Aravive, as well as funds as a consultant to Aravive, Aveo, Arcus, Alpine Bioscience, BMS, Exelixis, Merck, Eisai, Nimbus, and Adicet. Bradley A. McGregor reports consulting fees from Arcus, BMS, Daiichi, Eisai, Exelixis, Gilead, Lily, Pfizer as well as research funding to institution from BMS, Exelixis, Gilead, and Pfizer. Ulka N. Vaishampayan reports consulting fees from BMS. Novartis, Merck, Exelixis, Pfizer, Glilead and Alkermes, as well as speaker fees from Bayes and Exelixis. Eric Jonasch reports research support from Abbvie, Arrowhead, Aveo, BMS, Corvus, Merck, NiKang, ProFoundBio, Telix, honoraria from Aveo, Clinical Care Options, DAVA, EBSCO, Eisai, Exelixis, GSK, IDEO Oncology, i3 Health, Ipsen, Kaplan, Merck, Novartis, NiKang, Petra Drugstore, Plexus, leadership position in NCCN Guidelines (Vice-Chair Kidney Cancer Panel), member of the NCI RCC Steering Committee, and board Member of the International Kidney Cancer Coalition. Katie Coleman is employed by the Rare Cancer Research Foundation and has received honoraria from Exelixis for a speaking engagement related to patient advocacy. Nizar M. Tannir reported receiving and personal fees (honoraria) from Calithera Biosciences during the conduct of the study; and grants (sponsored trial) from Calithera Biosciences, Bristol Myers Squibb (BMS), Nektar Therapeutics, Arrowhead Pharmaceuticals, and Novartis, as well as personal fees (honoraria) from Calithera Biosciences, BMS, Eisai Medical Research, Merck Sharp & Dohme (MSD), Deka Biosciences, Neoleukin Therapeutics, Exelixis, and Ono Pharmaceutical outside the submitted work. Daniel M Geynisman reports honoraria from Targeted Oncology, consulting fees from Pfizer, Exelixis, AstraZeneca, Seattle Genetics/Astellas, Merck, and Bristol-Myers Squibb, as well as research funding to institution from Merck, Astellas Pharma, Harpoon Therapeutics, Arvinas, and CG Oncology. Walter M. Stadler reports consulting fees for participation in Data and Safety Monitoring Board from Astra-Zeneca, Merck, Pfizer, and Treadwell Therapeutics, other consulting fees from Astra-Zeneca, Aveo, Caremark/CVS, EMA Wellness, Fortress Biotech, and Xencor, speakers bureau for CME programs from Dava Oncology, Global Academyc for Medical Education, OncLive, PeerView, Research to Practice, and Vindico, research funding to institution from Abbvie, Amgen, Astra-Zeneca, Astellas (Medivation), Bayer, Bristol-Myers-Squibb, Boehringer-Ingelheim, Calithera, Corvus, Eisai, Exilixis, Genentech (Roche), Johnson & Johnson (Janssen), Merck, Novartis, Pfizer, Seattle Genetics, X4Pharmaceuticals, Xencor, stock holdings from Fortress Biotech, Expert Witness for Sandoz, as well as miscellaneous fees from Cancer (ACS), Up-To-Date, and the Kidney Cancer Journal. Yousef Zakharia reports advisory board / consulting fees from Bristol Myers Squibb, Amgen, Janssen, Eisai, Exelixis, Genzyme Corporation, Pfizer, EMD Serono, Astellas, and Seagen, Grant/research institutional support from Pfizer, Exelixis, and Eisai, as well as honoraria for data safety monitoring board membership from Janssen Research and Development. Daniel D. Shapiro has no disclosures., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)