bluuebunny/crossref_metadata_2025 huggingface dataset:
Systematic review of time to definitive treatment for intermediate-risk and high-risk prostate cancer: Are delays associated with worse outcomes?
Authors: Nguyen David-Dan , Haeuser Lorine , Paciotti Marco , Reitblat Chanan , Cellini Jacqueline , Lipsitz Stuart R. , Cone Eugene Blanchard , Trinh Quoc-Dien
Published: March 2021

233

Background: Prostate cancer (PCa) is an indolent disease, especially when detected at a localized stage. Unlike other tumors that may benefit from timely receipt of definitive therapy, it is generally accepted that treatment delays for localized PCa are acceptable, especially for low-risk PCa. We sought to determine if treatment delays for intermediate-risk and high-risk PCa negatively impacted oncological outcomes. Methods: We conducted a systematic review of the literature with searches of Medline, EMBASE, and the Cochrane Database of Systematic Reviews, from inception to June 30, 2020. General study characteristics as well as study population and delay information were collected. The outcomes of interest extracted included biochemical recurrence (BCR), pathological features (positive surgical margins, upgrading, extracapsular extension, and other pathological features), cancer-specific survival, and overall survival. Due to significant heterogeneity between studies, a meta-analysis was not possible. Results: After identifying 1793 unique references, 24 manuscripts met criteria for data extraction, 15 of which were published after 2013. Based on our review, delays up to 3 months are safe for all PCa and are not associated with worse oncological outcomes. Some studies identified worse oncological outcomes as a result of delays beyond 6 to 9 months. However, these studies are counterbalanced by others finding no statistically significant association with delays up to 12 months. Studies that did find worse outcomes as a result of delays identified a higher risk of BCR and pathological findings, but not worse survival. Conclusions: Definitive treatment for intermediate-risk and high-risk PCa can be delayed up to 3 months without any oncological consequences. Some evidence suggests that delays beyond 6-9 months are associated with a higher risk of BCR and varying worse pathological findings; as such, care should be given to provide definitive treatment within 9 months. To date, there is no evidence of worse cancer-specific or overall survival as a result of delayed treatment for intermediate-risk and high-risk PCa.
Post-radical prostatectomy (RP) outcome for patients with high-risk prostate cancer treated with intense neoadjuvant hormone therapy (NHT): Results of a pooled analysis of contemporary clinical trials.
Authors: McKay Rana R. , Berchuck Jacob E , Kwak Lucia , Xie Wanling , Silver Rebecca , Bubley Glenn , Chang Peter K. , Wagner Andrew , Zhang Zhenwei , Kibel Adam S. , Taplin Mary-Ellen
Published: March 2021

238

Background: Patients with high-risk prostate cancer have an increased risk of recurrence and death from prostate cancer. Intense NHT prior to RP has been associated with favorable pathologic responses in a subset of patients with high-risk disease. We conducted a pooled analysis of post-RP outcomes of four, multicenter, randomized, clinical trials of intense NHT prior to RP. Methods: All patients included were enrolled on trials evaluating intense NHT followed by RP. The primary endpoint was time to biochemical recurrence (BCR), defined as the time from RP to prostate specific antigen (PSA) >0.1 ng/mL or start of first post-RP therapy. Secondary endpoints included metastasis-free survival (MFS), overall survival (OS), and time to testosterone recovery. We evaluated outcomes in the overall population, favorable responders (defined as a pathologic complete response or minimum residual disease ≤ 5 mm at RP), and non-responders. We correlated pathologic parameters, including RP pathologic response, PTEN status, ERG status, and presence of intraductal carcinoma with BCR. Results: 121 patients were included of whom 78.5% (n=95) had high-risk disease by NCCN risk categories. Following NHT, 20.7% (n=25) had 0-5 mm of residual tumor (including 9.1%, n=11, with pathologic complete response). Overall, 52 patients (43.0%) experienced BCR, of whom two were exceptional responders (Table). Testosterone recovery was observed in 94.0% of patients (n=109/116). PTEN loss and presence of intraductal carcinoma were associated with shorter time to BCR. Conclusions: In this pooled analysis of clinical trials, we demonstrate that patients who achieve a favorable pathologic response to NHT prior to RP experienced a decreased PSA relapse rate and prolonged time to BCR. Larger residual tumor volumes and tissue-based parameters, including PTEN loss and intraductal carcinoma, were associated with BCR. Additional follow-up is warranted to evaluate the impact on long-term outcomes. Clinical trial information: NCT00298155; NCT00924469; NCT01547299; NCT02268175 . [Table: see text]
Sixty-day unplanned readmissions after robot-assisted versus open-radical prostatectomy.
Authors: Lingamaneni Prasanth , Baral Binav , Moturi Krishna Rekha , Shrivastava Trilok , Darweesh Omnia , Gupta Shweta
Published: March 2021

244

Background: Options for clinically localized prostate cancer include radical prostatectomy, radiation therapy and active surveillance. Robot-assisted radical prostatectomy (RARP) is increasingly being used, and now accounts for the majority of radical prostatectomies performed in the United States. The aim of our study was to evaluate differences in the patient population undergoing open versus robot-assisted prostatectomy, and to compare 60-day readmissions after index hospitalization for radical prostatectomy. Methods: We utilized the Nationwide Readmission database (NRD) to obtain data on patients with prostate cancer admitted in 2016 and 2017 for radical prostatectomy in the United States. We used T-test to compare means of continuous variables and chi-square test to compare proportions of categorical variables. Multivariable logistic regression was used evaluate risk factors for 60-day unplanned readmissions. Results: A total of 115,551 patients met the inclusion criteria, of which 80.1% underwent RARP. Patients undergoing RARP were slightly older (64.8 vs 63.1 years, p < 0.0001), more likely to have private insurance (51.7% vs 44.3%, p < 0.0001) and undergo surgery at a teaching hospital (83% vs 74.6%, p < 0.0001). Importantly, open prostatectomy (OP) patients had higher rates of co-morbidities, including, hypertension, diabetes mellitus, chronic kidney disease, obstructive lung disease, heart failure, coronary artery disease and malnutrition (p < 0.01 for these co-morbidities). Hospital stay was longer in those who underwent OP (3.1 vs 1.7 days, p < 0.0001), and they were more likely to be discharged to nursing facility (3.0% vs 0.4%, p < 0.0001) or with home health care (10.9% vs 4.8%, p < 0.0001). Hospitalization charges were higher in the RARP population ($60k vs 57k, p = 0.04). Inpatient mortality was low in both groups (0.3% for OP and ~0% for RARP, p < 0.001). 60-day readmission rate was higher in those who underwent OP (9.3% vs 5.0%, p > 0.0001). Overall, the three leading causes for readmission included sepsis (10.6%), post-procedure infection (8.4%) and venous thromboembolism (VTE, 8.3%). Even after adjustment for age and comorbidities, those who underwent OP had higher risk of all-cause readmission (aOR 1.39, 95% CI 1.25-1.53, p < 0.001) and readmissions for sepsis (aOR 1.36, 95% CI 1.02-1.81, p = 0.03) and post-procedure infection (aOR 1.38, 95% CI 1.06-1.81, p = 0.02). Risk of readmission for VTE was similar in both groups. Conclusions: Nationwide, there are differences in demographics and comorbid illness burden in prostate cancer patients selected for open and robot-assisted radical prostatectomy. Better short-term outcomes in the RARP cohort may be partially attributed to lower comorbidity burden in this group. However, despite adjustment for comorbidities, higher risk for all-cause readmissions and readmissions for infectious complications persisted in the OP group.
Extraperitoneal versus transperitoneal approach for robot-assisted radical prostatectomy: An updated systematic review and meta-analysis.
Authors: Uy Michael , Cassim Raees , Kim Jaehoon , Hoogenes Jennifer , Shayegan Bobby , Matsumoto Edward
Published: March 2021

261

Background: Extraperitoneal RARP (EP-RARP) has recently become a popular surgical approach and is often compared to the transperitoneal RARP (TP-RARP). We conducted a systematic review and meta-analysis of the available literature to evaluate the differences in peri-operative characteristics, oncological and functional control, and surgical complications between EP-RARP and TP-RARP. Methods: A comprehensive search of PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, Google Scholar, and select conference abstract publications was performed for eligible studies comparing outcomes between EP-RARP versus TP-RARP. This was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was prospectively registered with PROSPERO. A leave-one-out sensitivity analyses was performed to control for heterogeneity and risk of bias. Results: A total of 16 studies (three randomized controlled trials, five prospective, and eight retrospective studies) were included with a total pooled population of 3897 patients including 2201 (56.5%) EP-RARPs and 1696 (43.5%) TP-RARPs. When compared to TP-RARP, EP-RARP offers faster operative time (MD: -14.4 minutes; 95% CI: -26.3, -2.3; p = 0.02), decreased length of post-operative stay (MD: -0.9 days, 95% CI: -1.3, -0.4, p < 0.0001), decreased rates of post-operative ileus (RR: 0.2, 95% CI: 0.1, 0.7, p = 0.009) and inguinal hernia formation (RR: 0.2, 95% CI: 0.1, 0.5, p = 0.001). There were no significant differences in total complications, estimated blood loss, positive surgical margins, or urinary continence at 6 months post-RARP. Conclusions: Based on the available evidence, EP-RARP delivered similar oncological and functional outcomes, while also offering faster operative time, decreased length of post-operative stay, and decreased rates of post-operative ileus and inguinal hernia formation when compared to the TP-RARP. These findings provide evidence-based data for surgical approach optimization and prompts future research to examine whether these findings hold true with recent advances in single-port RARP and outpatient RARP.
Evaluation of treatment patterns and outcomes in patients diagnosed with genitourinary (GU) cancers with linked claims plus prior authorization data.
Authors: Lal Lincy S. , Elliott Caitlin , Korrer Stephanie , DaCosta Byfield Stacey , Chastek Benjamin , Patel Tejas
Published: March 2021

284

Background: Integration of clinical and claims data allows for the examination of outcomes and characteristics which is essential for real world evidence generation and clinical decision making. We describe utilization of clinical data collected from an oncology Prior Authorization (PA) program integrated with claims data to evaluate treatment patterns, resource utilization, and total costs of care during therapy for patients with newly diagnosed metastatic and non-metastatic renal (R), bladder (B), and testicular (T) cancers. Methods: Commercially insured patients with a GU cancer diagnosis, from 2/2016 to 12/2019 with both clinical information from a PA tool (based on NCCN guidelines) and claims from the Optum Research Database were identified. Demographics, clinical information (metastatic status and line of therapy), treatment duration, resource utilization, and all-cause costs were collected, and uploaded to a dynamic web-based Tableau dashboard. Analysis was conducted for non-metastatic and metastatic settings based on the first observed treatment episode. Drug additions or switches incremented line of therapy; single drug discontinuations did not. All cost data were adjusted to 2019 values. Results: A total of 3,736 patients were included; 13% were censored (i.e. on treatment at the end of the study period). 916 patients (25%) were metastatic and 2,820 (75%) were in their adjuvant/neoadjuvant (A/N) line. 60% of the population was ≥55 years old and 85% were male. The top regimen in A/N line for each cancer type were: nivolumab (R), BCG(B), bleomycin + carboplatin/cisplatin+ etoposide (T). The top regimen in metastatic cancer were: nivolumab (R), carboplatin/cisplatin + gemcitabine (B), bleomycin + carboplatin/cisplatin + etoposide (T). The median duration of A/N line ranged from 50(B) to 119(R) days while the median duration for metastatic line range from 71(T) to 82(R) days. The highest rate of inpatient admissions was observed in patients with R (31%). Of the three cancers, R was the most expensive in the A/N and metastatic settings with mean (standard deviation) costs of $192,308 ($269,358) and $136,293 ($146,632), respectively. Conclusions: Combination of clinical and claims data provide valuable information on real world outcomes in routine clinical care and may support treatment selection decisions at the point of care.
The impact of hypertension on response rates in patients with renal cell carcinoma.
Authors: Maslov Diana , Tawagi Karine , KC Madhav , Goel Richa , Yuan Helen , Bamnolker Adi , Blake Zoe , Song William , Johnson Daniel , Matrana Marc Ryan
Published: March 2021

287

Background: There are many clinical trials that demonstrate the benefits of immunotherapies and targeted therapies in patients (pts) with advanced or metastatic RCC (mRCC). Most of these studies specifically exclude many real-world pts with comorbidities such as autoimmune disease, heart failure, and hypertension. Data on treatment efficacy and adverse events in patients with a history of uncontrolled hypertension is lacking, as there have been few studies analyzing more recently approved RCC drug regimens in real-world practice. Methods: We retrospectively collected data from pts with mRCC treated with immunotherapy and/or targeted therapies. Patient characteristics, performance status, treatment type, reason for treatment discontinuation, treatment response/progression per RECIST v1.1, survival, and presence of clinical trial exclusion criteria such as hypertension, heart failure, presence of autoimmune disease, renal or liver failure, and International Metastatic RCC Database Consortium (IMDC) Risk score were collected. Results: A total of 198 pts were included. The majority of patients received Tyrosine Kinase Inhibitors (TKIs) (42.42% pazopanib (n = 84), 21.71% sunitinib (n = 43), 13.64% cabozantinib (n = 27)), whereas 10.61% were on combination of axitinib + pembrolizumab (n = 21) and 11.62% received ipilimumab + nivolumab (n = 23), and. 71.72% of patients who qualified for systemic therapy had a history of uncontrolled hypertension, whereas 28.28 % of total patients had no history of uncontrolled hypertension. The median time on first-line treatment was 5.17 months. A history of hypertension did not significantly affect Overall Survival (OS), 15.90 months median OS for those with hypertension vs 27.80 median OS for those with no hypertension (p = 0.38). Median OS for all patients was 22.80 months. There was also no difference in response rate between those with a history of hypertension vs those with no history of uncontrolled hypertension (p = 0.65) or in Progression Free Survival (PFS) (p = 0.97) Data on how many patients developed exacerbations of hypertension on therapy will be available at time of presentation. Conclusions: Uncontrolled hypertension typically excludes patients from clinical trial enrollment. We found no difference in median OS in those with a history of hypertension compared to those with normal blood pressures. Further large-scale studies are needed to further determine outcomes in patients with hypertension on systemic therapy for mRCC.
Association of cabozantinib residual concentration (Ctrough) and blood clearance (Cl/F) with toxicity (tox) and progressive disease (PD) in metastatic renal cell carcinoma (mRCC) patients (pts): Results from a monocentric pharmacokinetics (PK) study.
Authors: Cerbone Luigi , Combarel David , Foulon Stéphanie , Geraud Arthur , Alves Carolina , Colomba Emeline , Carril Lucia , Derosa Lisa , Flippot Ronan , Mir Olivier , Escudier Bernard , Paci Angelo , Albiges Laurence
Published: March 2021

292

Background: Cabozantinib is a TKI with a substantial efficacy in mRCC. It is associated with a relevant tox leading frequent dose modifications (DM) or drug discontinuations (DD). While an exposure/safety relation has been demonstrated for this drug, an exposure/efficacy relation is still unknown. Cl/F is a measure of elimination of a drug from blood or plasma and lower Cl/F of cabozantinib has been previously associated with increased DM rate in mRCC. Methods: We performed a monocentric PK (INDS MR 5612140520) study in patients with mRCC. Blood draw for assessment of cabozantinib PK was performed at least 8 hours from the last drug dose. Ctrough was estimated with the following equation: Ctrough=Cmeas*0,5DI-24/t1/2. Ctrough and Cl/F were compared in patients with or without a relevant tox and in PD pts vs SD/PR pts. Relevant tox was defined either as G3-4 tox or G2 tox leading to DM or DD. Differences in Ctrough and CL were assessed between the groups with Mann Withney U test. Results: From 01.10.19 to 31.08.20 66 pts were included in this analysis. Twenty one relevant tox and 29 PD were observed. Ctrough was higher in pts experiencing relevant tox than in those who did not: 624,6 ng/ml (IQR 494-1030,2 ng/ml) vs 505,2 ng/ml (IQR 329,2-910,2), p0.012. Conversely Cl/F was lower in relevant tox vs not tox1,85 l/h (IQR 1,4-2,2 l/h) vs 2.27 l/h (IQR 1,7-3,2), p 0.024. In PD pts, Ctrough was lower than in SD/PR pts: 419ng/ml (IQR 317,2 -549,1 ng/ml) vs 554 ng/ml (IQR 416,9-795,6), p 0.0105, while Cl/F was higher in PD patients: 2,6 l/h (IQR 2,14-3,44 l/h) vs SD/PR patients 1.9 l/h (1,930 l/h;IQR 1,35-2,53 l/h); p= 0.011. Time from day cycle 1 to PK blood draw was significatively longer in non-tox pts and numerically longer in PD pts, which have the lowest Ctrough and the highest Cl/F. Conclusions: Cabozantinib toxicity is associated to a higher Ctrough and a lower Cl/F. Cabozantinib PD is associated to a lower Ctrough and a higher Cl/F. Cl/F should be assessed alongside with Ctrough in Cabozantinib PK blood test; Ctrough may decrease and conversely Cl/F may increase with time on treatment. [Table: see text]
Osteonecrosis of the jaw in metastatic renal cell carcinoma (mRCC) patients treated with zolendronic acid and denosumab: An observational retrospective multicenter trial.
Authors: Stellato Marco , Santini Daniele , Sepe Pierangela , Anesi Cecilia , Claps Melanie , Mennitto Alessia , Guadalupi Valentina , Zecca Ernesto , Bracchi Paola , Procopio Giuseppe , Verzoni Elena
Published: March 2021

299

Background: Bone is one of the most common site of metastasis occurring in 30% of metastatic renal cell carcinoma (mRCC) patients (pts)3,4. Skeletal metastases from mRCC are usually osteolytic and associated to high rate of morbidity and complication through skeletal related events (SRE). Bone-targeted therapies (BTT) such as zolendronic acid (ZOL AC) and denosumab (Dmab), shown to decrease the time-to-first and subsequent SREs12. Osteonecrosis of the jaw (ONJ) is a rare but potentially serious adverse event associated with BTT. It occurs in 1-2% of pts treated with BTT and in 10-17% of mRCC pts treated with ZOL AC or Dmab. Vascular endothelial growth factor-Tyrosine kinase inhibitors (VEGF-TKI) represent the backbone treatment for mRCC. Nevertheless, it is unclear whether the association of DMAB and ZOL AC to VEGF-TKITTagents could be associated to higher incidence of ONJ. Methods: We retrospectively collected data, from 2 Italian referring centers for mRCC, about 74 pts with bone metastases from mRCC who received, concurrently or sequentially to VEGF-TKI or immune-oncology (IO), AC ZOL and DMAB from January 2013 to January 2020. All pts provided informed consent for inclusion in the study. Results: All pts received VEGF-TKI as first line treatment. 17 pts received AC ZOL whereas 57 received DMAB. All pts received odontological consultation and orthopantomography before start BTT. The median time of Dmab and AC ZOL exposure was 11.6 months. ONJ occurred in 10/74 pts (7.4%): 6/10 pts were on first line treatment and 4/10 on second line. Treatments administered at the time of ONJ diagnosis were nivolumab (1/10), cabozantinib (2/10), sorafenib (1/10), sorafenib (1/10), sunitinib (4/10) and one pts was off therapy. Conclusions: In this real-life Italian population, treatment with BTT in mRCC pts treated with VEGF-TKI inhibitors and IO is associated to higher incidence of ONJ compared to previous report of pts treated with BTT for bone metastasis and lower compared to previous reports in mRCC. Despite the retrospective collection, we provided one of the largest sample of pts treated concurrently with VEGF-TKI or IO and BTT. Physicians should be careful in the use of BTT combined with other treatments in mRCC pts.
Long-term survival outcomes of cytoreductive nephrectomy combined with targeted therapy for metastatic renal cell carcinoma: A systematic review and individual patient data meta-analysis.
Authors: Esagian Stepan M. , Ziogas Ioannis A. , Kosmidis Dimitrios , Hossain Mohammad D. , Tannir Nizar M. , Msaouel Pavlos
Published: March 2021

317

Background: The role of cytoreductive nephrectomy (CN) in patients with metastatic renal cell carcinoma (mRCC) treated with targeted therapy agents remains controversial. We used reconstructed individual patient data (IPD) to compare the long-term survival outcomes of CN combined with targeted therapy vs. targeted therapy alone for mRCC. Methods: We performed a systematic review of the literature using the MEDLINE, Scopus, and Cochrane Library databases (end-of-search date: July 21, 2020). We reconstructed the Kaplan-Meier curves and subsequently recuperated IPD for overall (OS), progression-free (PFS) and cancer-specific survival (CSS) from individual studies. We performed one-stage random-effects frequentist and Bayesian meta-analyses of OS, PFS, and CSS using parametric and non-parametric estimates. We also performed a subgroup analysis focusing on upfront CN and excluding patients with deferred CN. The risk of bias was assessed using the ROBINS-I and RoB2 tools. Results: Fifteen studies fulfilling our inclusion criteria were identified, including fourteen retrospective cohort studies and one randomized controlled trial. No studies were found to be at critical risk of bias. A total of 3,990 patients were included, with 2,234 in the CN group and 1,756 in the non-CN group. Our frequentist meta-analysis showed superior OS (HR = 0.58, 95% CI: 0.54-0.62, p<0.0001) and CSS (HR = 0.63, 95% CI: 0.53-0.75, p < 0.0001) in favor of CN. No clinically meaningful differences were observed in the PFS between the two groups (HR = 0.90, 95% CI: 0.80-1.02, p=0.09). The OS benefit was also observed in the upfront CN subgroup (HR = 0.70, 95% CI 0.63-0.78, p<0.001). Similar results were obtained with non-parametric frequentist and Bayesian approaches (Table). Conclusions: The combination of CN and targeted therapy for mRCC is associated with superior long-term survival outcomes compared with targeted therapy alone. Careful patient selection based on prognostic factors is required to achieve optimal outcomes. [Table: see text]
Treatment response in the intact primary renal mass (P-Rmass) and its relationship to the overall response to treatment in patients with metastatic renal cell carcinoma (mRCC).
Authors: Emamekhoo Hamid , Kawsar Hameem I , Eickhoff Jens C. , Hester Danubia , Bice Tristan , Acharya Luna , Jaeger Ellen , Barata Pedro C. , Zakharia Yousef , Kilari Deepak , Wulff-Burchfield Elizabeth Marie , Kyriakopoulos Christos
Published: March 2021

329

Background: With the approval of more effective systemic treatments (syst Rx) such as tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI), the impact of cytoreductive nephrectomy (CN) on response to Rx and survival remains unknown. The majority of patients (pts) previously enrolled in clinical trials have had radical nephrectomy (RN) or CN prior to syst Rx. Therefore, the response of the P-Rmass to ICIs and the effect of intact P-Rmass on response to syst Rx is not well described. Methods: A retrospective review of 209 pts with mRCC who were treated with ICI in the first or second-line was conducted. Following the appropriate regulatory process, collaborators from 5 US sites collected clinical, pathological, and outcome data via chart review. The response was investigator-assessed for all pts with at least one post-treatment scan or evidence of clinical progression after treatment initiation. Overall radiographic response (ORR) includes complete response (CR) and radiographic response (Rad-resp) to treatment. Disease control rate (DCR) includes CR, Rad-resp, and stable disease. Results: Median age at diagnosis was 63 yrs and 69% were male. 102 pts (49%) had localized disease at diagnosis and underwent radical or partial nephrectomy, 3 (1%) had ablation/radiation of P-Rmass, 26 (12%) had CN, 9 (4%) had CN after an excellent response to syst Rx, 12 (6%) had a previous nephrectomy but developed a new Rmass (measurable target lesion), and 57 (27%) did not have CN and had an intact P-Rmass. 176 (84%) pts had clear cell histology. 27 (14%) and 23 (12%) had known sarcomatoid and rhabdoid features, respectively. Overall, 77 (37%) pts had a measurable Rmass while receiving syst Rx. 84 (40%), 93 (45%), and 10 (5%) pts received ICI (Ipilimumab/Nivolumab or Nivo), TKI, or Pembrolizumab/Axitinib in the first-line. 143 (68%) and 70 (33%) pts received second- and third-line treatment. 103 (72%) and 28 (19%) pts received ICI and TKI in the second-line, respectively. The best ORR and the Rad-resp in the intact P-Rmass in evaluable pts are summarized in the table below. ORR to ICI in the first or second-line were numerically higher in pts with an intact P-Rmass compared to pts who had nephrectomy, but this difference was not statistically significant (p= .38 and .35 respectively). Conclusions: The intact P-Rmass had a good response (62-70%) to the first-line syst Rx. Although the overall Rad-resp rates to ICI are numerically higher in pts with intact P-Rmass, this difference was not statistically significant. [Table: see text]
Rechallenge of nivolumab in metastatic renal cell carcinoma, an ambispective multicenter study (RENIVO).
Authors: Vauchier Charles , Auclin Edouard , Barthelemy Philippe , Carril Lucia , Ryckewaert Thomas , Borchiellini Delphine , Ajgal Zahra , Bennamoun Mostefa , Campedel Luca , Thiery-Vuillemin Antoine , Coquan Elodie , Crouzet Laurence , Berdah Jean Francois , Chevreau Christine , Ratta Raffaele , Flechon Aude , Lefort Felix , Gross-Goupil Marine , Thibault Constance , Oudard Stephane
Published: March 2021

330

Background: Immune checkpoint inhibitors (ICIs) in combination with another ICI or an antiangiogenic targeted therapy have been approved for frontline therapy in metastatic renal cell carcinoma (mRCC). However, progression disease (PD) often occurs and subsequent therapies are needed. Rechallenge of ICI may then be an option, but there is a lack of data regarding this strategy. Methods: This ambispective multicenter study included patients who received a rechallenge of Nivolumab (ICI-2) between January 2014 and September 2020, after a first-ICI therapy (ICI-1), regardless of the reason of the discontinuation. Patients could have either a non-ICI therapy or have a prolonged free-interval (≥ 12 weeks) between ICI regimens. Those with ongoing rechallenge at inclusion were followed prospectively. Primary endpoint was investigator-assessed best ORR. Results: 45 rechallenges were included from 16 centers. Median age was 60 years (range, 42-90), 64% were male. Most of them had clear cell histology (91%) and a Fuhrman or ISUP grade ≥ 3 (80%). Single-agent Nivolumab and Nivolumab-Ipilimumab association were used in 78% and 11% during ICI-1 and in 93% and 7% during ICI-2, respectively. Discontinuation for PD, toxicity or clinical decision occurred in 49%, 27% and 24% for ICI-1 and in 94%, 3% and 3% for ICI-2, respectively. The ORR were 51% (n = 23) at ICI-1 and 16% (n = 7) at ICI-2. One patient had a complete response during both ICI-1 and ICI-2 and two had a partial response at ICI-2 although they had PD as best ICI-1 response. After a median follow-up of 14.9 months (mo), median duration of response for ICI-2 was 5.1 mo (95% CI, 2.7-not reached [NR]). For ICI-1 and ICI-2: median progression-free survival (PFS) was 11.4 mo (95% CI, 9.8-23.5) and 3.5 mo (95% CI, 2.8-9.7); median overall survival was NR (95% CI, 37.8-NR) and 24 mo (95% CI, 9.9-NR). Poor prognostic factors for PFS at ICI-2 were Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 2, presence of liver metastases, inflammatory syndrome and PFS under ICI-1 > 6 months. Grade ≥ 3 immune-related adverse events occurred in 24% (n = 11) during ICI-1 but only in 4% (n = 2) during ICI-2. There was no treatment-related death. Conclusions: Our study suggests that resumption of ICI with Nivolumab has a moderate efficacy in mRCC and acceptable tolerance. Predictive factors of response are needed to propose this strategy to selected mRCC patients. Larger prospective cohorts are needed to confirm these results. [Table: see text]
Safety and efficacy of nivolumab in older patients (pts) with renal cell carcinoma: Results of a sub-group analysis of the GETUG-AFU 26 NIVOREN multicenter phase II study.
Authors: Mourey Loic , Dalban Cécile , Negrier Sylvie , Chevreau Christine , Gravis Gwenaelle , Thibault Constance , Laguerre Brigitte , Barthelemy Philippe , Borchiellini Delphine , Gross-Goupil Marine , Geoffrois Lionnel , Rolland Frederic , Thiery-Vuillemin Antoine , Joly Florence , Ladoire Sylvain , Tantot Florence , Escudier Bernard , Albiges Laurence
Published: March 2021

331

Background: NIVOREN GETUG AFU 26 study, is a french multicenter prospective study to evaluate safety and efficacy of Nivolumab (N) in a broad “real world setting” in mRCC after failure of 1 or 2 tyrosine kinase inhibitors. Methods: Between February 2016 and July 2017, 729 pts were enrolled across 27 institutions. Primary objective of the trial was safety assessed by grade ≥ 3 treatment related adverse event (TRAE). We report here results of older patients above 70 years old ([70;75[; [75;80[; ≥ 80) compared with their younger counterparts. Results: Overall, 720 patients were treated (median age 64 (22;90)). Among them 205 pts were ≥ 70 (28.5%) divided as follow: [70-75[:107 (14.9%) / [75-80[: 68 (9,4%) / ≥ 80: 30 (4,2%). Patients’ characteristics (Table) were similar in younger and older patients except for IMDC risk groups (IMDC) classification with less poor prognostic in pts ≥ 75 and fewer brain metastasis in pts ≥ 70. Treatment duration was similar across age groups despite a rate of discontinuation for TRAE increasing with age. Regarding efficacy, there was a non-significant trend toward improved response rate and progression free survival and lower specific survival with increasing age. Conclusions: In this large “real world” setting study a significant number of old pts were included. Prognostic profile appears better in older pts included. There is no signal for an excess of toxicity in this population and efficacy is comparable to younger patients. Age alone should not prevent prescribing N in mRCC. Clinical trial information: NCT03013335 . [Table: see text]
Diagnostic utility of (18)f-fluciclovine positron emission tomography (FACBC) in biochemically recurrent (BCR) prostate cancer (PCa) based on prior primary treatment modality for localized disease and the impact of FACBC findings on treatment selection.
Authors: Sharifi Marina Nasrin , Lovrec Petra , Eickhoff Jens C. , Kenarsary Aria , Jarrard David Frazier , Floberg John , Cho Steve Y. , Kyriakopoulos Christos , Emamekhoo Hamid
Published: March 2021

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Background: Management of BCR PCa requires accurate assessment of location and extent of recurrent disease. FACBC has been shown to be a sensitive modality for detection and localization of recurrent disease but treatment guidelines are based on the findings of conventional (conv) imaging, including computed tomography, magnetic resonance imaging, or bone scintigraphy, and little is known about how prior treatment impacts FACBC findings and concordance with conv scans. Methods: This single-center retrospective study included 137 patients (pts) who had FACBC for BCR at the University of Wisconsin-Madison from 10/2017-10/2019. Clinical, pathological, imaging, and treatment data were collected by chart review. Pts were classified by type of primary treatment for localized PCa, either radical prostatectomy (RP) or radiation therapy (RT). Findings of conv scans performed within 4 weeks prior or any time after FACBC were collected. Results: 105 pts had RP and 32 pts had RT as their primary PCa treatment. Gleason score and PSA at diagnosis were similar between groups. Median PSA at time of FACBC was higher in the RT compared to RP group (3.3 vs 0.7 ng/dL) and median time from initial diagnosis to FACBC was longer (70 vs 55 months). Frequency of (+) FACBC findings was higher in the RT group (66% vs 47%); only 3% of pts in the RT group had a (-) FACBC compared to 29% in the RP group. The rate of (+) lesions in the prostate/prostate bed was higher in the RT group (41% vs 22%), while the rate of (+) lesions in pelvic nodes and distant sites was similar between groups. Of 69 pts who also had conv imaging, 61% had concordant conv imaging findings. In the RT group, conv and FACBC findings were similar in 47% of pts and not similar in 28%. In the RP group, conv and FACBC findings were similar in 26% of pts and not similar in 17%. Management after FACBC is listed in table. Median time from FACBC to first (+) conv scans was 6 (range: 0-18) and 5 (range: 0-17) months for RT and RP groups, respectively. Conclusions: In this large retrospective cohort, pts treated with initial RT had a longer median time from diagnosis to FACBC and higher median PSA at the time of FACBC compared to the RP group. RT patients had a higher rate of (+) FACBC findings but were more likely to continue on observation. The median time from FACBC to first (+) conv scan was 5-6 months, supporting the role of FACBC in earlier detection of recurrent disease in both groups of patients. Further analysis of concordance between FACBC and conv imaging is in process. [Table: see text]
Illustration of temporal evolution in patients with metastatic renal cell carcinoma (mRCC) using both circulating tumor DNA (ctDNA) and tissue-based genomic data.
Authors: Zengin Zeynep Busra , Weipert Caroline , Hsu Joann , Salgia Nicholas , Hensel Chuck , Maughan Benjamin Louis , Rathi Nityam , Goel Divyam , Agarwal Neeraj , Choueiri Toni K. , Pal Sumanta K.
Published: March 2021

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Background: We have previously demonstrated the feasibility of ctDNA assessment in mRCC and preliminarily showed agreement between ctDNA and tissue-based genomic findings (Zengin et al ESMO 2020). Our data suggested that the degree of agreement is dependent upon the temporal separation of blood and tissue samples. We sought to further explore this temporal impact in a separate validation cohort. Methods: Patients (pts) with mRCC who underwent ctDNA genomic profiling were identified. ctDNA analysis was performed using a CLIA-certified 73-74 gene panel (Guardant360). From this cohort we identified a subset of pts who also underwent tissue-based genomic profiling using either a whole exome sequencing platform (GemExtra [TGen, Phoenix, AZ]) or a targeted next generation sequencing platform (Foundation Medicine [Cambridge, MA] or Tempus [Chicago, IL]). Only alterations covered by both assays were included for the current analysis. The difference in the proportion of alterations detected on tissue and ctDNA was compared between these cohorts and at a 6-mo landmark using the χ2 test. Results: In total, ctDNA and tissue based genomic profiling was assessed in 112 pts (M:F, 81:31); with most common histology was clear cell (85.7%). Median time between ctDNA and tissue assessments was 9.8 months (IQR 1.15-23.7). When examining paired samples in which >1 ctDNA alteration was detected, 32% (43/133) of alterations detected on tissue were also detected in ctDNA. This proportion increased to 43% (29/67) when samples collected within 6 months of each other, and was 51% (28/55) in samples collected within 3 months of each other. There was no significant difference in the frequency of shared mutations between the cohorts (P=0.09; Table). Conclusions: Our study confirms that ctDNA and tissue-based genomic profiling continue to provide consistently high levels of agreement. Notably, the percentage of samples with ≥1 ctDNA alteration detected was significantly lower in both cohorts compared to previous studies in RCC. More shared alterations were found on ctDNA when both ctDNA and tissue-based assessment were obtained at closer intervals. [Table: see text]
Prognostic biomarkers of systemic inflammation in patients on active surveillance for metastatic renal cell carcinoma (mRCC): A biobank analysis.
Authors: Chauhan Vishwani , Malik Jahangeer , Sundaramurthy Aravindhan , Symeonides Stefan N. , Stares Mark
Published: March 2021

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Background: A subset of patients with metastatic renal cell carcinoma (mRCC) follow an indolent disease course. Given the toxicity and non-curative nature associated with systemic anti-cancer therapy (SACT), some patients may benefit from initial active surveillance (AS). However, selecting patients suitable for this approach is challenging. Biomarkers of systemic inflammation predict survival in mRCC, both independently and as part of the International Metastatic Database Consortium (IMDC) risk score. We sought to use these biomarkers to characterise the time to initiation of SACT (tSACT) in mRCC patients on AS. Methods: 126 mRCC patients clinically assessed and commenced on AS prior to any systemic therapy were retrospectively identified from a regional mRCC clinical database. Patients who underwent metastasectomy for oligometastatic disease at any time were excluded. The primary endpoint, tSACT, was defined as the time from radiological diagnosis of mRCC until SACT initiation, or death, or censorship if continuing AS at follow-up date. Inflammatory biomarkers from routine blood tests (haemoglobin, white cell count, neutrophil count, platelets, C-reactive protein (CRP), albumin) and the IMDC score, measured at the time of diagnosis of mRCC, were recorded. The relationship between these and tSACT was examined using Kaplan-Meier and Cox-regression methods. Results: 66 (52%) patients had commenced SACT. 17 (13.5%) had died without commencing SACT (median survival of the 17 was 40.4 months, range 9.1-130.2 months, and comorbidities may have affected fitness for starting therapy or led to all-cause mortality). 43 patients remained on AS, with minimum and median follow-up of 12.6 months and 39.6 months respectively. The median tSACT was 17.2 months (IQR 8.8-34.8 months). On univariate analysis, CRP and albumin were predictive of time on AS ( p= 0.01 and p= 0.049 respectively). On multivariate analysis, only CRP was independently associated with tSACT ( p= 0.035), stratifying tSACT from 9.1 months (CRP > 10) to 20.9 months (CRP≤10) ( p= 0.009). 111 (88.1%) patients were IMDC 0-1, while 12 (9.5%) and 3 (2.4%) were IMDC 2 or 3 and may have had comorbidities that influenced the initial AS decision. In our cohort the IMDC risk score did not predict time on AS. Conclusions: These results highlight that some patients with mRCC may undergo active surveillance for a marked time period before SACT initiation. We identify routine biomarkers of the systemic inflammatory response that predict time to systemic therapy. In particular CRP, a simple measure of inflammation, stratifies the time to initiation of SACT across a clinically significant time period. This simple, widely available test may help to objectively inform clinical decisions about AS in patients in mRCC. Additional experience is necessary to further define the risks and benefits of this approach.
Impact of concurrent ACE inhibitors and ARBs on outcomes with immune-checkpoint inhibitors (ICIs) for patients (pts) with metastatic renal cell carcinoma (mRCC).
Authors: Nuzzo Pier Vitale , Curran Catherine , Adib Elio , Freeman Dory , Nassar Amin , Alaiwi Sarah Abou , Bakouny Ziad , McGregor Bradley Alexander , Choueiri Toni K. , Jain Rakesh K. , McKay Rana R. , Sonpavde Guru
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Background: The renin-angiotensin system (RAS) is involved in regulation of angiogenesis and cell proliferation and may improve drug delivery by enhancing tumor perfusion partly by downregulating transforming growth factor (TGF)-β. Since (TGF)-β appears to be associated with resistance in patients receiving immune checkpoint inhibitors (ICIs), we investigated whether angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs) may enhance the outcomes of mRCC pts receiving ICI. Methods: Data from mRCC pts who received ICIs at the Dana-Farber Cancer Institute (DFCI) was obtained. Data for ACEI and ARB administration was collected with concurrent administration defined as ongoing therapy from the time of starting ICI . The Kaplan-Meier method and Cox were used to evaluate the impact of concurrent ACEI/ARB on overall survival (OS). Results: Data was available for 134 pts. The mean age was 63 years (Range 37-85)). 94 (70%) pts were male. The therapies included Nivolumab+/-Other (104), Atezolizumab+/-Other (21), Pembrolizumab+/-Other (8) and Durvalumab +Tremelimumab (1). 35 (25%) pts received ICI as first line treatment, 52 (39%) received as second line treatment, and 48 (36%) received as third line or higher. Out of the 134 pts, 39 (29%) had been treated with an ACEI or ARB during ICI treatment. Out of the 39 pts who had ACEI or ARB, 2 (5%) had complete response (CR) as best response, 11 (28%) had partial response (PR), 17 (46%) had stable disease (SD) and 9 (23%) had progressive disease (PD). Out of the 95 pts who did not receive ACEI or ARB, 3 pts (3%) had CR as their best response to ICI, 19 (21%) had PR, 39 (43%) had SD, and 29 (32%) had PD, (5 patients’ best response were unevaluable). The median OS for those who had ACEI/ARBs and did not have ACEI/ARBs was 32 months and 20 months respectively. Univariable analysis revealed that patients who received ACEI/ARBs had improved OS (Logrank p-value = 0.002; HR = 2.5 [95%CI: 1.4 - 4.5]). Conclusions: In this hypothesis-generating study, concurrent ACEI/ARBs are associated with better outcomes for mRCC pts receiving ICIs. Given the availability of ACEI/ARBs, it is important to validate this result in a larger dataset and after controlling for known prognostic factors.
Quantifying publication rates and time to publication for urologic oncology podium presentations.
Authors: Mikhail Mark , Chua Kevin , Patel Hiren V. , Tabakin Alexandra L. , Doppalapudi Sai Krishnaraya , Ghodoussipour Saum , Kim Isaac Yi , Jang Thomas L , Srivastava Arnav , Singer Eric A.
Published: March 2021

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Background: The American Urological Association (AUA) annual meetings serve as a large platform for unpublished research. Among the selected abstracts, podium presentations represent the most impactful submissions. Furthermore, between large meeting attendance and social media promotion, authors can disseminate their findings to a potentially large audience prior to final manuscript publication. While all AUA abstracts do undergo peer review, it is not with the same level of scrutiny that full-length manuscripts receive. Thus, we investigated the publication rates, impact factors, and time to publication of urologic oncology podium presentations at the AUA. Methods: Of 875 podium presentation abstracts from the 2017 AUA Annual meeting, 394 (45.0%) were classified as urologic oncology. We chose 2017 to allow for a three-year window for publication. Abstracts were assessed for subsequent publication between January 1, 2015 and May 31, 2020 with a pre-determined PubMed search protocol. Abstract authors were searched for individually, with key terms being added sequentially until <30 results were generated in PubMed. Each search result was then reviewed until a matching publication was found. Abstracts were deemed published if at least one author of the presented abstract was a manuscript author and/or at least one conclusion in the presented abstract was included in the conclusions of the publication. Publication rates, time to publication, and 2019 journal impact factors were collected. Results: Of 394 urologic oncology podium presentations at the 2017 AUA, 228 (57.9%) focused on prostate cancer, while 81 (20.6%) and 58 (14.7%) presentations focused on kidney and bladder cancer, respectively (table). Overall, 211 (53.6%) podium presentations were published. Median time from presentation to publication was 13.6 months (IQR: 7.5-21.5). There were 9 (2.3%) publications that were published prior to the submission deadline and 57 (14.5%) podium presentations that were published prior to the 2017 AUA meeting. The number of articles published at one, two and three years after the meeting was 90, 170 and 202, respectively. The median journal impact factor of all published works was 3.4 (IQR: 2.7-5.9). Conclusions: While AUA podium presentations disseminate valuable data, approximately half of these presentations were not published in peer-reviewed journals within three years. Therefore, care must be taken when promoting data or adopting new practices based on these presentations alone. [Table: see text]
Impact of comorbidity burden on renal cell carcinoma prognosis: A Danish nationwide cohort study.
Authors: Horsbøll Trine Allerslev , Dalton Susanne Oksbjerg , Christensen Jane , Petersen Astrid , Azawi Nessn H. , Donskov Frede , Andersen Ole , Nørgaard Mette , Lund Lars
Published: March 2021

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Background: The incidence of renal cell carcinoma is increasing worldwide and have a 5-year relative survival rates of around 75%. Comorbidity has been found to be associated with complications and mortality after renal cancer surgery. No studies have focused on comorbidity as a prognostic factor in a nationwide cohort of patients with renal cell carcinoma with long-term follow-up. Purpose: The primary aim was to evaluate the prognostic impact of comorbidity on survival in older (≥70 years) and younger (<70 years) patients diagnosed with renal cell carcinoma. Methods: We established a nationwide register-based cohort of 7,894 patients aged 18 or more diagnosed with renal cell carcinoma in Denmark between 2006 and 2017, and followed their vital status for up to 13 years. We computed 1- and 5-year overall survival and hazard ratios (HRs) of death according to comorbidity status using Charlson Comorbidity Index (CCI) among patients aged < 70 years and ≥ 70 years. Results: In all, 36% of the patients had registered comorbidity at the time of diagnosis. Survival decreased with increasing CCI score. It did though increase for all groups of CCI scores (0, 1-2 and 3+) over time. For patients without comorbidity diagnosed in 2006-2008 and 2015-2017, 5-year survival rate increased from 57% to 69%. For patients with a CCI score of 1-2 vs 3, the 5-year survival rate increased from 46% to 62% vs 39% to 44%. In age- and gender-stratified analyses, patients with a CCI score of 1-2 and 3+ had increased mortality compared to patients without registered comorbidity (HR 1.15, 95 % CI 1.06-1.24) and (HR 1.56, 95 % CI 1.40-1.73). Patterns were similar for older (≥70 years) and younger (<70 years) patients. Particularly, diagnoses of congestive heart failure, peripheral vascular and cerebrovascular disease, dementia, chronic pulmonary disease, preexisting renal and liver disease, diabetes and lymphoma led to increased mortality. Conclusions: Comorbidity leads to inferior survival outcomes in patients with renal cell carcinoma, irrespective of age, despite an overall increasing survival. These data may guide patient counseling and prompt initiatives for controlling comorbidity.