bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term results of radiation with or without anti-androgens (AAT) in patients receiving salvage prostate bed radiation therapy (sRT) post prostatectomy.
Authors: Lukka Himu , Pugh Stephanie L. , Shipley William U. , Major Pierre , Sartor A. Oliver , Dayes Ian S. , Bahary Jean-Paul , Efstathiou Jason A. , Pisansky Thomas Michael , Zeitzer Kenneth Lee , Lawton Colleen Anne , Dess Robert Timothy , Camarata Andrew S , Balogh Alexander G. , Souhami Luis , Rosenthal Seth A. , Seiferheld Wendy , Feng Felix Y , Sandler Howard M.
Published: January 2024

320

Background: sRT is used in men with prostate cancer (PC) recurrence following radical prostatectomy (RP) signaled by a persistent or delayed elevation in PSA. It was previously reported that the use of AAT with RT improved cancer control and overall survival (OS). Long-term follow-up (FU) results are presented here. Methods: From 1998to 2003, 760 eligible post-RP patients with Stage pT3N0 or with pT2N0 and positive margins and PSA from 0.2 to 4.0 ng/mL were randomly assigned on a double-blinded, placebo-controlled trial of RT + placebo vs. RT + anti-androgen therapy (AAT) (24 months of bicalutamide, 150mg daily) during and after RT (64.8 Gy in 36 fractions prostate bed). The primary endpoint was OS estimated using Kaplan-Meier method. Time to PC death and metastatic PC (competing risk of death without an event) was estimated using cumulative incidence. The hazard ratio (HR) was obtained using Cox models (OS) and subdistribution HRs (sHRs) used the Fine-Gray model (time to PC death and metastatic PC). All tests are one-sided based on study design. Results: Median FU for surviving patients was 19 years. OS at 18 years was 53% [95% confidence interval (CI): 47-58%] for RT + AAT and 43% [95% CI: 38-48%] for RT + placebo (adjusted HR 0.82 [95% CI: 0.67-1.00], p = 0.025). The 18-year incidence of centrally reviewed PC deaths were 18% [95% CI: 14-22%] RT + AAT and 28% [95% CI: 23-32%] RT + placebo (adjusted sHR = 0.57 [95% CI: 0.42-0.78], p<0.001). The 18-year incidence of metastatic PC was 22% [95% CI: 18-26%] and 31% [95% CI: 26-35%] for AAT and placebo arms respectively with adjusted sHR = 0.59 [95% CI: 0.44-0.80, p<0.001]. Subgroup analyses is shown in the Table. Conclusions: Long term results of 24-month duration AAT during and after sRT are consistent with the primary report with significantly improved long-term OS, reduced incidence of metastatic PC and PC death for RT+AAT. Statistically significant metastatic PC was noted for Gleason score 8-10, study entry PSA>1.5 and margin positive patients and borderline significance was observed in patients with study entry PSA 0.7-1.5. Clinical trial information: NCT00002874 . [Table: see text]
Neoadjuvant darolutamide plus androgen deprivation therapy for high-risk/very high-risk localized prostate cancer: A multicenter, open-labeled, single-arm phase II trial.
Authors: Zhuang Junlong , Wang Yuwen , Zhang Shun , Qiu Xuefeng , Zhou Feng , Fu Yao , Wei Xuedong , Xu Linfeng , Guo Hongqian
Published: January 2024

321

Background: Radical prostatectomy (RP) is associated with adverse surgical outcomes and an increased risk of disease progression in patients with high-risk/very high-risk localized prostate cancer (HRLPC/VHRLPC). This study aimed to evaluate the efficacy and safety of neoadjuvant darolutamide, a next-generation androgen receptor inhibitor, plus androgen deprivation therapy (ADT) for patients with HRLPC/VHRLPC undergoing RP. Methods: In this multicenter, single-arm phase II clinical trial, patients aged 18-75 year with HRLPC/VHRLPC (defined as Gleason ≥ 8 and/or cT3-4N0-1 and/or PSA ≥ 20 ng/mL). Patients with at least one of the following features were diagnosed with VHRLPC: cT3b-cT4, primary Gleason pattern 5, 2 or 3 high risk features, > 4 cores with Grade Group 4 or 5. Eligible patients received 6-month neoadjuvant darolutamide plus ADT followed by RP. The primary endpoint was pathological response rate (the proportion of patients with pathologic complete response [pCR] or minimal residual disease [MRD]). The secondary endpoints included safety, PSA progression-free survival, positive surgical margins rate, downstaging rate and PSA response rate. Results: Thirty patients were enrolled, and all patients had received robotic-assisted RP. The median age was 71.0 (interquartile range [IQR], 65.2-73.0) years, and the median PSA level was 37.8 (IQR, 21.0-94.7) ng/mL at baseline. A majority of the patients had VHRLPC (93.3%), while 6.7% had HRLPC, among whom N1 disease, cT3-4, Gleason 8-10, and PSA ≥ 20 ng/mL accounted for 26.7%, 86.7%, 90% and 77% of cases, respectively. The median prostate volume before RP was 19.4 mL (IQR, 15.6-28.4). Twenty-seven patients (90%) had undetectable PSA levels (＜0.01 ng/mL). The pCR rate was 6.7% and the MRD rate was 33.3%, resulting in a pathological response rate of 40.0%. Twenty patients (66.7%) achieved downstaging, and only four case (13.3%) had positive surgical margins. Eleven patients (36.6%) had extracapsular extension. The details of clinical and pathological outcome after neoadjuvant therapy are described in the Table. Conclusions: Darolutamide plus ADT for six months before RP improved clinical and pathological responses in men with HRLPC/VHRLPC, with favorable safety profile. Clinical trial information: NCT05249712 .[Table: see text]
Safety and clinical validity of tumor genomic testing for guiding active surveillance selection in men with NCCN intermediate-risk prostate cancer.
Authors: Lenz Lauren , Clegg Wyatt , Iliev Diana , Korman Howard , Morgan Todd Matthew , Hafron Jason , DeHaan Alexander , Tutrone Ronald F. , Richardson Timothy , Cline Kevin , Yonover Paul M. , Jasper Jeff , Gutin Alexander , Finch Robert , Slavin Thomas Paul , Cohen Todd
Published: January 2024

336

Background: Clinicopathologic features are considered the gold standard for predicting prostate cancer (PCa) disease severity and guiding decisions on the use of active surveillance (AS) or definitive treatment (DT). However, tumor genomic testing has been shown to provide valuable information as an addition to clinical risk stratification measures, allowing for more accurate identification of AS candidates. This study evaluated the safety of genomic testing for guiding AS selection in patients with National Comprehensive Cancer Network (NCCN) intermediate-risk PCa. Methods: In this retrospective observational cohort study, patients with NCCN intermediate-risk PCa underwent Prolaris testing at diagnosis from 9/2015–12/2018. The Prolaris test combines a molecular cell cycle progression score with clinicopathologic features (USCF Cancer of the Prostate Risk Assessment [CAPRA] score, inclusive of Gleason score), generating a Combined Clinical Risk (CCR) score to identify patients as candidates for AS or DT. Patients with a CCR-based 10-year disease-specific mortality (DSM) risk ≤3.2% were recommended to AS. Clinical follow up data, including initial treatment selection and time to metastasis, were retrospectively collected from the treating clinics. Kaplan-Meier estimates were used to evaluate the safety of AS in patients who initially selected AS. Cox proportional hazards models were used to evaluate CCR as a predictor of metastasis in all patients. Results: In total, 3204 patients were included in this analysis, with 1468 (46%) recommended to AS and 1736 (54%) recommended to DT. Among the 973 (30%) patients who initially selected AS, 613 (63%) were recommended to AS and 360 (37%) were recommended to DT. In patients who were recommended to AS and initially selected AS, the observed risk of metastasis within 5 years of diagnosis was 0.37% (95% confidence interval [CI], 0.09%–1.47%). Patients who were recommended to AS had a significantly lower rate of metastasis than patients who were recommended to DT after accounting for initial treatment decision (AS vs DT) and CAPRA score (hazard ratio 4.20 [95% CI, 1.41–18.04], P-value = 0.03). Conclusions: For patients with NCCN intermediate-risk PCa who were identified by genomic testing as candidates for AS, AS is safe based on the very low observed metastasis risk. The CCR score is a strong predictor of metastasis beyond clinicopathologic factors.
Prostate extracellular vesicles and prediction of clinically significant prostate cancer: A prospective single-institution pilot study.
Authors: Britton Cameron J , Andrews Jack R. , Arafa Ali , Kim Yohan J , Rangel Laureano J , Schulte Phillip J. , Joshi Vidhu B. , Ahmed Mohamed E. , Karnes R. Jeffrey , Lucien Fabrice
Published: January 2024

337

Background: Prostate cancer remains the most common solid organ malignancy among males in the United States. Commercial biomarkers and multiparametric MRI have been utilized to better triage men with elevated PSA and determine patients most likely to have clinically significant prostate cancer (csPCa) upon prostate biopsy. We studied the combination of MRI with PSA-based and novel extracellular vesicle (EV)-based biomarkers to determine the optimal pre-biopsy testing to reduce the number of unnecessary biopsies. Methods: Men presenting to our clinic with elevated PSA (≥ 2 ng/ml) were prospectively enrolled from October 2019 to March 2022. All men underwent multiparametric MRI and blood draws to determine prostate health index (PHI) scoring, EV density, and PSA density. MRI-fusion biopsy was performed with both systematic and targeted prostate sampling, with clinicians blinded to prior blood testing results. Blood concentrations of prostate EV (ProsEVs) were measured by nanoscale flow cytometry using antibodies against PSMA and STEAP1. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated, and receiver operator characteristic (ROC) curves were constructed separately for all patients, those without prior diagnosis of PCa, and biopsy-naïve patients. Bootstrapping analysis was performed to provide more accurate assessment of the predictive ability of all combinations. Results: Ultimately, 175 men enrolled and underwent MRI, blood testing, and prostate biopsy. Among the 175 patients included, 101 (58%) had never undergone biopsy, 38 (22%) had a previous negative biopsy, and 36 (21%) were on active surveillance (AS) for GS6 disease. AUC of mpMRI (PI-RADS≥3) to predict clinically significant PCa was 0.66 with a sensitivity, specificity, NPV and PPV of 95.2%, 37.6%, 76.0% and 79.26%. MRI combined with STEAP1-EV density had an AUC of 0.77 with a sensitivity, specificity, NPV and PPV of 90.1%, 46.7%, 64.4% and 80.9%. A multivariable model including MRI, STEAP1-EV density, PSA density and PHI density outperformed other combinations with an AUC, sensitivity, specificity, NPV and PPV of 0.90, 89.2%, 68.7%, 72.8% and 88.1%. Conclusions: Combination of mpMRI with ProsEV and PSA derivatives demonstrated better predictive ability for csPCa on biopsy compared to imaging or serum testing alone. Inclusion of prostate volume with biomarkers further increased predictive ability which could lead to a decrease in number of unnecessary biopsies for men with benign conditions and indolent cancer.
PSMA-based PET as an imaging biomarker of androgen receptor signaling in high-risk localized and locally advanced prostate cancer (PCa).
Authors: English Keara , Deville Curtiland , Anabaraonye Nancy
Published: January 2024

341

Background: The purpose of this prospective, nonrandomized, pilot imaging study (NCT02420977) is to evaluate prostate-specific membrane antigen (PSMA), [18F]DCFPyL (DCFPyL), as a PET/CT imaging biomarker of androgen receptor (AR) signaling in newly diagnosed PCa. Methods: 23 men with treatment-naïve, newly diagnosed high-risk prostate cancer were enrolled. Patients underwent DCFPyL PET/CT imaging and MRI/ultrasound fusion-guided prostate biopsy before and after 2-3 months of nADT (LHRH agonist and anti-androgen), followed by definitive IMRT. We measured the total number of lesions, lesion location, maximum standardized tumor uptake value (SUVmax), PSA, and changes in those variables between baseline and follow-up scans. Concordance between biopsy pathology results and PSMA imaging parameters before and after ADT was evaluated. Results: 3 patients were excluded after baseline PET/CT due to high-burden metastases, small cell histology, and declining to proceed further. 20 patients remained for evaluation. At baseline, 19/20 and 8/20 had at least 1 avid intraprostatic and extraprostatic lesion, respectively, with a 50 total lesions (28 prostate, 19 nodal, 3 bone); median intraprostatic and extraprostatic SUVmax were respectively 9.6 (range: 3.3-56.8) and 7.0 (range: 2.3-61.9). Post-nADT scans revealed 32 lesions (19 prostate, 11 nodes, 2 bone); median intraprostatic and extraprostatic SUVmax decreased respectively to 4.1 (range 1.9-27.8) and 3.2 (range: 1.7-8.9). 3/19 (15.8%) of the patients demonstrated complete uptake resolution of the avid intraprostatic foci, 15/19 (78.9%) showed decreased uptake (58.3% median decrease in SUVmax), and 1/19 (5.26%) showed increased SUVmax. Of the 8 patients with extraprostatic lesions, 2/8 (25%) demonstrated complete uptake resolution, 5/8 (62.5%) showed partially decreased uptake (66.67% median decrease in SUVmax), and 1/8 (12.5%) showed increased SUVmax. One of the same patients still had 2 lesions, for a total of 13 intraprostatic target lesions. Regarding concordance between pathologic results and PSMA imaging response pre- and post-nADT, 14/19 (73%) had biopsies fully concordant with PSMA scan (i.e. residual tumor and residual PET avidity), 4/19 (21%) had biopsies mostly concordant with the scan (i.e. complete pathologic response with partial PET response or vice versa), and 1/19 (5%) had a biopsy discordant with the PSMA scan (i.e. no pathology response, but complete response on PSMA). Conclusions: Post-nADT PET detected fewer PSMA-positive lesions with overall decreased or resolved tumor uptake, except for 2 separate patients with increased intra- and extraprostatic uptake. 95% of post-nADT PSMA scans were fully or mostly concordant with post-nADT biopsies, suggesting that PSMA scans may be a clinically useful, prognostic imaging biomarker for disease status evaluation post-nADT. Clinical trial information: NCT02420977 .
Patterns of PSMA PET/CT scan usage for initial staging and recurrence in a multi-centered hospital system.
Authors: Bennett Richard , Li Eric , Ho Austin Y. , Aguiar Jonathan , Mahenthiran Ashorne Krithiesh , Kumar Sai , Suk-ouichai Chalairat , Neill Clayton , Patel Hiten Dilip , Schaeffer Edward M. , Savas Hatice , Ross Ashley
Published: January 2024

36

Background: PET PSMA-based imaging for prostate cancer staging has been approved since late 2020 and was widely available in our medical system by July 2021. We sought to examine the patterns of use of PSMA PET/CT and conventional imaging for staging since this time. Methods: We retrospectively identified men who were diagnosed with presumptive NCCN unfavorable intermediate risk (UIR), high risk, or very high risk (VHR) and men who underwent staging work-up for biochemical recurrence (BCR) from July 2021 – June 2023. Patient clinical, pathological, and imaging variables were collected. Sufficient conventional imaging for initial staging was defined as the use of a bone scan and one or more of an MRI or CT scan. The date of staging was determined by the initiation of staging with conventional imaging or the date of PSMA scan if used. Results: In the study period, 899 men were diagnosed with presumptive NCCN UIR-VHR disease. Among these individuals 32% (290/899) underwent no or insufficient staging, 26% (230/899) underwent staging with conventional imaging only, and 42% (379/899) underwent initial staging evaluations that included PET PSMA. The frequency of PET PSMA used for initial staging increased from 24% (20/82) to 80% (167/208) over the 2-year study period. 1173 men with biochemical recurrence who underwent a staging work-up were identified. Median PSA of these men was 1.37 ng/mL (IQR 0.23, 6.59 ng/mL). The frequency of PET PSMA imaging increased in these men from 91% (225/246) to 98% (296/303) over the 2-year study period. When ordering both PSMA and conventional imaging for initial staging, providers tended to order PSMA scans after initial conventional imaging orders (72%) rather than before (18%) or on the same day (11%). Conclusions: The use of PSMA PET/CT imaging rose since its implementation in our system in July 2021 with PSMA PET being utilized in 80% of patients being initially staged and 98% of those staged at BCR. Conventional imaging and Axumin PET are rarely used in BCR. If both PET PSMA and conventional imaging were ordered for initial staging, PET PSMA was typically performed after conventional imaging. Growing data may inform best sequencing and use of conventional imaging in the PSMA-PET era.
Association between thymectomy and incidence of renal cell carcinoma (RCC).
Authors: Barragan-Carrillo Regina , Ebrahimi Hedyeh , Chawla Neal Shiv , Salgia Nicholas , Castro Daniela V. , Chehrazi-Raffle Alex , Dizman Nazli , Hsu Joann , Meza Luis A , Zengin Zeynep Busra , LeVee Alexis Ann , Tripathi Abhishek , Dorff Tanya B. , Bergerot Cristiane Decat , Bergerot Paulo Gustavo , Eilber Karyn , Dallas Kai , Pal Sumanta Kumar
Published: January 2024

371

Background: Recently, thymectomy in adults has been linked to a higher incidence of several malignancies (Kooshesh et al NEJM 2023). Accompanying translational studies suggest that depleted T-cell production (both CD4+ and C8+) and decreased clonality may selectively drive the pathogenesis of immunogenic cancers such as RCC. We sought to confirm this finding in a large population-based cohort. Methods: We interrogated the California Office of Statewide Health Planning and Development (OSHPD) database, which collects information from all inpatient admissions, emergency room visits, and inpatient/outpatient procedures in the state. Patients who underwent thymectomy and nephrectomy (specifically for RCC) were identified from Jan 1, 2012, to Dec 31, 2019, using CPT and ICD-9/10 codes. The frequency of nephrectomy following thymectomy was computed. The frequency of both surgical interventions in the general population was derived by comparing their respective incidence in the OSHPD database against age-matched California census data. Chi square test was used to determine differences among groups. Fisher’s exact test was used to determine if the incidence of nephrectomy following thymectomy was different from the incidence of nephrectomy overall. Results: During the study period, 1,969 pts (mean age 56) underwent thymectomy and 31,093 pts (mean age 57) underwent nephrectomy. Relative to patients who underwent thymectomy, a larger proportion of patients undergoing nephrectomy were male (57% vs 45%) and Hispanic (28% vs 18%) (p<0.01)., while a smaller proportion was Asian (7% vs 18%) (p<0.01). Expressed as a percentage of the underlying age-matched population (18,343,792 pts), 0.01% of pts received thymectomy, and 0.17% of pts underwent nephrectomy. A total of 11 pts underwent nephrectomy following thymectomy, suggesting an incidence of 0.56% in this cohort. This was significantly higher than the incidence of nephrectomy in the population at large (P=0.002). The median age of patients who had a nephrectomy for RCC with a prior thymectomy was considerably younger than the general population who underwent a nephrectomy (mean age 52 vs. 57 years). Conclusions: In a large population-based study, we observed a significantly higher rate of nephrectomy for RCC in patients who had received prior thymectomy. These results bolster previous studies done in smaller datasets. Further work is needed to define causality and clarify the mechanism of this association.
Patterns of early 18F-FDG PET response to nivolumab (NIVO) and ipilimumab nivolumab (IPINIVO) in patients with metastatic renal cancer (MRC).
Authors: Charnley Natalie , Rosof-Wiliams Diana , Dobson Mike , Cox Susan , Amin Nisreen , Parikh Omi , Thompson Catherine , Danwata Falalu Dahiru , Cain John
Published: January 2024

374

Background: Immunotherapy with IPINIVO and NIVO is a standard treatment in MRC. This leads to recruitment and activation of immune cells. The ‘immune burst’ is seen at 1-4 weeks. Glycolysis leads to cellular 18F-FDG uptake. This can reflect malignancy. Sensitivity for renal tumours is poor, though high SUV suggests aggressive behaviour. Sensitivity for metastases can be 90% This study investigated 18F-FDG uptake in patients with MRC prior to treatment with immunotherapy. A scan was also performed at 2 weeks to assess a possible ‘flare’, due to glycolysis of the immune infiltrate, before significant standard radiological change was expected. Methods: Twenty six patients with MRC were enrolled. 8 patients had IPINIVO first line, and 18 had NIVO second line. Patients had a PET scan before and 2 weeks after treatment. Maximal standardised uptake values (SUV) were measured and corrected (COR) to the hepatic SUV. Results: All patients had some 18F-FDG avid metastases. SUVs varied within the same patient. For IPINIVO patients SUVmax was 17, mean 5.8 (3.7 and 2.5 COR respectively) and for NIVO patients SUV max was 25.1, mean 5.1. (7.6 and 2.3 COR respectively). There was no difference in mean SUV in the 2 groups (p=0.5). For NIVO patients there was a trend for patients who had a longer response to first line tyrosine kinase inhibitor, hence better prognosis, to have a lower SUV. (p=0.18) For NIVO there was a 12.4 % mean increase in SUV (p=0.06) In 8/16 patients there was a >20% increase in SUV in the measured metastases ( mean 50.4 % increase, range 22.2 – 142.9 ). Flare occurred at a range of tumour sites. Only metastases which were 18F-FDG avid had a flare. In 4 patients there was a >20% decrease in SUV. (Mean 41.2 Range -21.2% to -55.3%) For IPINIVO in 4/8 patients there was a >20% increase in SUV, mean 57.2 (Range 21- 134%) Flare only occurred in lymph nodes and an adrenal gland. In 2 patients there was a >20% decrease in SUV. (Mean - 50.7 Range -21.2% to -64%) Two patients had normal tissue flare: in thyroid, and mediastinal nodes. Conclusions: This is the first study to demonstrate tumour 18F-FDG flare in patients with MRC following immunotherapy, which may be due to influx and activation of glycolytic immune cells. There is a suggestion that tumour biology, and response to first line tyrosine kinase inhibitor is reflected in the SUV of metastases in patients having treatment with second line nivolumab.
Health-related quality of life (HRQoL) profile and clinical outcomes in first-line (1L) advanced renal cell carcinoma (aRCC): A modelling analysis based on CheckMate 9ER (CM9ER) trial.
Authors: Bedke Jens , Giles Rachel H. , Powles Thomas , Derosa Michael , Floden Lysbeth , Purnajo Intan , Lothgren Mickael , Ogareva Alessia , Cella David
Published: January 2024

384

Background: Cabozantinib plus nivolumab (CN) is a 1L therapy for aRCC. In the CM9ER trial CN had superior efficacy to sunitinib (SUN) and showed HRQoL benefit. We investigated the relationship between clinical outcomes, treatment and early deterioration in HRQoL dimensions in the CM9ER population. Methods: Using the CM9ER intention-to-treat (ITT) population (median follow-up 32.9 months) we: (a) explored time-to-event outcomes for CN vs SUN (b) identified determinants of HRQoL benefit by performing ordinal regression using the 19-item Functional Assessment of Cancer Therapy – Kidney Symptom Index (FKSI-19) item scores at week 13 (c) investigated relationships between early (week 13) deterioration in FKSI-19 items and clinical outcomes using a cox proportional modeling framework. First, univariate Cox proportional hazard modeling assessed the predictiveness of early FKSI-19 item deterioration (sig. threshold p ≤ 0.20). Items with significant univariate associations with the outcome were included in multivariate regression modeling (sig. threshold p ≤ 0.10). Treatment and baseline stratification factors (geographic region, baseline IMDC score, PD-L1 status) remained in all models. Results: All CM9ER ITT patients (N = 651; CN, 323; SUN, 328) were included. Compared with SUN, CN patients had a longer median duration of treatment (94.6 wks vs 36.5 wks), time to disease progression (83.1 wks vs 42.1 wks) and time to first grade 3/4 adverse event (16.3 wks vs 12.0 wks). FKSI-19 items with early deterioration favoring CN vs SUN ( p ≤ 0.05) were: lack of energy; pain; fatigue; bone pain; weak all over; nausea; bothered by treatment side effects; able to work. The table reports variables significantly associated with clinical outcomes ( p ≤ 0.05). Conclusions: Early deterioration in bone pain and sleep were associated with increased risk of mortality, and early deterioration in pain with reduced risk of toxicity-related discontinuation. We found no association between early FKSI-19 item deterioration and risk of progression or tumor shrinkage. Controlling for other variables, CN (vs SUN) treatment was positively and significantly associated with increased chance of tumor shrinkage, survival and progression-free survival, independent of early HRQoL deterioration. Clinical trial information: NCT03141177 . [Table: see text]
Gastrointestinal metastases in renal cell carcinoma: A retrospective multicenter GETUG (Groupe d’Etude des Tumeurs Uro-Genitales) study.
Authors: Carneiro Florian , Vinceneux Armelle , Larroquette Mathieu , Rony Maelle , Carril Lucia , Laguerre Brigitte , Blazevic Ilfad , Barthelemy Philippe , Teyssonneau Diego , Goujon Morgan , Linassier Claude , Thiery-Vuillemin Antoine , Roubaud Guilhem , Mourey Loic , Albiges Laurence , Gravis Gwenaelle , Gross-Goupil Marine , Cancel Mathilde
Published: January 2024

391

Background: Among patients with renal cell carcinoma (RCC), bone and visceral metastases have a poor prognosis, while endocrine gland metastases have a more favorable prognosis. Gastrointestinal metastases (GIMs) are rare, and their prognosis is still poorly understood. Objectives: To report clinical presentations, patients’ characteristics, therapeutic strategies, and prognosis of GIMs from RCC. Methods: We retrospectively collected data from RCC patients presenting GIMs, in 10 French GETUG centers, between 2000 and 2021. Results: We identified 74 patients with 87 GIMs, mostly gastric or duodenal. The median age at GIM diagnosis was 69 years and 76% of the patients already had other metastases. GIMs occurred after a median of 5.4 years (IC95%=[4.2-7.1]) and 1.9 years (IC95%=[1.2-3.8]) from RCC diagnosis and first metastasis, respectively. GIMs were symptomatic in 52 patients (70%), with anemia in 41 patients (55%) and/or gastrointestinal bleeding in 31 patients (42%). Only 22 asymptomatic patients (30%) were fortuitously diagnosed. The management of GIMs consisted of systemic treatment only in 29 GIMs (33%), local treatment only in 23 GIMs (26%), and both local and systemic treatment in 18 GIMs (21%). For 17 GIMs (20%), there was no therapeutic modification. After diagnosis of GIM, median overall survival was 19 months. Conclusions: We report the largest retrospective cohort of GIMs in RCC patients. They should be suspected in case of anemia or gastrointestinal bleeding in any patient with a history of RCC. Their management varies widely depending on their location in the digestive tract and whether they are symptomatic.
Real world evidence comparison of first-line (1L) immune-oncology(IO)/tyrosine kinase inhibitor (TKI) vs. IO/IO combination therapy in renal cell carcinoma (RCC).
Authors: Bolan Patrick , Hui Gavin , Low Yen , Gombar Saurabh , Fan Alice C. , Parikh Divya Ahuja , Shah Sumit , Srinivas Sandy , Khaki Ali Raza
Published: January 2024

402

Background: IO/IO and IO/TKI are the preferred first-line combinations for treatment of RCC. While these combinations have been superior to sunitinib, no head-to-head clinical trials have been completed, which leaves uncertainty about the preferred combination. Here, we have leveraged ASCO Cancerlinq data to compare overall survival for RCC patients (pts) receiving first line IO/IO vs. IO/TKI combinations. We hypothesized that IO/IO and IO/TKI would have similar survival. Methods: We performed a retrospective cohort study comparing IO/IO vs IO/TKI therapy for pts with metastatic RCC. We used the Atropos health platform, which is a commercial platform and queried ASCO CancerLinq data for this study. We identified pts with kidney cancer who received IO/IO or IO/TKI combinations between 2019 and 2023. For our primary analysis, we included only pts with ICD10 code consistent with clear cell [cc]RCC, but also did a secondary analysis including all pts with kidney cancer. The IO/TKI pts received either avelumab/axitinib, pembrolizumab/axitinib, nivolumab/cabozantinib, pembrolizumab/lenvatinib, or atezolizumab/cabozantinib within two weeks of each other. The IO/IO pts were identified as pts receiving ipilimumab and nivolumab within 2 weeks of each other without interceding TKI. We conducted a survival analysis of time to death using Cox proportional hazards regression to compare the two groups. The analysis was performed under three different confounder adjustment scenarios: without adjustment, with basic matching on sex and age, and with high dimensional propensity score (hdPS) using inverse probability of treatment weighting. Results: A total of 584 pts (286 IO/IO and 296 IO/TKI) with kidney cancer and 146 with ccRCC (75 IO/IO and 71 IO/TKI) were included. Mean age was 63-65 years and 30-35% female sex across groups. Table shows the restricted mean survival time (RMST) and HR for the Cox models. In the ccRCC cohort, 20 pts with IO/IO and 7 with IO/TKI died with RMST of 947 and 1071 days, respectively (hdPS HR 0.35, p=0.03). In the RCC cohort, 76 pts with IO/IO vs 49 with IO/TKI died with RMST 1126 vs 1017 (hdPS HR 0.61, p=0.04). Conclusions: In this exploratory, hypothesis-generating analysis of CancerLinq data, pts treated with IO/TKI had longer OS vs those treated with IO/IO. Limitations include the retrospective nature of the study, low power, lack of randomization, and potential unmeasured confounding factors (e.g., confounding by indication). Further investigation and prospective validation are needed to confirm these findings. [Table: see text]
Retrospective study assessing the use of angiotensin converting enzyme inhibitors or angiotensin receptor blockers to reduce toxicity from tyrosine kinase inhibitors in metastatic renal cell carcinoma.
Authors: Miller Theodore Joseph , Maddukuri Ashok , Elias Michael , Wheelden Megan , Trivedi Naman , Zhu Junjia , Joshi Monika
Published: January 2024

411

Background: The main toxicities associated with tyrosine-kinase inhibitors (TKIs) in the treatment of renal cell carcinoma (RCC) are proteinuria and hypertension. Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have established reno-protective and anti-hypertensive effects and can help with toxicity in mRCC. We hypothesize that use of ACEIs/ARBs is an effective method to decrease the degree of proteinuria and hypertension in patients treated with TKIs for metastatic/advanced renal cell carcinoma (mRCC). Methods: Single Institution retrospective study; mRCC patients (pts) who received TKI and ACEIs/ARBs and had urine protein measurements available at baseline and at 4-6 wk follow up post ACEs/ARBs were included in the analysis. Primary endpoints included improvement in grade of proteinuria and BP in mRCC pts on TKI treatment at baseline and with addition of ACEIs/ARBs. Secondary endpoints included number of dose interruptions (DI), BUN and creatinine changes. Paired statistical tests were used to compare the selected outcome variables between baseline and post ACE/ARB measures: for example, nonparametric Wilcoxon Signed-rank test for paired quantitative data and McNemar test for paired binary data. Results: Out of 71 screened patients between 2020-2023, N of 22 mRCC (N=22, 72.7% male, 77.3% white; 9% Hispanic; N=14 for TKI+ immunotherapy; N=8 TKI alone) pts were selected. ACEIs/ARBs treatment was associated with significantly reduced levels of proteinuria at 4–6wk follow-up. At baseline vs. follow-up, pts were found to have significantly lower proteinuria overall after ACEI/ARBs (p=0.0147), and 45.4% of pts had clinically insignificant proteinuria vs. 22.7% at baseline. Additionally, DI rates for TKI were significantly lower for pts placed on ACEIs/ARBs, with an 81% chance that pts with prior DI would not experience similar event in the follow-up period (p=0.003). Reductions in BP, creatinine, and TKI dosing were seen but not statistically significant (p>0.05 for all measures). Conclusions: In our small study, degree of proteinuria was notably reduced with administration of ACEIs/ARBs. Further findings show fewer DI of TKIs with ACEIs/ARBs use. Our findings suggest a potential role for ACEIs/ARBs in managing toxicity in patients undergoing TKI based therapy for mRCC. Future studies are needed to evaluate the use of ACE/ARB from the time of initiation of TKI based therapy to reduce the toxicities and improve the adherence to mRCC treatment which may result in better outcomes.
Impact of timing of immunotherapy and cytoreductive nephrectomy on outcomes in metastatic renal cell carcinoma: Results from the CKCis database.
Authors: Park Changsu , Ghosh Sunita , Moria Feras Ayman , Wood Lori , Bjarnason Georg A. , Bhindi Bimal , Heng Daniel Yick Chin , Castonguay Vincent , Pouliot Frederic , Kollmannsberger Christian K. , Bosse Dominick , Basappa Naveen S. , Finelli Antonio , Fallah-rad Nazanin , Breau Rodney H. , Lalani Aly-Khan A. , Tanguay Simon , Graham Jeffrey , Saleh Ramy R.
Published: January 2024

416

Background: Immunotherapy-based systemic treatment (ST) is the standard of care for most patients diagnosed with metastatic renal cell carcinoma (mRCC). Cytoreductive nephrectomy (CN) has historically shown benefit for select patients with mRCC but its role and timing are not well-understood in the era of immunotherapy. The primary objective of this study is to assess patient outcomes in patients who received ST only, CN followed by ST (CN-ST) and ST followed by CN (ST-CN). Methods: The Canadian Kidney Cancer information system (CKCis) database was queried to identify patients with de novo mRCC who received immunotherapy-based ST for mRCC between January 2014 to June 2023. These patients were classified into three categories as described above. Cox proportional hazards models were used to assess the impact of the timing of ST and CN on overall survival (OS) and progression free survival (PFS), after adjusting for IMDC risk group. Complications of ST and CN for these cohorts were collected. Results: A total of 588 patients were included in this study. 331 patients received ST only, 215 patients received CN-ST and 42 patients received at least one dose of ST prior to CN. Patient and disease characteristics including age, gender, performance status, IMDC risk category, comorbidity, histology, type of ST and metastatic sites are reported and globally well-balanced. OS analysis favoured patients who received ST-CN (hazard ratio [HR] 0.30, 95% confidence interval [CI] 0.13-0.68) and CN-ST (HR 0.68, CI 0.47-0.97) over patients who received ST only. PFS analysis showed a similar trend for ST-CN (HR 0.45, CI 0.26-0.77) and CN-ST (HR 0.9, CI 0.68-1.17). The most common cause of ST delay or cessation was treatment toxicity, followed by progression of disease. The most common perioperative complication was bleeding, followed by infection. Conclusions: This study examined baseline features and outcomes associated with the use and timing of CN and ST using real world data through the CKCis database. Patients selected to receive CN after ST seem to have improved outcomes. There were no appreciable differences in ST toxicity or perioperative complications across groups. Limitations include the small number of patients in the CN-ST group and residual confounding and selection bias that may influence the outcomes in patients undergoing CN.
Nucleosome profiling at AR binding sites (ARBS) to provide a prognostic tool for metastatic castration-resistant prostate cancer (mCRPC).
Authors: Dai Chao , Zhu Lisha , Fettke Heidi , Gan Shuang , Du Pan , Jia Shidong , Azad Arun
Published: January 2024

42

Background: Prostate cancer is the second leading cause of cancer death for men in the U.S., and metastatic castration-resistant prostate cancer (mCRPC) is the most advanced form. In previous work, we have reported prognostic significance of PTEN-PI3K-AKT pathway and DNA damage response aberrations detected in cell-free DNA (cfDNA) of mCRPC. Here we utilized nucleosome profiling pattern at androgen receptor (AR) binding sites to further investigate AR signaling pathway dysregulation of mCRPC. Methods: Using the next-generation sequencing PredicineScore liquid biopsy assay (low-pass whole genome sequencing, LP-WGS), we profiled cfDNA fragment coverage centered around AR binding sites (ARBS). For 118 mCRPC patient samples, we quantified sample-level ARBS nucleosome profiling abnormality score (ARBS score) by comparing its centric fragment coverage with normal plasma background using standard Z-score. ARBS score was correlated with clinical outcomes including PSA response rate (PSA RR), progression-free survival and overall survival (OS). Results: By comparing ARBS nucleosome profiling and normal plasma background, we found that mCRPC plasma samples had significant ARBS nucleosome depletion, reflective of transcription factor binding and persistent AR signaling. Notably, ARBS nucleosome depletion was prostate cancer specific, and did not occur in other examined cancer types. ARBS score was highly correlated with tumor fraction (R=0.82), indicating that high tumor fraction mCRPC sample had higher AR binding. Importantly, we found that high ARBS score (>2) in pre-treatment samples (n=86) was associated with significantly shorter OS and lower PSA RR compared with low ARBS (≤2) group for patients receiving AR pathway inhibitor (ARPI) or taxane chemotherapy (13.4 vs. 19.4 months, p=7.3×10-3, 45.7% vs. 77.5%, p=5.2×10-3). By integrating genome-wide DNA methylation profiling, we further found that ARBS was hypo-methylated in mCRPC patients, and identified a strong negative correlation between DNA methylation beta value and ARBS score (R=-0.83). Conclusions: ARBS nucleosome profiling abnormality inferred from LP-WGS can serve as a key prognostic tool for mCRPC patients. Patients with high ARBS score had worse clinical outcomes, highlighting the potential clinical utility of cfDNA fragmentomics analysis for mCRPC patient stratification. Integration of mutation, copy number variation and fragmentomics profiling of ARBS may further enhance our understanding of molecular aberrations and treatment outcomes in mCRPC.
A phase II study of neoadjuvant tislelizumab and axitinib in patients with locally advanced non-metastatic clear cell renal cell carcinoma (accRCC).
Authors: Zhang Shun , JI Changwei , Liu Guangxiang , Guo Hongqian
Published: January 2024

420

Background: PD-1/PD-L1 combined with vascular endothelial growth factor (VEGF) inhibitors improves survival in patients with advanced renal cell carcinoma (RCC), but the role of perioperative application in patients with localized RCC has not been established. In this phase II trial, we investigate the safety and role of tislelizumab and axitinib in downsizing tumors in patients with non-metastatic clear cell RCC prior to surgical resection. Methods: In this investigator-initiated study, 20 patients with high-risk non-metastatic ccRCC (clinical stage T2a-4 and/or N1, M0 lesions) were enrolled to receive 12 weeks of neoadjuvant ticelizumab and axitinib prior to nephrectomy. The primary endpoint was the objective response rate (complete and partial response) after neoadjuvant treatment according to RECIST v1.1. Secondary endpoints were disease-free survival (DFS), overall survival (OS), surgical outcome and safety. Results: By September 2023,13 eligible pts were enrolled. 11 pts have completed neoadjuvant therapy, with a median age of 60 (range 45-73) years, among whom 9 pts underwent surgery as planned without any delay. One patient progressed during treatment and received further systemic therapy. In 9 pts evaluable for efficacy, the investigator-assessed confirmed ORR was 55.5%. The median reduction of primary renal tumor size was 26.2% (range 12.5-45%). Pathologic results showed that one patient (11.1%) achieved a complete response (CR) by RECIST 1.1 and four patients achieved a partial response (PR). One patient who was considered unresectable became resectable at the end of treatment. Two patients were converted from radical to partial nephrectomy. The most common neoadjuvant therapy-related AEs were hematologic toxicity, hypothyroidism, nausea, vomiting, decreased appetite, fatigue, diarrhea, and elevated ALT/AST. There were no Gr4/Gr5 TRAEs. No direct intraoperative complications and no drug-related surgical complications postoperatively. Conclusions: As a neoadjuvant therapy for accRCC, the combination of tislelizumab and axitinib has clinical efficacy and a manageable safety profile. Clinical trial information: NCT05172440 .
Key parameters that influence surgical strategy in localised kidney cancer.
Authors: Pikul Maksym , Heidenreich Axel , Stakhovsky Eduard , Semko Sofiya , Pfister David A. , Voylenko Oleg , Paffenholz Pia , Kononenko Oleksii , Vitruk Iuriy , Stakhovskyi Oleksandr
Published: January 2024

423

Background: The goal of this studywas to select the key factors affecting choice between radical nephrectomy (RN) and partial nephrectomy (PN) for patients with localized RCC based on clinical and nephrometry data. Methods: A special retrospective cohort study was conducted in National Cancer Institute of Ukraine, which results were further validated on patient dataset in urological department of University Clinic of Cologne. The Institutional Review Boards and the local ethics committees of both high-volume centres approved the study. The main nephrometry parameters of tumor location in the kidney were analysed according to the R.E.N.A.L nephrometry score. The remaining functional parenchymal volume (RFPV) was calculated using the special formula. To determine the relationship between the risk of RN or PN, the multivariate predictive modelling method containing 12 parameters was used (Artificial Neural Networks [ANN]). Data validation based on referential centre experience using ROC-curve analysis to detect clinical applicability of the null hypothesis was performed. Results: Based on the analysis, for polary and laterally located tumors, the risk of RN was conditioned only by RFPV. The average critical value of RFPV for polar lesions was X6crit = 58% (in X6 < X6crit, RN was predicted); for lateral tumors - X6crit = 67% (in X6 < X6crit, RN was predicted). For medial location, the risk of RN only depended on the tumor size. Average critical value of the tumor size in the medial location was X7crit = 38 mm (in X7 > X7crit, RN was predicted). Based on the ROC curve comparison, there were no statistically significant differences between the AUCLin_12 and AUCMLP_3 (p = 0.12); thus, the reduced amount of the factor indicators from 12 to 3 did not worsen the model predictive qualities. Designed during primary analysis hypothesis was successfully validated in a referent centre on the cohort of 300 patients. Out of the cohort - 14 (4.6%) patients experienced false positive/negative outcome, which resulted in a radical/partial nephrectomy out of the hypothesis margins. Predictive model is characterized by high sensitivity (95.2%) and specificity (95.4%) in selecting patients for partial nephrectomy. Conclusions: For the polar and lateral tumor locations, the functioning parenchymal volumes of over 58 and 67% respectively serve as PN indications. However, for the medial lesions, the primary PN indication is a tumor size less than 38 mm.
Cytoreductive nephrectomy in patients with metastatic renal cell carcinoma treated with immunotherapy: A systematic review and meta-analysis.
Authors: Zhao Fengnian , Chen Junru , Liu Haoyang , Zeng Hao
Published: January 2024

427

Background: lmmunotherapy is changing the treatment of patients with metastatic renal cell carcinoma (mRCC). In recent years, many immune checkpoint inhibitors (ICls) have been introduced, and ICl-combination therapies have changed the treatment landscape for patients with mRCC. However, the role of cytoreductive nephrectomy (CN) in patients with mRCC receiving ICls is not clear. We aimed to assess the role of ICl-combination therapies in patients receiving /not receiving CN. Methods: PubMed, Embase, and Cochrane Library databases were searched for English-language clinical trials, cohort studies, and case-control studies evaluating OS in patients with mRCC who underwent /did not undergo CN (end-of-search date: 1 April 2023). The hazard ratio [HR] and 95% confidence interval [CI] for OS obtained by multivariate analysis were extracted and aggregated. Meta-analysis was performed using Review manager 5.4.1, and p<0.05 was defined as a statistical significance. Results: Eleven studies met the eligibility criteria. Receiving CN+ICI combination therapy was associated with significantly better OS than patients receiving ICI combination therapy alone (HR: 0.56，95% CI: 0.46-0.69, P < 0.001). In subgroup analyses, thinking about the number of lines for immunotherapy, CN provided OS benefit when immunotherapy was used as either first-line (HR: 0.54, 95% CI: 0.41-0.70, P < 0.001) or non-first-line treatment (HR: 0.59, 95% CI: 0.44-0.81, P = 0.001). In terms of tumor pathologic type, CN also provided OS benefit no matter the pathologic type was only clear cell renal cell carcinoma (ccRCC) (HR: 0.52, 95% CI: 0.28-0.95, P = 0.03) or not (HR: 0.54, 95% CI: 0.39-0.75, P < 0.001). For the choice of drugs, CN provided OS benefits with nivolumab/nivolumab + ipilimumab (HR: 0.50, 95% CI: 0.32-0.79, P = 0.003) or immunotherapy combined with tyrosine kinase inhibitors (HR: 0.59, 95% CI: 0.48-0.73, P < 0.001). About the timing of CN, CN also provided OS benefit when performing before immunotherapy (HR: 0.63, 95% CI: 0.54-0.73, P < 0.001) or no strictly restricted (HR: 0.49, 95% CI: 0.33-0.74, P = 0.0007). Conclusions: CN brings good effect on OS in mRCC patients treated with ICI-combination therapies. In ICI-combination therapy era, the role of CN still deserves attention.