bluuebunny/crossref_metadata_2025 huggingface dataset:
KEYNOTE-365 cohort B: Pembrolizumab (pembro) plus docetaxel and prednisone in abiraterone (abi) or enzalutamide (enza)–pretreated patients with metastatic castration-resistant prostate cancer (mCRPC)—New data after an additional 1 year of follow-up.
Authors: Appleman Leonard Joseph , Kolinsky Michael Paul , Berry William R. , Retz Margitta , Mourey Loic , Piulats Josep M. , Romano Emanuela , Gravis Gwenaelle , Gurney Howard , De Bono Johann S. , Boegemann Martin , Emmenegger Urban , Joshua Anthony M. , Massard Christophe , Sridhar Srikala S. , Conter Henry Jacob , Li Xin Tong , Schloss Charles , Poehlein Christian Heinrich , Yu Evan Y.
Published: March 2021

10

Background: For men with mCRPC, systemic therapies such as docetaxel and cabazitaxel improve survival, but more effective treatments are needed. KEYNOTE-365 (NCT02861573) is a phase 1b/2 study to examine the safety and efficacy of pembro in combination with 4 different study medications (cohorts A, B, C, D) in mCRPC. Previous data from cohort B with a median of 20 months of follow-up showed that pembro + docetaxel and prednisone was well tolerated and had antitumor activity in patients (pts) with mCRPC previously treated with abi or enza. New efficacy and safety data after an additional year of follow-up are presented. Methods: Cohort B enrolled pts who did not respond to or were intolerant to ≥4 weeks of abi or enza in the prechemotherapy mCRPC state and whose disease progressed within 6 months of screening (determined by PSA progression or radiologic bone/soft tissue progression). Pts received pembro 200 mg IV every 3 weeks (Q3W), docetaxel 75 mg/m2 IV Q3W, and oral prednisone 5 mg twice daily. Primary end points were safety, PSA response rate (PSA decrease >50% from baseline), and ORR per RECIST v1.1 by blinded independent central review. Efficacy and safety were assessed in all pts as treated. Results: Of the 104 treated pts, median age was 68.0 years (range, 50-86), 23.1% had PD-L1–positive tumors (combined positive score ≥1), 25.0% had visceral disease, and 50.0% had measurable disease. Median time from enrollment to data cutoff was 32.4 months (range 13.9-40.3); 101 pts discontinued, primarily because of disease progression (77.9%). Efficacy outcomes are reported in the table below. Treatment-related adverse events (TRAEs) occurred in 100 pts (96.2%); the most frequent (≥30%) were diarrhea (41.3%), fatigue (41.3%), and alopecia (40.4%). Grade 3-5 TRAEs occurred in 46 pts (44.2%). Five pts (4.8%) died of AEs; 2 were treatment-related pneumonitis. Conclusions: After another year of follow-up, pembro + docetaxel and prednisone showed improved ORR and PSA response rates compared to the prior dataset in pts with mCRPC previously treated with abi or enza. Safety was consistent with known profiles of each agent and will be further evaluated in a phase 3 study (KEYNOTE-921). Clinical trial information: NCT02861573. [Table: see text]
Clinical outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) receiving radium-223 (Ra-223) early versus late in the treatment sequence.
Authors: Mbuagbaw Lawrence , Lowther Jennifer , Lee-Ying Richard M.
Published: March 2021

136

Background: Ra-223 is the only targeted alpha therapy shown to prolong overall survival (OS) in men with mCRPC. The purpose of this real-world study is to evaluate clinical outcomes of patients (pts) when Ra-223 is used early (second-line) or late (third or later lines) for mCRPC. Methods: We used administrative databases in Ontario (2012-2017) to estimate OS from start of second-line life prolonging therapy (LPT), event free survival (EFS; time from start of second-line LPT to start of fourth-line or death) using counting process models, comparing 2 cohorts of patients: Early Ra-223 (2nd line) vs Late Ra-223 (3rd or later line). All models are adjusted for relevant fixed and time-varying covariates, including age, prostate specific antigen, hemoglobin, Charlson Comorbidity Index (CCI), use of bone health agents, prior systemic treatments, Gleason score, TNM score, Androgen Deprivation Therapy (ADT) and standardized pain score. Results: Data from 598 men in Ontario with mCRPC who received at least 2 lines of LPT, including Ra-223 in second line or later were analyzed (Early Ra-223=253; 42.3%; Late Ra-223=345; 57.7%). The mean age (standard deviation) at the start of first-line LPT was 72.2 years (8.8). Patients in the early Ra-223 cohort had a longer time from diagnosis of prostate cancer to receiving first-line LPT, a longer time from start of first-line to start of second-line LPT, and were less likely to receive docetaxel. The median number of Ra-223 cycles was 5 (range 3-6) and 4 (range 3-6) and the mean number lines of total LPT was 2.7 ± 0.9 (2.0 - 7.0) and 3.8 ± 0.9 (3.0 - 7.0) in the early and late Ra-223 cohorts, respectively. OS was better in the Early Ra-223 cohort compared to the Late Ra-223 cohort (Hazard Ratio [HR] 0.79; 95% Confidence Interval [CI] 0.66-0.95). EFS was better in the Early Ra-223 cohort compared to the Late Ra-223 cohort (HR 0.71; 95% CI 0.58-0.86). Time to first hospitalization and time to first emergency department visit was longer in the early Ra-223 cohort. Conclusions: Real-world data from Ontario, suggests that patients who received Ra-223 in second-line versus third-line or later had better outcomes. Patients who received Ra-223 early received less chemotherapy, but had better survival. The selection of patients who may benefit the most from Ra-223, and the optimal timing of the Ra-223 in the sequence of treatments, are being evaluated in a larger Canadian study including data from four Canadian provinces (REACTIVATE NCT04281147 ).
ctDNA pathogenic variants (PVs) in homologous recombination repair (HRR) genes in patients with metastatic CRPC.
Authors: Jaeger Ellen , Ledet Elisa Marie , Moses Marcus W. , Manogue Charlotte , Lewis Brian E. , Layton Jodi Lyn , Barata Pedro C. , Sartor A. Oliver
Published: March 2021

138

Background: HRR PVs can serve as predictive biomarkers and two PARP inhibitors are approved for metastasic CRPC (mCRPC) pts. Published data are predominantly focused on tissue-based assays, but obtaining tissue from mCRPC pts is problematic. In a large tissue based series (PROfound), 4047 mCRPC pts had tumor samples submitted for genomic testing but only 69% had interpretable results. No data were published from PROfound enumerating pts without available tissue to submit. Herein we assess frequency of PVs from selected HRR genes using a ctDNA assay. Methods: 292 mCRPC pts at Tulane Cancer Center were assessed for detectable HRR ctDNA changes using the Guardant 360 assay (which assesses the HRR genes BRCA1, BRCA2, and ATM). Results: 20/292 (6.8%) pts had a PV in ATM. However only 4/292 (1.4%) had > 1% mutant allelic fraction. Germline testing occurred in 18/20 of the ctDNA ATM PV pts and 0/18 had a germline PV. The PROfound series had 6.3% somatic PVs in ATM. 18/292 pts (6.2%) had a PV in BRCA2 and 12/292 (4.1%) had a mutant allelic fraction of > 1%. Germline testing was performed in 17/18 with BRCA2 ctDNA PVs and 9/17 had germline PVs. The PROfound series had 9.7% somatic BRCA2 PVs. BRCA1 PVs were detected in 6/292 (2.1%) pts and 3/292 (1%) had a mutant allelic fraction > 1%. 6/6 of the ctDNA PVs has germline testing and 1/6 had a BRCA1 PV. The PROfound series had 1.3% somatic PVs in BRCA1. Conclusions: Using ctDNA essay, it is feasible to measure PVs in only a small subset of HRR genes in mCRPC pts. These assays fail to detect deep deletions, a known and important mechanism of HRR gene loss. The ctDNA mutant allelic fractions are often low. The ability of ctDNA PVs using this assay to predict treatment effects are unknown.
Comprehensive genomic profiling of matched primary prostate cancer tissue and cell-free DNA (cfDNA) to assess ontogeny of BRCA1/BRCA2 mutations.
Authors: McFarland Taylor Ryan , Nussenzveig Roberto , Swami Umang , Sayegh Nicolas , Kessel Adam , Sharma Prayushi , Li Haoran , Kohli Manish , Maughan Benjamin Louis , Pal Sumanta K. , Agarwal Neeraj
Published: March 2021

166

Background: Both olaparib and rucaparib have recently been approved for the treatment of metastatic castration resistant prostate cancer (mCRPC) with BRCA1/2 mutations (BRCAm). In the PROFOUND trial, 36.9% of men had either no tissue or tissue that was inadequate for genomic profiling (PMID: 32343890). A recent report suggests BRCAm may be an early event in the evolution of prostate cancer (PMID: 29662167). This suggests comprehensive genomic profiling (CGP) of primary prostate tissue may suffice to guide treatment selection, even years after tissue collection. Herein, we investigate the ontogeny of BRCAm by comparing CGP of matched primary prostate cancer tissue to CGP of cfDNA. Methods: Eligibility criteria included men diagnosed with metastatic prostate cancer that had matched CGP of both primary prostate cancer tissue and cfDNA. Genomic profiling was performed by CLIA certified laboratories. Only somatic mutations detectable by both platforms were used for concordance analysis. Results: We identified 198 patients that had matched CGP of primary prostate tissue and cfDNA. Thirteen men had a pathogenic BRCAm in at least one test. Of these 13 positive test for BRCAm, 2 were rearrangements, 1 copy number loss, and 5 were germline mutations. Both platforms tend to filter out germline alterations therefore, they were not included in the estimation of concordance. Overall somatic BRCAm concordance between primary prostate tissue and cfDNA was 196/198 (98%). Notably, no new BRCAm were identified in cfDNA with a median difference of 23.62 (0.1 - 232.2) months between prostate cancer tissue and cfDNA collection. Conclusions: There were no BRCAm detected only in cfDNA, suggesting that BRCAm is an early event in the ontogeny of prostate cancer. Based on this, it is unlikely that delaying sequencing would benefit patients with advanced prostate cancer. In the event that tissue is unavailable or inadequate for CGP, profiling of cfDNA is a valuable alternative for detection of BRCAm.
Addressing financial toxicity in urologic oncology patients.
Authors: Parikh Divya Ahuja , Srinivas Sandy , Kerr Elizabeth , Patel Manali I.
Published: March 2021

170

Background: Financial toxicity, or the financial burden related to cancer care, is a source of distress for urologic oncology patients. This study aimed to address financial toxicity among prostate, kidney and bladder cancer patients and test the feasibility of a lay-health worker (LHW) and social work (SW) driven intervention. Methods: LHW assessed financial burden in urologic oncology patients with advanced cancer who presented for return visits at a single academic center. The LHW collected responses to three statements on a Likert scale – “I worry about the financial problems I will have in the future because of my illness or treatment”, “My cancer or treatment has reduced satisfaction with my present financial situation”, and “I feel financially stressed”. Patients who responded, “Very much” (4) or “Quite a bit” (3) to all statements were offered a one-on-one consultation with a trained SW. The SW provided personalized recommendations after review of patients' financial information, insurance status, and out of pocket costs. SW referred patients to appropriate support services including those offered by the hospital, government, nonprofits and private corporations. Pre-specified outcomes included pre/post-intervention financial toxicity and patient satisfaction with the intervention. Results: 145 patients (67%) agreed to be screened for financial toxicity by the LHW. Most participants were White (n = 100, 69%), male (n = 130, 90%), married (n = 104, 72%) and with incomes > $100,000 (n = 111, 77%). The majority had prostate cancer (n = 87, 60%), followed by kidney cancer (n = 36, 25%) and bladder cancer (n = 22, 15%). 12% (n = 26) responded “I worry about the financial problems I will have in the future because of my illness or treatment”, “Very much” or “Quite a bit”. 14% (n = 20) responded “My cancer or treatment has reduced satisfaction with my present financial situation”, “Very much” or “Quite a bit”. 12% (n = 17) reported “I feel financially stressed”, “Very much” or “Quite a bit”. A total of 14 patients were eligible for the intervention and were referred for a one-on-one SW consultation. Post-intervention results indicated excellent patient satisfaction with the intervention and a significant improvement in financial toxicity. 100% of patients reported the SW “provided financial resources that were beneficial to me”, and 78% (n = 11) had a decrease in financial toxicity score post-intervention (average decrease = -1, p = 0.05038). Conclusions: In this single institution study of prostate, kidney and bladder cancer patients with overall low baseline financial burden a LHW and SW driven intervention was feasible and effective in reducing financial toxicity.
Understanding racial disparities in survival among U.S. veterans with localized high-risk prostate cancer, 2004-2019.
Authors: Parikh Ravi Bharat , Chhatre Sumedha , Talwar Ruchika , Medvedeva Elina , Cashy John , Malkowicz S. Bruce , Narayan Vivek , Mamtani Ronac , Robinson Kyle William , Jayadevappa Ravishankar
Published: March 2021

202

Background: Known racial disparities in prostate cancer outcomes between African-American (AA) and non-Hispanic White (W) men may be ameliorated in the Veterans Health Administration (VA), a large national equal-access health system. We examined factors contributing to racial disparities in mortality among men with high-risk localized prostate cancer diagnosed in the VA. Methods: In this retrospective cohort study, we used linked administrative, survey, and electronic health record data from the Veterans Health Administration (VA) Corporate Data Warehouse to identify AA and W Veterans who were diagnosed with high-risk localized PC, as defined by D’Amico criteria, between January 1, 2004 and December 31, 2013. Patients were followed through December 31, 2019. The primary outcome was all-cause mortality. We used hierarchical Cox regression models, sequentially adjusting for covariates related to social determinants of health (e.g. travel time, marital status), clinical factors at diagnosis (e.g. PSA, Gleason, comorbidity), diagnosing facility, and prostate cancer treatment and adherence to American Cancer Society survivorship care guidelines. Results: Among 21,338 Veterans receiving continuous VA-based care (median age at diagnosis 66 years [interquartile range [IQR] 61-74]), 7,472 (28.7%) were AA, 9,404 (44.1%) died, and median follow-up was 8.4 years (IQR 6.1-11.1). After adjusting for all covariates, AA Veterans (adjusted hazard ratio [aHR] 0.84, 95% confidence interval [CI] 0.83-0.91) had improved overall survival compared to W Veterans. This association persisted in all hierarchical regressions (see Table), was present in all pre-specified subgroups, and was strongest among Veterans living in rural domiciles (aHR 0.70, 95% CI 0.64-0.77). Conclusions: AA Veterans with high-risk localized prostate cancer had improved long-term survival compared to W Veterans, which stands in contrast to prior studies among non-Veterans. Equal access to care may improve racial disparities in prostate cancer, although future studies should clarify mechanisms of improved survival for AA Veterans with prostate cancer in order to provide insights for ameliorating outcome disparities in non-Veterans with prostate cancer. [Table: see text]
Multimodal biomarkers overcome sampling bias to predict presence of aggressive localized prostate cancer.
Authors: Berman David Monty , Lee Anna YW , Lesurf Robert , Patel Palak , Ebrahimizadeh Walead , Bayani Jane , Boufaied Nadia , Jamaspishvili Tamara , Guerard Karl-Philippe , Dion Dan , Lee Laura A , Venkateswaran Vasundara , Chevalier Simone , Brimo Fadi , Buttyan Ralph , Thomson Axel A , Park Paul C , Lapointe Jacques , Boutros Paul Christopher , Bartlett John
Published: March 2021

209

Background: Histopathologic investigation of diagnostic prostate biopsies both confirms the presence of disease and estimates its potential for distal spread via tumour grade. The accuracy of biopsy grading is limited by intra-tumoral heterogeneity, inter-observer variability, and other factors. To improve risk stratification at the time of diagnosis, we sought to create objective molecular biomarkers of radical prostatectomy grade that are resistant to sampling error and should be useful when applied to biopsy tissue. Methods: We developed and validated a robust objective biomarker of prostate cancer grade using pathologic grading of prostatectomy tissues as the gold standard. We created training (333 patients) and validation (202 patients) cohorts of Cancer of the Prostate Risk Assessment (CAPRA) low- and intermediate-risk prostate cancer patients. To address intra-tumoral heterogeneity, each tumor was sampled at two locations. We profiled the abundance of 342 mRNAs complemented by 100 canonical DNA copy number aberration loci (CNAs) and 14 hypermethylation events. Using the training cohort with cross-validation, we evaluated models for training classifiers of pathologic Grade Group ≥2, Restricting to strategies resulting in true negative rates ≥0.5, true positive (TP) rates ≥0.8, we selected two strategies to train classifiers, PRONTO-e and PRONTO-m. Results: The PRONTO-e classifier comprises 353 mRNA and CNA features, while the PRONTO-m classifier comprises 94 mRNA, CNA, methylation and clinical features. Both classifiers (PRONTO-e, PRONTO-m) validated in the independent cohort, with respective TP rates of 0.809 and 0.760, false positive rates of 0.429 and 0.262, F1 scores of 0.709 and 0.724, and AUCs of 0.792 and 0.818. Conclusions: Two classifiers were developed and validated in separate cohorts, each achieved excellent performance by integrating different types of molecular data. Implementation of classifiers with these performance characteristics could markedly improve current active surveillance approaches without increasing patient morbidity and may help better inform patients on their individual need for definitive therapy versus active surveillance.
Clinical significance of the sonazoid-enhanced ultrasound for prostate cancer.
Authors: Akatsuka Jun , Kimura Go , Toyama Yuka , Hasegawa Hiroya , Mikami Hikaru , Endo Yuki , Takeda Hayato , Hayashi Tatsuro , Kondo Yukihiro
Published: March 2021

212

Background: This was a prospective study to evaluate the diagnostic accuracy of the Sonazoid-enhanced ultrasound (SEU) for prostate cancer. The primary end-point was accuracy of SEU to detect prostate cancer. The exploratory end-point was to analyze the prognostic significance of SEU positibity after radical prostatectomy (RP) in patients diagnosed as prostate cancer. Methods: In all cases locations of suspected prostate cancer were examined with SEU, digital rectal examination (DRE), B-mode (B), and power-doppler ultrasound (PDU) before prostate biopsy. We compared the sensitivity, specificity, PPV, NPV, and accuracy of SEU, RE, B, and PD. Among prostate cancer cases, effect of SEU positivity on biochemical recurrence (BCR) after radical prostatectomy was compared with that of DRE, B, and PDU. Results: Of 687 cases 416 cases (60.6%) were prostate cancer. The sensitivity, specificity, PPV, NPV, and accuracy were 52.9%, 63.5%, 69.0%, 46.7%, and 57.1% by DRE, 69.2%, 43.9%, 65.5%, 48.2%, and 59.2% by B, 66.6%, 59.0%, 71.4%, 53.5%, and 63.6% by PDU, and 66.1%, 70.1%, 77.2%, 57.4%, and 67.7% by SEU, respectively. SEU was the highest in specificity, PPV, NPV, and accuracy rate. Eighty three patients underwent radical prostatectomy. The SEU + group (69.3%) had a significantly poor prognosis compared to the SEU− group (88.7%) on the five-year BCR-free survival rate (p < 0.05). Univariate analysis showed SEU+ (HR 3.5; p = 0.02), DRE+ (HR 2.7; p = 0.04), PDU+ (HR2.6; p = 0.09), and B+ (HR 2.0; p = 0.21). SEU was the highest prognostic factor on BCR after radical prostatectomy. Conclusions: Sonazoid was able to visualize even small blood vessels in the prostate. SEU showed the highest accuracy for cancer detection and was the highest prognostic factor on BCR in the univariate analysis. To obtain the maximum benefit of Sonazoid, further examinations are needed.
Analysis of rectal dose during prostate stereotactic body radiotherapy in MR-guided radiotherapy.
Authors: Sritharan Kobika , Dunlop Alex , Mitchell Adam , Mohajer Jonathan , Smith Gillian , Tree Alison
Published: March 2021

242

Background: The Unity MR-Linac combines a 7-MV Linac with 1.5T magnetic resonance (MR) imaging capability and it enables adaptive radiotherapy, whereby the target and organs at risk are recontoured and a plan is optimised daily. During treatment a session MR image is taken first, on which the target and organs-at-risk are contoured, and a plan created. A verification image is taken prior to dose delivery to identify intra-fractional changes. If present, the daily treatment plan is shifted to reflect the anatomy. A post-treatment image is acquired at the end of treatment. This study evaluates the dosimetric changes to the rectum caused by intra-fractional changes during treatment delivery for prostate stereotactic body radiotherapy (SBRT) calculated on the verification and post-treatment images. Methods: The first five patients treated on the MR-Linac with 5-fraction SBRT to the prostate are included in this study. For each patient, the rectum was contoured on the verification and post-treatment MR images for each of the five fractions. The dose delivered to the rectum with the original treatment plan was then calculated on each image and the V36Gy rectal dose constraint was noted. Results: Out of the 25 fractions, a post treatment image was not performed in one fraction; 24 fractions were therefore analysed in total. The rectal V36Gy dose constraint exceeded the mandatory target of 2cc on 50% of the verification images and 46% of the post-treatment images. In 6 fractions the rectal V36Gy was greater than 2cc on both the verification and post-treatment images suggesting this rectal constraint was exceeded throughout treatment. In 17% of patients, the volume of rectum receiving 36Gy increased at each timepoint an image was taken during the treatment workflow. Conclusions: The rectal V36Gy dose constraint is susceptible to minor changes in rectal filling, which may often lead to higher than the accepted dose constraint. Thus, a single planning CT scan is unlikely to be representative of dose delivered. Adaptive radiotherapy can reduce this uncertainty somewhat, but intra-fraction dose re-optimisation would be required to ensure the rectal V36Gy remains acceptable at all times.
Patterns of care and treatment outcomes in locoregional squamous cell carcinoma of the prostate.
Authors: Weil Christopher , Hutten Ryan , Tward Jonathan David , Lloyd Shane , Johnson Skyler B
Published: March 2021

260

Background: Primary pure prostate squamous cell carcinoma (PSCC) is a rare, aggressive disease accounting for less than 0.5-1% of prostate cancer diagnoses. PSCC is a distinct entity from adenocarcinoma with historically poor outcomes, often presenting in younger patients with lower urinary tract symptoms and normal PSA. There are currently no established treatment guidelines. Case reports are limited but describe multiple treatment approaches including various combinations of surgery, platinum and non-platinum-based chemotherapy, radiotherapy and androgen deprivation therapy, with selected reports showing longer survival times with a combined modality approach. Methods: Seeking to identify practice patterns and treatment outcomes, we performed a retrospective analysis of the United States National Cancer Database to identify 66 males with locoregional, nonmetastatic primary pure squamous cell carcinoma of the prostate and treated with surgery, chemotherapy, and/or radiotherapy between 2004 and 2015. Clinical factors in analysis included pretreatment PSA, clinical T-stage, histology, treatment modality and demographic factors including age, comorbidity index, race, insurance status and treatment facility type. Patients were stratified into treatment groups consisting of local therapy alone (n = 40, 60%), local therapy and chemotherapy (n = 13, 20%), chemotherapy alone (n = 7, 11%), and observation (n = 6, 9%). Survival analysis was estimated using the Kaplan-Meier method and analyzed with log-rank testing. A Cox proportional hazards model was used to evaluate the association between patient characteristics and survival. Univariable and multivariable logistic regression was performed to identify covariates associated with receipt of each treatment modality. Results: With an overall median follow-up of 21.9 months, median survival was 19.7 months for patients treated with local therapy alone, 10.9 months with chemotherapy alone, and 36.5 months with combined local therapy and chemotherapy. Overall survival was not statistically significant between treatment groups. Statistically significant predictors of death included age (HR 1.1, 95% CI [1.03-1.17]) and clinical stage ≥T3a (HR 4.05, 95% CI [1.35-12.2]). Statistically significant predictors of receipt of chemotherapy were clinical stage T3a or greater (OR 34.6, 95% CI [2.65-364]) and age (OR 0.91, 95% CI [0.82-99]). Conclusions: This analysis represents the largest reported cohort analysis of locoregional pure PSCC. Unfortunately, due to the rarity of this disease, prospective or randomized trials to determine the optimal treatment strategy are not feasible. Despite limitations in sample size, and in the absence of prospective data, this analysis suggests the addition of chemotherapy to local therapy is a reasonable treatment approach in appropriately selected patients and may result in improved survival.
Delaying surgery for clinical T1b-T2bN0M0 renal cell carcinoma: Oncologic implications in the COVID-19 era and beyond.
Authors: Srivastava Arnav , Patel Hiren V. , Kim Sinae , Shinder Brian , Sterling Joshua , Tabakin Alexandra L. , Polotti Charles , Saraiya Biren , Mayer Tina M. , Kim Isaac Yi , Ghodoussipour Saum , Patel Hiten Dilip , Jang Thomas L , Singer Eric A.
Published: March 2021

283

Background: During COVID-19, many operating rooms were reserved exclusively for emergent cases. As a result, many elective surgeries for renal cell carcinoma (RCC) were deferred, with an unknown impact on outcomes. Since surveillance is commonplace for small renal masses, we focused on larger, organ-confined, RCCs. Our primary endpoint was pT3a upstaging and our secondary endpoint was overall survival (OS). Methods: We retrospectively abstracted cT1b-cT2bN0M0 RCC patients from the National Cancer Database (NCDB), stratifying them by clinical stage and time from diagnosis to surgery. We selected only those patients who underwent surgery. Patients were grouped by having surgery within <1 month, 1-3 months, or >3 months after diagnosis. Logistic regression models measured pT3a upstaging risk. Kaplan Meier curves and Cox proportional hazards models assessed OS. Results: 29,746 patients underwent partial or radical nephrectomy. Delaying surgery >3 months after diagnosis did not confer pT3a upstaging risk among cT1b (OR=0.90; 95%CI: 0.77–1.05, p = 0.170), cT2a (OR=0.90; 95%CI: 0.69–1.19, p=0.454), or cT2b (OR=0.96; 95%CI:0.62–1.51, p=0.873) masses (Table). In all clinical stage strata, non-clear cell RCCs were significantly less likely to be upstaged (p<0.001). A sensitivity analysis, performed for delays of <1, 1-3, 3-6, and >6 months, also showed no increase in upstaging risk. Conclusions: Delaying surgery up to, and even beyond, 3 months does not significantly increase risk of tumor progression in clinically localized RCC. However, if deciding to delay surgery due to COVID-19, tumor histology, growth kinetics, patient comorbidities, and hospital capacity/resources, should be considered. [Table: see text]
Outcomes and prognostic factors in metastatic renal cell carcinoma patients with brain metastases.
Authors: Dogan İzzet , Iribas Ayca , Paksoy Nail , Ekenel Meltem , Vatansever Sezai , Basaran Mert
Published: March 2021

289

Background: The study aimed to evaluate the outcomes and prognostic factors in patients with brain metastatic renal cell carcinoma (bmRCC). Methods: The data of 322 patients with renal cell carcinoma, between 2012 and 2020, were retrospectively reviewed. The clinicopathological features and treatments of the patients with bmRCC were recorded. Overall survival (OS) and prognostic factors were evaluated with Kaplan-Meier analysis and Cox-regression analysis. Results: Forty (12.4%) of the patients had bmRCC. The median follow-up period was 7.3 months (range, 0.2-55.5). The male/female ratio was 2.3, and the median age at diagnosis was 62 years (range, 25-84). Seventeen (42.5%) of the patients were de-novo metastatic, and nine (22.5%) of the patients had brain metastases at presentation. The most common extracranial metastatic sites of the disease were lung (72.5%), bone (47.5%), lymph node (27.5%), and liver (12.5%). Twenty-four (60%) patients previously had received various therapies (tyrosine kinase inhibitor, checkpoint inhibitors, or palliative radiotherapy). After brain metastases developed, 92% of the patients received brain radiotherapy (whole-brain radiotherapy or stereotactic radiosurgery), and twenty-five (62.5%) patients received different therapies. Nine patient received sunitinib, nine patient pazopanib, five patient nivolumab, and two patient axitinib. A total of 32 (80%) patients died during the study period. The median OS was 8.8 months (range, 2.9-14.6) for all patients with bmRCC. Six months- and one-years overall survival ratios were 60% and 40%, respectively. In univariate analysis, the number of brain metastasis (p = 0.352), the localization of brain metastasis (p = 0.790), the longest size of brain metastasis (p = 0.454), the number of extracranial metastatic sites (p = 0.812), de-novo metastatic disease (p = 0.177), primary tumor localization (left or right) (p = 0.903), and tumor grade (p = 0.093) were not statistically significant factors on OS. However, age (p = 0.02), a history of nephrectomy (p < 0.001), receiving brain radiotherapy (p = 0.005), and type of treatment (p = 0.044) was statistically significant. Only, the effect of brain radiotherapy on OS (p = 0.011) was confirmed in multivariate analysis. Conclusions: The prognostic data of patients with bmRCC is limited. In this study, we observed that the prognosis of patients with bmRCC was poor. Despite a small number of patients, we detected that the effect of tyrosine kinase inhibitors and nivolumab was comparable, and receiving brain radiotherapy was a prognostic factor for OS.
Factors associated with palliative care (PC) utilization in advanced and metastatic renal cell carcinoma (RCC).
Authors: Patel Hiren V. , Sterling Joshua , Srivastava Arnav , Kim Sinae , Saraiya Biren , Mayer Tina M. , Jang Thomas L , Singer Eric A.
Published: March 2021

297

Background: Palliative care (PC) offers various benefits for patient with cancer that include, but are not limited to, decrease in disease-specific symptoms and improvement in functional status. Several oncological guidelines have adopted early integration of PC into oncologic care to improve quality of life among patients with advanced malignancies. However, PC utilization patterns and factors associated with its use in advanced renal cell carcinoma (RCC) remain poorly understood. Methods: Using the National Cancer Database (NCDB), we abstracted patients with stage III and IV RCC from 2004-2014 and evaluated PC utilization amongst this cohort. Socioeconomic and clinical factors were compared for patient receiving and not receiving PC for advanced RCC. Multivariable logistic regression identified factors that were associated with receipt of PC. Results: We identified 20,122 and 42,014 patients with stage III and IV RCC, respectively. Among this cohort, 329 and 9,317 patients received PC for stage III and IV RCC, respectively. From 2004 to 2014, PC utilization has been stable at ~1% for stage III RCC and has significantly increased from 17% to 20% for stage IV RCC. Multivariable analysis demonstrated that Blacks, income >$48,000, regions outside of Northeast, stage III RCC, and patients that received surgery were less likely to receive PC. Patients that were female, with more comorbidities, uninsured or with government insurance, lower educational status, treated at academic or integrated cancer program, with sarcomatoid histology, receiving systemic therapy were more likely to receive PC. Conclusions: While PC utilization has significantly increased for stage IV RCC, there are several demographic, socioeconomic, and clinical factors that predict PC usage among patients with advanced RCC. Taken together, this suggests the need for more equitable and systematic use of PC among patients with advanced RCC.
ASSET: Alternative schedule sunitinib in metastatic renal cell carcinoma (RCC)—Cardiopulmonary exercise testing (CPET).
Authors: Harrison Michael Roger , Bartlett David , Zhang Tian , Armstrong Andrew J. , Coburn Aubrie , Coyne Brian , Anand Monika , Oyekunle Taofik , Wu Yuan , Khouri Michel , George Daniel J.
Published: March 2021

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Background: Sunitinib (SUN) is a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) approved for treatment of advanced RCC and high risk RCC after nephrectomy. Evidence suggests that a 2 week (wk) on, 1 wk off schedule (2/1) of SUN administration may be more tolerable than the standard 4 wk on, 2 wk off schedule (4/2). We investigated changes in cardiopulmonary function and related parameters over time in RCC patients treated with both schedules of SUN. Methods: Patients starting SUN for RCC, with KPS ≥80 and normal organ and marrow function, were enrolled and randomized 1:1 to schedule 4/2 or 2/1. Subjects were required to be able to walk and jog on a treadmill and to complete an acceptable CPET at baseline (BL). Primary endpoint was change in peak oxygen uptake (VO2peak) on both schedules at 12 wk from BL. Key secondary endpoints were change from BL to 12 wk in: left ventricular ejection fraction (LVEF), upper and lower body strength (1-RM), functional measures (chair stand, timed up-and-go [TUG], 6-minute walk test [6MWT], quality of life (QOL; FACT-Fatigue, FKSI-19), anxiety and depression (HADS) and exercise behavior (Godin Leisure Score). ANCOVA models controlling for baseline values were used to analyze the primary and secondary endpoints. Results: Between 11/20/2017 and 6/24/2019, 9 out of a planned 30 patients consented to participate at Duke. Two patients declined to participate and 7 patients were enrolled on study: 4 on Arm A and 3 on Arm B. All 7 patients completed the 12 wk study. Median age, BMI, and VO2peak were 65 yrs, 30.5 kg/m2, and 19.2 ml kg−1 min−1. We observed no difference in the primary endpoint of VO2peak between arms (p=0.84). We report BL to 12 wk change scores for all patients starting SUN (Table). In addition, mean change scores (SE) for QOL by FACIT-Fatigue and FKSI-19 were -2.88 (1.5) and 1.2 [9.8]; anxiety and depression by HADS 1.14 (1.3); and physical activity 1.14 (1.7). Conclusions: We observed non-significant declines in most measures of physical fitness and function during the first 12 wk of treatment with SUN. To our knowledge, this is the first reported study of these parameters in patients with RCC. Given that a VEGF TKI, alone and with an immune checkpoint inhibitor, remains a standard of care for metastatic ccRCC, studies should be undertaken to examine whether exercise training can prevent declines in physical fitness and function. Clinical trial information: NCT03109015 . [Table: see text]
Health-related quality-of-life outcomes from a phase II open-label trial of two different starting doses of lenvatinib in combination with everolimus for treatment of renal cell carcinoma following one prior VEGF-targeted treatment.
Authors: Bergerot Cristiane Decat , Rha Sun Young , Pal Sumanta K. , Koralewski Piotr , Stroyakovskiy Daniil , Alekseev Boris , Parnis Francis , Castellano Daniel , Lee Jae-Lyun , Sunela Kaisa , Ciuleanu Tudor , Heng Daniel Yick Chin , Glen Hilary , Wang Jinyi , Bennett Lee , Pan Janice , O'Hara Karen , Puente Javier
Published: March 2021

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Background: Renal cell carcinoma (RCC) is the most common type of kidney cancer, constituting 80% to 85% of primary renal neoplasms. Preserving health-related quality of life (HRQOL) is an important goal during RCC treatment, but HRQOL analyses in prospective clinical trials in RCC are limited. We report changes in HRQOL, a secondary endpoint of this phase II trial. Methods: HRQOL data were collected during a multicenter, randomized, open-label phase II study comparing the safety and efficacy of two different starting doses of lenvatinib (18 mg vs. 14 mg daily [QD]) in combination with everolimus (5 mg QD), following one prior vascular endothelial growth factor–targeted treatment (NCT03173560). HRQOL was measured using three different instruments, including the FKSI-DRS, EORTC QLQ-C30, and EQ-5D-3L. Change from baseline HRQOL was assessed using linear mixed-effects models. Deterioration events for time to deterioration (TTD) analyses were defined using established thresholds for minimally important differences in the change from baseline for each scale (i.e., 10 points for EORTC, 3 points for FKSI-DRS, 0.08 points for EQ-5D index, and 10 points for EQ-VAS). The distribution of TTD and median TTD for each treatment arm were estimated using the Kaplan-Meier method. Results: Baseline characteristics, including baseline scores of the 343 participants randomly assigned to 14 mg QD lenvatinib (n = 172) and 18 mg QD lenvatinib (n = 171), were well balanced. The average scores for the 18 mg QD group were generally higher, with lower symptom severity than the 14 mg QD group. The least squares mean estimates for change from baseline were favorable for the 18 mg QD group over the 14 mg QD group for the FKSI-DRS and most EORTC QLQ-C30 scales; however, the differences between treatments did not exceed the minimally important difference for clinical significance. Both study arms showed an increase diarrhea severity. Median TTD was longer among participants in the 18 mg QD group than those in the 14 mg QD group for most scales. Conclusions: In most scales, participants who received an 18 mg QD lenvatinib starting dose had better HRQOL and longer time to deterioration than those who received a 14 mg QD starting dose. These findings suggest that the approved treatment regimen of an 18 mg starting dose of lenvatinib in combination with everolimus remains favorable for RCC treatment, following one prior vascular endothelial growth factor–targeted treatment. Clinical trial information: NCT03173560 .
A prospective phase II/III study of PSMA-targeted 18F-DCFPyL-PET/CT in patients (pts) with prostate cancer (PCa) (OSPREY): A subanalysis of disease staging changes in PCa pts with recurrence or metastases on conventional imaging.
Authors: Durack Jeremy C. , Alva Ajjai Shivaram , Preston Mark A. , Pouliot Frederic , Saperstein Lawrence , Carroll Peter R. , Pienta Kenneth J. , Rowe Steven P. , Patnaik Akash , Probst Stephan , Stambler Nancy , Jensen Jessica , Wong Vivien , Siegel Barry A. , Morris Michael J.
Published: March 2021

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Background: Conventional imaging and bone scintigraphy are suboptimal modalities for identifying PCa. PSMA-based imaging is highly promising for PCa detection. 18F-DCFPyL is a novel PSMA-targeted radiopharmaceutical for positron emission tomography (PET) that may be useful in staging of PCa. The diagnostic performance, detection rate, and potential impact of 18F-DCFPyL on staging of pts with high- risk PCa have been previously reported. Here we report on the impact of 18F-DCFPyL on staging of pts with PCa recurrence or metastases on conventional imaging. Methods: 18F-DCFPyL-PET/CT was evaluated in 117 men with radiologic evidence of local recurrence or metastatic disease on baseline anatomical imaging (CT, MRI) or whole-body bone scintigraphy and in whom at least one lesion was deemed amenable to biopsy. A single dose of 9 mCi (333 MBq) of 18F-DCFPyL was administered via intravenous injection, followed by PET/CT acquisition 1 to 2 hours thereafter. Based on TNM staging: prostatic (T), pelvic LN (N), extra-pelvic LN (M1a), bone (M1b) and other visceral organs/soft tissue (M1c), 18F-DCFPyL-PET/CT detection rates including lesion counts were systematically analyzed. Three central, blinded, and independent readers evaluated the 18F-DCFPyL scans. Results: In this study, 82 (70%) patients had baseline radiographic M1 stage disease (14 patients with M1a, 50 patients with M1b, 18 patients with M1c) and 33 (28%) patients were M0 stage at baseline by central conventional imaging review; two patients were unevaluable. 18F-DCFPyL-PET/CT up-staged 58% (19/33) of pts from M0 to M1, of whom 91% (10/11) who underwent an extra-pelvic biopsy were confirmed to have M1 disease by pathology, including 9 patients with M1b and 1 patient with M1a. Of the patients who were staged M1 at baseline, 18F-DCFPyL-PET/CT upstaged 16% (10/64; M1a to M1b or M1c: n = 4; M1b to M1c: n = 6) of pts to a higher M1 sub-stage and down-staged 22% (18/82) to M0. Conclusions: 18F-DCFPyL-PET/CT identified M1 disease in the majority of patients examined who otherwise had locoregional disease. These data suggest that 18F-DCFPyL-PET/CT may be a useful tool in properly staging men with both metastatic and nonmetastatic relapsed disease, which could lead to superior treatment paradigms than currently exist using conventional imaging. Clinical trial information: NCT02981368.
Long-term survival of favorable-risk patients with metastatic renal cell carcinoma treated with second-line axitinib in a multicenter phase II study.
Authors: Tsimafeyeu Ilya , Borisov Pavel S. , Semenov Andrey , Leonenkov Roman , Novikova Olga , Gamayunov Sergey , Mikhailova Nadezhda , Bondarenko Anastasia , Abdelgafur Ahmed
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Background: Tyrosine kinase inhibitors remain possible treatment options in favorable risk patients newly diagnosed with metastatic renal cell carcinoma (mRCC). In phase II study (FavorAx), axitinib showed the activity in mRCC patients with a favorable risk and history of prior VEGFR-directed therapy. Here we present the outcomes from expansion study cohort with 4 years follow-up. Methods: Patients were required to have clear-cell mRCC, favorable risk according to IMDC criteria, and to have received first-line treatment with sunitinib or pazopanib. Prior treatment with other agents was not permitted. Axitinib was given orally at a starting dose of 5 mg twice daily with possible dose titration. Treatment was continued until disease progression according to RECIST version 1.1, unacceptable toxicity, death, or withdrawal of consent. All patients were assessed for efficacy. Endpoints included progression-free survival (PFS, primary); overall survival (OS), objective response rate (ORR), and safety (secondary). Results: A total of 55 patients were assessed, 58% of whom were male. Median age was 64 years. 29 (53%) patients had 2 and more metastatic sites. 73% and 27% of patients received first-line sunitinib or pazopanib. The median PFS was 19 months (95% CI, 15–23) and the median OS was 29.4 months (95% CI, 21.5–37). The 4-year OS rate was 36%. The objective response rate was 31% and 2 (3.6%) patients achieved a complete response. Disease progression was the single reason for discontinuation of axitinib. After disease progression, 62% of patients received third-line therapy. The toxicity was consistent with previously reported data. The most common adverse events associated with axitinib were hypertension, fatigue, and diarrhea, each occurring in more than 20% of patients. Conclusions: Second-line axitinib continues to show efficacy in favorable risk patients with mRCC. Long-term OS and PFS were observed with axitinib. Clinical trial information: NCT02700568 .
Combination therapy with avelumab (Ave) and cabozantinib (Cabo) in patients (pts) with newly diagnosed metastatic clear cell renal cell carcinoma (mccRCC).
Authors: Li Haoran , Swami Umang , Boucher Kenneth M , Gupta Sumati , Hawks Josiah , Sirohi Deepika , Agarwal Neeraj , Maughan Benjamin Louis
Published: March 2021

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Background: Immune therapy combinations are now standard first-line therapy for pts with mccRCC. Cabo modulates key components of the immune system such as decreasing regulatory T-cells and increasing T-effector cell populations and is approved for treatment of mRCC. We hypothesize that Ave + Cabo will be safe and show clinical activity in mccRCC. Methods: Prospective phase I clinical trial using a 3+3 design with three planned dose cohorts: Cabo 20mg/day, 40mg/day and 60mg/day + Ave (10mg/kg q2weeks) in each arm. The primary endpoint was safety and identification of the recommended phase II dose (RP2D). Key secondary endpoints included objective response rate (ORR) and radiographic progression free survival (PFS). No dose modifications were allowed for Ave but dose delays were permitted. Dose reductions were allowed for Cabo. There were an additional 3 patients included in the final dose cohort as a confirmation of the RP2D. RECIST 1.1 was used to determine ORR. Treatment beyond progression was allowed. Results: Twelve patients with newly diagnosed mccRCC were enrolled from 08/2018 through 03/2020. Three patients were enrolled into the 20 and 40mg cohorts each, six patients enrolled in the 60mg cohort. IMDC risk: favorable 4 patients, intermediate 6 patients, poor 2 patients. No dose limiting toxicities were observed in any cohort. Only one SAE related to study treatment was observed, thromboembolism, after the DLT period. Immune related adverse events (irAE) occurred in six patients (50%) and included hypothyroidism, colitis, nephritis, allergic rhinitis and rash. Six patients required dose reductions of cabozantinib after the DLT period: one in the 40mg cohort and five in 60mg cohort, most frequently due to oral mucositis and hand foot syndrome. One patient discontinued Ave due to irAE (nephritis). No patients discontinued Cabo due to toxicity. The ORR was 33% (all PR). The clinical benefit rate (CR+PR+SD) was ~ 92%. One patient experienced PD on the first scan and then continued on the protocol treatment without further progression at the time of this report (follow up to date ~ 7 months). Seven of 12 pts are still on protocol treatment. Conclusions: Ave + Cabo in mccRCC is safe and preliminarily efficacious. Even though the DLT was not met in any of the cohorts, based on dose reduction required in 5 of 6 pts in the Cabo 60 mg cohort after the DLT period, the recommended RP2D dose for the combination is Cabo 40mg/day and Ave 10mg/kg q2 weeks. Safety and efficacy data will be elaborated in the meeting. * NA & BLM: equal contribution Clinical trial information: NCT03200587 .