bluuebunny/crossref_metadata_2025 huggingface dataset:
Third analysis of a randomized trial of finite abiraterone acetate (AA) plus LHRH agonist (LHRHa) versus LHRHa in biochemically recurrent, non-metastatic hormone-naïve prostate cancer (M0HNPC).
Authors: Hahn Andrew Warren , Wang Xuemei , Efstathiou Eleni , Hwang Hyunsoo , Zurita Amado J. , Spetsieris Nicholas , Boukovala Myrto A , Wang Jennifer , Araujo John C. , Pilie Patrick Glen , Siddiqui Bilal A. , Subudhi Sumit Kumar , Corn Paul Gettys , Aparicio Ana , Tu Shi-Ming , Logothetis Christopher
Published: February 2022

135

Background: In pre-operative studies, a short duration of AA + LHRHa produced marked cytoreduction in a subset of men with high-risk prostate cancer (PCa). However, in M0HNPC, androgen signaling inhibition (ASI) is reserved for men with short PSA doubling time. We reasoned that the subset of men who experience cytoreduction with pre-operative AA + LHRHa would also benefit from a short duration of AA + LHRHa at PSA recurrence. This report is a one-year follow-up of our second analysis (ASCO Annual Meeting 2018; PMID 34536949). Methods: FINITE is a phase II trial that randomized (1:1) to two treatment groups, 8 months of LHRHa alone or LHRHa plus AA 1000 mg and prednisone 5 mg daily (NCT01786265). Eligible patients had a rising PSA after definitive therapy and no prior systemic therapy. At disease progression, men were eligible for crossover to 8 months of the alternative therapy. The primary endpoint was PSA-free survival at 12 months (≤ 0.1 ng/dL). Time to PSA progression was calculated from date of initial treatment to date of PSA progression, defined as first occurrence of a rising PSA, if PSA remained detectable after treatment, or when the PSA ≥ 1 ng/dL, if it was undetectable after treatment and confirmed 4 weeks thereafter. The probabilities of PSA progression were defined using the Kaplan-Meier method. Results: 199 men were randomized, and 197 received initial treatment (LHRHa = 99, LHRHa + AA = 98). Median age at enrollment was 65 years, median PSA was 0.95 ng/dL (range 0.1 – 33.3), and median testosterone was 342.5 ng/dL (10-986). At data cut-off (October 1, 2021), men who received LHRHa + AA were more likely to be PSA-free 12 months after completing treatment (34% vs. 19%, p = 0.02). 168 men (85%) had experienced PSA progression, and median time to PSA progression was 24.3 months for entire cohort. Receipt of LHRHa + AA was associated with longer time to PSA progression than LHRHa alone (27.2 vs. 19.9 months, p = 0.003). Conclusions: Our findings support that finite treatment with AA + LHRHa produces more durable disease-free survival than LHRHa. The finite duration of AA + LHRHa is a toxicity-sparing approach that may allow for a transition from a treatment to curative paradigm for a subset of men with M0HNPC. Further analyses will aim to link the subset of men who benefit from finite AA + LHRHa between localized high-risk PCa and M0HNPC. Clinical trial information: NCT01786265.
Characteristics of prostate cancer patients captured by facility-based versus geography-based cancer registries.
Authors: Filson Christopher Paul , Modi Parth K. , Ward Kevin C.
Published: February 2022

237

Background: Cancer registries provide valuable information related to cancer epidemiology, treatment, and outcomes. However, the sampling for inclusion can impact generalizability of findings to other settings. We use a population-based cancer registry to evaluate demographics, cancer factors, and treatment patterns based on eligibility for a facility-based cancer registry. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) database to identify men diagnosed with prostate cancer (site = C61.9) in 2018. Exposure was whether data were reported from a facility accredited by American College of Surgeons’ Commission on Cancer (CoC), providing eligibility for the National Cancer Database (NCDB) (i.e., NCDB-eligible). Outcomes of interest included demographics, tumor factors (e.g., biopsy grade), and treatment. Bivariate testing and multivariable regression analyses tested for significant associations between exposure and outcomes of interest. Results: We identified 57,713 men diagnosed with prostate cancer in 2018, of which 32,384 (61.9%) were eligible for inclusion in NCDB. NCDB-eligible men were younger (66.6 vs 67.8 years, p < 0.001), less likely to be Hispanic/Latino (8.0% vs 14.4%, p < 0.001), and more likely to reside in a county with median income over $75,000 (39.7% vs 33.3%, p < 0.001). NCDB eligibility varied widely by registry, from 96.1% in Connecticut to 44.7% in Utah. The proportion of localized cancer patients with Grade Group 1 cancer on biopsy was higher among men ineligible for NCDB (41.4% vs 26.9%, p < 0.001). The proportion of patients with more advanced disease at presentation was higher among NCDB-eligible patients (metastatic: 9.4% vs 6.8%; regional: 18.7% vs 8.7%; p < 0.001). For patients with localized or regional cancer, treatment was identified more frequently among NCDB-eligible patients for both low-risk (38.5% vs 22.7%, p < 0.001) and high-risk tumors (84.9% vs 64.2%). Among treated patients, use of radical prostatectomy was more common among NCDB-eligible patients (low risk: 58.9% vs 43.1%; high risk: 53.7% vs 43.4%, p < 0.001). Conclusions: Prostate cancer patients eligible for inclusion in the facility based NCDB have important differences in demographics, severity of cancer risk, and treatment patterns compared to those who are not eligible. Generalizations related to epidemiologic trends, practice patterns, and outcomes for prostate cancer patients in the NCDB should be interpreted with caution.
Radiation technique and outcomes following moderately hypofractionated treatment of low risk prostate cancer: A secondary analysis of the NRG oncology RTOG 0415 randomized clinical trial.
Authors: Carpenter David James , Salama Joseph Kamel , Lee W. Robert , Boyer Matthew J
Published: February 2022

243

Background: While intensity-modulated radiotherapy (IMRT) is commonly used to deliver moderately hypofractionated radiotherapy (MHRT) for prostate cancer (PC), IMRT has not been prospectively compared to three-dimensional conformal radiotherapy (3D-CRT) in the context of MHRT. This secondary analysis of the phase III RTOG 0415 trial compares survival outcomes and toxicity across RT technique between IMRT and 3D-CRT for low-risk PC. Methods: The phase III, non-inferiority trial RTOG 0415 randomized patients with low risk PC to either MHRT (70Gy at 2.5Gy/fraction) or conventionally fractionated radiation (CFRT; 73.8Gy at 1.8Gy/fraction) with stratification by RT technique. A secondary analysis for differences in overall (OS), biochemical recurrence free survival (BRFS), or toxicity by EPIC scores and Common Terminology Criteria for Adverse Events (CTCAE) was performed. For patient and tumor characteristics, continuous data were compared with Wilcoxon rank sum test and categorical data with Chi-squared test, as appropriate. Rates of BRFS and overall survival (OS) were calculated using the Kaplan-Meier method. Results: 1079 patients received the allocated intervention with a median follow up of 5.8 years. RT technique was balanced between treatment arms, with 79.1% of patients receiving IMRT. RT protocol compliance was > 95% for both IMRT and 3D-CRT. There were no significant differences in BRFS between patients treated with 3D-CRT versus IMRT for all patients (p = 0.33), those randomized to CFRT (p = 0.78), or those randomized to MHRT (p = 0.24). Overall survival did not differ by RT technique as well. For all patients, there was no difference in acute and late GI and GU toxicity rates across RT technique. For patients treated with MHRT, late grade 2 GU toxicity was more common with IMRT than 3D-CRT (31.3% vs 23.4%; p = 0.004). On logistic regression analysis, only poor baseline urinary function, defined as an EPIC score of 90 or below, correlated with acute (p < 0.001) or late (p < 0.001) GU toxicity. Baseline bowel function did not correlate to GI toxicity. Conclusions: RT technique did not impact survival outcomes or toxicity rates following MHRT for low risk PC. Higher rates of late CTCAE grade 2+ GU and GI toxicity observed within the RTOG 0415 MHRT arm were not disproportionally observed following 3D-CRT than IMRT. These data highlight the need for careful consideration of target delineation and normal tissue constraints in the selection and delivery of appropriate RT technique.
Real-world evidence of patient-reported outcomes following definitive radiation therapy for prostate cancer: Findings from an Australian population-based clinical outcomes registry.
Authors: Ong Wee Loon , Evans Melanie , Papa Nathan , Millar Jeremy Laurence
Published: February 2022

244

Background: We aimed to evaluate patient-reported functional outcomes (PRO) following definitive radiation therapy (RT) for prostate cancer (PCa) in a real-life population-based setting. Methods: The population-based Victorian Prostate Cancer Outcomes Registry (PCOR-Vic) captures approximately 90% of all PCa cases in the state. From 2015 onwards, all men in PCOR-Vic were contacted to complete the Expanded Prostate Cancer Index Composite short-form 26 (EPIC-26) at 12-month post-treatment. The EPIC-26 included urinary incontinence, urinary obstructive, bowel, sexual and hormonal function domain scores, ranging from 0 to 100, with higher score representing better outcomes. We estimated differences in the EPIC-26 domain scores between different RT techniques using linear regression, adjusting for patient, tumor, and treatment related factors, including the use of androgen deprivation therapy (ADT). The nature of recruitment methods and data collection in PCOR-Vic precluded us from measuring EPIC-26 prior to treatment, and hence this was not adjusted for in our analyses. Results: Between 2015 and 2020, there were 1,898 men treated with definitive RT who completed the EPIC-26 questionnaires and were included in this study – 1551 (82%) had external beam radiation therapy (EBRT) alone, 91 (5%) had EBRT with brachytherapy boost (EBRT+BT), 204 (11%) had low-dose-rate brachytherapy (LDR-BT) alone, and 52 (3%) had high-dose-rate brachytherapy (HDR-BT) alone. There were 1,140 (60%) men who had ADT with RT – 68% with EBRT alone, 76% with EBRT+BT, 4% with LDR-BT, and 21% with HDR-BT (P < 0.001). Compared to men who had EBRT alone, men who had LDR-BT had higher adjusted mean EPIC-26 urinary incontinence (8.6 points; 95%CI: 5.3-12.0; P < 0.001), sexual (13.5 points; 95%CI: 9.2-17.8; P < 0.001) and hormonal score (6.8 points; 95%CI: 3.5-10.1; P < 0.001) at 12-month post-treatment. Compared to men who had EBRT alone, there were no statistically significant differences in all five EPIC-26 domain scores in men who had EBRT+BT or HDR-BT alone. Conclusions: This is the first Australian real-world evidence on PRO for different RT modalities for PCa on a population-based level. We observed better urinary incontinence, sexual and hormonal function in men who had LDR-BT compared to EBRT, but no significant differences between men who had EBRT, EBRT+BT or HDR-BT.
Comparison of the medical costs between active surveillance and other treatment for early prostate cancer in Japan: From the data of PRIAS JAPAN study.
Authors: Kato Takuma , Sugimoto Mikio , Kakehi Yoshiyuki , Tohi Yoichiro , Matsumoto Ryuji , Shinohara Nobuo , Yokomizo Akira , Fukuhara Hiroshi , Mitsuzuka Koji , Sasaki Hiroshi , Egawa Shin , Inokuchi Junichi , Eto Masatoshi ,   PRIAS-JAPAN study group
Published: February 2022

280

Background: As the number of prostate cancer patients increases, the cost of treatment is becoming an urgent issue. To compare the costs between active surveillance, robot-assisted laparoscopic prostatectomy (RALP), Brachytherapy (BT), Intensity Modulated Radiation Therapy (IMRT), and Androgen deprivation therapy(ADT). Methods: The costs of protocol biopsies in the first year of AS performed between January 2010 and June 2020, and the treatment costs of RALP, BT, and IMRT performed between May 2019 and June 2020 at Kagawa university hospital were analyzed. The cost of ADT was assumed to be the cost of the LH-RH analog over 5 years. The inpatient treatment cost for each treatment was calculated from our DPC data, and for IMRT, the treatment cost was calculated by the outpatient cost at the time of irradiation. AS-eligible patients were defined as less than 74 years old, less than T2, less than GS6, and less than two positive cores. We estimated the total number of AS-eligible patients in Japan based on the data of the J-CAP study and the data of cancer statistics in 2017 and estimated the total treatment cost of AS-eligible patients based on the data of treatment breakdown of T1/T2 patients in the J-CAP study. In addition, we used the data from PRIAS-JAPAN to calculate the AS continuation rate, protocol biopsy acceptance rate, and the breakdown of secondary treatments. We simulated the 5-year treatment cost for AS patients using the system. Results: The median treatment costs for AS (n = 45), RALP (n = 68), BT (n = 27), and IMRT (n = 44), and ADT were US$1.24 thousand, US$ 14.6 thousand, US$14.8 thousand, US$ 12.9 thousand, and US$8.16, respectively. The number of AS-eligible patients in Japan was estimated to be 5414, and the total cost of AS, RALP, BT, IMRT, HT, and ADT over 5 years was estimated to be US$3.07 million, US$34.8 million, US$8.46 million, US$11.09 million, and US$14.05 million, respectively. If 50% and 100% of the patients in each treatment group chose AS as their first treatment, the total cost of treatment would be reduced by US$18.6 million and US$38.5 million, respectively. Conclusions: The prevalence of AS will contribute to reducing the cost of prostate cancer treatment.
Healthcare resource utilization (HRU) and costs among patients with Von Hippel-Lindau disease (VHL)-associated renal cell carcinoma (RCC): A retrospective administrative claims analysis.
Authors: Jonasch Eric , Song Yan , Freimark Jonathan , Berman Richard , Nguyen Ha , Signorovitch James , Sundaram Murali
Published: February 2022

305

Background: VHL disease is an inherited condition characterized by the formation of benign and malignant tumors in multiple organs, and RCC affects up to 40-70% of patients with VHL disease. However, real-world evidence on HRU and direct healthcare costs related to VHL-RCC is lacking. This study sought to address the gap in the literature by evaluating HRU and healthcare costs associated with the disease. Methods: Patients with VHL disease were identified from the Optum Clinformatics claims data using an algorithm based on combinations of manifestations of the disease. Among the patients identified, those with at least 1 diagnosis of RCC were further selected. The index date was defined as the date of first observed RCC diagnosis in the data, and the study period extends up to 5 years after index date or the end of continuous enrollment, whichever was earlier. A minimum continuous enrollment of 12 months prior to and 3 months after the index date was required. All-cause and RCC-related HRU and healthcare costs were evaluated among eligible patients with VHL-RCC. HRU was expressed as events per person-month and cost was expressed as average monthly cost. HRU and healthcare costs related to other VHL disease-related tumors were also assessed, including central nervous system (CNS) hemangioblastomas (Hb), retinal Hb, and pancreatic neuroendocrine tumors (pNETs). Results: 160 patients with VHL-RCC were included in the analyses. Mean age of the patients was 51.5 years and 89 (56%) were male. During the study period, patients with VHL-RCC incurred 0.10 hospitalizations (0.52 inpatient days), 1.49 outpatient visits, 0.09 emergency department (ED) visits, and 0.17 other medical visits per person-month on average. This translated to a monthly all-cause healthcare cost of $4,276, which included $2,222 inpatient, $1,318 outpatient, $188 ED, $63 other medical visits, and $485 pharmacy costs. $1,627 out of the all-cause cost per month was RCC-related, which was mainly driven by inpatient costs for RCC ($1,184/month). There were also notable costs associated with other tumor types: $2,159/month for CNS Hb, $601/month for retinal Hb, and $3,306/month for pNETs on average. Among patients with VHL-RCC who received surgical procedures for different tumors, the average hospitalization or outpatient visit costs were $28,356 for nephrectomies, $70,515 for CNS Hb surgeries, $2,887 for laser therapy of retinal Hb, and $81,825 for pNET surgeries. Conclusions: VHL-RCC is associated with significant HRU and healthcare costs due to the needs of managing RCC as well as tumors in other organs caused by VHL disease. This highlights the multi-disciplinary nature of VHL disease and the need for novel effective therapies to prevent or delay the recurrence of VHL-related tumors in order to mitigate the economic burden related to the disease.
Characterizing IMDC prognostic groups in contemporary first-line combination therapies for metastatic renal cell carcinoma (mRCC).
Authors: Ernst Matthew Scott , Navani Vishal , Wells J Connor , Donskov Frede , Basappa Naveen S. , Labaki Chris , Pal Sumanta K. , Meza Luis A , Wood Lori , Ernst D. Scott , Szabados Bernadett , McKay Rana R. , Parnis Francis , Suárez Cristina , Yuasa Takeshi , Kapoor Anil , Alva Ajjai Shivaram , Bjarnason Georg A. , Choueiri Toni K. , Heng Daniel Yick Chin
Published: February 2022

308

Background: The combination of immuno-oncology agents (IO) ipilimumab and nivolumab (IPI-NIVO) and combinations of IO with vascular endothelial growth factor targeted therapies (IOVE) have demonstrated efficacy in clinical trials for the first-line treatment of mRCC. This study seeks to establish real-world clinical benchmarks based on the International mRCC Database Consortium (IMDC) criteria using vascular endothelial growth factor targeted therapy (VEGF-TT) treated patients for context. Methods: The IMDC database (IMDConline.com) was used to identify patients with mRCC who received first-line IPI-NIVO, IOVE (axitinib/pembrolizumab, lenvatinib/pembrolizumab, cabozantinib/nivolumab, or axitinib/avelumab) and VEGF-TT (sunitinib or pazopanib) from 2002-2021. The primary endpoint was overall survival (OS) and was calculated from time of initiation of first-line therapy to death or last follow up. Log-rank tests were conducted to compare favorable, intermediate, and poor risk OS outcomes within treatment groups. Overall response rates (ORR) and complete response (CR) rates were calculated based on physician assessment of best clinical response. Results: In total, 692 patients received IPI-NIVO, 244 received IOVE, and 7152 received VEGF-TT. Baseline characteristics for IPI-NIVO, IOVE, and VEGF-TT, respectively, were as follows: median age (interquartile range) 63 (56-69), 64 (57-70), and 63 (56-70); male 72%, 74%, and 72% (p=0.74); non-clear cell histology 15%, 10%, and 13% (p=0.15); sarcomatoid features 24%, 15%, and 13% (p<0.0001); brain metastasis 8%, 4%, and 8% (p=0.04); liver metastasis 18%, 14%, and 18% (p=0.17); underwent nephrectomy 61%, 79% and 80% (p<0.0001). OS and ORR are reported in the table. P-values (log rank) for OS between risk groups were significant for IPI-NIVO (p<0.0001), IOVE (p=0.0005), and VEGF-TT (p<0.0001). Conclusions: These findings provide real-world survival and response benchmarks for contemporary first-line mRCC treatments and could be helpful for patient counselling. In addition, these findings mirror the efficacy of combination therapies established in clinical trials against VEGF-TT monotherapy. IMDC criteria continue to risk stratify patients in these novel combination therapies.[Table: see text]
Nemvaleukin alfa in patients with advanced renal cell carcinoma: ARTISTRY-1.
Authors: Calvo Emiliano , Boni Valentina , Chaudhry Arvind , Debruyne Philip R. , Rosen Seth D , Wang Yan , Sun Lei , Desai, MD Monali , Dalal Rita P. , Du Yangchun , Graham Julie R. , Tomczak, MD Piotr
Published: February 2022

330

Background: Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel engineered cytokine that selectively binds to the intermediate-affinity IL-2 receptor, preferentially activating and expanding antitumor CD8+ T and NK cells, with minimal expansion of Tregs. Nemvaleukin is under investigation for the treatment of advanced solid tumors, including renal cell carcinoma (RCC), in the ARTISTRY-1 trial (NCT02799095). Demonstration of single-agent activity is essential to validate the potential therapeutic benefit of nemvaleukin, both as monotherapy and in combination with a checkpoint inhibitor (CPI), particularly in patients (pts) with limited treatment options, such as CPI-experienced pts with RCC. Methods: Pts with advanced RCC who had previously responded (either objective response or stable disease [SD]) to a CPI alone or as part of a combination were enrolled into an RCC-specific cohort of ARTISTRY-1 Part B. Nemvaleukin 6 µg/kg IV monotherapy was administered daily for 5 days every 14 days in cycle 1 and every 21 days in cycles 2+. Pts with disease progression (PD; after ≥2 cycles) or SD (after ≥4 cycles) could be enrolled into Part C to receive nemvaleukin and pembrolizumab combination therapy. Outcomes presented include antitumor activity (RECIST v1.1), pharmacodynamics, and safety as of August 2021. Results: Twenty-seven pts with RCC received nemvaleukin monotherapy in Part B. Median age was 69 y (range, 39-77); median prior lines of therapy was 2 (range, 1-7). Four of 21 evaluable pts had a best overall response of partial response (1 confirmed, 1 unconfirmed, 2 awaiting confirmation); 11 had SD. Nemvaleukin induced robust expansion of CD8+ T and NK cells with minimal effect on Tregs. The most frequently reported adverse events (AEs), regardless of causality (N = 27), were pyrexia (59.3%), chills (55.6%), nausea (29.6%), and anemia (29.6%). The most frequently reported grade ≥3 nemvaleukin-related AEs are shown in the table. One pt had an AE (nemvaleukin-related bronchospasm) resulting in treatment discontinuation. There were no deaths due to treatment-related AEs. Four pts are continuing monotherapy in Part B (up to 1 y) and 10 have rolled over to Part C (combination therapy). Of the 8 evaluable pts with PD on Part B who subsequently received combination therapy in Part C, 1 had a confirmed partial response and has now been on treatment for almost 1 y and 5 had SD. No additional safety signals were observed. Conclusions: Nemvaleukin was generally well tolerated as monotherapy and in combination with pembrolizumab, and provided evidence of single-agent tumor response and disease control in CPI-experienced pts with advanced RCC. Clinical evaluation of nemvaleukin among pts with advanced RCC is ongoing. Clinical trial information: NCT02799095. [Table: see text]
Prolonging utilization of systemic therapy in oligoprogressive metastatic renal cell carcinoma using stereotactic body radiation therapy.
Authors: Muddasani Ramya , Govindarajan Ameish , Salgia Sabrina , Salgia Nicholas , Zengin Zeynep Busra , Meza Luis A , Hsu Joann , Chehrazi-Raffle Alex , Dizman Nazli , Chawla Neal Shiv , Malhotra Jasnoor , Bergerot Cristiane Decat , Philip Errol James , Castro Daniela V. , Dandapani Savita V. , Tripathi Nishita , Sayegh Nicolas , Pal Sumanta K.
Published: February 2022

336

Background: SBRT in indicated for the management of locally recurrent and oligometastatic mRCC as per National Comprehensive Cancer Network guidelines. Our study evaluates both the efficacy of radiotherapy (RT) in prolonging systemic treatment along with RT toxicity in the oligoprogressive RCC setting. Methods: A single institution retrospective data collection was performed in which we identified mRCC patients who experienced oligoprogression (defined as <1 sites of progressive disease) while on an FDA approved systemic therapy and were concurrently treated with SBRT, while remaining on the same therapy. Clinicopathologic characteristics and SBRT-related data along with duration of systemic therapy (DOT) were collected. DOT was then quantified into two categories which included the duration of systemic therapy prior to oligoprogression (DOT[P]) and duration of systemic therapy after completion of SBRT (DOT[S]). The ratio of DOT[S]/DOT[P] was calculated to determine the impact of SBRT on systemic treatment prolongation. Results: 23 patients diagnosed with mRCC meeting criteria were identified, 91% (n = 21) with clear cell histology and 9% (n = 2) with papillary histology. At the time of oligoprogression, 15 patients (65%) were on immunotherapy, 7 patients (30%) were on targeted therapy, and 1 patient (5%) was on combination therapy. We noted the preponderance of patients were on a first-line therapy at the time of oligoprogression (n = 10, 43%). A median of 2 (range, 1-3) lesions were treated per patient, with lung being the most frequent site (n = 14, 40%). The median total dose of SBRT was 30 Gy (range, 27-50 Gy) with a median dose per fraction of 6 Gy (range, 3-12 Gy). SBRT related toxicities, all of which were grade <2, were noted in 5 patients (22%), of which fatigue was the most frequent side effect (n = 3, 13%). Median DOT[S] was 13.4 months (range, 0.5-37.7 months) and the median DOT[P] was 12.8 months (range, 0.4-46.3 months). Results demonstrated a median DOT[S]/DOT[P] ratio to be 1.3 (range, 0.01-25.8). Conclusions: Based on our data, we discovered the addition of SBRT to systemic therapy during oligoprogression is not only well-tolerated, but that this treatment had clinical benefit in prolonging time on systemic therapy for patients with mRCC. The utilization of SBRT may prolong lines of therapy, thereby decreasing additional toxicities associated with exposure to new regimens.
Phase 2 study of neoadjuvant cabozantinib in patients with locally advanced non-metastatic clear cell renal cell carcinoma.
Authors: Bilen Mehmet Asim , Liu Yuan , Nazha Bassel , Brown Jacqueline T , Osunkoya Adeboya O. , Williams Sierra , Session Wilena , Yantorni Lauren Beth , Russler Greta , Caulfield Sarah , Joshi Shreyas S. , Narayan Vikram M. , Filson Christopher Paul , Ogan Kenneth , Kucuk Omer , Carthon Bradley Curtis , Kissick Haydn , Master Viraj A.
Published: February 2022

340

Background: Cabozantinib is a small molecule inhibitor of the tyrosine kinases c-Met, AXL and VEGFR2 that has been shown to reduce tumor growth, metastasis, and angiogenesis. After the promising results from the METEOR, CABOSUN and Checkmate-9ER trials, cabozantinib was approved for use in patients with advanced renal cell carcinoma (RCC). The increased response rates with cabozantinib in metastatic RCC, along with the other neoadjuvant TKI data, support an expanded role for cabozantinib in the neoadjuvant setting. Methods: Patients with clinical stage ≥ T3Nx or TanyN+ or deemed unresectable by the surgeon with biopsy-proven clear cell RCC were eligible for this study, and received cabozantinib at a starting dose of 60 mg daily for 12 weeks. The primary outcome was objective response rate per RECIST v1.1 (complete and partial responses) at week 12 after the administration of cabozantinib as determined by independent radiologist review. Secondary outcomes included safety, tolerability, clinical outcome (DFS, OS), surgical outcome and quality of life. Results: As of 20 September 2021, 16 biopsy-proven clear cell RCC patients were treated with neoadjuvant cabozantinib. The median age was 56 years (range: 41-84 years) and 81.2% male. All patients completed 12 weeks of treatment, and 15 of them underwent surgery as planned without any delay after completion of 4 weeks wash-out. One patient refused to undergo surgery due to personal reasons and received further systemic treatment. Five patients (31.2%) experienced a partial response, and 11 patients had stable disease. There was no progression of disease while on cabozantinib. Median reduction of primary renal tumor size was 24% (range: 6-45%). The one patient who was deemed to be unresectable became resectable at the end of treatment. Two patients were converted from radical to partial nephrectomy. The most common AEs were diarrhea, nausea, fatigue, hypertension, anorexia, and palmar-plantar erythrodysesthesia syndrome. Intraoperatively, we did not experience any immediate complications. Postoperatively, no surgical complications related to the drug were noted. No treatment related grade 4 or 5 AEs related to cabozantinib or surgery occurred. Two patients had died at the time of analysis (1 due to COVID and 1 unknown cause). Conclusions: Cabozantinib was clinically active and safe in the neoadjuvant setting in patients with locally advanced non-metastatic clear cell RCC. Additional data will be reported including long term outcomes, correlative studies, quality of life, and frailty/sarcopenia indices. Clinical trial information: NCT04022343.
A multicenter real-world study reviewing systemic anticancer treatment choices and drop off rates between treatment lines for metastatic renal cell carcinoma in the United Kingdom: In the immunotherapy era.
Authors: McGrane John , Frazer Ricky , Challapalli Amarnath , Ratnayake Gihan , Lydon Anna , Parslow Dominique Siobhan , Sharma Anand , Moon Niall , Gupta Senjuti , Walters Sara , Driver Megan , Alexander Rebecca , Kingdon Sarah , Khan Muhammad , Bahl Amit
Published: February 2022

358

Background: The treatment landscape of metastatic renal cell carcinoma (mRCC) has evolved over the last few years with several systemic anti-cancer therapies (SACT) licensed across different lines of treatment. A previous real world study in the UK had demonstrated a significant attrition rate between each line of therapy suggesting less than half of patients who received first line SACT then received second line therapy and less than a fifth of first line SACT patients reach third line. Methods: We conducted a retrospective analysis of all patients treated between January 2018 and end of June 2021 to see if advancement in treatment options had impacted on the drop-off rates. Data was collected from 5 UK sites. Patients were identified from electronic SACT database. All reimbursed treatment options including the COVID interim treatment guidelines options were included. Patients who received SACT as part of a clinical trial were also included. Patients who remained on the respective lines of treatment were censored. Results: Data for 515 patients (372 male: 143 female) who received first-line SACT for mRCC were included in the analyses. IMDC prognostic groups were 103 favourable, 236 intermediate, 127 poor (49 not available). On progression 69% of patients were able to receive second-line therapy and 34% were able to receive third-line therapy. Of the 515 first-line therapies, 24% of patients received frontline ipilimumab and nivolumab, 10% received TKI and IO combination and 63% received single agent VEGF TKI. Second-line nivolumab or cabozantinib (43% and 40% respectively) were the most commonly prescribed options. Third-line cabozantinib 61% and nivolumab 16% remain the most used options. Across all lines of therapy progressive disease was the primary reason for discontinuation. 5% switched treatment due to toxicity. Conclusions: These results suggest that, with more treatment options available, including combination/ immunotherapy therapies, more patients are able to receive second and third-line therapies. Despite this, nearly one third of patients only receive one line of treatment which highlights the need to deliver the most efficacious treatments first to optimise patient outcomes. Moreover, single agent TKI was the most commonly used first-line SACT despite advances in the management pathway. Data analysing the impact of COVID on treatment selection will be presented.[Table: see text]
A prospective randomized parallel-controlled pilot trial of stereotactic body radiation therapy versus radiofrequency ablation for the management of small renal masses.
Authors: Hoogenes Jen , Swaminath Anand , Mironov Oleg , Tajzler Camilla , Cassim Raees , Millan Braden , Matsumoto Edward , Kapoor Anil
Published: February 2022

363

Background: The potential of ablative technologies as an alternative to surgery for the treatment of small renal masses (SRMs) ≤4cm is unclear. Our objective was to evaluate the feasibility and toxicity of stereotactic body radiation therapy (SBRT) and radiofrequency ablation (RFA) for SRMs in a prospective randomized pilot trial. Methods: Patients scheduled for renal cell carcinoma (RCC) treatment at a single academic center were approached for the pilot trial, with the aim of recruiting 24 patients. Participants were assigned 1:1 to SBRT or RFA. Imaging (CT or MRI) using a renal tumor protocol is completed at 3, 6, 9, and 12 months post-procedure. Biopsies were completed prior to the procedure and at 12 months. Multiple clinical parameters were collected. Follow-up visits will occur at 6 month intervals following the trial up to 5 years. SBRT included an initial simulation session and a single image-guided treatment session with a prescribed dose of 25 Gy. RFA was conducted by either percutaneous or laparoscopic access with 2 cycles of 8 minutes duration each upon reaching target temperature. Results: Beginning in December 2019, 24 patients were recruited and randomized (SBRT = 11; RFA = 13). Eleven had SBRT, 8 RFA, 3 have not yet had treatment, and 2 became ineligible. Median age for all patients was 67 (53,85) and 17 were male. A total of 17 patients had clear cell RCC, 6 had papillary RCC (type 1), and 1 had chromophobe RCC. All patients had T1a disease. Mean procedure length (minutes) for SBRT and RFA was 15.5±7.4 and 10.5±3.9, respectively. Two patients (both SBRT) had a 12-month biopsy showing no evidence of recurrence or metastases, while two patients (1 RFA, 1 SBRT) had a 9-month CT showing no recurrence. Data are pending for the remaining patients. An early grade 2 flare-up occurred in one SBRT patient. Conclusions: Recruitment and randomization of patients with SRMs in a SBRT vs. RFA prospective trial is feasible on a timeline that allows for regular follow-up and imaging. To date, both treatment modalities have been shown to have excellent short-term safety profiles.
Complimentary transcriptomic-metallomic analysis identifies risk of relapse for clear-cell renal cell carcinoma (ccRCC) patients.
Authors: Gulati Shuchi , Vemuri Bhargav , Secic Dina , Shamsaei Behrouz , Plas David R. , Cunningham John T. , Meller Jarek , Landero Julio Alberto , Czyzyk-Krzeska Maria F.
Published: February 2022

378

Background: Patients with localized or locally advanced ccRCC undergo surgical resection by partial or radical nephrectomy. Approximately 50% of tumors recur within five years after surgery. Currently the only FDA approved drug in the adjuvant setting is sunitinib. However, the absence of an overall survival benefit and the prevalence of side effects limit widespread use of sunitinib. Accurate identification of patients at high risk of recurrence would enhance targeted adjuvant therapy, while sparing low-risk patients from side effects. A single scoring system, transcriptomic signature or genomic classifier, is unlikely to accurately define prognosis. Here, we describe an integrated transcriptomic-metallomic classifier to assess the risk of relapse in localized ccRCC. Methods: We investigated the transcriptomic landscape of Caucasian male patients with stage III ccRCCs who remained disease free (S3DF) or relapsed (S3RL) within 24 months after surgery using the TCGA Firehose Legacy cohort. In a separate cohort of S3RL and S3DF ccRCCs, copper (Cu) content and molecular distribution were analyzed by size exclusion chromatography coupled to inductively coupled plasma mass spectrometry (SEC-ICP-MS). Results: Transcriptomic analysis identified that S3RL tumors were enriched for genes encoding subunits of mitochondrial electron transport chain (ETC) and mitochondrial ribosomal proteins (MRPs), an indication that mitochondrial activity may contribute to the relapse. In contrast, S3DF tumors were enrichedfor genes related to immune responses, including genes encoding members ofMHC-II, suggesting tumor control by the immune system. We established a setof 23 genes (23G) as a signature that stratified ccRCCsinto distinct groups characterized by low, intermediateand high risk of relapse after surgery. Importantly, SEC-ICP-MS analysis identified augmented distribution of Cu to the Cu cytochrome c oxidase complex (Cu-COX) in tumor mitochondria from S3RL, consistent with the prediction of increased ETC activity in the transcriptomic analysis. Conclusions: Integration of the 23G transcriptomic signature and Cu-COX complex measurements in locoregional ccRCC can serve as a prognostic biomarker for recurrence, and as a predictive classifier for novel treatments, including inhibitors of ETC for the S3RL tumors. In particular, a combination classifier using both measurements may have a stronger prognostic/predictive power as compared to either biomarker alone.
Characterization of aberrant alternative splicing landscape in patients with renal cell carcinoma (RCC).
Authors: Govindarajan Ameish , Hegde Apurva M. , Chawla Neal Shiv , Dizman Nazli , Zengin Zeynep Busra , Meza Luis A , Muddasani Ramya , Chehrazi-Raffle Alex , Malhotra Jasnoor , Castro Daniela V. , Salgia Sabrina , Bergerot Cristiane Decat , Tripathi Nishita , Sayegh Nicolas , Philip Errol James , Hsu Joann , Byron Sara A. , Pirrotte Patrick , Pal Sumanta K.
Published: February 2022

386

Background: Aberrant alternative splicing (AS) events have been implicated in the initiation and progression of various cancers; however, the detailed nature of their role in RCC is yet to be fully elucidated. Our study aims to characterize AS events in RCC tumors using a novel AS pipeline (Bisbee). Methods: We retrospectively identified patients (pts) with RCC who had tumor-normal whole exome sequencing and tumor whole transcriptome sequencing (GEMExtra, Ashion Analytics) performed as part of their routine clinical care. AS events from RNA sequencing data were identified and further characterized as (1) alternative splice 3’ site (A3), (2) alternative splice 5’ site (A5), (3) exon skipping (ES), (4) intron retention (IR), and (5) mutually exclusive exons splice events (MUT). The Bisbee outlier analysis was performed against normal kidney tissues from the GTEx tissue library to further identify tumor-associated splice events. Outlier splice events were categorized as either non-coding/protein loss/silent, isoform switch, novel, or unknown. Results: Overall, 147 RCC pts (77% male) with RNA sequencing data were included in this analysis. Median age at diagnosis was 60 (range 31-94) and 97% of pts had metastatic RCC. The distribution of histology was 85% clear cell RCC followed by 11% papillary RCC. The AS analysis identified 25,928 outlier splice events. Approximately 60% of these were predicted to be protein-coding events, with the majority arising from IR and ES. These were followed by A3, A5, and MUT, in descending order of frequency. We also examined tumor-associated novel outlier events where 70% of analyzed RCC tumor samples noted 34 tumor-associated novel events were present, shared in most of the cohort and found an enrichment for IR events leading to frame disruptions. Data of splice variants will be presented at the meeting. Conclusions: In depth examination of this large cohort suggests that IR resulting from AS events occur frequently within RCC. Further efforts to investigate the association of AS events and clinical outcomes are underway.
CT abdomen only for active surveillance in patients with stage I germ cell tumor (GCT): A multi-institutional study.
Authors: Ahmadi Hamed , Benidir Tarik , Saoud Ragheed , Anson-Cartwright Lynn , O’Malley Martin , Eggener Scott E. , Hamilton Robert James , Daneshmand Siamak
Published: February 2022

410

Background: Active surveillance (AS) for stage I germ cell tumor (GCT) typically includes periodic imaging of chest, abdomen and pelvis. Efforts to modify the surveillance protocols aim to minimize radiation exposure in this young patient population. We report our multi-institutional effort to assess the effect of omitting CT pelvis. Methods: Using data from three major referral centers for GCT (University of Southern California, University of Toronto, and University of Chicago), all patients with stage I GCT who experienced recurrence on AS were selected. Clinicodemographic information including recurrence pattern (tumor marker (TM), imaging, physical exam (PE), or a combination of these) were collected. Bifurcation of the common iliac arteries was defined as the anatomic landmark between CT abdomen and pelvis. The location of recurrent nodal disease was determined accordingly. Results: A total of 270 patients were included. 122(45%) patients had non-seminomatous GCT (NSGCT). 17(6%) patients had history of cryptorchidism and 38 (14%) had history of scrotal/inguinal surgery. The median time to recurrence for seminoma and NSGCT was 16 months (IQR 8–27) and 6 months (IQR 4–13), respectively. The most common method for detecting recurrence was imaging-only (49%) followed by combination of TM and imaging (43%). A total of 43/270(16%) patients had pelvic/inguinal nodal recurrence (PNR). Prior hernia repair was significantly higher in patients with pelvic/inguinal nodal disease compared to their counterparts (19%vs2.5%;p=0.01). PNR was detectable only by imaging in 16/270(6%) patients. However, in 11/16(69%) patients, PNRe was either visible on CT abdomen cuts or there was simultaneous retroperitoneal recurrence. Overall, only 5/270(1.8%) patients (4 seminoma, 1 NSGCT) had PNR only detectable on CT pelvis. Conclusions: CT abdomen only, chest imaging, TM and PE detect majority of recurrences in stage I GCT and CT pelvis could be safely omitted during AS. Future modification in AS protocols of stage I GCT may be warranted.[Table: see text]
Nerve sparing retroperitoneal lymph node dissection in clinical stage IIA/B seminoma: The COTRIMS trial.
Authors: Heidenreich Axel , Paffenholz Pia , Nestler Tim , Pfister David A.
Published: February 2022

418

Background: Retroperitoneal radiation therapy or systemic chemotherapy with 3 cycles PEB represent the guideline recommended treatment options in marker negative clinical stage IIA/B seminoma. Despite a high cure rate of 90% to 94% and 82% to 90% in CS IIA and IIB, respectively, both therapeutic options are associated with significant long-term toxicities. It was the aim of our trial to evaluate the feasibility, oncological efficacy and treatment associated morbidity of primary nsRPLND in stage IIA/B seminoma. Methods: 16 patients with marker negative clinical stage IIA and IIB classical seminoma of the testis were recruited in the prospective trial. Patients with primary metastatic stages IIA/B or patients who developed metastatic during active surveillance for clinical stage I seminoma could be recruited. Metastatic disease following carboplatin therapy for clinical stage I seminoma represented an exclusion criteria. Informed consent was obtained after educational talk about the standard treatment options. Surgery associated complications were classified according to Clavien-Dindo. Progression-free survival and overall survival were calculated by Kaplan-Meier curves. Results: Mean age was 37.2 (21-54) years. Mean follow-up is 21.2 (1-36) months. All patients were treatment-naïve and 9 (56.2%) and 7 (43.8%) patients were diagnosed with stage IIA/B at time of primary diagnosis or during active surveillance for clinical stage I disease, respectively. 13 (81.2%) and 3 (18.8%) patients were diagnosed with stage IIA and IIB disease, respectively. 14 (87.5%) and 2 (12.5%) patients underwent open and robot assisted ns RPLND, respectively. Mean OR time was 131 (105-195) min, mean blood loss was < 150ml and the mean hospitalization time was 4.5 (3-9) days. We did not observe surgery associated complications > Clavien Dindo grade 3a. 14/16 (87.5%) patients preserved antegrade ejaculation. Histology of the resected lymph nodes revealed metastatic seminoma in 12 (75%) patients; 1 and 3 patients demonstrated embryonal carcinoma and inflammatory disease, respectively. 2/16 (12.5%) patients developed an outfield relapse 4 and 6 months postoperatively. Both patients were salvaged by systemic chemotherapy with 4 cycles PEB. Conclusions: NsRPLND results in a high cure rate at midterm follow-up and it is associated with a low frequency of treatment associated morbidities making this approach a feasible alternative to standard radiation therapy or systemic chemotherapy. Clinical trial information: DRKS00025384.
Final results of a multicenter prospective phase II clinical trial of gemcitabine and cisplatin as neoadjuvant chemotherapy in patients with high-grade upper tract urothelial carcinoma.
Authors: Yip Wesley , Coleman Jonathan , Wong Nathan Colin , Sjoberg Daniel D. , Bochner Bernard H. , Dalbagni Guido , Donat S. Machele , Herr Harry W. , Pietzak Eugene J. , Hakimi A. Ari , Kim Kwanghee , Al-Ahmadie Hikmat A. , Vargas Hebert Alberto , Meraney Anoop M. , Baccala Angelo Angelino , Apolo Andrea B. , Iyer Gopa , Teo Min Yuen , Rosenberg Jonathan E. , Bajorin Dean F.
Published: February 2022

440

Background: Neoadjuvant chemotherapy (NAC) has proven survival benefits for invasive urothelial carcinoma of the bladder, yet its role in upper tract urothelial carcinoma (UTUC) remains undefined. We conducted a phase II multicenter trial of NAC with gemcitabine and cisplatin (GC) in patients with high-risk UTUC prior to extirpative surgery to evaluate major outcomes of response, survival, and tolerability. Methods: Eligible patients with defined criteria for high-risk localized UTUC received four cycles of GC prior to surgical resection and lymph node dissection. The primary study endpoint was pathologic response rate (defined as < pT2N0). Patients with progressive disease prior or unable to proceed to surgery were considered treatment failures. Secondary endpoints included time to disease progression (PFS), overall survival (OS), and safety and tolerability. Results: Among 57 patients evaluated, 36 (63%) demonstrated pathologic response, meeting the primary endpoint of the study. A complete response was noted in 11 patients (19%), defined as pT0N0. Forty patients (70%) tolerated all four cycles of GC, and all patients proceeded to surgery. The 90-day ≥ grade 3 surgical complication rate was 7.0%. With a median follow up of 42.3 months among survivors, six patients succumbed to disease. Two and five-year PFS were 76% (95% CI 66, 89) and 61% (95% CI 47, 78). Two and five-year OS were 93% (95% CI 86, 100) and 79% (95% CI 67, 94). Patients demonstrating pathologic response had improved PFS and OS compared to those who did not (two-year PFS 91% vs 52%, log-rank p < 0.001, two-year OS 100% vs 80%, log-rank p < 0.001). Conclusions: NAC for high-risk UTUC demonstrates outcomes of favorable pathologic response, is well tolerated requiring minimal delay to surgery without significant perioperative complication risk, and thus should be considered a new standard of care option for patients with high-risk UTUC. Better survival outcomes in patients with favorable pathologic features after NAC indicate a potential clinical benefit to this approach. Clinical trial information: NCT01261728.