bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stereotactic radiotherapy and pembrolizumab for oligometastatic renal tumors: The RAPPORT trial.
Authors: Siva Shankar , Bressel Mathias , Wood Simon , Shaw Mark , Loi Sherene , Sandhu Shahneen Kaur , Tran Ben , Azad Arun , Lewin Jeremy Howard , Cuff Katharine , Neha Nitika , Colyer Duncan , Neeson Paul J. , Liu Howard , Chander Sarat , Moon Daniel , Goad Jeremy , Murphy Declan G. , Lawrentschuk Nathan , Pryor David 
Published: March 2021

277 Background: Pembrolizumab monotherapy, whilst not standard of care, has demonstrated efficacy in clear cell renal cell carcinoma (ccRCC). The first-line KEYNOTE-427 study demonstrated an overall response rate (ORR) of 34%, and a median progression-free survival (PFS) of 7.1 mo (McDermott D et al. J Clin Oncol 2020; 38:S15; 5069-5069). Stereotactic ablative body radiotherapy (SABR) is an option for oligometastatic ccRCC, but patients often develop distant progression or relapse within irradiated sites. The RAPPORT study (NCT02855203) was a multi-institutional single arm, phase I/II study evaluating safety and efficacy of SABR and pembrolizumab. Methods: Patients with up to 2 lines of prior systemic therapy with 1-5 oligometastases from ccRCC were eligible. A single fraction of 20Gy SABR to all metastatic sites was given (or 10 fractions of 3 Gy of conventional radiotherapy [CRT] if SABR was not feasible), followed by pembrolizumab 200mg administered Q3W for 8 cycles. The primary objective was safety (CTCAEv4.03), with secondary key objectives of efficacy (RECIST1.1) by disease control rate (DCR), defined as complete response (CR), partial response (PR) or stable disease for at least 6 months, ORR, PFS and overall survival (OS). Results: Thirty patients were enrolled and received protocol treatment. The median follow-up was was 2.3 years. The median age was 62 (range 47-80) years, 23 patients (77%) were male. Twenty-three patients (77%) were treatment naïve, 1 patient (3%) had a prior interleukin-2 therapy and 6 patients (20%) had a prior tyrosine kinase inhibitor. Nine patients (30%) had prior metastasectomy. Eighty-three oligometastases were treated (median of 3 per patient), of which 64 (77%) received SABR, and 19 (23%) received CRT. There were 8 adrenal, 11 bone, 43 lung, 12 lymph node and 9 soft tissue metastases irradiated. Four patients (13% [95%CI: 4-31%]) had one or more grade 3 treatment-related AE: Pneumonitis (n=2), dyspnoea (n=1) and elevated ALP/ALT (n=1). There were no grade 4 or 5 AEs. All eight cycles of pembrolizumab were completed by 24 (80%) patients. DCR was 83% (95%CI: 65-94%). ORRs are tabulated below. Median PFS was 15.6 mo. Estimated 1 and 2-year OS was 90% (95%CI: 72-97%) and 74% (95%CI: 53-87%), respectively, while PFS was 60% (95%CI: 40-75%) and 45% (95%CI: 27-62%), respectively. Freedom from local progression at 2-years was 92% (95%CI: 80-97%). Conclusions: The combination of SABR and pembrolizumab in oligometastatic renal cell carcinoma is well tolerated with excellent local control. Durable responses and encouraging PFS were observed with this approach, which warrants further investigation. Clinical trial information: NCT02855203 . [Table: see text]
Biomarker-based phase II study of sapanisertib (TAK-228), an mTORC1/2 inhibitor in patients with refractory metastatic renal cell carcinoma (mRCC).
Authors: McGregor Bradley Alexander , Adib Elio , Xie Wanling , Stadler Walter Michael , Zakharia Yousef , Michaelson M Dror , Alva Ajjai Shivaram , Farah Subrina , Nassar Amin , Harshman Lauren C , Kwiatkowski David J. , McKay Rana R. , Choueiri Toni K. 
Published: March 2021

306 Background: Approved rapalogs inhibit mTORC1 and have limited activity in mRCC, possibly due to compensatory feedback loops. Sapanisertib addresses the incomplete inhibition of the mTOR pathway through targeting of both mTORC1 and mTORC2 with antitumour activity demonstrated in patients with mRCC. In this multicenter, single arm phase II trial, we evaluated the efficacy of sapanisertib in patients with mRCC progressing on standard therapies (NCT03097328). Methods: Eligible mRCC patients had an ECOG performance status of 0-2 and had progressed on standard therapies. Prior therapy with rapalogs (everolimus, temsirolimus) and variant RCC histologies were permitted. Patients had a baseline biopsy and received treatment with sapanisertib 30 mg by mouth weekly until unacceptable toxicity or disease progression. The primary endpoint was overall response rate (ORR) by RECIST 1.1. Tissue biomarkers of mTOR pathway activation were explored. Results: We enrolled 38 mRCC patients (clear cell = 28; variant histology = 10) between August 2017 and November 2019. The majority had intermediate (76%) or poor risk (11%) by IMDC criteria. Twenty (53%) had received ≥ 3 lines of therapy; 13 (34%) patients received prior rapalogs. Median follow-up was 10.4 months (range 1-27.4) and median duration of therapy was 1.6 (range 0.3-13.8) months. ORR by central review was 2 of 38 (5.3% 90%CI: 1%-15.6%). 31.6% of all patients and 30.7% of those with prior rapalog exposure had some tumor shrinkage during course of treatment. Median progression free survival (PFS) was 2.5 months (95% CI 1.8,3.7). Twelve patients (32%) developed treatment-related grade 3 adverse events (AEs) with no grade 4 or 5 toxicity reported; 6 patients (16%) required dose reduction and 4 (11%) discontinued therapy for AEs. Oncopanel tumor sequencing identified alterations in the mTOR pathway in 6 of 29 patients ( MTOR n = 2, PTEN n = 3, TSC1 n = 1.) Reduced PTEN expression by immunohistochemistry was seen in 7 of 19 patients. There was no association between mTOR pathway mutations or PTEN loss and response to sapanisertib. Conclusions: In this study we demonstrate minimal activity of sapanisertib in patients with treatment refractory mRCC with no clear benefit among patients with mTOR/PTEN pathway alterations. Additional treatment strategies are needed for patients with refractory mRCC.
Efficacy of gemcitabine plus doxorubicin (Gem + Dox) in patients with renal medullary carcinoma (RMC).
Authors: Wilson Nathaniel , Wiele Andrew James , Surasi Devaki Shilpa , Rao Priya , Sircar Kanishka , Shah Amishi Yogesh , Genovese Giannicola , Karam Jose A. , Wood Christopher G. , Tannir Nizar M. , Msaouel Pavlos 
Published: March 2021

324 Background: Renal medullary carcinoma (RMC) is one of the most lethal renal cell malignancies with a median overall survival (OS) of only 13 months from diagnosis (Shah et al. BJU Int., 2017). RMC predominantly affects young individuals of African descent and is characterized by loss of the tumor suppressor SMARCB1 in all cases. Platinum-based chemotherapy produces a best response rate of 29% and is the recommended front line therapy for RMC (Msaouel et al. Clin Genitourin Cancer, 2019). However, there is little data on subsequent therapies. We recently showed that loss of SMARCB1 induces replication stress that renders RMC cells vulnerable to nucleoside analogs such as gemcitabine (Gem) and topoisomerase inhibitors such as doxorubicin (Dox) (Msaouel et al. Cancer Cell, 2020). We therefore hypothesized that Gem + Dox would demonstrate clinical activity against RMC. Methods: We conducted a retrospective study of patients who were treated with Gem + Dox for metastatic RMC at our institution. A blinded board-certified radiologist reviewed all restaging images to assess best radiographic response as defined by RECIST v1.1 and, when applicable, date of progression. Adverse events (AEs) were evaluated using the CTCAE version 5.0 grading estimated from chart documentation. Results: Between 01/2005 and 09/2020, we identified 16 patients with RMC that were treated with Gem + Dox and were evaluable for survival outcomes (Table). All but 1 patient (94%) had received prior platinum-based chemotherapy. Gem + Dox produced a partial response in 3/14 evaluable patients (21.4%) and stable disease as best response in 10/14 (71.4%), resulting in a median progression-free survival of 3.0 months (mo) with 95% CI 1.5-4.5 mo. The median overall survival (OS) from the start of Gem + Dox was 9.8 mo (95% CI 3.3-16.2) and the median OS from diagnosis was 18.6 mo (95% CI 11.3-25.9). Gem + Dox was well tolerated with no grade ≥ 4 AEs and the most common grade 2 or 3 AE’s were cytopenias (3/17), nausea (3/17), and fatigue (2/17). There were no grade ≥ 2 reported events of cardiotoxicity, but 3 patients discontinued treatment due to reaching recommended maximum dose of Dox. Conclusions: Gem + Dox demonstrated clinical benefit in patients with RMC and was well tolerated in most patients, supporting its use in patients with RMC whose disease progressed on prior platinum-based chemotherapy. Further investigation is warranted to determine and target mechanisms of resistance. [Table: see text]
Outcomes for patients in the pembrolizumab+axitinib arm with advanced renal cell carcinoma (RCC) who completed two years of treatment in the phase III KEYNOTE-426 study.
Authors: Plimack Elizabeth R. , Powles Thomas , Bedke Jens , Pouliot Frédéric , Stus Viktor , Waddell Tom , Gafanov Rustem , Nosov Dmitry , Alekseev Boris , McDermott Raymond S. , Markus Maurice , Tartas Sophie , Kryzhanivska Anna , Bondarenko Igor , Szczylik Cezary , Lin Jianxin , Perini Rodolfo F. , Molife L. Rhoda , Atkins Michael B. , Rini Brian I. 
Published: March 2021

327 Background: In the randomized, open-label, phase III KEYNOTE-426 study (NCT02853331), pembrolizumab + axitinib significantly improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) versus sunitinib as first-line therapy for advanced RCC. Per protocol, patients could discontinue pembrolizumab or axitinib and continue the other agent. Pembrolizumab was stopped for all patients at 2 years. Axitinib could be continued until progression or toxicity. This exploratory subgroup analysis of KEYNOTE-426 describes outcomes of patients who completed 2 years of pembrolizumab. Methods: Patients included in KEYNOTE-426 were treatment naive, with clear cell RCC, KPS ≥70%, and measurable disease (RECIST v1.1). Patients were randomly assigned 1:1 to receive pembrolizumab 200 mg intravenously every 3 weeks for up to 35 doses + axitinib 5 mg orally twice daily or sunitinib 50 mg once daily (4 weeks on/2 weeks off) until progression, toxicity, or withdrawal. Primary end points of the original analysis were OS and PFS. Key secondary end points were ORR and safety. Results: Of 432 patients treated with pembrolizumab + axitinib, 129 (29.9%) completed 2 years of study therapy. Median (range) age of these patients was 61 (36-82) years, and 72.1% were male; 42 (32.6%) and 87 (67.4%) patients had International mRCC Database Consortium favorable and intermediate/poor risk, respectively, consistent with the intention-to-treat population (31.9% vs 68.1%). Median (range) follow-up (time from randomization to data cutoff) was 31.1 (24.0-37.7) months. For patients who completed 2 years of study therapy, the OS rates at 36 months was 93.8% (95% CI, 85.5%-97.4%). The PFS rates at 24 and 36 months were 72.7% (95% CI, 64.0%-79.7%) and 57.7% (95% CI, 46.3%-67.5%), respectively. The ORR was 85.3%, and the CR rate was 14.0%. 59.7% of patients experienced grade 3-5 treatment-related adverse events and 8.5% experienced grade 3-5 immune-mediated adverse events. Conclusions: In this exploratory analysis, a significant proportion of patients in the pembrolizumab + axitinib arm completed 2 years of pembrolizumab with ongoing clinical benefit. Clinical trial information: NCT02853331 .
Clinical utility of the AJCC eighth edition pT1 subclassification and impact on practice patterns in stage I seminoma.
Authors: Badia Rohit R , Woldu Solomon L. , Patel Hiten Dilip , Singla Nirmish , Srivastava Arnav , Cheaib Joseph G , Pierorazio Phillip M. , Bagrodia Aditya 
Published: March 2021

377 Background: The American Joint Committee on Cancer 8th edition staging guidelines for testicular cancer established a 3 cm cutoff to subclassify stage T1 seminomas (<3 cm = pT1a and ≥3 cm = pT1b). The efficacy of this cutoff in predicting metastatic disease and impact on treatment patterns has not been studied. Methods: We retrospectively reviewed patients with pT1 testicular seminoma in the National Cancer Database from 2004-2016. Receiver operating curves (ROC) were used to determine the efficacy of the 3 cm tumor cutoff in identifying metastatic disease, and multivariable regression was used to compute the effect of tumor size on the rate of adjuvant therapy among stage I patients. Results: 10,134 patients with pT1 seminoma were evaluated. The current size cutoff of 3 cm for subclassification did not exhibit high discrimination in identifying metastatic disease (area under ROC: 0.546). Surveillance has grown as the preferred treatment after orchiectomy – 32.1% in 2004 to 81.2% in 2015. However, the rate of adjuvant therapy for pT1, stage I seminomas associated positively with tumor size even with adjustment for year of diagnosis. For tumors above 3 cm, the odds ratio stabilized around 1.9. By using the 3cm cutoff to guide adjuvant therapy, up to 85% of T1b patients may be overtreated. Conclusions: The 3 cm cutoff for subclassification of stage I seminoma does not predict metastatic recurrence but is associated with increased receipt of adjuvant therapy. A 3 cm cutoff and the pT1a/b classification may therefore contribute to overtreatment in many young patients with a long life expectancy for whom minimizing adverse effects should be prioritized.
Do females have worse surgical outcomes after radical cystectomy? Impact of gender on 30-day complications in a national cohort.
Authors: Kotamarti Srinath , Silver Michael , Wood Andrew , Teper Ervin , Silver David , Schulman Ariel 
Published: March 2021

402 Background:: Men have higher rates of bladder cancer and are more likely to undergo cystectomy than women, yet women seem to have worse oncologic outcomes. This is attributed to biologic factors including adverse histologic variants and social factors including delay in diagnosis. There is early evidence that women also have worse surgical outcomes. We further examined the role of gender in 30-day perioperative outcomes following radical cystectomies in a national cohort. Methods: We examined the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) from 2012 to 2016. The database was searched for CPT codes reflecting radical cystectomy and a diagnosis of “cancer of the bladder.” Frailty was estimated by the modified frailty index (functional status, diabetes, chronic obstructive pulmonary disorder, history of chronic heart failure, and hypertension requiring medication.) To compare demographic and perioperative characteristics between genders, Chi-Square analyses were performed for categorical variables, student’s t test to compare averages, and the Wilcoxon rank sum test for operative time and length of stay (LOS). Results: 4,681 radical cystectomies were identified including 842 (18.0%) females. Of the female cohort, average age was 68.6 (+/-11.2 years), 77.3% was Caucasian and 278 (33%) had a BMI of at least 30. There were no differences appreciated between genders with regards to age, average ASA score, frailty, or minimally-invasive approach (all p=NS). Compared to males, female gender was associated with longer operative time (350 vs. 336 min, p<0.009), length of stay (LOS) (8 vs 7, p<0.001) and lower rates of discharge to home (79.9% vs 87.0%, p<0.0001). Reoperation (4.8% vs. 6.0%), readmission (22.2% vs 20.6%), and death within 30 days (1.9% vs. 2.0%) were similar. Clavien 3 or greater was also similar among gender (Table). Conclusions: Female patients comprise a minority of radical cystectomies with slightly longer LOS and less home discharge than men, yet 30-day major complications, reoperation and mortality appear similar. [Table: see text]
The prognostic impact of bone metastasis in urothelial carcinoma treated with first-line platinum-based chemotherapy.
Authors: Alqaisi Husam , Veitch Zachary William Neil , Stecca Carlos , Kaiser Jeenan , North Scott A. , Samnani Sunil , Alimohamed Nimira S. , Sridhar Srikala S. 
Published: March 2021

415 Background: Metastatic urothelial carcinoma (mUC) is an aggressive disease with a median overall survival (OS) of ≈ 15 months. In the first-line setting, key prognostic factors include ECOG performance status, white blood cell count, and response to treatment per the Galsky nomogram. Bone metastases (BM) in mUC are associated with morbidity and mortality but are grouped with visceral disease; hence, their impact on prognosis is not well established. We aimed to assess the survival impact of BM in mUC patients treated with first-line platinum-based chemotherapy (PBC). Methods: A retrospective collection of patient and tumor characteristics, with clinical response to treatment (complete response [CR], partial response [PR]; stable disease [SD] or progressive disease [PD]) for patients treated at Princess Margaret Cancer Centre, Tom Baker Cancer Centre, and Cross Cancer Institute from 2005-2018 was performed. Progression-free survival (PFS) and OS were estimated using the Kaplan-Meier method. Univariate (UVA) followed by multivariate analysis (MVA) of patient variables [Cox] using PFS and OS was performed. Results: Overall 376 mUC patients were included; 222 (59%) had soft-tissue metastases (STM) only, 70 (19%) had bone-only metastases, and 84 (22%) had both STM and BM. Overall, 35% had PR or CR, 19% had SD, and 39% had PD (7%: unknown response). The median PFS and OS for the whole cohort were 5.6 months (95%CI: 4.8-6.4) and 9.7 months (95% CI: 8.8-10.8) respectively. Select UVA by metastatic site showed inferior PFS for bone-only (p=0.03) and combination STM and BM (p=0.017). Only combination STM and BM were significant on UVA for OS (p=0.002). MVA showed that bone-only metastases (p=0.03) and ECOG 3-4 (p<0.0001) were associated with worse PFS (Table). Predictors of worse OS were the combination of STM and BM (p=0.02), ECOG 3-4 (p=0.001), and WBCs ≥ULN (p=0.02), (Table). Conclusions: BM are a significant predictor of worse outcomes for mUC patients treated with first-line PBC. Consideration as a treatment stratification factor for future studies is suggested. Strategies for the treatment of mUC patients with BM (ie: bone targeted agents) in the first-line setting should be addressed in future trials. [Table: see text]
Impact of angiotensin blockade on response to PD1/L1 inhibitors for patients with metastatic urothelial carcinoma (mUC).
Authors: Skelton William Paul , Jain Rohit K. , Curran Catherine , Pond Gregory Russell , Naqvi Syeda Mahrukh Hussnain , Kim Youngchul , Nuzzo Pier Vitale , Alaiwi Sarah Abou , Nassar Amin , Jain Rakesh K. , Sonpavde Guru 
Published: March 2021

453 Background: The renin-angiotensin system (RAS) is involved in regulation of angiogenesis and cell proliferation. Preclinical data also indicate that angiotensin inhibition may improve drug delivery by enhancing tumor perfusion partly by downregulating transforming growth factor (TGF)-β. Since (TGF)-β appears to be associated with resistance in patients (pts) with metastatic urothelial carcinoma (mUC) receiving PD1/L1 inhibitors, we hypothesized that angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs) may enhance the outcomes of mUC pts receiving PD1/L1 inhibitors. Methods: Data from mUC pts who received PD1/L1 inhibitors as monotherapy were obtained: pts from the Dana-Farber Cancer Institute (DFCI) served as the discovery dataset, while data from Moffitt Cancer Center (MCC) served as the validation dataset. Data for ACEI and ARB administration was collected with concurrent administration defined as ongoing therapy from the time of starting PD1/L1 inhibitor treatment. A logistic regression was used to investigate the impact of concurrent ACEI/ARB on any regression of tumor (ART, any decrease in size of tumor on scan) as the primary endpoint defined as any tumor regression after controlling for known prognostic factors (performance status, sites of metastasis, neutrophil/lymphocyte ratio, platelet count, hemoglobin). Overall survival (OS), the secondary endpoint, was analyzed using Cox proportional hazards regression. Results: Data was available for 178 pts from DFCI (discovery dataset) with mUC who received a PD1/L1 inhibitor of whom 153 (86%) had received prior platinum and 33 pts (18.5%) received concurrent AECI/ARBs. Multivariable analysis controlling for known prognostic factors revealed that patients who received ACEIs or ARBs had greater ART (HR 3.0 [95% CI 1.25-7.17], p = 0.014) and improved OS, (HR 0.49 [95% CI 0.28-0.88] p = 0.016). In the MCC validation dataset, 101 pts were available of whom 59 (58.4%) had received prior platinum and 22 pts (21.8%) received concurrent ACEI/ARBs. Univariate analysis showed that those patients who were treated with ACEI/ARB had an improved ART (OR 3.32 [95% CI 1.22-9.06] p = 0.019). On multivariable analysis, there was a borderline significant association of ACEI/ARB with ART (OR = 3.03, p = 0.075), but no association was observed with OS. Conclusions: In this hypothesis-generating study, concurrent angiotensin inhibitors including ACEI or ARBs were associated with tumor regression in mUC pts receiving PD-1/L1 inhibitors. The inconsistent association with OS may be partly due to modest sample size and comorbidities associated with the need for ACEI/ARBs. These results require validation in a prospective study.
Efficacy of immune checkpoint blockade in patients with advanced upper tract urothelial cancer and mismatch repair deficiency or microsatellite instability (MSI).
Authors: Andreev-Drakhlin Alexander , Shah Amishi Yogesh , Adriazola Ana Cecilia , Shaw Leah , Lopez Lidia , James Marihella , Matin Surena F. , Alhalabi Omar , Gao Jianjun , Siefker-Radtke Arlene O. , Goswami Sangeeta , Xiao Lianchun , Venkatesan Aradhana M. , Campbell Matthew T 
Published: March 2021

487 Background: Tumors deficient in DNA mismatch repair (dMMR) exhibit a microsatellite unstable phenotype characterized by high tumor mutational burden and an immunogenic tumor microenvironment. Despite the histology-agnostic approval of pembrolizumab for advanced dMMR/MSI cancers, responsiveness of dMMR/MSI upper tract urothelial cancers (UTUC) to immune checkpoint (IC) blockade remains largely unknown. Methods: Consecutive records of patients (pts) from a single institution with locally advanced unresectable or metastatic dMMR/MSI UTUC who received IC therapy were analyzed. The primary endpoint was assessment of objective response rate (ORR) using RECIST v1.1. Secondary endpoints were progression-free survival (PFS) and overall survival (OS) using the Kaplan-Meier technique. dMMR/MSI status was evaluated by immunohistochemistry (IHC) and/or polymerase chain reaction (PCR). Results: Ten pts were identified with locally advanced unresectable (N = 3) or metastatic (N = 7) dMMR/MSI UTUC who received therapy with IC blockade (pembrolizumab = 7, nivolumab = 2, atezolizumab = 1). Median age was 65.5 (range = 46 – 90). Six pts were male. Seven pts had germline dMMR. MSI was detected by PCR in three pts and dMMR by IHC in seven pts (PMS2/MLH1 loss = 4, MSH2 loss = 1, MLH1 loss = 1, MSH6 loss = 1). Five pts received systemic chemotherapy (2 cisplatin based, 1 carboplatin based, 2 other) prior to IC therapy with two pts (40%) achieving partial response (PR). At a median follow-up of 15.5 months (range: 2 – 43 months), all pts were alive, and none experienced disease progression. PFS and OS at 15.5 months were 100%. The observed ORR was 90% (CI, 55.5%, 99.8%), including 8 pts who achieved complete remission (CR). The median time to best response was 4 months (range: 2 – 8 months). Toxicity leading to treatment discontinuation: 1 (grade 3) pancytopenia, 1 (grade 2) pneumonitis, 1 (grade 2) SICCA-like symptoms. Conclusions: Immunotherapy with IC inhibitors demonstrates excellent clinical activity in advanced dMMR/MSI UTUC. Further studies integrating these agents earlier in the disease course are warranted in this rare but important subgroup. Given the extremely high complete response rate in this population consideration of preference to IC therapy as initial therapy should be entertained if these findings are validated.