bluuebunny/crossref_metadata_2025 huggingface dataset:
Early replacement of CT scanning by abdomino-pelvic ultrasound as a safe alternative in the follow-up of patients with germ cell tumors.
Authors: Baciarello Giulia , Hamilou Zineb , Fayard Florence , Gizzi Marco , Albiges Laurence , Loriot Yohann , Massard Christophe , Di Palma Mario , Escudier Bernard J. , Fizazi Karim
Published: March 2017

420

Background: Late relapse in patients with germ cell tumors (GCT) are rare events. As there is no consensus for follow-up (FU) protocols, it is unclear if shorter duration of CT scanning is safe while reducing unnecessary exposure to radiation. Methods: At the completion of their treatment, all patients with Stage I, metastatic good or intermediate prognosis seminoma and non-seminoma (NSGT) underwent physical exam, serum tumor markers and imaging at regular intervals. We retrospectively identified 2 groups of patients with different FU strategies: those with regular CT scan of the chest, abdomen and pelvis for 3 years or less, then followed by abdomino-pelvic ultrasound (Group 1); and those with CT scanning continued beyond 3 years (Group 2). Results: Between December 1997 and March 2016, 203 patients were included: 80 (39.4%) in Group 1 and 123 (60.6%) in Group 2. The mean duration of FU was 6.7 ± 2.4 years in Group 1 and 8.1 ± 2.5 years in Group 2 (p < 0.001). After year 3 the median number of abdomino-pelvic ultrasound in Group 1 was 5 (4-6) and the median number of CT scanning in Group 2 was 6 (5-8). Five (2.4%) relapses were identified: 1 in Group 1 and 4 in Group 2. Relapse was revealed by symptoms in 2 patients with NSGT (1 in each group) who had been lost for FU. Three patients underwent local treatment (2 surgeries for teratoma relapses and 1 radiotherapy for seminoma relapse) and are still disease-free. International prognostic factors score was low and intermediate for the first 2 patients, very low for seminoma relapse and low for teratoma relapses. Conclusions: Patient follow-up by regular abdomino-pelvic ultrasound instead of CT scan appears a feasible alternative after the third year in patients with GCT, with no excess risk of incurable relapses. Prospective validation is required.
The impact of the Affordable Care Act on treatment of testicular cancer.
Authors: Francis John Joseph , Abouassaly Robert , Gonzalez Christopher , Meropol Neal J. , Kutikov Alexander , Smaldone Marc C. , Psutka Sarah P. , Williams Stephen Bentley , Kim Simon P.
Published: March 2017

422

Background: The passage of the Affordable Care Act (ACA) in 2010 aimed to improve access for uninsured patients to private health insurance. Yet, the impact of the ACA on the number of privately insured young patients and on the timeliness of medical care for serious medical conditions, remain unclear. Thus, we sought to ascertain changes in insurance status and evaluate timeliness of post-orchiectomy definitive therapy for young men diagnosed with testicular cancer following passage of the ACA. Methods: From the National Cancer Database, we identified all patients 18 – 50 years of age diagnosed with stages I – III testicular cancer from 2007 to 2013. Patients were divided into groups at the time of diagnosis; 2007 – 2009 (pre-ACA) and 2011 to 2013 (post-ACA). Only patients who had undergone radical orchiectomy and had a reported insurance status were included in analysis. The primary outcomes were insurance type at diagnosis and time to treatment of secondary therapy following orchiectomy (systemic chemotherapy, radiation therapy, or surgery {Retroperitoneal lymph node dissection; RPLND}). Results: Overall, 17,945 patients were included in analysis with 53.5% diagnosed with pure seminoma and 46.5% diagnosed with nonseminomatous germ cell tumor (NSGCT). In comparing pre- and post-ACA cohorts, the percentage of patients with private health insurance decreased following the passage of the ACA (74.1% vs. 71.2%; p < 0.01). Similarly, the percentage of patients without any insurance increased between the two time frames (12.7 % vs. 13.4%; p < 0.01). More patients presented with clinical stage II and III disease following the passage of the ACA (28.9% vs. 31.9%; p < 0.01). Compared to patients without health insurance, privately insured patients received more timely secondary definitively therapy with radiation therapy (49.9 vs. 60.9 days, p < 0.01) and chemotherapy (41.5 vs. 45.7 days, p < 0.01) but no difference in the time to RPLND (18.8 vs. 16.7 days, p = 0.70). Conclusions: The impact of the ACA on patients with testicular cancer shows minimal worsening in the number of privately insured young men and increasing rates of advanced testis cancer. This was not in agreement with our hypothesis and suggests the ACA is not benefiting young men with this malignancy.
Effect of alvimopan on gastrointestinal recovery and length of hospitalization after retroperitoneal lymph node dissection for testicular cancer.
Authors: Radadia Kushan Dilip , Farber Nicholas , Tabakin Alexandra , Milas Lee , Jang Thomas
Published: March 2017

424

Background: Alvimopan use in enhanced recovery programs has reduced the hospital LOS in patients undergoing major abdominal surgeries. Retroperitoneal lymph node dissection (RPLND) for testicular cancer may be associated with delayed GI recovery prolonging hospital LOS. In this study, we evaluate whether alvimopan is associated with enhanced GI recovery and shorter hospital LOS in men undergoing RPLND for testicular cancer. Methods: From 2010 to 2016, 29 patients underwent RPLND by a single surgeon (23 post-chemotherapy). All patients underwent bilateral template dissection. Data for patients who received alvimopan was prospectively collected and compared to a historical cohort of patients who did not receive alvimopan. Primary outcomes measured were hospital LOS and recovery of GI function. Mann-Whitney Wilcoxon and Chi square tests were used to determine statistical significance between the two groups. Results: Of 29 men who underwent RPLND, 8 received alvimopan and 21 did not. There were no differences in preoperative or operative variables between the groups (Table). Median hospital LOS for men receiving alvimopan was 4 days compared to 6 days for those who did not (p=0.074). The median time to return of flatus in men receiving alvimopan was 2 days compared to 4 days for those who did not (p=0.0023). The median time to first bowel movement (BM) in men receiving alvimopan was 2.5 days compared to 4 days for those who did not (p=0.0028). Conclusions: Alvimopan significantly reduced the median time to return of flatus and to first BM after RPLND. Furthermore, there was a trend towards shorter hospital LOS in those receiving alvimopan. [Table: see text]
Is sarcopenia a useful prognostic indicator in patients with squamous cell carcinoma of the penis?
Authors: Christodoulidou Michelle , Burden Sorrel , Gibson Debra , Attipa Charalampos , Ramachandran Navin , Nigam Raj , Malone Peter , Mitra Anita , Lal Simon , Richards Toby , Muneer Asif
Published: March 2017

426

Background: Sarcopenia is a decrease in skeletal muscle mass and is a quantifiable marker of frailty associated with poor oncological outcomes. Currently there are no studies using sarcopenia as a prognostic indicator for patients with penile cancer. This study investigated the association of sarcopenia with mortality and morbidity outcomes in penile cancer patients in a specialist centre. Methods: A retrospective case-controlled study was performed. Patient cohort comprised 50 patients with metastatic penile cancer ( > pN2 disease) and 50 patients with non-metastatic disease (N0) ; minimum follow-up period of 2 years. Sarcopenia was classified as a skeletal muscle index < 55cm2/m2 and was measured using software and CT imaging. Results: Sarcopenia was present in 31% of our cohort (n = 100). A univariate analysis showed a statistically significant association between the following parameters and patient mortality; sarcopenia (p = 0.005), metastatic disease (p = 0.001), tumour stage (p = 0.001), sarcomatoid squamous cell carcinoma (p = 0.009), CIS (p = 0.034), lymphovascular invasion (LVI) (p = 0.001) and perineural invasion (p = 0.002). Logistic regression analysis found an association between mortality and sarcopenia (p = 0.035) and metastatic disease (p = 0.000) and approached statistical significance with LVI (p = 0.061). Subdividing our cohort into metastatic and non-metastatic groups, showed that sarcopenia was associated with mortality in patients with metastatic disease but was not associated with post-operative complications or chemo-radiotherapy toxicity. Interestingly, sarcopenia was associated with post-operative infection in patients undergoing surgery for non-metastatic disease (p = 0.027). Additionally, for every day remaining in hospital after the 4th post-operative day, there was a 1.275 increase in the risk of death in patients with sarcopenia. Conclusions: Sarcopenia has a potential role as a novel prognostic indicator and could be used as a risk stratification tool in patients with metastatic penile cancer when deciding treatment options. By identifying this subgroup, additional nutritional support and a supervised exercise program can be implemented to improve the morbidity rate.
A phase II study of atezolizumab (atezo) with or without bevacizumab (bev) versus sunitinib (sun) in untreated metastatic renal cell carcinoma (mRCC) patients (pts).
Authors: McDermott David F. , Atkins Michael B. , Motzer Robert J. , Rini Brian I. , Escudier Bernard J. , Fong Lawrence , Joseph Richard Wayne , Pal Sumanta K. , Sznol Mario , Hainsworth John D. , Stadler Walter Michael , Hutson Thomas E. , Ravaud Alain , Bracarda Sergio , Suarez Cristina , Choueiri Toni K. , Choi YounJeong , Huseni Mahrukh A. , Fine Gregg Daniel , Powles Thomas
Published: March 2017

431

Background: While targeting VEGF improves outcomes for mRCC pts, resistance invariably develops, often within the first year. Here, we describe the efficacy and safety of atezo (anti-PD-L1) with bev (anti-VEGF) and atezo monotherapy vs sun (TKI) in first-line mRCC. Methods: Treatment-naïve mRCC pts were enrolled in a hypothesis generating Ph II study (IMmotion150; NCT01984242) and randomized to atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w, atezo alone or sun 50 mg PO QD 4 wk on/2 wk off. Crossover to atezo + bev after disease progression was allowed for pts receiving atezo or sun. PD-L1 expression was scored on tumor-infiltrating immune cells (IC, SP142 IHC assay). Coprimary endpoints were PFS (RECIST v1.1 by independent review [IRF]) in ITT pts and pts with PD-L1 expression on ≥ 1% of IC (PD-L1+). Results: Baseline characteristics were comparable across arms and between ITT and PD-L1+ pts. The majority of sun and atezo pts subsequently received atezo + bev. Median survival follow up was 20.7 mo. The PFS HR in ITT pts for atezo + bev vs sun was 1.00 and 1.19 for atezo vs sun. In PD-L1+ pts, the PFS HR for atezo + bev vs sun was 0.64 and 1.03 for atezo vs sun (table). Tx-related Gr 3-4 AEs were seen in 40%, 16% and 57% of pts in the atezo + bev, atezo and sun arms, respectively. AEs leading to death occurred in 3%, 2% and 2% of pts, respectively. Conclusion: Atezo + bev resulted in encouraging antitumor activity in the PD-L1+ subgroup of first-line RCC pts. Atezo + bev safety is consistent with the known profile of atezo and bev individually. The clinical benefit of atezo + bev vs sun will be evaluated in the ongoing Ph III study IMmotion151 (NCT02420821). Clinical trial information: NCT01984242. [Table: see text]
Comparative effectiveness of tumor response assessment methods: Standard-of-care versus computer-assisted response evaluation.
Authors: Allen Brian , Florez Edward , Sirous Reza , Lirette Seth T , Griswold Michael , Remer Erick M. , Wang Zhen J. , Bieszczad Jacob E , Cox Kelly L , Goenka Ajit H. , Howard-Claudio Candace M , Kang HyunSeon , Nandwana Sadhna B , Sanyal Rupan , Shinagare Atul B. , Henagen J. Clark , Storrs Judd , Davenport Matthew S. , Rini Brian I. , Smith Andrew Dennis
Published: March 2017

432

Background: In clinical trials and clinical practice, tumor response assessment with computed tomography (CT) defines critical end points in patients with metastatic disease treated with systemic agents. Methods to reduce errors and improve efficiency in tumor response assessment could improve patient care. Methods: Eleven readers from 10 different institutions independently categorized tumor response according to three different therapeutic response criteria using paired baseline and initial post-therapy CT studies from 20 randomly selected patients with metastatic renal cell carcinoma treated with sunitinib as part of a completed phase III multi-institutional study. Images were evaluated with a manual tumor response evaluation method (standard-of-care) and with computer-assisted response evaluation (CARE) that included stepwise guidance, interactive error-identification and correction methods, automated tumor metric extraction, calculations, response categorization, and data/image archival. A cross-over design, patient randomization, and two-week washout period were used to reduce recall bias. Comparative effectiveness metrics included error rate and mean patient evaluation time. Results: The standard-of-care method was on average associated with one or more errors in 30.5% (6.1/20) of patients while CARE had a 0.0% (0.0/20) error rate (p<0.001). The most common errors were related to data transfer and arithmetic calculation. In patients with errors, the median number of error types was 1 (range 1-3). Mean patient evaluation time with CARE was twice as fast as the standard-of-care method (6.4 vs. 13.1 minutes, p<0.001). Conclusions: Computer-assisted tumor response evaluation reduced errors and time of evaluation, indicating better overall effectiveness than manual tumor response evaluation methods that are the current standard-of-care.
Changes in tumor burden and IMDC class after active surveillance (AS) for metastatic renal cell carcinoma (mRCC).
Authors: Bimbatti Davide , Sava Teodoro , Massari Francesco , Ciccarese Chiara , Fantinel Emanuela , Dalla Volta Alberto , Artibani Walter , Tortora Giampaolo , Iacovelli Roberto
Published: March 2017

435

Background: Targeted therapies (TT) improved survival in mRCC but treatment-related toxicities may worsen quality of life and lead to treatment discontinuation. AS is a feasible strategy in pts with indolent disease but effects on tumor burden (TB) and prognosis have not been investigated. Methods: In this retrospective study we included pts who received AS at our centre. The TB, defined as the number of sites of disease, was collected with the IMDC class, just before and after AS. The time on surveillance (ToS) was defined as the time from the start of AS to the beginning of therapy or last follow-up. The OSs were collected from the start of AS or TT. Results: 48 pts started AS from January 2007 to April 2016. After a median follow up of 37.3 months, 79.2% are still alive. At baseline the main sites of metastases were: lung (56%), nodes (25%), pancreas (14%), adrenal gland (8%), CNS (8%), and bone (6%). TB was one site in 65 %, two in 31%, and >2 sites in 4%. The IMDC prognostic class was favorable in 68,8%, intermediate in 25%, and poor in 6.3% of pts. After a median ToS of 16.7 months (95% CI 9.6-23.7), 34 patients (70.8%) started a TT, only 1/24 patient had progression as the best response. Significant difference in ToS were found where pts with good (19.9 mos) or intermediate (17.7 mos) class were compared to the poor group (5.2 months) (p<0.04). At the beginning of TT, the main sites of metastases were: lung (71%), nodes (44%), bone (15%), adrenal gland (15%), pancreas (15%), and CNS (9%). The TB was one site in 35%, two in 47%, and >2 sites in 18%; and 14 pts had new sites of disease. The IMDC class changed in four patients from good to intermediate. The median OSs was not reached from the start of surveillance and was 64.4 months from the start of TT. Conclusions: AS is an option for management of mRCC pts with good and intermediate prognosis. AS allows to delay the start of TT avoiding toxicity and worsening quality of life. Despite the fact pts in AS have increased TB and rarely a worsening of prognostic class, the survival remains longer and the effectiveness of subsequent therapy seems not to be affected.
Single-nucleotide polymorphisms (SNPs) associated with outcomes in patients with localized and metastatic renal cell carcinoma (RCC).
Authors: Garrigos Carmen , Espinosa Marta , Osman Ignacio , Ávila Rainiero , Medina Rafael , Melendez Ricardo , Salinas Ana , Perez Valderrama Begona , Duran Ignacio
Published: March 2017

437

Background: Despite major advances in the knowledge of the molecular basis of RCC, prognosis is still defined using clinical and pathological parameters. Moreover, no valid predictive biomarkers exist to help us selecting the best treatment for each patient. The aim of this work is analyzing the expression and determining the prognostic and predictive value of 64 key SNPs in 18 genes related with angiogenesis or metabolism of antiangiogenics in patients (pts) with both localized and advanced RCC treated at Hospital Universitario Virgen del Rocío. Methods: DNA from formalin fixed paraffin embedded tumor and non-tumor samples from 99 pts with RCC (26 advanced/ 73 localized) was extracted with QiAGEN Kit and amplified with a specific primers pool for every SNP as determined by the manufacturer (Lifetech). 64 SNPs were chosen based on their Minor Allele Frequency by HapMap, linkage disequilibrium by Haploview, and information from SNP data base (dSNP) and were studied by TaqMan OpenArray (Lifetech). The presence of the selected SNPs was correlated with clinical features, disease free survival (DFS), overall survival (OS), and response to treatment (RR). SPSS v16 was utilized for statistical analyses. Results: In pts with localized RCC, 6 SNPs in 3 genes involved in angiogenesis predicted for worse DFS (VEGFR2: rs10013228, rs2071559; PDGFRA: rs2228230) and shorter OS (VEGFR2: rs10013228; VEGFR3: rs6877011, rs307826) (p<0.05). In the advanced setting, 7 SNPs in genes related to both angiogenesis and metabolism of antiangiogenics determined inferior OS (IL8: rs2227543, NR1l2: rs3814055, NR1l3: rs2307424, PDGFA: rs9800958, PDGFRB: rs2302273) and worse RR (VEGFA: rs699947, rs3025010 p<0.01)). Additionally 3 SNPs in PDGFR-B and VEGF isoforms predicted for better RR (PDGFRB: rs17708574 (p=0.08), VEGFB: rs594942 (p=0.03), VEGFC: rs2016110 (p=0.07). Conclusions: Genetic analysis of RCC patients might provide valuable prognostic/predictive information. A set of SNPs in genes critical to angiogenesis and metabolism of antiangiogenics seem to determine post-surgical outcomes and treatment response in our series. These results are promising. Validation of the results is ongoing.
Patients with metastatic renal cell carcinoma who have benefit from axitinib dose titration: Analysis from a randomized, double-blind, axitinib dose titration phase II study.
Authors: Tomita Yoshihiko , Uemura Hirotsugu , Oya Mototsugu , Shinohara Nobuo , Habuchi Tomonori , Fujii Yosuke , Kamei Yoichi , Umeyama Yoshiko , Bair A H. , Rini Brian I.
Published: March 2017

438

Background: Axitinib is a potent, selective inhibitor of VEGF receptors. In a randomized, double-blind, phase II study in patients with metastatic renal cell carcinoma, median overall survival (OS) was 42.7 months who underwent axitinib titration versus (vs.) 30.4 months in placebo titration (hazard ratio [HR]: 0.785; 95% confidence interval: 0.485, 1.272). OS Kaplan-Meier curves for two arms appeared to cross over at approximately 24 months and thus we investigated baseline characteristics associated with OS benefit from axitinib titration. Methods: Patients received axitinib 5 mg twice daily (BID) for 28 days. Patients who met the dose titration criteria were randomized 1:1 to axitinib titration or placebo titration. Patients who did not meet the dose titration criteria continued axitinib 5 mg BID. Baseline characteristics were compared between patients with OS ≥ 24 and < 24 months who were randomized to axitinib titration and subsequently, multivariate analysis for baseline characteristics was conducted to investigate effect of interaction with axitinib titration. Results: Fifty-six patients underwent axitinib titration with 53 evaluable for this analysis. Thirty-three patients had an OS ≥ 24 months and had significantly fewer metastatic sites (≤2, ≥3: 52/48% vs. 10/90%), compared to the 20 patients with OS < 24 months. In addition, a lower percentage of patients with OS ≥ 24 months had lymph node metastasis (45 vs. 75%), liver metastasis (15 vs. 45%), duration from diagnosis to treatment <1 year (36 vs. 85%), and baseline hemoglobin (Hb) < LLN (lower limit of normal) (33 vs. 75%), compared to the patients with OS < 24 months. In multivariate analysis in total of 112 patients who were randomized to axitinib or placebo titration, duration from diagnosis and baseline Hb were significantly associated with favorable OS with axitinib titration (p<0.1). Conclusions: Duration from diagnosis and baseline Hb are associated with favorable OS with axitinib titration. Clinical trial information: NCT00835978.
Comparison of different prognostic scores versus physician’s subjective prognosis in patients with advanced/metastatic renal cell carcinoma treated with temsirolimus in regular clinical setting: An analysis of the STAR-TOR registry.
Authors: Boegemann Martin , Woike Michael , Gillhaus Johanna , Schrader Andres Jan
Published: March 2017

441

Background: In treatment of metastatic renal cell carcinoma (mRCC) patients several prognostic scores are used: the MSKCC-, IMDC-, and for pts treated with Temsirolimus (TEMS) the Hudes-score. We assessed prognostic value of these scores in TEMS treated cohort and compared the results with physician’s prognosis. Methods: A German multicenter registry for pts with mRCC (NCT00700258) was established to evaluate the safety and efficacy of TEMS in clinical routine. We retrospectively analyzed the data to compare established prognostic scores with risk assessment by the treating physician and match them with survival outcomes. Results: From 02/2008-05/2015, 547 mRCC pts were treated with TEMS. Risk was calculated for 305 (MSKCC), 248 (IMDC), and 187 (Hudes) pts. Physician’s prognosis was documented for 530 pts. Multivariate survival analyses are shown in table below. Abbreviations: g (good), i (intermediate), p (poor), n-p (non-poor). Conclusions: Risk assessment by treating physician is as meaningful as objective prognostic scores. In this data set, IMDC and Hudes performed worse than the MSKCC score. Physician’s risk assessment independently discriminates better between good and intermediate risk. The MSKCC score performs better for discrimination between an intermediate and a poor prognosis. Thus, the physician seems to be able to identify a subset of patients with a good prognosis while the MSKCC score can identify pts which are falsely placed in poor risk group by the physician. [Table: see text]
Effect of benign and tumor parenchyma metabolomic profiles on compensatory renal growth in renal cell carcinoma surgical patients.
Authors: Rosenzweig Barak , Rubinstein Nimrod Daniel , Reznik Eduard , Zareba Piotr , Shingarev Roman , Juluru Krishna , Akin Oguz , Hsieh James , Jaimes Edgar A , Russo Paul , Susztak Katalin , Coleman Jonathan , Hakimi A. Ari
Published: March 2017

446

Background: Pre-operative kidney volume is an independent predictor of glomerular filtration rate in renal cell carcinoma patients. Compensatory renal growth (CRG) can ensue prior to nephrectomy in parallel to tumor growth and benign parenchyma loss. We aimed to test whether renal metabolite abundances significantly associate with CRG, suggesting a causative relationship. Methods: Tissue metabolomics data from 49 patients, with a median age of 60 years, were previously collected and the pre-operative fold-change of their contra to ipsi-lateral benign kidney volume served as a surrogate for their CRG. Contra-lateral kidney volume fold-change within a 3.3 +/- 2.1 years follow-up interval was used as a surrogate for long-term CRG. Using a multivariable statistical model we identified metabolites whose abundances significantly associate with CRG. Results: We identified 13 metabolites in the benign (e.g. L-urobilin) and 163 metabolites in the malignant (e.g. 3-indoxyl-sulfate) tissues to significantly associate with CRG. Benign/tumor fold change in metabolite abundances revealed three additional metabolites with a significant positive association with CRG (e.g. p-cresol sulfate). At the pathway level, we show that fatty-acid oxidation is highly enriched with metabolites whose benign tissue abundances strongly positively associate with CRG, whereas in the tumor tissue significant enrichment of dipeptides (positive association) and benzoate, glycolysis/gluconeogenesis, lysolipid and nucleotide sugar pentose (negative associations) sub-pathways were observed. The effect of metabolite abundances in the benign tissue on long term CRG provided further support for positive association of fatty-acid metabolism sub-pathway enrichment, where sphingolipid, monoacylglycerol, long chain fatty acids, and mid chain fatty acids were enriched for a negative association. Conclusions: These data suggest that specific biological processes in the benign as well as in the tumor parenchyma strongly influence compensatory renal growth.
Cabozantinib (C) exposure-response (ER) modeling of safety endpoints in patients (pts) with renal cell carcinoma (RCC) in the phase III METEOR study.
Authors: Lacy Steven , Hutmacher Matthew M , Yang Bei , Motzer Robert J. , Escudier Bernard J. , Powles Thomas , Choueiri Toni K. , Nielsen Jace
Published: March 2017

447

Background: ER models were previously developed to characterize the relationship between C exposure and efficacy endpoints in RCC pts in the phase III METEOR study (J Clin Oncol 34, 2016 [suppl; abstr 2565]). Higher C exposure correlated with decreased tumor size and improved progression-free survival and objective response rate. Model-based predictions showed that C would be effective at the 60 mg starting dose evaluated in METEOR as well as dose levels of 40 and 20 mg resulting from dose reduction. In the current study, ER models were developed to characterize the relationship between C exposure and safety endpoints in RCC pts. Methods: The ER analysis included 318 RCC pts who had received at least one C dose and had at least one measurable C concentration. Time-to-event Cox proportional hazard ER models were developed to characterize the relationship between various individual predicted C exposure measures and the likelihood of dose modification and 6 specific adverse events (AEs): fatigue/asthenia, palmar-plantar erythrodysesthesia (PPE), nausea/vomiting, diarrhea, hypertension, and stomatitis. Results: A statistically significant relationship was identified between individual predicted C clearance (CL/F) and the rate of dose modification (p <0.0001), with the risk of dose modification decreasing with increasing CL/F. An increase in average C concentration was associated with increased risk of fatigue/asthenia (Grade ≥3), PPE (Grade ≥1), hypertension (systolic blood pressure [BP] >160 mmHg or diastolic BP >100 mmHg), and diarrhea (Grade ≥3). The predicted hazard ratios for these AEs were 2.01, 2.21, 1.85, and 1.78, respectively, based on the predicted steady-stage average C concentration for a 60 mg dose relative to a 20 mg dose. Statistically significant ER relationships were not identified for nausea/vomiting (Grade ≥3) or stomatitis (Grade ≥3). Conclusions: Based on the ER analysis, higher C exposures resulting from lower C CL/F are predicted to increase the dose modification rate. Reduced C exposures resulting from dose reduction are predicted to decrease the risk of fatigue/asthenia, PPE, hypertension, and diarrhea while maintaining clinical benefit. Clinical trial information: NCT01865747.
IVOIRE: Results of a prospective multicentre cohort study in advanced renal carcinoma.
Authors: Voog Eric , Campillo-Gimenez Boris , El Kouri Claude , Priou Frank , Rolland Frederic , Laguerre Brigitte , Elhannani Chaza , Merrer Jacques , Joly Florence , Pfister Christian , Malhaire Jean-pierre , Delva Remy , Cojocarasu Oana , Cumin Isabelle , Ligeza-poisson Catherine , Schlurmann Friederike , Monpetit Erik , Deniel Lagadec Delphine , Marhuenda Fanny , Grude Francoise
Published: March 2017

451

Background: Sequential targeted therapy is standard in patients (pts) with clear-cell renal carcinoma (CCRCC). Clinical Practice Guidelines exists only for first and second lines (ESMO recommendations). Exploratory recommendations for next treatments (ttt) have been proposed according to their MSKCSS risk. In 3rd line, pts without prior everolimus were proposed to receive it. Pts who have failed 2nd line ttt with everolimus were proposed to rechallenge Tyrosine Kinase Inhibitor only if they experimented a disease control ≤ 6 months in 1st line. For 4thline, TKI or everolimus were rechallenged according to the previously quoted criteria. Poor risk pts are not presented here. Methods: IVOIRE was a prospective multicentric study including pts treated according to these guidelines. Objectives were overall survival (OS) and for each line Best Objective Response (BOR - RECIST 1.1) and Disease Control Time (DCT: time from day 1 of ttt to the day before the next one). Results: 301 locally advanced/metastatic RCC pts have been included in 17 French centers between Sept 2011 and Sept 2014: 71% men; median age 66 years [35-90]; CCRCC: 89%; grade III-IV Führmann: 68%; tumor resection: 90%. Pts received between 2 and 8 ttt lines, including mainly TK and mTOR inhibitors, or rarely (< 5%) immunotherapies in 1st line (IFN, IL-2 and bévacizumab only). Median OS was 57 [51-70] months. Results are summarized in table. Important clinical benefit (L1: 79%; L2: 65%; L3: 59%; L4 : 38%; L5: 39%) and DCT could be observed until ttt line 5. A long DCT in 1st line was predictive of a best OS (p=0.001). Indeed, pts with short 1stline DCT (11 to 54 weeks) had a shorter median OS (32 months [23-61]] while pts with long DCT (>54 weeks) had a longer median OS: 79 months [65-100]. Conclusions: Our results confirm that clinical benefit remained important to beyond the first lines and that DCT in the first line was predictive of the global OS. Ttt sequence analysis and tolerance will be shown at the meeting. [Table: see text]
Effect of NKTR-214 on the number and activity of CD8+ tumor infiltrating lymphocytes in patients with advanced renal cell carcinoma.
Authors: Hurwitz Michael E. , Diab Adi , Bernatchez Chantale , Haymaker Cara L. , Kluger Harriet M. , Tetzlaff Michael T. , Gergel Ivan , Tagliaferri Mary , Imperiale Michael , Aung Sandra , Hoch Ute , Zalevsky Jonathan , Hwu Patrick , Sznol Mario , Tannir Nizar M.
Published: March 2017

454

Background: Patients with low baseline CD8+ T-cells within the tumor microenvironment (TILs) have a poor response to immune checkpoint inhibitors. Agents designed to specifically activate and expand CD8+ T cells may improve clinical outcomes in patients with low TILs. NKTR-214 is a CD-122-biased agonist designed to provide sustained signaling through the heterodimeric IL-2 receptor pathway (IL-2Rβɣ) and preferentially activate and expand NK and effector CD8+ T cells over CD4+ T regulatory cells. Methods: A dose escalation, open-label, trial was initiated to assess the safety of NKTR-214 and explore immune changes in the blood and tumor microenvironment in patients with advanced solid tumors. NKTR-214 was administered IV in an outpatient setting with initial dosing at 0.003 mg/kg. Pre and post treatment blood and tumor samples were analyzed for immune phenotyping, gene expression, T cell receptor diversity, and changes in the tumor microenvironment by immunohistochemistry. Results: Among 25 patients dosed, 15 had RCC (10@0.006mg/kg, 4@0.009mg/kg, and 1@0.012mg/kg). Treatment with NKTR-214 was well tolerated and the MTD was not reached. One patient experienced DLTs (Gr3 syncope and hypotension) at 0.012 mg/kg. There were no immune-related AEs. Of 12 patients evaluable for response, 75% had SD at their first on treatment scan. Of 5 patients, who were immune checkpoint naïve with ≥ 1 prior TKI treatments, 3 experienced tumor shrinkage, 1 with PR per RECIST 1.1 (unconfirmed). Interrogation of the tumor microenvironment revealed many significant immunological changes post treatment, including increase in total and proliferating NK, CD8+, and CD4+ T cells. There was good correlation between increase in activated CD4+ and CD8+ T cells in peripheral blood with an increase in T cell infiltrates within the tumor tissue. Conclusions: NKTR-214 increased immune infiltration in the tumor and anti-tumor activity in patients who previously progressed on TKIs, with a favorable safety profile. The ability to alter the immune environment and increase PD-1 expression on effectors T cells may improve the effectiveness of anti-PD-1 blockade. A trial combining NKTR-214 and nivolumab is enrolling. Clinical trial information: 02869295.
Meta-analysis of disease free survival (DFS) as a surrogate for overall survival (OS) in localized renal cell carcinoma (RCC).
Authors: Harshman Lauren Christine , Xie Wanling , Moreira Raphael Brandao , Gustavo Ruiz , Sweeney Christopher , Choueiri Toni K.
Published: March 2017

459

Background: OS is a critical endpoint for adjuvant RCC trials testing the benefit of early systemic therapy to increase cure rates, but requires long duration and significant patient resources. We explored the potential use of DFS as a surrogate for OS when assessing the efficacy of adjuvant therapy in localized RCC. Methods: We performed a systematic literature review following the PRISMA statement. Inclusion criteria required randomized controlled trials (RCT) for adjuvant systemic therapy in localized RCC, which reported on both DFS and OS. DFS was defined from randomization or nephrectomy (R/N) to the first evidence of clinical recurrence (loco-regional or distant) or death from any cause. OS was defined from R/N to death from any cause. We extracted data on hazard ratio (HR) and 5-year event free rate from Kaplan Meier estimates. We performed a meta-analysis and correlated these estimates for OS and DFS, weighted by number of DFS events. R-square >0.7 would indicate a strong correlation and potential surrogacy. Results: Of the more than 315 studies screened, 10 studies investigating various forms of cytokine and vaccine immunotherapy and angiogenesis inhibitors (e.g., sunitinib, sorafenib, thalidomide) between 1987 and 2016 were eligible for the analyses. The total enrolled patients were 5,497, with median follow-up ranging 3 to 10 years. Conclusions: Across trials of adjuvant systemic therapy for localized RCC, we observed a moderate correlation between 5 yr DFS and OS rate and between treatment effects (HRs) on these endpoints. Future meta-analyses of more mature trials in the era of modern adjuvant targeted therapy are needed to evaluate the surrogacy of intermediate endpoints. Further granularity may be achieved using individual patient data to assess different and earlier time points for surrogacy than are commonly reported. [Table: see text]
Stereotactic body radiotherapy for high-risk prostate cancer (5 treatment days): Toxicity results of a phase II trial.
Authors: Kishan Amar Upadhyaya , Fuller Donald B. , Steinberg Michael L. , Ramirez Victoria , Agazaryan Nzhde , Ruan Dan , Cao Minsong , Kupelian Patrick , King Christopher R.
Published: March 2017

46

Background: Stereotactic body radiotherapy (SBRT) for high-risk prostate cancer (CaP) remains investigational not only due to undetermined efficacy but also due to concerns for the potential toxicity when the treatment volumes extend beyond the prostate gland itself. Methods: Men with high-risk CaP, as defined by Gleason score > = 8, clinical stage T3-T4, or initial PSA > = 20 ng/mL, were enrolled on a multicenter phase II trial and were treated with 40 Gy to prostate and 25 Gy to pelvic nodes in 5 fractions and 9 months neoadjuvant and concurrent ADT. Treatment with ADT and pelvic nodal radiation was at the discretion of the treating physician. Follow-up assessment was with CTCAE v4 and Expanded Prostate Composite Index (EPIC). Results: A total of 61 patients were treated, with a median follow-up of 12 months. Forty (64.4%) received ADT and 23 (37.1%) received nodal radiation. The median initial PSA was 8.1 ng/mL and 8% of patients had clinical T3-T4 disease; 45.9% and 39.3% had Gleason score 8 and 9-10 disease, respectively. No grade 3 or higher toxicities were seen. Rates of acute and late grade 2 genitourinary toxicities were 13.1% and 6.7%, respectively; rates of acute and late grade 2 gastrointestinal toxicities were 6.6% and 8.2%, respectively. Mean changes in EPIC urinary incontinence, urinary obstructive, and bowel domain scores at 4 months were -0.35, +1.44, and -2.38, respectively. For the 32 patients with evaluable EPIC scores at 12 months, mean changes on EPIC urinary incontinence, urinary obstructive, and bowel domain scores at 4 months were -1.04, -2.70, and -6.76, respectively. The percentages of patients with minimum clinically important change in EPIC urinary incontinence, urinary obstructive, and bowel domain scores at 4 months were 11.9%, 21.4%, and 26.2%, respectively. At 12 months, these figures were 13.9%, 30.6% and 27.8%. The receipt of ADT and/or nodal radiation had no significant effect on either physician- or patient-reported toxicity profiles (p > 0.1, Fisher’s exact test). Conclusions: SBRT regimens can be safely utilized to deliver the entire course in 5 treatment days in patients with high-risk localized CaP. Clinical trial information: NCT02296229.
Prognosis of renal cell carcinoma with bone metastases: Experience in 300 consecutive patients.
Authors: Ruatta Fiorella , Derosa Lisa , Albiges Laurence , Massard Christophe , Loriot Yohann , Fizazi Karim , Escudier Bernard
Published: March 2017

463

Background: Bone metastases (BMs) are associated with significant morbidity and shorter survival in metastatic renal cell carcinoma (mRCC). Our purpose was to identify prognostic factors for mRCC patients (pts) with BMs. Methods: Data from mRCC pts with BMs, treated at Gustave Roussy between April 1992 and March 2016, were retrospectively collected. Age, sex, ECOG-Performance Status (PS), Memorial Sloan-Kettering Cancer Center (MSKCC) score, histology, number and site of BMs, concomitant metastases (presence and sites), therapy for BMs (radical resection or palliative surgery, radiotherapy, other local and systemic treatments), time to BMs, and outcome were analyzed. Synchronous solitary bone metastasis (SSBM) was defined as a single bone metastasis without concomitant visceral lesions at the initial diagnosis of RCC. Overall survival (OS) was calculated from the date of BMs diagnosis to death or last follow-up using Kaplan-Maier method and modelled with Cox-regression analysis. Results: Three hundred pts were identified. Median time to BMs was 32.4 months (range 0–324 months). In 64 pts (21%), bone was the only metastatic site and 22 of them (7%) had a SSBM; 236 pts (79%) had concomitant metastases in other sites. Median OS was 23.22 months. SSBM pts had better OS then those with concomitant metastases (40 vs. 20 months; p<0.001). At univariate analysis, number of BMs (p<0.0001), spinal column as site of BMs (p<0.005), concomitant metastases (p<0.0001), Fuhrman grade (p<0.001), non-clear cell histology (p<0.003), and MSKCC score (p<0.001) were significantly associated with poor prognosis. At multivariate analysis, concomitant metastases remained predictor of poor prognosis while good MSKCC, radical resection, and SSBM were predictors of better OS. Conclusions: To our knowledge,this is the largest single-institution experience evaluating prognosis in pts with BMs from RCC. This study suggests that MSKCC score, number of BMs (1 vs. >1) and radical resection are prognostic factors. Additionally, in presence of solitary bone metastasis without other concomitant metastases at the initial diagnosis of RCC, bone surgery should be considered to achieve local tumor control and increase survival.
Outcomes of PD-1/PD-L1 responders who discontinue therapy for immune-related adverse events (irAEs): Results of a cohort of patients (pts) with metastatic renal cell carcinoma (mRCC).
Authors: McKay Rana R. , Martini Dylan , Moreira Raphael Brandao , Hamieh Lana , Norton Craig , Mullane Stephanie Anne , Walsh Meghara K. , Michaelson Dror , McDermott David F. , VanAllen Eliezer , Harshman Lauren Christine , Choueiri Toni K.
Published: March 2017

467

Background: Nivolumab, a monoclonal antibody against PD-1, has been shown to improve survival for pts with mRCC. The current standard of care is to administer treatment on a continuous basis until progression or toxicity. Outcomes of pts who experience a response to treatment and then discontinue therapy for irAEs have not been fully characterized. The purpose of this analysis was to evaluate outcomes of responders to PD-1/PD-L1 targeted therapy (TT) who discontinue treatment for irAEs. Methods: We identified pts with mRCC having experienced a response to PD-1/PD-L1 TT, which was subsequently discontinued for an irAE. Clinical characteristics, response, and survival data were collected. Results: We identified 9 mRCC pts who were treated with a PD-1/PD-L1 inhibitor, experienced a response to therapy, and subsequently discontinued treatment for an irAE. 8 had clear cell histology and 1 had translocation RCC. 7 pts were treatment naive. 2 pts had International mRCC Database Consortium favorable risk, 4 intermediate risk, and 3 poor risk disease. 44% (n = 4) of pts received PD-1/PD-L1 monotherapy and the overall median duration of therapy was 5 months (mos) (range 4-15). There was 1 complete response, 7 partial responses, and 1 stable disease (17% shrinkage). Treatment was discontinued for the following irAEs: arthritis, uveitis, arthropathy, hypophysitis, myositis, blepharitis, hepatitis, rash, pericarditis, and amylase and lipase elevations. After PD-1/PD-L1 treatment discontinuation, 4 (44%) pts remained progression free with a median time off therapy of 20 mos (range 10-44) and median time on therapy of 9 mos (range 4-15). 5 (56%) pts progressed within 6 mos (range 2-6) of treatment discontinuation and median time on therapy was 4 mos (range 3-10). Conclusions: We demonstrate that some pts can have persistent clinical benefit after discontinuation of PD-1/PD-L1 TT for irAEs. Larger studies are warranted to evaluate the need for continuous drug dosing in all pts, identify pts in which continuous dosing is not required, and evaluate long-term outcomes in this population.
Effects of change in surgical approach in T3 renal cell carcinoma (RCC) with intracaval thrombus on complications and survival.
Authors: Vallinga Marleen Suzanne , Leliveld Anna Maria , Peeters Paul M.J.G. , De Jong Igle J.
Published: March 2017

471

Background: In patients with T3 RCC with venous tumor thrombus reaching the inferior vena cava, without metastatic disease, a nephrectomy with cavotomy is performed. Before 2000, surgical approach of level 3-4 caval tumorthrombus included sternotomy and cardiopulmonary bypass with circulatory arrest, with high morbidity and mortality rates. After the routine use of liver mobilization around 2000, sternotomy became less necessary. We compared perioperative characteristics, complications and survival pre- and post-2000. Methods: We retrospectively studied 91 patients, operated between 1984 and 2016 in a referral hospital. Patients with a T3 RCC and caval thrombus underwent a radical nephrectomy with thrombectomy. Data on patient and tumor characteristics, operation approach, complications (Clavien-Dindo classification), hospital stay, progression and survival were collected and analyzed using Mann-Whitney U, Chi-Square, and Log-Rank tests. Results: 91 patients (56 male) with a mean age of 65 years were included. 33% had a level 3 or 4 cava thrombus. Surgical management before 2000 included sternotomy with circulation arrest in 32% and liver mobilization in 10%. After 2000, the number of sternotomies lowered to 8% while liver mobilization increased to 74%. See table 1 for perioperative outcomes and complications. Disease specific survival was significant longer in patients operated after 2000 (estimated mean 70 vs. 94 months, p = 0.03). Only N stage influenced progression free survival, patients N+ showed worse survival (p < 0.01). Conclusions: The change in surgical approach including liver mobilization significantly decreased complication rates, blood loss, transfusion rate, hospital stay and increased disease specific survival. [Table: see text]
T cell infiltration in matched renal biopsy (bx) and nephrectomy (nx) samples in renal cell carcinoma (RCC).
Authors: Zahoor Haris , Pavicic Paul G , Przybycin Christopher , Elson Paul , Diaz-Montero C. Marcela , Finke James , Rayman Patricia A. , Gilligan Timothy D. , Grivas Petros , Ornstein Moshe Chaim , Garcia Jorge A. , Rini Brian I.
Published: March 2017

472

Background: T cell infiltration in tumors has been investigated as a biomarker of response to checkpoint inhibitors. A neo-adjuvant trial of checkpoint inhibition in locally-advanced RCC is ongoing at Cleveland Clinic, where T cell infiltration in pre-treatment renal mass bx will be compared to post-treatment nx specimens. However, there are no data regarding the association of T cell infiltration in matched bx and nx samples without intervening treatment. Understanding this association will enable further study of this potential biomarker in future neo-adjuvant studies. Methods: Matched bx and nx samples (without intervening systemic therapy) were identified from patients with non-metastatic RCC. Demographic and pathological data were collected from chart review. Selected tissue sections from bx and nx samples of each patient were reviewed, and marked for tumor and intra-tumoral lymphocytes by the pathologist. Immunohistochemistry (IHC) was utilized to stain these selected tissue sections for T cell markers (CD3, CD4 and CD8). Intra-tumoral T cells were then quantified in the pre-marked tissue sections as counts per total tumor area surveyed, using Image-Pro Plus (Media Cybernetics, Inc.). Spearman correlation (ρ) was used to measure the strength of association of T cell infiltration between matched samples. Results: 30 matched pairs were investigated. The median interval between bx and nx was 2.8 (0.2-87.7) months. Clear cell was the most common histology (29/30; 97%). 15/30 (50%) had grade 3-4 tumors, 2/19 (11%) patients had sarcomatoid features, 7/25 (29%) had necrosis, and 8/28 (29%) had lymphovascular invasion. We found a positive correlation between the frequencies of CD8+ T cells between matched bx and nx samples (ρ= 0.39; p=0.03). CD3+ and CD4+T cells did not show significant correlation. (Table) Conclusions: Bx material can be used to accurately assess the degree of CD8+T cell infiltration in RCC. [Table: see text]