bluuebunny/crossref_metadata_2025 huggingface dataset:
Distinguishing fibrosis/necrosis from teratoma or viable disease in the retroperitoneum in post-chemotherapy, nonseminomatous testicular germ cell tumor using quantitative CT texture analysis.
Authors: King Kevin George , Bhanvadia Sumeet , Ghodoussipour Saum , Hwang Darryl , Varghese Bino , Cen Steven Yong , Daneshmand Siamak , Duddalwar Vinay
Published: February 2018

563

Background: In metastatic nonseminomatous testicular germ cell tumor (NSGCT), post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) is indicated for residual masses > 1 cm because of these 45% will be fibrosis/necrosis, 45% will be teratoma and 15% will be viable malignancy. There is no imaging test that reliably distinguishes lymph nodes (LNs) with tumor (teratoma or malignancy) from LNs with fibrosis/necrosis. We evaluated whether quantitative CT texture analysis (TA) could make this differentiation. Methods: Pre- and post-chemotherapy CTs (all same phase and slice thickness) were reviewed in 22 NSGCT patients with RP LNs > 1 cm post chemotherapy. After manual segmentation of RP LNs on a 3D workstation, 187 TA metrics were derived, using 2D/3D gray-level co-occurrence matrix (GLCM), 2D/3D gray-level difference matrix (GLDM), and spectral analysis. Metrics were derived 2 ways: from post-chemotherapy CTs alone, and also as a difference between pre- and post-chemotherapy CTs, resulting in 374 metrics. PC-RPLND pathology was correlated with CT data at 88 LN stations in these 22 patients. Results: 15 imaging metrics showed a significant difference (p ≤ 0.05) between LN stations with only fibrosis/necrosis and those with teratoma or viable tumor. Seven were derived from the difference between pre- and post-chemotherapy CTs: 4 using a 2D GLCM (coronal standard deviation, coronal square root of variance, coronal mean, and coronal sum of average), and 3 using a 2D GLDM (axial variance, axial square root of variance, and coronal variance). The other 8 were derived from post-chemotherapy CTs alone: 7 using a 2D GLCM (sagittal square root of variance, sagittal standard deviation, coronal square root of variance, coronal mean, coronal standard deviation, coronal sum of average, and coronal entropy) and 1 using a 2D GLDM (sagittal sum entropy). Conclusions: CT TA shows promise in differentiating necrosis from teratoma or viable tumor in RP LNs in post-chemotherapy NSGCT. A larger study is needed to further test this method, towards a long-term goal of potentially allowing some patients to avoid PC-RPLND.
Effect of number of computed tomography (CT) scans during follow-up (FUP) of patients with clinical stage I (CSI) seminoma: A trial-level meta-analysis.
Authors: Giannatempo Patrizia , Raggi Daniele , Tagliabue Elena , Catanzaro Mario , Biasoni Davide , Torelli Tullio , Stagni Silvia , Nicolai Nicola , Piva Luigi , Salvioni Roberto , Mariani Luigi , Necchi Andrea
Published: February 2018

564

Background: Despite the overall high cure-rate for patients (pts) with CSI seminoma (sem) regardless of the intervention used, huge discrepancy exists in the number of CT scans that are proposed to pts during FUP period, mainly during active surveillance (AS). The impact of such discrepancy in diagnosing pts with a high-risk relapse was assessed in published literature with a meta-analysis (MA). Methods: We searched for arms of studies of AS or active treatment (AT, adjuvant chemotherapy and radiotherapy) in pts with CSI sem. Meta-analytic techniques were used to pool and compare study level data of AS and AT groups and to study the impact of the number of CT scans (as a continuous variable) during FUP upon the % of pts with CSIII or with IGCCCG intermediate (int) prognosis sem at relapse. Results: 22 studies were analyzed (33 arms, n = 11025 pts). 39.6% had a high-risk sem, 38.8% (n = 4274) underwent AS vs 61.2% (n = 6751) AT. The number of CT scans ≤2y ranged 4-8, and 0-7 for AS and AT groups. Overall, 922 pts experienced a relapse (651 in AS and 271 in AT arms), 73.9% <2y and 22.3% at 2-5y FUP. Statistical modeling showed that the estimated rates of CSIII relapse (6% in AS, 32% in AT group, p = 0.0068) and int prognosis relapse (2% in AS, 11% in AT group, p = 0.0051), were divergent for the two groups. A higher number of CT scans in the first 2 years of FUP tended to reduce the occurrence rate of both endpoints, but failed to reach statistical significance in AS (p = 0.334 for CSIII, unidentifiable for int prognosis relapse), as well as in AT (p = 0.438, p = 0.103). The number of CT scans in 3-5y FUP had an even weaker prognostic effect. Similar trends were observed in AS cohort after adjusting for the CSI risk group. Conclusions: In this trial-level MA we did not find a statistically-significant association between the number of CT scans performed during FUP of CSI sem pts and the diagnosis of high-risk relapses. Huge discrepancy in the total number of CT scans was generally found between arms. In contrast, as expected, the pattern of relapse of CSI sem was different according to the treatment group. Based on these results, there is room for consistently reducing the number of CT scans during FUP of CSI sem pts undergoing AS.
Outcomes of male patients with germ cell tumors and bone metastases: A mono-institutional retrospective study.
Authors: Moriceau Guillaume , Boyle Helen Jane , Bonnin Nathalie , Sajous Christophe , Peyrat Patrice , Pommier Pascal , Rivoire Michel , Flechon Aude
Published: February 2018

570

Background: Bone metastases (BM) are considered as intermediate or poor prognosis according to the international classification of Germ Cell Tumors (GCT). The present study compares the outcomes between patients with bone disease at initial diagnosis and bone disease at relapse and between seminoma and non-seminoma GCT. Methods: We investigated retrospectively all male-patients presenting GCT with BM at initial diagnosis or at relapse, between 2005 and 2015, in a single institution. Results: Thirty-nine patients were included. Median age was 36 (from 20 to 67). Nineteen patients presented with BM at initial diagnosis (49%) and 20 patients presented BM at relapse (51%). Histologically, 13 patients (33%) presented a seminoma and 26 patients (67%) a non-seminoma GCT. Twenty-four patients (62%) had multiples bone metastatic sites. Vertebra was the most frequent location (70%). Bone surgery was performed for five patients with seminoma (38%) and four patients with non-seminoma GCT (15%). Median overall survival (OS) was 130.9 months for the 19 patients with BM at initial diagnosis and 15.2 months for the 20 patient with BM at relapse HR 5.3 95%CI[1.75;16.06], p < 0.001. Median progression free survival (PFS) was 120.10 months for patients with BM at initial diagnosis and 9.21 months for patients with BM at relapse, HR 3.02 95%CI[1.16;7.83], p < 0.0016. Survivals are longer for patients with seminoma than patients with non-seminoma GCT. Median PFS was 9.41 months for the 13 patient with non-seminoma GCT and not achieved for the 26 patients with seminoma, HR 0.15, 95%CI [0.003;0.65], p 0.001 . Median OS was 18.7 months for the 13 patient with non-seminoma GCT and not achieved for the 26 patients with seminoma, HR 0.16 95% CI [0.004;0.7], p 0.002. Conclusions: BM of GCT are associated with a worse prognosis especially for non-seminoma subtype and/or when BM arise at relapse. This data highlights the importance of the first line therapeutic strategy as the corner stone of treatment for patients with GCT.
Association of age and sex with mortality following adjuvant therapy for renal cell cancer (RCC): Subgroup analysis of the ASSURE (E2805) trial.
Authors: Mamtani Ronac , Wang Xin Victoria , DiPaola Robert S. , Dutcher Janice P. , Haas Naomi B.
Published: February 2018

575

Background: The benefit of vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) as adjuvant therapy for RCC remains a subject of controversy. Given the uncertain risk-benefit ratio, identifying subgroups expected to derive benefit or harm from therapy could lead to a more precise approach to therapy. Because of known sex-differences in the pharmacokinetics and tissue distribution of VEGF-TKIs, we assessed the interaction of age and sex on treatment outcomes among patients in the phase III ASSURE trial (Adjuvant Sorafenib or Sunitinib for Unfavorable RCC). Methods: ASSURE included 1,943 patients with ≥ pT1b resected RCC. There was no OS or DFS benefit with adjuvant sunitinib or sorafenib relative to placebo. In this post-hoc subgroup analysis of age and sex based on the median age of 56 years, Cox regression computed hazard ratios (HR) and 95% confidence intervals (CIs) for OS and DFS with sunitinib or sorafenib compared to placebo across age- and sex-specific strata (males ≤ 56 years [n = 689], males > 56 years [n = 620], females ≤ 56 years [n = 317], and females > 56 years [n = 317]). Models were adjusted for race, histology, and UISS risk group. A 3-way interaction term was calculated for sex, age, and treatment. Results: Treatment with sunitinib was associated with increased mortality among women > 56 years (sunitinib vs placebo [HR OS 2.38; 95% CI, 1.39-4.07]), but not in women ≤ 56 years or in men of any age. Similarly, among women > 56 years, the risk of disease recurrence was increased with sunitinib relative to placebo (HR DFS 1.53; 95% CI, 1.03-2.28). There were no statistically significant differences in OS or DFS associated with sorafenib (women > 56 years: HR OS 1.50, 95% CI, 0.83-2.71; HR DFS 1.23, 95% CI, 0.81-1.89). The 3-way interaction between age, sex, and sunitinib treatment on mortality was statistically significant (p = 0.0166). Conclusions: Adjuvant sunitinib after nephrectomy was associated with increased mortality among older women, which may be explained by increased risk of RCC recurrence. These findings, if validated, highlight the importance of considering sex and age on VEGF-TKI treatment outcomes, future study designs, and RCC tumor biology. Clinical trial information: NCT00326898.
Phase II study of enzalutamide monotherapy with radiation therapy for intermediate risk prostate cancer.
Authors: Bubley Glenn , Kaplan Irving D. , Werner Lillian , Bhatt Rupal Satish , Taplin Mary Ellen , Mahoney Kathleen Margaret , Nguyen Paul ,   Taplin
Published: February 2018

58

Background: Castrating androgen deprivation therapy (ADT) is standardly prescribed in combination with radiation therapy (RT) for intermediate or high-risk prostate cancer (PCa). ADT is associated with multiple side effects including weight gain, loss of libido, hot flashes and muscle atrophy. In contrast, enzalutamide monotherapy is associated with much fewer side effects. Methods: At Dana-Farber/ Harvard Cancer Center we performed an open label phase II study of enzalutamide for 6 months as neo- and adjuvant treatment for intermediate risk PCa patients (NCCN criteria) receiving RT. The primary endpoint was the proportion of patients achieving a PSA response of ≤0.2 . This endpoint is predictive of long term PSA response in a similar risk-group of patients treated with RT and ADT. PSA values were obtained at baseline and monthly on 6 cycles of enzalutamide (160mg/day). 79.2 Gy in 44 fractions of IMRT was started between 6 and 10 weeks after the initiation of enzalutamide. Quality of life questionnaires, hormone levels and anthropomorphic measurements were obtained. Results: 45 of 60 evaluable patients had a PSA ≤0.2 at the end of 6 months of enzalutamide. With a sample size of 64 evaluable patients, if the number achieving a PSA level is ≤0.2 is 44 or more, the null hypothesis is rejected with a target error rate of alpha = 0.10. Also 54 of 60 evaluable patients had a PSA of ≤0.5ng/ml. Importantly, less than half of the participants experienced erectile dysfunction or decreased libido and these were predominantly grade I. Less than a quarter of patients reported hot flashes (all grade I). Waist circumference did not change with therapy. The most frequent grade 2 or greater events were hypertension and gynecomastia. Testosterone and free testosterone levels rose significantly on enzalutamide therapy. Conclusions: Enzalutamide monotherapy with RT may be as effective as castrating ADT, and associated with fewer side effects. Larger, randomized trials are needed to further evaluate enzalutamide monotherapy, instead of ADT, to be used in combination with RT. Clinical trial information: NCT0208988.
A randomized phase II trial of pazopanib (PAZ) versus temsirolimus (TEM) in patients (pts) with advanced clear-cell renal cell carcinoma (aCCRCC) of intermediate and poor-risk (the TemPa trial).
Authors: Tannir Nizar M. , Ross Jeremy Aaron , Devine Catherine E , Chandramohan Anuradha , Wang Xuemei , Lim Zita Dubauskas , Wang Jennifer , Corn Paul Gettys , Zurita Amado J.
Published: February 2018

583

Background: TEM has level 1 evidence in aRCC with poor-risk disease. No trial compared a VEGFR-TKI with TEM as first-line (1L) therapy in this disease state. Methods: We randomly assigned (1:1) treatment-naïve pts with aCCRCC and > = 3 risk factors (as per Hudes et al., NEJM 2007) to receive PAZ 800 mg po qd or TEM 25 mg iv qw. Pts were offered to receive the alternative agent at disease progression (PD). The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), objective response rate (ORR) and safety. A blinded radiologist assessed the radiographic response using RECIST v1.1. A sample size of 90 pts was based on an assumption of improved median PFS from 3.8 mo with TEM to 6.1 mo with PAZ. Pts were stratified by prior nephrectomy (Nx). The Kaplan-Meier method was used for PFS and OS analysis, and the Fisher’s exact test was used for comparison of ORR between PAZ and TEM. Results: The study was closed to new patient enrollment when the results of the CheckMate 214 and CABOSUN studies were presented at ESMO 2017. A total of 69 pts were eligible and evaluable (median age 61, 52 males [75%], 44 [64%] had poor-risk by IMDC criteria). Thirty pts [43%] had prior Nx. Thirty-five pts received PAZ (intermediate-risk 13, poor-risk 22) and 34 pts received TEM (intermediate-risk 12, poor-risk 22). Of the 69 pts, 67 had PD or died. The median PFS was 5.2 mo (95% CI: 3.6 –7.4) for PAZ and 2.6 mo (95% CI: 1.9 –4.2) for TEM (p = 0.16). In 1 pt, no date of death was available. Of the remaining 68 pts, 58 (85.3%) have died. The median OS was 12.0 mo (95% CI: 8.3–20.1) for PAZ and 7.4 mo (95% CI: 5.3–17.4) for TEM (p = 0.61). Sixty-eight pts were evaluable for response: 9/35 pts (26%) who received PAZ and 2/33 pts (6%) who received TEM had partial response (p = 0.046). Adverse events (AEs) were consistent with the known safety profiles of PAZ and TEM. Only 2 pts in each arm discontinued treatment due to AEs. Conclusions: PAZ extended PFS and OS and yielded a significantly higher ORR than TEM as 1L therapy in pts with aCCRCC and intermediate/poor-risk disease. Clinical trial information: NCT01392183.
Targeting bacteroides in the stool microbiome and response to treatment (Rx) with first-line VEGFTKI in metastatic renal cell carcinoma (mRCC).
Authors: VanAlstine Sidney , Froerer Camryn , Hahn Andrew W , Gilreath Jeffrey , Agarwal Neeraj , Stenehjem David D. , Bailey Erin B.
Published: February 2018

584

Background: Diarrhea occurs in ~50% patients with mRCC receiving VEGFTKIs, and is a common cause of VEGFTKI Rx dose reductions/delays/interruptions. Stool bacteroides level directly correlates with diarrhea in these patients on Rx with VEGFTKI (Pal SK, Clinical Cancer Research 2015, PMID:26152743). Hypothesis was that mRCC patients on incidental antibiotics (ABX) which also target stool bacteroides will have less diarrhea, leading to improved Rx compliance, and improved outcomes on VEGFTKI. Methods: A retrospective study of mRCC patients with MSKCC intermediate or poor risk mRCC on 1st line VEGFRTKIs between 2005-2017. ABX usage was categorized by ABX bacteroides sensitivity at anytime during Rx with 1st line VEGFTKI along with the total number of days on ABX. 1st line VEGFRTKI progression free survival (PFS) was assessed by Kaplan-Meier and Cox proportional hazard models. Results: 145 patients with intermediate (n = 123, 85%) or poor risk (n = 22, 15%) mRCC on a VEGFTKI were identified. ABX were prescribed incidentally in 50 (34%) patients. 18 patients were prescribed ABX with bacteroides coverage of which 13 had ABX with high sensitivity for bacteroides. The median number of days supplied of all ABX was 7 (IQR 1-15 days). The median number of days supplied of ABX with bacteroides coverage was 6 (IQR 1.5-15.5 days). The median PFS in those prescribed ABX with bacteroides sensitivity was 18 months versus 8 months in those prescribed no ABX (p = 0.067), and 9 months in those prescribed ABX without bacteroides sensitivity. Duration of bacteroides ABX coverage resulted in a hazard ratio of 0.92 (95% CI 0.83-0.99, p = 0.043) for each additional day an ABX with bacteroides coverage was prescribed compared to those with no ABX. Conclusions: In these hypothesis generating data, incidental targeting of stool bacteroides with ABX correlated with improved PFS in mRCC patients on 1st line VEGFTKIs. Data need validation. Equal contribution: SAV, CDF, AWH
Changeable prognosis and associated prognostic factors for conditional survival estimates in metastatic renal cell carcinoma patients receiving the first-line targeted therapy.
Authors: Kang Minyong , Sung Hyun Hwan , Jeon Hwang Gyun , Jeong Byong Chang , Park Se Hoon , Jeon Seong Soo , Lee Hyun Moo , Choi Han Yong , Seo Seong Il
Published: February 2018

587

Background: Conditional survival (CS) indicates the probability that patient would survive additional periods, given that the patients has previous survivorship after diagnosis or initial treatment. Here, we aim to evaluate the CS probabilities in mRCC patients who underwent targeted therapy with tyrosine kinase inhibitors (TKI) and to identify the significant prognostic factors of the CS over time. Methods: A total of 1,498 mRCC patients receiving 1st line TKI was finally analyzed from Korean multicenter database of mRCC. Kaplan-Meier survival estimates was used to calculate overall and cancer-specific CS rates by using following formula: CS(α│β) = S(α+β)/S(β), where CS(α│β) indicates the likelihood of additional α years survivorship in the person who has already survived for β years after initial diagnosis or treatment, and S(χ) is the actual survival rate. The Cox regression analysis was used to determine the predictors of CS depended on clinicopathological features. Results: We observed that 1, 2, 3, 4, and 5-year conditional cancer-specific survival (CSS) gradually increased as patients who have all additional survivorships after initial treatment, compared to those with baseline survival estimation. Also, 1, 2, 3, 4, and 5-year conditional OS rates also increased after additional 1, 2, 3, 4, and 5 year survivorships following first-line TKI treatment. Furthermore, we found that key predictive factors of OS and CSS were changed over time in multivariate analysis. While several variables, such as BMI, histologic subtypes, pT stage, were identified as prognosticators of CSS at baseline, they were not remained as independent predictors after 1 yr survivorship. Conversely, only previous metastatectomy was determined as a key prognostic factor for conditional OS over time until 4 yr survivorship after initial TKI treatment. Conclusions: Our study offers valuable information for practical survival estimation and relevant predictive factors for patients with mRCC receiving targeted therapy.
Optimizing axitinib treatment selection following first-line sunitinib in metastatic renal cell carcinoma.
Authors: Bracarda Sergio , Bamias Aristotelis , Casper Jochen , Negrier Sylvie , Sella Avishay , Staehler Michael D. , Tarazi Jamal Christo , Felici Alessandra , Rosbrook Brad , Jardinaud-Lopez Monica , Escudier Bernard
Published: February 2018

589

Background: The treatment landscape for metastatic renal cell carcinoma (mRCC) is continuously evolving, with several new first-line (1L) and second-line (2L) treatment options. In the AXIS trial, axitinib resulted in significantly longer progression-free survival (PFS) vs sorafenib in the 2L treatment of mRCC. In these post-hoc exploratory analyses of AXIS, possible key drivers for successful 2L treatment with axitinib after sunitinib were evaluated. Methods: AXIS was an open-label, randomized, phase III trial (NCT00678392) in patients (pts) with mRCC who failed 1 prior systemic therapy. Univariate and multivariate analyses evaluated potential predictive factors for improved PFS (investigator-assessed) and overall survival (OS) with axitinib. PFS (independent review), OS and objective response rate (ORR) for axitinib vs sorafenib according to these predictive factors were assessed. Results: In all, 389 pts received 1L sunitinib: 194 and 195 pts received 2L axitinib and sorafenib, respectively. Based on multivariate analyses of PFS and OS, predictive factors favoring 2L axitinib treatment were identified as: non-bulky disease (sum of the longest diameter < 98 mm), favorable/intermediate (Fav/Int) risk (Memorial Sloan Kettering Cancer Center or International Metastatic Renal Cell Carcinoma Database Consortium criteria), no bone and no liver metastases. Thus, pts were grouped according to these factors. In pts with favorable risk factors (n = 86), a significantly longer median (95% confidence interval [CI]) PFS was observed in axitinib (n = 39; 13.9 [7.8–17.7] mo) vs sorafenib pts (n = 47; 4.7 [3.5–6.7] mo; hazard ratio [HR] 0.476 [95% CI 0.263–0.863]; P= 0.0126). Median (95% CI) OS (32.4 [23.8–not evaluable] mo vs 35.0 [23.9–35.0] mo; HR 0.902 [95% CI 0.457–1.780]; P= 0.7661) and ORR (both 12.8%) were similar between the 2 groups. More pts had stable disease ≥20 weeks with axitinib (38.5%) vs sorafenib (21.3%). Conclusions: In the continuously changing treatment landscape for mRCC, axitinib remains a suitable 2L treatment option, particularly in pts with non-bulky disease, Fav/Int risk and no bone nor liver metastases, characterized by an impressive PFS. Clinical trial information: NCT00678392.
Epidural block in local kidney cancer as a way to preserve the adrenal function influencing urine formation processes.
Authors: Frantsiyants Elena , Kit Oleg Ivanovich , Kozlova Larisa S. , Rozenko Dmitry A. , Bandovkina Valeria A. , Cheryarina Natalia D. , Dimitriadi Sergey N , Ushakova Natalya D. , Rozenko Ludmila Ya. , Duritskiy Maksim N.
Published: February 2018

592

Background: Our purpose was to study the dynamics of cortisol (C) and aldosterone (A) in the blood plasma in patients receiving surgery with the epidural block (EB) for local kidney cancer. Methods: 58 patients aged 56.5±8.7 years underwent partial nephrectomy with warm ischemia for 15-20 minutes (EB – 35 patients, standard anesthesia (SA) - 23 patients). EB involved catheterization of the epidural space at Th10-L1 with the following infusion of a mixture of ropivacaine 2 mg/ml and epinephrine 2 μg/ml at 6-10 ml/hr using a syringe doser, intraoperatively and within the first three postoperative days. The levels of C and A were studied by radioimmunoassay in the blood plasma of patients before the surgery (b/s), 40 min after the start of the surgery (40' s/s) and on days 1 and 3 after the surgery (a/s). Results were compared to the levels in the blood plasma of 32 healthy donors (N). Results: C and A exceeded N in all patients b/s (p < 0.01). C increased by an order of magnitude 40' s/s only in SA (p < 0.001), while A increased in all patients, compared to the levels b/s. C decreased by 1.5 times in EB on day 1 a/s; C in SA was similar to the levels b/s; A decreased to similar levels in all patients but was still higher than N by 1.4 times on average (p < 0.01). The C levels remained stable in all patients on day 3; A levels became normal in EB only, while in SA they were 2.1 times lower which caused the loss of salts and fluid. Conclusions: SA affected the regulation of the adrenal function by the central nervous system and urine formation processes in the kidney. In SA, abnormal C and A levels preserve for a longer period of time enhancing the water and salt imbalance in the body. Significant decrease of C and the normalization of A in EB indicate the preservation of the adrenal function influencing urine formation processes in the kidney. In local kidney cancer, it is advisable to use epidural block instead of standard anesthesia as the latter blocks regulatory functions of the central nervous system.
The impact of switching systemic treatment after radiosurgery (SBRT) for oligo-progressive, metastatic renal cell carcinoma (mRCC).
Authors: Barata Pedro C. , Kotecha Rupesh , Mendiratta Prateek , Juloori Aditya , Angelov Lilyana , Chao Samuel T. , Elson Paul , Koshkin Vadim S. , Ornstein Moshe Chaim , Gilligan Timothy D. , Grivas Petros , Wood Laura S. , Rini Brian I. , Garcia Jorge A.
Published: February 2018

599

Background: Local therapy such as SBRT is increasingly applied to RCC metastases when progression involves a limited number of metastatic sites (oligo-progression; O-PD). We aimed to assess the clinical outcome of patients (pts) with O-PD who changed systemic treatment upon SBRT (SWITCH) compared with those who remained on same therapy after SBRT (STAY); and also with the group of pts who progressed systemically (PD-SYS) and changed systemic treatment as well. Methods: Retrospective analysis of clear-cell mRCC pts treated with SBRT to brain or spinal metastases was undertaken. Clinical outcomes and treatment duration on current therapy of pts in the SWITCH, STAY and PD-SYS groups were compared. Treatment duration was defined as the time interval between SBRT and discontinuation of current systemic therapy for STAY group and discontinuation of first subsequent therapy in the SWITCH and PD-SYS groups. Results: A total of 100 pts with mRCC who had SBRT were identified, including 44 in STAY, 23 in SWITCH and 33 in PD-SYS. Median age was 58 yrs (range 36-79), 76% men, 66% ECOG PS 0-1, 60% IMDC intermediate risk. 61 pts received SBRT to brain and 40 pts to spine with 87% local control rate. Most common systemic treatments at time of SBRT included anti-VEGF (72%), mTOR (11%), PD-1 inhibitors (10%), other (7%). Median treatment duration for STAY was 5.2 months (95% CI, 3.5-6.9) compared with 5.0 months (95% CI, 4.3-5.7) for SWITCH (p = 0.549) and 2.6 months (95% CI, 1.5-3.7) for the PD-SYS group (p = 0.002, compared to all O-PD pts). Median OS was 24.2 months (95% CI, 8.7-39.7) and 27.1 (95% CI, 12.7-41.9) months for STAY and SWITCH groups, respectively (p = 0.461) and 8.5 months (95% CI, 2.1-14.9) in the PD-SYS group (p = 0.014, compared to all O-PD pts). Conclusions: SBRT for pts with mRCC in brain or spine was feasible with excellent local control. The decision to allow pts to remain on their current systemic therapy did not compromise treatment duration or survival. Pts with progressive disease outside SBRT-treated sites had a worse outcome.
Pilot trial of ibrutinib plus nivolumab in patients (pts) with metastatic renal cell cancer (mRCC): Results from a dose-finding cohort.
Authors: Lara Primo , Parikh Mamta , Robles Daniel , Lara Frances , Meyers Frederick J. , Pan Chong-xian
Published: February 2018

600

Background: Immune checkpoint inhibitor therapy (CPI) has transformed the management of pts with mRCC, with a fraction experiencing durable tumor responses. However, most eventually develop disease progression after either an initial response to CPI or while on CPI. Newer agents that modulate immune response can possibly potentiate CPI therapy. The ITK/ETK/BTK inhibitor ibrutinib has been reported to inhibit myeloid derived suppressor cells in preclinical models and to potentiate CPI. We conducted an investigator-initiated pilot trial of ibrutinib plus the PD1 inhibitor nivolumab in mRCC pts, particularly in those previously exposed to CPI. Here we report initial safety and efficacy results from the dose-finding cohort. Methods: Pts with mRCC of any histologic subtype and who have completed at least one line of prior systemic therapy including prior CPI were eligible. Pts must have acceptable end-organ function and Zubrod PS of 0-2. Treatment consisted of nivolumab 240 mg IV q2 weeks plus ibrutinib 560 mg (dose level 0) or 420 mg (dose level -1) orally once daily. Cycle length was 28 days. Dose limiting toxicity (DLT) was defined as any Grade(Gr) 3+ adverse event (AE) attributable to therapy. Results: As of 9/18/17, 12 pts have been enrolled, six to each dose level. Patient characteristics: Mean age = 62 years (range 44-78); Male sex = 7 (58%); White race = 9 (75%); Prior CPI = 11 (92%). Three pts experienced one DLT each in dose level 0 (all Gr3): elevated lipase, hypoalbuminemia, & nausea. Only 1 DLT has been seen thus far in dose level -1 (Gr3 infection). The most common Gr3+ AEs include anemia (n = 5), ALT elevation (4), AST elevation (3), nausea (3), hypoalbuminemia (2), esophagitis, infection, lipase increase, and vomiting (1 each). Two pts with prior CPI had partial tumor response (1 confirmed, 1 unconfirmed). Conclusions: Ibrutinib at a dose of 420mg orally once daily in combination with nivolumab 240mg IV q 2 weeks appears feasible and tolerable in mRCC patients. No unique immune-related AEs have been seen thus far. Anti-tumor activity was seen in 2 pts previously exposed to PD1-targeted therapy. Further evaluation of this combination is warranted. (Supported by Pharmacyclics and UCDCCC). Clinical trial information: NCT02899078.
Phase 1 study of glutaminase (GLS) inhibitor CB-839 combined with either everolimus (E) or cabozantinib (Cabo) in patients (pts) with clear cell (cc) and papillary (pap) metastatic renal cell cancer (mRCC).
Authors: Tannir Nizar M. , Fan Alice C. , Lee Richard J. , Carthon Bradley Curtis , Iliopoulos Othon , Mier James Walter , Patel Manish R. , Meric-Bernstam Funda , DeMichele Angela , Voss Martin Henner , Harding James J. , Srinivasan Ramaprasad , Shapiro Geoffrey , Telli Melinda L. , Munster Pamela N. , Carvajal Richard D. , Jenkins Yonchu , Whiting Samuel H. , Bendell Johanna C. , Bauer Todd Michael
Published: February 2018

603

Background: CB-839 is a first-in-class inhibitor of GLS that targets tumor glutamine utilization, a pathway upregulated in kidney cancer. CB-839 combines with E or Cabo in pre-clinical RCC models to inhibit metabolic pathways resulting in enhanced anti-tumor activity. The CX-839-001 study includes cohorts evaluating the safety, efficacy and recommended Phase 2 dose (RP2D) of CB-839 in combination with E (CBE) or Cabo (CB-Cabo) in pts with mRCC. Here we report results from the CBE and CB-Cabo cohorts. Methods: Eligibility criteria included mRCC with cc or pap histology, ECOG 0-1, RECIST measurable disease and, for cc pts, treatment with at least 1 prior anti-VEGF therapy. Pts received escalating doses of CB-839 (PO BID) in a 3+3 design, either 400-800 mg with E (10 mg PO QD) or 600-800 mg with Cabo (60 mg PO QD). Tumor response (RECIST 1.1) was assessed every 8 wks. Results: 27 pts (22 cc, 3 pap, 2 other) were enrolled in CB-E escalation (n = 17) and expansion (n = 10) cohorts (7 at 400 mg, 13 at 600 mg, 7 at 800 mg) and 11 pts (9 cc, 2 pap) in CB-Cabo escalation cohorts (6 at 600 mg, 5 at 800 mg). Median prior lines of therapy was 2 for CBE (including 64% of cc pts with ≥2 prior anti-VEGF therapies) and 3 for CB-Cabo (range 0-6). A maximum tolerated dose was not reached; 800 mg was selected as the RP2D for CB-839. The most common treatment-related Gr≥3 AEs were fatigue (11%), anemia, hyperglycemia, and neutropenia (7% each) for CBE (N = 27) and diarrhea (14%) and platelet count decreased (14% including 1 DLT at 600 mg) for CB-Cabo (N = 7). Of 24 evaluable CBE pts there was 1 PR and 21 SD for a disease control rate (DCR = CR + PR + SD) of 92% with a median PFS of 7.1 mo (95% CI 4 - 11). For 9 evaluable CB-Cabo pts the ORR and DCR were 44% (4 PR) and 100%, respectively. Conclusions: The tumor metabolism inhibitor CB-839 combines with full dose of RCC targeted therapies, E and Cabo, with good tolerability and encouraging clinical activity in heavily-pretreated mRCC pts. CB-Cabo ORR and DCR of 44% and 100% are promising, and CBE DCR of 92% and PFS of 7.1 mo compare favorably to historical E monotherapy. Randomized Phase 2 studies have been initiated (CBE) or are planned (CB-Cabo). Clinical trial information: NCT02071862.
Sixteen-year percutaneous renal mass ablation trends: Results from the Ablation of Renal Masses Outcomes Registry (ARMOR).
Authors: Maxwell Aaron Wilhelm Palmer , Cornelis Francois H. , Baird Grayson L. , Jihad Marwah , Patel Dharam , Hurtado Elizabeth , Durack Jeremy C.
Published: February 2018

620

Background: Existing data suggest that percutaneous renal mass ablation offers favorable rates of disease control with lower cost and fewer complications relative to surgical interventions. Despite increasing utilization, little is known about changes in practice patterns and patient selection over time as new technologies have emerged and indications for renal ablation have been refined. Methods: Institutional review board approval was granted with a waiver of informed consent to review data from the multinational Ablation of Renal Masses Outcomes Registry (ARMOR), which is composed of adult ablation patients with biopsied renal masses. Patient demographics, ablation modality, timing of renal biopsy, malignancy rate, method of anesthesia, and type of imaging guidance from 2001-2016 were reviewed. Analyses were conducted using generalized mixed modeling assuming normal or binary distribution with sandwich estimation, where observations were nested within participating institutions. Variables were modeled over time using SAS/GLIMMIX with significance set at α = 0.05. Results: Data from 768 patients at eleven institutions were available for review. Average patient age was 67.7±11.7 years (male:female, 1.9:1), which remained unchanged throughout the study period. Radiofrequency ablation (RFA) was the most commonly utilized modality from 2001-2007 but decreased thereafter, with cryoablation favored from 2008-2012. By 2016, RFA, microwave (MWA), and cryoablation were all used with relative equipoise, though a significant trend toward increased MWA utilization was found beginning in 2010 (OR: 1.28; p = 0.004). A significant increase in the frequency of same-day biopsy was observed relative to pre-ablation biopsy (OR: 1.16; p = 0.003) alongside a trend toward increasing rates of benign histology (p = 0.08). Use of CT guidance and general anesthesia increased by 4% and 5%, respectively. Conclusions: ARMOR data illustrate fluctuating practice patterns, with increasing use of microwave ablation technology. Growing utilization of concurrent renal mass biopsy and ablation may be contributing to the observed trend toward increased rates of ablation for benign tumors.
Racial diversity among histology of renal cell carcinoma at an urban medical center.
Authors: Wong Kevin , Shusterman Michael , Goel Sanjay , Negassa Abdissa , Lin Juan , Sharma Janaki Neela , Gartrell Benjamin Adam
Published: February 2018

622

Background: Non-Hispanic Blacks (NHB) with renal cell carcinoma (RCC) are more likely to have papillary RCC (pRCC) than Non-Hispanic Whites (NHW). Little is known about the histology of RCC in Hispanics (H). The Montefiore-Einstein Cancer Center (MECC) serves a diverse population in the Bronx, NY. We sought to investigate histological subtype-specific associations with established RCC risk factors in an ethnically diverse patient population to elucidate prospective relationships between those factors and racial differences in RCC histology. Methods: : The MECC tumor registry was used to identify patients ≥18 years of age treated with partial or radical nephrectomy between January 2000 and December 2015. An institutional software program and individual chart review were used to obtain demographic data (including self-reported race, age, and sex), pathology data, and RCC risk factors (hypertension, diabetes, smoking status, renal function, weight). Data were modeled by multinomial logistic regression to estimate odds ratios (ORs) and 95% CIs. Results: 1010 RCC cases were identified (232 NHW, 383 NHB, 181 H, and 214 other). Histology was 530 clear cell (ccRCC), 257 papillary (pRCC), 100 chromophobe (cRCC), and 123 other. Individuals with pRCC compared to ccRCC were more likely to be NHB than NHW (OR 4.41; 95%CI 2.81,6.93) and more likely to have a higher Fuhrman grade (OR 1.5; 95%CI 1.03,2.07), but were less likely to be female (OR 0.50; 95%CI 0.35,0.72) or H than NHW (OR 0.518, 95%CI 0.271,0.991). Individuals with cRCC compared to ccRCC were also more likely to be NHB than NHW (OR 2.23, 95%CI 1.06,4.67) and to have higher Fuhrman grade (OR 1.82, 95%CI 1.06,3.14). Conclusions: In the MECC dataset, histology of RCC varies by race, confirming earlier reports that non-ccRCC is more common in NHB than NHW. We also report for the first time that pRCC is less common in H than NHW. These associations will be evaluated in additional larger national data sets and may help elucidate reasons for disparate RCC outcomes among various races and ethnicities.
Meaning and significance of low density area (LDA) of renal cell carcinoma (RCC) on computed tomography (CT).
Authors: Shibayama Keita , Kimura Go , Hayashi Tatsuro , Akatsuka Jun , Kimata Ryoji , Horiuchi Kazutaka , Hamasaki Tsutomu , Kondo Yukihiro
Published: February 2018

628

Background: LDA in solid RCC on CT is often interpreted as ‘central necrosis’ in routine clinical practice. However, the details of clinicopathological (CP) features of LDA of RCC on CT and their prognostic significance have not been shown. We retrospectively investigated LDA of RCC to clarify the CP features and prognostic significance. Methods: Of 428 surgically treated patients for RCC between January 2007 and March 2017 at Nippon Medical School hospital, we found 267 cases who had dynamic CT performed before operation. Among them, we selected and analyzed 199 consecutive cases whose tumor had low density area and whose cancer status resulted in no evidence of disease after surgery. We first examined pathological features of LDA. Then, we examined the correlation between pathological features of LDA and CP parameters and prognosis. The differences of values between the three groups were examined with the Kruskal-Wallis test. Recurrence free survival (RFS) was examined with the Kaplan-Meyer curves and the log-rank test. Results: The histology of LDA was divided into two groups: central necrosis (+) or (-: NN). Central necrosis (+) group was further divided into two subgroups: with neutrophilic infiltration (NI+) and without NI (NI-). This means that, in the end, there were three groups according to microscopic findings: group A (NI+, n = 20, 10%), B (NI-, n = 55, 28%), C (NN, n = 124, 62%). The pathological features of the NN group were composed of hyaline degeneration, hydropic degeneration, fibrosis, scars, and so on. The results of the comparison between CP parameters among the three groups were as follows: C-reactive protein, WBC, platelet, and alkaline phosphatase are statistically higher, and hemoglobin, triglyceride, and albumin were statistically lower in group A. CT value was statistically lower in group A and B. Median follow-up was 35months, and 3-year RFS (group A, B, C, p value) was (49.8%, 77.9%, 94.3%, p < 0.0001). Conclusions: In RCC patients only about one-third of LDA on CT was shown to be central necrosis. Necrosis with NI was clinically most closely associated with poor prognosis. Central necrosis may be predictive from lower CT values compared to non-necrotic tissues.
Renal cell carcinoma (RCC) primary tumor shrinkage on vascular endothelial growth factor (VEGF)-targeted therapy (TT): A pooled analysis.
Authors: Bosse Dominick , Lin Xun , Simantov Ronit , Lalani Aly-Khan A. , Derweesh Ithaar , Chang Steven Lee , Choueiri Toni K. , McKay Rana R.
Published: February 2018

629

Background: Cytoreductive nephrectomy (CRN) is an important treatment modality in patients (pts) with advanced RCC, however the role and timing in the context of VEGF-TT remains under investigation. The aim of this study is to determine the efficacy of VEGF-TT to induce primary tumor shrinkage in advanced RCC. Methods: We conducted a pooled analysis of 12 Pfizer-sponsored trials in pts with metastatic RCC treated with sunitinib, sorafenib, axitinib, bevacizumab, termsirolimus or interferon-α. Primary endpoint was the primary tumor objective response rate (ORR) by RECIST in pts who have not undergone prior nephrectomy. Kaplan-Meier method was used to estimate median overall survival (OS) of responders (PR or CR) v. non-responders. Cox regression adjusting for demographics, histology type, prior therapy, metastasis sites, IMDC risk factors and neutrophil-to-lymphocyte ratio was used to compare OS between pts with and without primary tumor ORR. Results: 565 (12%) out of 4736 pts included had their primary tumors intact, of which 360 (8%) received VEGF-TT. In pts with primary tumor intact, 87% had clear-cell RCC and IMDC risk group were 4% favourable, 33% intermediate, 39% poor, 24% unknown. 35% had bone metastasis and 32% had liver metastases. 65% had ECOG performance status ≥1. Compared to pts with prior nephrectomy, primary tumor intact pts were more likely to have bone or liver metastases or to be IMDC poor risk. Primary tumor ORR was 17% (95% exact CI, 14, 20) in all pts, 19% (95% exact CI, 16, 23) in first line treated pts and 23% (95% Exact CI, 19, 28) in pts treated with VEGF-TT (any line). Primary tumor ORR was 20% (95% exact CI, 15, 26) in IMDC intermediate risk pts and 9% (95% exact CI, 5 – 13) in the poor risk. No pts had PD as best response in their primary tumor at the time they stopped systemic therapy. Median OS was 33.98 months in pts with primary tumor ORR and 9.8 months in pts without ORR, adjusted HR 0.42 [95%CI, 0.28, 0.6; p < 0.0001]. Conclusions: VEGF-TT resulted in primary tumor shrinkage in 23% of pts with IMDC intermediate and poor risk advanced RCC who have not undergone CRN. VEGF-TT may potentially facilitate future CRN in select pts. Trials assessing the utility of CRN are underway.
Dose escalation of cabozantinib as a viable option for the treatment of mRCC.
Authors: Boegemann Martin , Krabbe Laura-Maria , Schrader Andres Jan , Semjonow Axel , Klaile Yvonne , Schlack Katrin
Published: February 2018

636

Background: Cabozantinib (C) is a tyrosin kinase inhibitor (TKI) specific for VEGFR, MET and AXL. The phase-3 registration trial METEOR showed that C significantly improved progression-free and overall survival compared to Everolimus in patients with advanced/metastatic renal cell carcinoma (RCC) after failure of at least one VEGFR TKI and C was granted approval. In METEOR, starting dose for C was 60 mg once daily and dose de-escalation to 40 or 20 mg or stopping of C was done based on toxicity. The median dose was 43 mg. The dose had to be reduced in 62% of patients. By packing insert of C the recommended starting dose is 60 mg. We assumed that starting with 40 mg of C and escalating to 60 mg after getting accustomed to side effects may lead to a higher median dose of C. Methods: We report 20 RCC patients all started with C 40 mg and escalated to 60 mg when possible. We calculated the median time on therapy and the median dose and determined the best response. Results: The median time on C was 77 days for the patients having stopped therapy (n = 9). The median dose of C for the whole cohort was 46.0 mg. For the patients still on therapy (n = 11), the median dose was 47.7 mg. Eleven (55%) patients could be escalated to 60 mg (10 (91%) remained on 60 mg) and only 5 (25%) of patients had to be de-escalated to 20 mg. C did not have to be stopped due to toxicity. For best response, 47% reached partial remission, 13% stable and 40% progressive disease. Conclusions: Starting with 40 mg of C and escalating to 60 mg when possible may lead to a higher median dose of C compared to standard vice versa and seems to achieve responses comparable with the METEOR trial. These findings are limited by the small number of patients but warrant a prospective trial directly comparing both the escalating and de-escalating dosing schemes.
Imaging modalities used for follow-up of localized renal cell carcinoma (RCC) and subsequent effect on overall survival after recurrence: RECUR-database analysis.
Authors: Beisland Christian , Dabestani Saeed , Stewart Grant , Bensalah Karim , Guðmundsson Eirikur , Lam Thomas B , Gietzmann William , Zakikhani Paimaun , Marconi Lorenzo , Fernandèz-Pello Sergio , Monagas Serenella , Williams Samuel P , Torbrand Christian , Powles Thomas , van Werkhoven Erik , Meijer Richard Paul , Volpe Alessandro , Staehler Michael D. , Ljungberg Borje , Bex Axel
Published: February 2018

637

Background: Cross-sectional imaging (CSI) has emerged as preferred imaging modality for staging and follow-up (FU). Moreover, the 2017 EAU RCC guidelines discourage the use of Chest X-Ray (CXR). In an international database (RECUR) data were collected to compare imaging modalities in contemporary FU, and to explore if more frequent use of CSI translates into improved overall survival (OS) after recurrence. Methods: Consecutive non-metastatic RCC patients treated with curative intent at 12 institutes across 8 European countries between 2006 and 2011, with at least 4 years of FU were included. Leibovich or UICC risk group (RG) (low, intermediate, high), recurrence characteristics, type of FU imaging (CSI (CT or MRI) vs. Conventional (CXR or Ultrasound)) and survival data were recorded. Isolated local, solitary and oligometastatic recurrences were considered potentially curable (PC) while all others were considered probably incurable (PI). Patients were analysed according to type of imaging that resulted in detection of recurrence (CSI vs. conventional) and if > or < 50% of all FU imaging were CSI based. Landmark analysis of OS after recurrence was performed for CSI and conventional imaging. Results: In 1612 patients, 336 (21%) had a recurrence. Of these, 122 were PC and 213 PI. Of the 17333 FU imaging procedures performed, 7953 were CT (46%), 6540 (38%) were CXR, 183 (1%) were MRI and 2651 (15%) were Ultrasound (US) investigations. The overall CT thorax/CXR- ratio decreased significantly across the risk groups, being 1.0, 0.46 and 0.35 in the high, intermediate and low RG, respectively (p < 0.001). Moreover, between the high RG and the other RG`s the overall CT Abd/US-ratio also decreased (3.2, 1.7 and 1.7, respectively)(p < 0.001). There was no significant difference in OS between patients with PC or PI recurrences based on type of imaging with which the recurrence was detected, nor on the ratio of CSI ( > / < 50%) during FU. Conclusions: More than 50% of FU imaging was conventional, with CSI more often used in high risk groups. The present study suggests that the type of imaging (conventional vs. CSI) for detection of recurrence does not affect subsequent OS.