bluuebunny/crossref_metadata_2025 huggingface dataset:
Adjuvant radiotherapy use after radical cystectomy in muscle-invasive bladder cancer: A survey of U.S. radiation oncologists.
Authors: Solanki Abhishek Ashok , Martin Brendan , Korpics Mark , Small Christina , Harkenrider Matthew M. , Mitin Timur
Published: March 2017

369

Background: Historic trials suggested significant toxicity with adjuvant radiotherapy (ART) after radical cystectomy for muscle-invasive bladder cancer (MIBC). However, recent trials have found improved locoregional control and the 2016 NCCN guidelines recommend ART consideration for select patients at high risk of local recurrence. ART practice patterns among U.S. radiation oncologists (ROs) are unknown, and we performed a survey to explore current trends. Methods: We conducted a survey of U.S. ROs regarding the management of patients with cT2-3N0M0 transitional cell MIBC. Responses were reported using descriptive statistics. Chi-square and univariate logistic regression (UVA) of clinical and demographic covariates were conducted, followed by multivariable logistic regression analyses (MVA) to identify factors predicting for ART use. Results: 277 ROs completed our survey. Nearly half (46%) use ART for MIBC. In ART-users, indications for ART include gross residual disease (93%), positive margins (92%), pathologic nodal involvement (64%), pT3 or T4 disease (46%), lymphovascular invasion (16%), and high-grade disease (13%). On UVA, ART use was associated with the number of years in practice (p=.043), pre-cystectomy RO consultation (p=0.004), primarily treating MIBC patients fit for cystectomy (p=0.009), and intensity-modulated radiotherapy (IMRT) use (p=0.009). On MVA, routine pre-cystectomy RO consultation (odds ratio [OR] 1.91, 95% confidence interval [CI]: 1.04-3.51; p=.037) and IMRT use (OR 2.77, 95% CI: 1.48-5.22; p=.002) remained associated with ART use. Conclusions: ART use is controversial in bladder cancer, yet is unexpectedly commonly used among U.S. radiation oncologists treating patients with MIBC after radical cystectomy. NRG GU001 is a randomized trial currently accruing patients with high-risk pathologic findings for observation or ART after cystectomy, and will hopefully clarify the role of ART and help identify patients benefiting from this adjuvant therapy. Whenever possible, patients should be enrolled in this study.
Overall survival advantage with radical prostatectomy for prostate cancer.
Authors: Kosarek Christopher David , Williams Stephen Bentley , Huo Jinhai , Chamie Karim , Smaldone Marc C. , Fang Justin Edwin , Ghaffary Cameron , Kerr Preston , Ynalvez Leslie , Kim Simon P. , Giordano Sharon Hermes , Chapin Brian F.
Published: March 2017

37

Background: To compare overall survival of patients who underwent radical prostatectomy or radiotherapy versus non-cancer controls in order to discern if there is a survival advantage according to prostate cancer treatment. Methods: A matched cohort study was performedusingthe Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. We identified 34,473 patients age 66 to 75 years without significant comorbidity from who were diagnosed with localized prostate cancer treated with surgery or radiotherapy between 2004 and 2011. These patients were matched to a non-cancer control cohort. We compared the rates of all-cause mortality that occurred within the study period. We used Cox Proportional Hazards Regression analysis to identify determinants associated with overall survival. Results: Of the total 34,473 patients who were included in the analysis, 21,740 (63%) received radiation therapy and 12,733 (37%) received surgery. When compared to the non-cancer control, there was no significant difference between the prostate cancer cohort and the non-cancer control group with exception of race/ethnicity (p < 0.001). There was improved survival in patients treated with surgery (hazard ratio [HR], 0.35; 95% CI, 0.32-0.38) as well as with radiotherapy (HR, 0.72; 95% CI, 0.68-0.75) when compared to non-cancer controls. There was significantly improved overall survival among both treatment groups with most benefit observed among patients who underwent surgery ( log rank p < 0.001). Conclusions: Using population based data, treatment with either surgery or radiotherapy demonstrated improved overall survival when compared to a cohort of matched non-cancer controls. Treatment with surgery resulted in longer overall survival compared to those receiving radiation therapy. These results suggest inherent selection-bias due to unmeasured confounding variables when using cancer registry data.
Systemic therapy and overall survival trends in patients with non-urothelial histologic variants of muscle invasive bladder cancer undergoing radical cystectomy.
Authors: Joshi Shreyas , Handorf Elizabeth , Correa Andres , Kutikov Alexander , Ristau Benjamin T. , Haifler Miki , Viterbo Rosalia , Greenberg Richard E. , Chen David , Uzzo Robert G. , Geynisman Daniel M. , Smaldone Marc C.
Published: March 2017

376

Background: Histological variants of urothelial carcinoma (UC) of the bladder have a poorer prognosis than histologically pure UC, and the role of neoadjuvant chemotherapy (NAC) in this group is unclear. Our objective was to evaluate NAC practice patterns and survival outcomes in patients with histologic variants undergoing radical cystectomy (RC). Methods: Patients with cT2-4N0-3M0 muscle invasive bladder cancer (MIBC) who underwent RC from 2003-2012 were selected from the National Cancer Database (NCDB). Patients were categorized by histology code as pure UC or histologic variants. Adjusting for patient and clinical characteristics, generalized estimating equations were used to test the association between histology and receipt of NAC. The association between receipt of NAC and overall survival (OS) was evaluated using Kaplan Meier curves and Cox regression models. Results: In 19,976 patients meeting inclusion criteria, receipt of NAC in histologic variants was less (11-14%) than in pure UC (22%), with the exception of micropapillary disease (23%) (Table). Median OS was lower in variant histologies than for pure UC (8.4 – 30.2 vs. 37.6 months). Receipt of NAC was associated with improved survival compared to RC or RC+adjuvant chemotherapy in patients with pure UC (HR 0.91, p=0.0016). There was no evidence of a survival benefit for NAC in the variant histologies, or that treatment effects differed by histology (P-val for interaction=0.84). Conclusions: In the NCDB, a substantial proportion of patients (13%) with histologic variants of MIBC undergoing RC receive NAC in the absence of a proven survival benefit. Clinical trials inclusive of patients with variant histologies are necessary to elucidate the role of NAC prior to RC. [Table: see text]
Clinical and translational investigation of pan-HDAC inhibition in advanced urothelial carcinoma (UC).
Authors: Gupta Sumati , Albertson Daniel Joseph , Parnell Timothy , Dalley Brian , O Shea John , Weston Alexis , Butterfield Andrew , Pappas Lisa M. , Schiffman Joshua David , Sharma Sunil , Agarwal Neeraj
Published: March 2017

379

Background: Pan-HDAC inhibitors were studied in two separate phase I pharmacokinetic solid tumor trials at Huntsman Cancer Institute. The objective of this study was to investigate the clinical efficacy of HDAC inhibition in those study subjects with UC and correlate response to molecular subtype of tumor with translational studies to validate clinical benefit. Methods: Patients with UC treated with a pan-HDAC inhibitor in two Phase I trials were included. RECIST 1.1 was used to categorize responses. Expression profiling and TCGA clustering were performed using archived tissue (obtainable for seven of the ten subjects). To elucidate the mechanisms of clinical benefit bladder cancer cell lines with varied mutational profiles and differential sensitivity to cisplatin were tested for sensitivity to panobinostat with characterization of phenotypic changes upon treatment. Results: Ten subjects with advanced UC received either belinostat or panobinostat. The best overall responses in the pooled data were: 1 complete response (CR), 1 partial response (PR), 6 stable disease (SD), 2 progressive disease (PD). The patient with CR had failed two prior lines of chemotherapy (including cisplatin), had a Cluster IV tumor and remains in CR for 3.5 years now. All tumors with SD belong to Cluster I. For those with SD, the progression free survival ranged from 6 to 7.5 months on treatment. One tumor with PR and one tumor with PD had characteristics partly consistent with Cluster III. Validating the broad spectrum of clinical activity of pan-HDAC inhibition, potent cytotoxicity with panobinostat was noted in bladder cancer cell lines with varied chromatin remodeling mutations. Panobinostat causes inhibition of colony formation, cell cycle arrest and proinflammatory cytokine release in these cells. Cisplatin-resistant HT1197 cells (with ARID1A mutation) are tenfold more sensitive. Conclusions: Pan-HDAC inhibition may be an effective treatment option in both luminal and basal subtypes of UC and in platinum-resistant setting. Translational studies suggest options for rational therapeutic combinations to enhance efficacy. HDAC inhibition may be particularly effective in UC with mutations affecting the SWI/SNF complex.
Intratumoral heterogeneity of ERBB2/HER2 expression in micropapillary urothelial carcinoma.
Authors: Isharwal Sumit , Huang Hongying , Nanjangud Gouri , Audenet Francois , Chen Yingbei , Gopalan Anuradha , Fine Samson , Tickoo Satish , Iyer Gopa , Rosenberg Jonathan E. , Bajorin Dean F. , Herr Harry W. , Donat S. Machele , Dalbagni Guido , Bochner Bernard H. , Solit David B. , Reuter Victor E. , Al-Ahmadie Hikmat
Published: March 2017

383

Background: Micropapillary urothelial carcinoma (MPUC) is a rare but an aggressive variant of urothelial carcinoma. Histologically, most of these tumors are associated with variable amounts of “not otherwise specified (NOS)” urothelial carcinoma. MPUC has been shown to be associated with ERBB2/HER2 amplification and protein overexpression. However, the status and distribution of these findings within the different components of tumors containing both MP and NOS urothelial carcinoma have not been addressed. Methods: We identified 44 cases of MPUC that had tissue available for FISH and IHC at our institute, of which an NOS component sufficient for both FISH and IHC was identified in 37 cases. We followed the updated ASCO/CAP Guidelines for breast cancer and as such amplification was defined by a HER2/CEP17 ratio of ≥ 2.0 or > 6 copies of the gene and HER2 overexpression was considered with IHC scores of 2+ and 3+. Results: In urothelial tumors with both MP and NOS components (n = 37), ERBB2 amplification in MP and NOS components was present in 25 and 16 cases respectively. ERBB2 amplification was significantly higher in the MP component compared to NOS component within the same tumor (67.57% vs. 43.24%, p = 0.049). HER2 overexpression in MP and NOS components was present in 25 and 13 cases respectively. HER2 overexpression was significantly higher in the MP component compared to NOS component within the same tumor (67.56% vs. 35.13%, p = 0.012). In addition, ERBB2 amplification strongly correlated with HER2 overexpression in both MP (rho = 0.65, p < 0.001) and NOS (rho = 0.74, p < 0.001) components. In this cohort (n = 44), tumor stage and lymph node status were significant predictors for overall survival (p = 0.01, < 0.001 respectively). However, ERBB2 amplification and HER2 overexpression in MP component were not associated with patients’ survival outcome (p = 1.00, 0.75 respectively). Conclusions: In MPUC, ERBB2 amplification and HER2 overexpression were preferentially but not exclusively identified in MP component compared to NOS component within the same tumor. Our findings provide evidence for intratumoral heterogeneity of ERBB2 amplification and HER2 expression in MPUC.
Effectiveness of platinum-based adjuvant chemotherapy for muscle-invasive bladder cancer: A weighted propensity score analysis.
Authors: Shimizu Fumitaka , Muto Satoru , Taguri Masataka , Ieda Takeshi , Okegawa Takatsugu , Yamaguchi Raizo , Horie Shigeo
Published: March 2017

392

Background: The clinical evidence of adjuvant chemotherapy (AC ) is less robust than neoadjuvant chemotherapy (NAC). However, several surveys suggest that urologists prefer to use AC more frequently than NAC. We evaluate the clinical benefit of adjuvant platinum based chemotherapy following radical cystectomy (RC) for muscle-invasive bladder cancer (BCa) in routine clinical practice. Methods: This observational study was conducted to compare the effectiveness of AC versus observation postcystectomy in patients with clinicallymuscle-invasive BCa. Cancer-specific survival (CSS) and overall survival (OS) between the AC group and RC alone group were compared using Kaplan-Meiyer method and log-rank test. After adjusting for background factors using propensity score weighting, differences in CSS and OS between these two groups were compared. Subgroup analyses by the pathological characteristics were performed. Results: In total, 322 patients were included in this study. Of these, 23% received AC postcystectomy. Clinicopathological characteristics showed that patients in the AC group were pathologically more advanced and were at higher risk than the RC alone group. In the unadjusted population, although it is not significantly, the AC group had lower overall survival (3-years OS; 61.5% vs 73.6%, HR 1.44, p = 0.243, log-rank test, AC vs RC alone). In the weighted propensity score analysis, although it is not significantly, AC group were superior than RC alone groups (OS: HR 0.65, 95%CI 0.39-1.09, p = 0.099, log-rank test, AC vs RC alone). Subgroup analyses showed that AC significantly reduced the hazard ratio of OS and CSS in ≥ pT3, pN+, ly+, and v+ subgroups. Conclusions: The weighted propensity score analyses showed that platinum-based AC might be associated with increased CSS and OS in patients with high-risk invasive BCa.
ATM/RB1 mutations to predict shorter overall survival (OS) in bladder cancer.
Authors: Yin Ming , Grivas Petros , Ali Siraj Mahamed , Hsu Joann , Vasekar Monali K. , Emamekhoo Hamid , Pal Sumanta K. , Li Sierra Min , Drabick Joseph J. , Joshi Monika
Published: March 2017

393

Background: DNA repair defect plays an important role in tumorigenesis, progression and treatment outcomes of urothelial cancer. Somatic mutations of ATM/RB1 genes are frequently found in urothelial cancer and have been associated with a better response to cisplatin-based neoadjuvant chemotherapy. However, their prognostic value overall in urothelial cancer have not been determined. Methods: Exome sequencing data of 130 urothelial bladder cancer patients (pts) from The Cancer Genome Atlas (TCGA) dataset were analyzed as a discovery cohort to determine the prognostic value of ATM and RB1 mutations. Results from discovery dataset were further validated by an independent cohort of 79 advanced urothelial cancer pts who received comprehensive genomic sequencing for urothelial cancer with FoundationOne. OS was measured from time of initial diagnosis and Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% confidence interval (CI). Results: In the discovery dataset, somatic mutations of ATM/RB1 genes were present in 24% of pts and were associated with significantly shorter OS [all stages: adjusted HR = 2.67, 95% CI, 1.45–4.92, P = 0.002; stage II-III only: adjHR = 2.76, 95% CI, 1.23–6.20, P = 0.014]. There was high mutation load in pts carrying ATM/RB1 mutations (median mutation count: 196 versus 160, P = 0.09). In the validation (stage IV) dataset, ATM/RB1 mutations were present in 31.7% of pts and tended to associate with shorter OS (adjHR = 1.97, 95% CI, 0.89–4.40, P = 0.094) and higher mutation load (median mutation load: 8.1 versus 7.2 per Mb, P = 0.136), although statistical significance was not reached. Conclusions: These results suggest that ATM/RB1 mutations may be considered as a poor prognostic biomarker in unselected urothelial cancer pts and may correlate with higher mutational load. Further studies are required to determine patient characteristics that can further stratify prognosis based on ATM/RB1 mutation status, and evaluate the potential predictive role of ATM/RB1 mutation status in response to immunotherapy.
Treatment patterns and outcomes in metastatic bladder cancer in community oncology settings.
Authors: Fisher Maxine , Shenolikar Rahul , Miller Paul J. E. , Walker Mark Stephen , Fenton Moon Jung ,   Authors
Published: March 2017

396

Background: Current real-world data on treatment patterns in metastatic bladder cancer in the community setting are limited. This study describes patient characteristics, treatment patterns, and efficacy outcomes for these patients in the community setting. Methods: Medical records data from adults diagnosed with stage IV or metastatic bladder cancer between 1/1/2008 and 6/1/2015 were retrospectively collected from a network of 10 US community oncology practices. Patient characteristics, treatment patterns, and efficacy outcomes were assessed. Comparisons across groups were conducted using standard analyses. Progression-free survival and overall survival (OS) were assessed using Kaplan-Meier analysis. Results: Of 508 patients, 75% were male, 79% white, 15% African American, and 71.5% were age ≥65 years (median age, 71 years; range 35-92 years). Overall, 76.4% were current or past tobacco users. The most prevalent comorbidities were diabetes (23.4%), renal disease (16.5%), and chronic obstructive pulmonary disease (COPD; 12.4%). Patients age ≥65 years vs <65 years had higher rates of renal disease (19.6% vs 9.0%; P=0.004), COPD (14.6% vs 6.9%; P=0.017) and congestive heart failure (CHF; 6.3% vs 2.1%; P=0.049), respectively. First-line platinum-based therapy was given to 56.3% of the patients, with the most common regimen being gem + carbo (23.6%) followed by gem + cis (17.0%). Overall, median OS was 9.4 months from diagnosis, 11.0 months from start of line-1, and 5.3 months from start of line-2. Cox regression analysis of OS from diagnosis showed that males (hazard ratio [HR]=1.26; P=0.046) and patients with impaired performance (HR=2.137; P<0.001) were at greater risk of death. Conclusions: Although platinum-based chemotherapy is currently the preferred treatment for metastatic bladder cancer in the community setting, there is a large unmet need in this population, particularly among the elderly. Gender and performance status were associated with efficacy outcomes.
Outcomes and predictors of survival in testicular sarcomas.
Authors: Alsidawi Samer , Westin Gustavo Figueiredo Marcondes , Okuno Scott H.
Published: March 2017

404

Background: Testicular sarcomas represent less than 1% of all testicular tumors in adults. Because of their rarity, little is known about the features and outcomes of these tumors. We present an analysis of the prognosis and survival predictors in patients with testicular sarcomas from the Surveillance, Epidemiology, and End Results Program (SEER). Methods: Using the SEER registry, we identified adults with testicular sarcomas between 1980 and 2013. Cases were identified using a combination of ICD-O-3 site and histology codes. The JMP and SEER*STAT 8.3.2 were used for statistical analysis. Overall survival (OS) was analyzed using the Kaplan-Meier method. The prognostic effect of variables was studied using Cox proportional hazards models. Results: We identified 264 patients with testicular sarcomas with a median follow-up time of 9.2 years. The median age at diagnosis was 55 years (range 15-94) and the median tumor size was 6.6 cm (range 0.7-45). 20% of patients with documented staging presented with de novo metastatic disease. Rhabdomyosarcomas were the most common histology (37%). The median OS was 129 months (95%; CI 85-180). OS rates at 1 year and 5 years were 85% and 62% respectively. 53% of deaths were related to cancer. 1-year OS rates for localized, locally advanced and metastatic disease were 91%, 93% and 53% (P<0.0001). Variables that were significant for survival in univariate analysis included age, histology, stage, and surgical resection. Factors that negatively affected survival in multivariate analysis were age >55 years (HR 2; 95% CI, 1.1-3.7), advanced stage (HR 4.8; 95% CI, 2.7-8.4) and surgical unresectability (HR 3.7; 95% CI, 1.1-9.3). Patients with rhabdomyosarcoma had favorable outcomes compared to other histologies (59% vs 17% alive at 10 years, P=0.01). Conclusions: Testicular sarcomas are rare entities with overall good prognosis after surgical resection. Patients presenting with distant metastases, however, have worse outcomes with only about 50% of the patients alive at 1 year. Rhabdomyosarcomas are the most common histology encountered and have relatively better survival. Younger age, earlier stage and surgical resection are factors associated with significantly better outcomes.
Incidence of secondary malignancies (SM) in patients (pts) with germ cell tumors (GCT) who received high-dose chemotherapy (HDCT): A retrospective study from the European Society for Blood and Marrow Transplantation (EBMT) database.
Authors: Necchi Andrea , Rosti Giovanni , Badoglio Manuela , Giannatempo Patrizia , Secondino Simona , Lanza Francesco , Pedrazzoli Paolo ,   EBMT Solid Tumors Working Party
Published: March 2017

409

Background: Little is still known about the incidence of SM in young adult pts with GCT after HDCT, owing to the rarity of the disease, and the need for long term follow-up (FUP) data registries. In Europe, the EBMT systematically collect relevant data and may provide a suitable platform for retrospective analyses. Methods: Criteria for patient selection included diagnosis of GCT, adult male gender, ≥ 2yr of FUP after the administration of HDCT. Summary statistics were used to describe pt characteristics and outcomes. χ2 tests were used to compare groups according to the length of FUP. Kaplan-Meier estimates were used to estimate overall survival (OS) since the diagnosis of SM. Log-rank test was used to compare OS in pt subgroups. Univariable Cox regression analyses examined clinical factors potentially associated with OS following SM diagnosis. Results: From 1981 to 2014, 9,153 autografts, accounting for 5,100 pts, have been registered. Of them, 1,855 had ≥ 2yr of FUP. Among the latter, a total of 56 cases of SM were identified (3.0%). 28 (50%) had solid SM, 22 (39.3%) hematologic SM (5 had uncoded SM). Median age at first HDCT was 34 years (IQR: 30-42), median age at development of SM was 42 (37-51). 26 pts (46.4%) received single HDCT cycle, 22 (39.3%) multiple HDCT cycles (8 unknown). 31 pts had ≥ 5 yr FUP, 25 pts 2-5 yr FUP. Solid SM were developed more frequently in those with longer FUP ( ≥ 5 yrs) compared to hematologic SM (p = 0.008). Median follow-up (FUP) was 76.9 months. Univariably, the type of SM (solid vs. hematologic) was significantly associated with OS. Hematologic vs solid SM: HR: 3.49 (95%CI: 2.09-10.47, p < 0.001). Median OS of pts who developed solid SM was 32.8 months compared to 7 months of those with hematologic SM. The retrospective nature of the data is the major limitation. Conclusions: The incidence of SM in GCT pts who have received HDCT is a concern. During the FUP, there seems to be a non-overlapping risk of developing solid or hematologic SM, with a significantly different prognostic impact. These data may be important to improve patient counselling and the planning of post-HDCT FUP.
Administration of high-dose chemotherapy (HDCT) with stem-cell support in patients (pts) with advanced germ cell tumors (GCT) 40 years of age or older: A retrospective study from the European Society for Blood and Marrow Transplantation (EBMT) database.
Authors: Necchi Andrea , Rosti Giovanni , Badoglio Manuela , Giannatempo Patrizia , Raggi Daniele , Secondino Simona , Lanza Francesco , Pedrazzoli Paolo ,   EBMT Solid Tumors Working Party
Published: March 2017

415

Background: The administration of HDCT in GCT pts ≥ 40 years may raise concerns, owing to the limited data on safety outcomes. Yet HDCT strategy may be the optimal one to achieve a cure in many cases. Consequently, understanding more on the outcomes of these pts and on safety of HDCT delivery has relevant clinical impact. Methods: Criteria for patient selection consisted of: GCT diagnosis, male gender, age ≥ 40 at the time of first HDCT course. Summary statistics were used to describe patient characteristics and outcomes. Probabilities for overall survival (OS) and transplant-related mortality (TRM) were calculated using the Kaplan-Meier method. TRM was defined as mortality from any cause other than disease progression within 100 days of HDCT. Results: From 11/1981 to 12/2015, 1,179 pts aged ≥ 40 have been registered, from 236 centers, in the EBMT database after having received single (n = 578) or multiple (n = 601) HDCT courses. Age distribution was: 917 pts 40-49, 236 pts 50-59, 26 pts 60-71. 56 had extragonadal GCT. Bone marrow was used as stem cell source in 85 pts (7.2%). Median follow-up was 38.6 months. Overall 74 TR deaths were found. Significant decrease of TRM was observed during the decades: 1981-1990 (8.3%), 1991-2000 (6.8%), 2001-2015 (4,1%, p = 0.024). Focusing on 2001-2015 period, no differences were found according to age: 40-49y (n = 673): 4.7%, 50-59y (n = 174): 1.8%, 60-71y (n = 23): 4,3% (p = 0.419). TRM for HD-carboplatin-etoposide regimen only (all pts > 1990) was as follows: 40-49y (n = 289): 2.9%, 50-71y (n = 90): 1.1% (p = 0.713). 2-y OS was consistent across all age subgroups. Causes of death were: infection/sepsis (46/74, 62.2%), organ failure (11/74, 14.9%), and cardiac toxicity (8/10.8%), other (9 pts). The retrospective nature of the data is a major limitation. Conclusions: The administration of HD-carboplatin-etoposide in GCT pts ≥ 40 and ≥ 50 years is feasible and is supported by adequate safety data. Collecting additional information on non-severe long-term sequelae is needed. These results may add important information to improve patient counselling.
Nationwide disparities in testicular cancer care delivery: Racial, ethnic, and economic markers of patient vulnerability.
Authors: Macleod Liam Connor , Cannon Shannon , Ko Oliver , Wright Jonathan L. , Schade George , Lin Daniel W. , Gore John L. , Dash Atreya
Published: March 2017

421

Background: Testis cancer is often curable, yet early presentation is a key determinant of survival and treatment morbidity. Testis cancer affects the young, who have less consistent primary care access. This may impede timely mobilization of complex healthcare resources needed for cancer care. We analyze the National Cancer Database (NCDB) for disparity in disease-specific outcomes. Methods: The NCDB identified adult males with testicular tumors (2004-2013). Four outcomes were selected as markers of care delays: higher stage presentation (defined as stage III+), large primary lesion at diagnosis, time to orchiectomy and overall mortality. Key exposures included race/ethnicity, socioeconomic factors and insurance status. Outcomes were assessed with multivariable hazards regression (survival) or logistic regression (others). Results: 31,964 men were eligible. Seventeen percent had higher stage presentation, 29% had a large primary, and 9.9% had delayed orchiectomy and 4.8% died during follow up. All outcomes were associated with multiple markers of patient vulnerability at the p < 0.001 level. The most consistent and greatest magnitude association was insurance status (e.g. for mortality Medicaid HR 1.9, 95% CI 1.6-2.3, uninsured HR 1.7, 95% CI 1.5-2.1, for large primary Medicaid OR 1.8, 95% CI 1.7-2.0, uninsured OR 2.1, 95% CI 2.0-2.3 [referent private payer]). In addition to markers of vulnerability, center case volume and travel burden were also associated with poor outcomes (p < 0.001). Conclusions: We find association between severity of disease and markers of patient vulnerability. Insurance had the greatest magnitude and most consistent association with poor outcomes and is therefore a priority for quality improvement. As access to primary care is expanded for the testis cancer population with the Affordable Care Act, it will be important to assess whether gains in coverage translate to improvements in cancer outcomes.
Impact of modern treatment strategies on second cancer incidence for patients with early stage seminoma: A population-based study in British Columbia.
Authors: Bahl Gaurav , Pathak Rima Sanjay , Ko Jenny J. , Sia Michael , Bowering Gale , Kollmannsberger Christian K. , Tyldesley Scott
Published: March 2017

423

Background: The purpose of this study is to examine the incidence of Second Cancers (SC) in patients with Stage I or II Seminoma treated in British Columbia (BC), and compare rates between patients managed with Radiation Therapy, Chemotherapy, or Active Surveillance. Methods: Consecutive patients with Stage I or II Seminoma (n = 1549, 21167 person years) diagnosed in British Columbia between 1984 and 2013 were identified from the BC Cancer Registry and included in this study. Patients were managed with Radiation Therapy (RT; n = 663), Chemotherapy (CT; n = 259) or Active Surveillance (AS; n = 624). Data was extracted from the registry and verified by individual patient chart review. Cumulative incidence rates were computed using competing risk analysis. Age and Sex Standardized Incidence Ratios (ASIR) were calculated (compared to the Canadian population). Results: After a median follow-up of 14 years (RT group: 21.5yrs, CT group: 10yrs, AS group: 8yrs), the 15 year Overall Survival was 91.4%. Only 15 patients died from progressive Seminoma, while 46 died from second cancers. A total of 115 patients developed SCs, and the cumulative incidence (CI) of SC, at 15 years, was: 5.9% for patients who received RT, 8.6% for those who had CT, and 4.9% for patients managed with AS. The higher CI for patients treated with CT, versus RT, was not statistically significant (p = 0.08). The ASIR for RT, CT and AS groups were 1.31 (95% Confidence Intervals: 0.92- 1.86), 2.57 (1.07- 6.15; p = 0.03), and 1.38 (0.75- 2.54), respectively. Patients who underwent treatment at ages 30-44yr and 45-59yr had a significantly higher ASIRs of 4.33 (2.1- 8.9; p < 0.001) and 1.8 (1.16- 2.8; p = 0.008). ASIR was not significantly different when stratified by radiation dose, field types, or year of diagnosis. Conclusions: We found no statistically significant difference in the Cumulative Incidence of Second Cancers for patients treated with Radiation Therapy versus Chemotherapy in our patient population. Longer follow-up for the CT group is required to confirm trends evident in our analysis.
A single-arm biomarker-based phase II trial of savolitinib in patients with advanced papillary renal cell cancer (PRCC).
Authors: Choueiri Toni K. , Plimack Elizabeth R. , Arkenau Hendrik-Tobias , Jonasch Eric , Heng Daniel Yick Chin , Powles Thomas , Frigault Melanie M. , Clark Edwin , Handzel Amir , Gardner Humphrey Athelstan , Morgan Shethah , Albiges Laurence , Pal Sumanta K.
Published: March 2017

436

Background: Savolitinib (HMPL504/Volitinib, AZD6094) is a potent, selective MET inhibitor (IC50 of 4nM). MET and its ligand, HGF, are known to play an important role in the molecular events underlying oncogenesis in PRCC, a disease without a clear standard of care and marked by alterations of chromosome 7 (containing both MET and HGF genes) in a majority of patients as well as gene amplification or MET kinase domain mutations (Albiges et al. 2014, Linehan et al., 2015). Methods: This study evaluates savolitinib in PRCC patients dosed at 600mg daily until disease progression. ORR is the primary endpoint. PFS & DoR are secondary endpoints. PRO & HRQoL questionnaires are exploratory endpoints. Eligibility includes naive and previously treated metastatic PRCC, ECOG PS 0 or 1. Archival tumor was used to centrally confirm PRCC pathology post hoc and to determine MET status using Next Generation Sequencing (Foundation Medicine Inc, USA). Results: As of 27 June 2016, 109 pts were dosed. Best response was PR n=8, SD n=43, PD n=48 and 10 patients were not evaluable for response. 44 pts are MET-driven (MET/HGF gene copy number gain or kinase domain mutations), 46 pts were MET-negative, 19 pts are status unknown. MET-driven pts included Papillary Type I & II histologies. All 8 responders were in the MET-driven group, 18% RR in this subset. Median PFS in the MET-driven group was 6.2 months (95% CI: 4.1–7.0) vs. 1.4 months (95% CI: 1.4–2.7) in the MET-negative group (p = 0.002). Overall 10/109 pts had AEs leading to discontinuation. 23/109 pts had ≥ Grade 3 toxicity related to savolitinib. The most common AEs (all grades) includes: nausea (39%), fatigue (27%), edema (18%), and abnormal LFTs (17%). One death from hepatic encephalopathy was considered related to savolitinib. PRO & HRQoL data was not statistically analysed, descriptive data support main efficacy findings. Conclusions: In the largest biomarker-profiled trial dedicated to PRCC, savolitinib was generally well tolerated with anti-tumor activity in MET-driven patients. These findings warrant further clinical investigation of savolitinib in MET-driven PRCC. Clinical trial information: NCT02127710.
Improved imaging-pathology correlation with MR imaging-derived, 3D-printed, patient-specific whole-mount molds of the prostate.
Authors: Costa Daniel N. , Chatzinoff Yonatan , Passoni Niccolo M. , Kapur Payal , Roehrborn Claus G , Xi Yin , Rofsky Neil , Torrealba Jose , Francis Franto , Futch Cecil , Hagens Phyllis , Notgrass Hollis , Otero-Muinelo Susana , Chopra Rajiv , Pedrosa Ivan
Published: March 2017

44

Background: A critical requirement for imaging-pathology correlation is adequate image registration. Since the prostate is deformable, sectioning the gland in a plane similar to imaging is challenging. To improve the in vivo imaging and ex vivo histology image registration, 3D-printed, patient-specific, MRI-derived molds (PSMs) for whole-mount processing have been proposed. This study compared the anatomical registration of preoperative MRI and prostate whole-mounts obtained with PSMs versus conventional whole-mount sectioning (WMS). Methods: Based on an a priori power analysis, 50 men who underwent 3T prostate MRI followed by radical prostatectomy were included. Two blinded and independent readers (R1, R2) outlined the contours of the gland and of the tumor in the MRI using regions of interest (ROIs). These were compared with the ROIs from the whole-mount histology, the reference standard, using PSMs in the study group (n=25) or conventional WMS in the control group (n=25). The spatial overlap across the MRI and histology data sets was calculated using the Dice similarity coefficient (DSC) for the prostate overall and tumor. Results were compared using Wilcoxon rank sum test. Results: The MRI-histopathology anatomical registration for the prostate gland overall and the tumor were significantly superior with the use of PSMs than with the use of WMS for both readers (Table). Conclusions: The use of PSMs for prostate specimen whole-mount sectioning provides significantly superior anatomical registration of in vivo multiparametric MRI and ex vivo prostate whole-mounts than conventional WMS. The use of PSMs should facilitate the exchange of information across imaging and pathology required for research and patient care. [Table: see text]
Safety and preliminary activity of hydroxychloroquine and aldesleukin in metastatic renal cell carcinoma (mRCC): A cytokine working group study.
Authors: Appleman Leonard Joseph , Logan Theodore F. , Normolle Daniel Paul , Ernstoff Marc S. , Parikh Rahul Atul , McDermott David F. , Monk Paul , Olencki Thomas , Friedland David , Maranchie Jodi Kathleen , Lotze Michael T.
Published: March 2017

440

Background: Aldesleukin (recombinant human interleukin-2) has been an FDA-approved treatment for mRCC since 1992, based on a 5-10% rate of durable complete remissions. Autophagy is a protective mechanism that enables cells to survive the metabolic stress of cancer therapy. Hydroxychloroquine (HCQ) inhibits cellular autophagy and has shown synergy with interleukin-2 in animal tumor models. We hypothesized that this combination would be tolerable and active in patients with mRCC. Methods: The Cytokine Working Group initiated a study of high-dose aldesleukin in combination with oral HCQ for patients with mRCC. Subjects receive up to 6 cycles of aldeskleukin, 600,000 International Units per kg, on a standard schedule. HCQ is administered orally starting 2 weeks prior to the first dose of aldesleukin and continuing up to one year. The initial HCQ dose was 600 mg daily, with a planned dose escalation to 1200 mg daily after safety was demonstrated in five subjects. Subjects were monitored for safety and tolerability as well as response per RECIST 1.1. Results: Five subjects were treated at the first dose level of 600 mg daily HCQ plus aldesleukin with no unexpected toxicity. Thirteen subjects were then treated at HCQ 1200 mg daily with aldesleukin. Of these, two experienced hypotension and tachycardia and 1 patient died from pulmonary emboli. The cardiac events were consistent with aldesleukin toxicity, but were observed earlier in the course of treatment than anticipated for aldesleukin alone. HCQ dose was therefore de-escalated to 600 mg daily, and 8 additional subjects have been enrolled with no unexpected toxicity. In 26 of 39 planned subjects, there has been 1 complete response (CR) and 1 partial response (near CR), both in the 600 mg cohort. As of Oct 24, 2016, after a median of 36.6 months of follow-up, seven out of 26 subject have died, with median overall survival not yet obtained (95% C.I. = (29.6 months,unknown)). Conclusions: HCQ in combination with aldesleukin was found to be tolerable at a dose of 600 mg daily, with expected toxicities. Clinical responses have been observed. Clinical trial information: NCT01550367.
The association between age-related macular degeneration (AMD) and renal cell carcinoma (RCC): A nested case-control study.
Authors: Keizman Daniel , Rouvinov Keren , Neumann Avivit , Yang Yu-Xiao , Gottfried Maya , Dresler Hadas , Leibovitch Ilan , Haynes Kevin , Mamtani Ronac , Boursi Shimon Ben
Published: March 2017

443

Background: Overexpression of vascular endothelial growth factor (VEGF) is implicated in the pathogenesis of both RCC and AMD. To date, there are no data on an association between AMD and RCC. In the present nested case control study, we aimed to evaluated the association between age-related macular degeneration and RCC risk. Methods: We conducted a matched case-control study within a population-representative database from the United Kingdom. Study cases were defined as individuals with any diagnostic code of RCC. For every case, four eligible controls were matched on age, sex, practice site, time, and duration of follow-up. Exposure of interest was diagnosis of AMD prior to cancer diagnosis. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for RCC were estimated using conditional logistic regression. Adjustment was performed for confounders associated with both AMD and RCC such as smoking, obesity, hypertension, and diabetes. Furthermore, in a secondary analysis, we evaluated the association between other non-VEGF associated retinopathies and RCC, and between AMD and pancreatic cancer, a malignancy characterized by hypovascularity in contrast to the hypervascularity of RCC. Results: The study population included 1,547 patients with RCC and 6,066 matched controls. Median follow-up time was 6 years (IQR 3-9). AMD diagnosis was associated with a significantly increased RCC risk (OR 1.89, 95% CI 1.09-3.29). In contrast, there was no association between other retinopathies and RCC risk (OR 0.8, 95% CI 0.56-1.15). AMD was associated with a lower risk for pancreatic cancer (OR 0.47, 95% CI 0.35-0.64). Conclusions: Patients with AMD may be at higher risk for RCC. Providers should consider screening for RCC within this population.
A novel strategy for axitinib dosing in the treatment of metastatic renal cell carcinoma.
Authors: Doherty Gary , Lynskey Deirdre , Matakidou Athena , Fife Kate , Eisen Tim
Published: March 2017

464

Background: The AXIS trial established axitinib as an effective second line treatment for patients with metastatic renal cell carcinoma (mRCC). The dosing schedule of axitinib in this trial begins at 5mg twice daily, with escalation of individual doses to 7mg and 10mg after consecutive 2 week intervals if tolerated. We observed significant drug-related toxicity using this dosing strategy, particularly after dose escalations, while clinical responses were often observed at the starting dose. We therefore switched to a pragmatic strategy where dose escalations were made only after disease progression or where a rapid response was deemed clinically pertinent. Methods: We performed a retrospective review of electronic health records and radiology of all patients with mRCC treated with axitinib for greater than 2 weeks at Addenbrooke’s Hospital, Cambridge, UK (a tertiary referral center), over a 40 month period to determine the clinical and radiological effects of dose escalations made according to the above strategy. Results: 42 patients fitting these criteria were identified; of these, 29 had at least one dose escalation event (DEE). A total of 58 DEEs were identified, with a median of 2 per patient, and the objective radiological consequences of 50 of these could be determined. The disease control rate (partial response or stable disease) after the first DEE instituted for disease progression was similar to that after the second DEE (68.8% versus 70%). 56% of all DEEs, and 62.5% of DEEs made as a result of disease progression, resulted in disease control. The median overall survival from the commencement of axitinib for all dose-escalated patients was 19.9 months, and 6.7 months for non-dose-escalated patients. The median survival for dose-escalated patients with a higher than median time on a prior tyrosine kinase inhibitor has not been reached at the time of data cut-off. The mean dose (for all patients) at 90 days after starting axitinib was 5.92 mg. Conclusions: These data suggest that dose escalation of axitinib after disease progression may be an effective dosing strategy for patients with mRCC, and may reduce toxicity through lower drug exposure. Our survival data compares favourably to the AXIS trial in a real practice population.
An exploratory study of radium-223 and vascular endothelial growth factor targeted therapy (VEGF TT) in patients (pts) with metastatic renal cell carcinoma (mRCC) and bone metastases (BM).
Authors: McKay Rana R. , Gray Kathryn P. , Polacek Laura , Pomerantz Mark M , Krajewski Katherine M. , Jacene Heather , Bellmunt Joaquim , Michaelson Dror , Harshman Lauren Christine , Choueiri Toni K.
Published: March 2017

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Background: BM frequently occur in pts with mRCC and are associated with worse survival. The primary aim was to investigate the effect of radium-223 with VEGF TT on bone turnover markers (BTMs) in mRCC pts with BM. Methods: Pts were stratified into cohort 1 (C1) if treatment (tx) naive (n=15) to receive pazopanib 800 mg daily or cohort 2 (C2) if previously treated (n=15) to receive sorafenib (SOR) 400 mg twice BID and could escalate to 600 mg BID at progression. All pts received radium-223 55 kBq/kg every 4 weeks x 6. A safety run-in was performed after 6 pts per cohort completed 2 cycles with criteria to halt enrollment if grade ≥3 tx-related adverse events (TRAEs) were observed in ≥80% of pts. Herein, we report the results of the safety run-in and early safety, biomarker, and imaging data for C2. Results: In the safety run-in, 5/12 (42%) pts experienced TRAEs including anemia, fatigue, liver test elevation, amylase elevation, rash, hand-foot-syndrome, and hypertension, and therefore enrollment continued. In C2, most pts had clear cell mRCC (n=10, 67%) and 47% (n=7) had liver metastases. 60% (n=9) received ≥3 prior txs. At the time of analysis, 8 (53%) pts discontinued tx with both agents for progression and 1 (7%) for toxicity. 5 pts (33%) received 6 doses of radium-223 and 2 (13%) remain on tx. 4 pts (27%) had SOR reductions and 4 (27%) had escalations. 5 pts (33%) had grade 3 TRAEs. Changes in BTM were assessed (Table). 33% of pts (n=5) had stable disease by RECIST, 27% (n=4) by Positron Emission Tomography Response Criteria in Solid Tumors, and 40% by MD Anderson Bone Response Criteria at first response assessment (FRA). Conclusions: Early data suggests that tx with radium-223 and SOR is safe and feasible. Tx resulted in early declines in BTM. Longer follow-up is needed to characterize the safety and effect on BTM. Clinical trial information: NCT02406521. [Table: see text]
Sunitinib versus sorafenib as first-line therapy followed by sorefenib and sunitinib for patients with metastatic renal cell carcinoma (RCC) with clear cell histology: A multicenter randomized trial, CROSS-J-RCC.
Authors: Tomita Yoshihiko , Naito Sei , Sassa Naoto , Takahashi Atsushi , Kondo Tsunenori , Koie Takuya , Obara Wataru , Kobayashi Yasuyuki , Teishima Jun , Takahashi Masayuki , Matsuyama Hideyasu , Ueda Takeshi , Yamaguchi Kenya , Kishida Takeshi , Shiroki Ryoichi , Saika Takashi , Shinohara Nobuo , Oya Mototsugu , Kanayama Hiroomi
Published: March 2017

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Background: SWITCH, a prospective, randomized sequential trial to evaluate SU/SO versus SO/SU, revealed no difference in first-line or total PFS or OS, but no direct comparison was obtained between 1st line sunitinib (SU) and sorafenib (SO) for clear cell (CC) metastatic renal cell carcinoma (mRCC). Methods: Treatment-naïve patients with CC mRCC, ECOG PS 0/1 and MSKCC favorable or intermediate risk were randomized to receive open-label SU/SO or SO/SU at the standard dosage and schedule. The primary endpoint was 1st line PFS, and secondary endpoints were total PFS and OS. The calculated sample size was 59 per group, with α = 0.05, β = 0.10, and a censoring rate of 15%. Results: Of 124 patients enrolled in this study from February 2010 to July 2012 from 39 institutions, 120 could be evaluated (SU/SO, 57 and SO/SU, 63). Baseline patients' characteristics in the SU/SO and SO/SU groups were as follows: favorable risk, 21% and 22%; and presence ofnephrectomy, 88% and 89%, respectively. First-line mPFS was 8.7 and 7.0 months in the SU/SO and SO/SU groups, respectively (HR, 0.67; 95% CI, 0.42–1.08; p= 0.095). There was no statistically significant difference in total (T)-PFS, 27.8 M, and 22.6 m (HR 0.73, CI 0.428-1.246; p=0.247), or OS 38.4 m and 30.9 m (HR 0.934, CI 0.588-1.485; p=0.773). Subgroup analyses showed that T-PFS was NR and 27.8 m (p=0.021) in the favorable risk, and 38.4 m and 16.1 m (p=0.009) in with less than 5 metastatic sites, 6.5 m and 13.6 m (p=0.025) without nephrectomy in the SU/SO and SO/SU groups, respectively. The most common adverse events (AEs) in case of first-line SU or SO (all grade, all cause) were hand–foot syndrome (71% vs. 86%), hypothyroidism (70% vs. 33%), fatigue (57% vs. 40%), hypertension (55% vs. 44%), and diarrhea (23% vs. 38%). AEs were generally lower during second-line therapy. Conclusions: There was no significant difference in first-line PFS, T-PFS, and OS between the two sequential treatments. Although fewer patients received second-line treatment in the SU/SO group, OS in this group was numerically longer than that in the SO/SU group. Clinical trial information: 01481870.