bluuebunny/crossref_metadata_2025 huggingface dataset:
A pharmacodynamic trial of sequential sunitinib (Su) with bevacizumab (Bev) in patients (Pts) with renal cell carcinoma and other advanced solid malignancies.
Authors: Bruce Justine Yang , Hammers Hans , Kolesar Jill , Stein Mark N. , Eickhoff Jens C. , Carmichael Lakeesha , Johnston Susan , Perlman Scott , Jeraj Robert , Liu Glenn
Published: February 2017

434

Background: Su treatment results in a compensatory increase in plasma VEGF levels. Acute withdrawal of Su results in a proliferative withdrawal flare, primarily due to elevated VEGF levels. Higher flare corresponded to shorter PFS. Concurrent Su plus Bev is poorly tolerated with high (37%) incidence of microangiopathic hemolytic anemia (MAHA). Based on biological rationale and to improve the toxicity profile, we evaluated a sequential design administering Bev during the Su treatment break. We planned to evaluate the ability of Bev to suppress the Su withdrawal flare using FLT PET/CT. Methods: Pts with no prior VEGF treatment were enrolled in this multi-institutional study. All pts had target lesions amenable to serial FLT PET/CT imaging. Su was given at 37.5 mg on day 1-28 every 6 weeks with Bev 5 mg/kg on day 29. If safe and tolerable, Su would increase to 50 mg. Once the Su dose was established, FLT PET/CT scans would be obtained at baseline (D1), week 4, and week 6 to evaluate pharmacodynamics of the sequential combination. Su pharmacokinetics and total, free, and bound VEGF levels were obtained on each cycle at D1, pre-Bev (D29), 4 hours post Bev (D29H4) and day 42 (D42). Results: Six pts enrolled in the safety cohort of Su 37.5 mg plus Bev. One pt experienced gr 1 MAHA and after discussion with CTEP, the trial was closed to further accrual. No imaging scans were obtained due to early closure. Data assessing VEGF dynamics appears in the table. Conclusions: Subclinical MAHA was seen despite using sequential Su with low dose Bev and this combination was not feasible for further development. As predicted, VEGF levels increased during Su exposure followed by a rapid decline after Bev. Due to the long half-life of Bev, we expected VEGF ligand suppression through D42, but instead observed a complete rebound in total/free VEGF levels by D42. VEGF ligand production may be increased as a result of Bev, implying a robust host compensatory mechanism to VEGF signaling pathway inhibition. A greater understanding of the compensatory mechanism would aid future sequencing strategies of new agents. Clinical trial information: NCT01243359. [Table: see text]
Dynamic molecular changes with VEGF targeted therapy in metastatic clear cell renal cancer.
Authors: Powles Thomas , Sharpe Kevin , Berney Dan , Kayani Irfan , Doshi Rukma , Stewart Grant Duncan , Reynolds Andrew , Bex Axel , Sarwar Naveed , Chowdhury Simon
Published: February 2017

437

Background: The purpose of this study was to investigate for specific molecular changes associated with VEGF targeted in metastatic clear cell renal cancer (mRCC). This was achieved by taking tissue before and after VEGF TKI therapy. Methods: The study combined the data from 3 similar phase II prospective studies, investigating the role of VEGF therapy (pazopanib or sunitinib) prior to planned nephrectomy in untreated mRCC. A structured treatment break occurred during the planned nephrectomy (4 weeks). Paired tumour samples before and after 12-16 weeks of pazopanib or sunitinib were collected from these studies. Histopathology assessment (Furman grade, Ki-67, vascular density [CD31]), growth factor expression [FGF-2, c-MET, S-6-protein kinase] and immune parameters (CD3, 4, 8, PDL-1, FOXP3) before and after therapy were compared. Sequential functional imaging [FDG-PET] was performed to address the relationship between the primary tumour and metastatic sites. Results: Overall 62 patients had sequential tissue taken from these 3 prospective trials. Adequate quantities of sequential tissue were available from 48 patients. Pathological examination of the matched pairs before and after VEGF TKI showed a significant increase in tumour grade, Ki-67, lymphocyte infiltrate, and necrosis (p>0.05), there was also a significant decrease in CD31 (p<0.05). Significant changes to FGF-2, c-MET and FOXP3 expression was seen in the treated samples (p<0.05). FDG-PET results from 23 patients showed a significant correlation in the response seen in the primary renal tumour and metastatic sites with sunitinib (r=0.46 p<0.001). During the structured treatment break for nephrectomy (4 weeks) 37% of patients had disease progression (RECIST v1.1) underlining the aggressive nature of the disease after VEGF TKI therapy. This was associated with an increased risk of death on multivariate analysis (HR: 3.17; 95% CI, 1.46-6.86, p<0.03). Conclusions: These results suggest VEGF targeted therapy is associated with a more aggressive tumor phenotype. Changes to immune parameters and up regulation of growth factors potentially implicated in resistance to VEGF targeted therapy occurred.
Partial nephrectomy in the setting of metastatic renal cell carcinoma.
Authors: Babaian Kara , Matin Surena F. , Tamboli Pheroze , Tannir Nizar M. , Jonasch Eric , Wood Christopher G. , Karam Jose A.
Published: February 2017

440

Background: Up to one-third of patients with renal cell carcinoma present with metastatic disease (mRCC). Cytoreductive nephrectomy remains the standard of care for appropriately selected patients. However, cytoreductive nephrectomy is not always practical. We sought to identify the indications and outcomes for partial nephrectomy (PN) in our cohort of patients with mRCC, with particular attention to different PN subgroups. Methods: Using our institutional database, 30 patients with mRCC who underwent PN between 1996 and 2011 were identified. Demographic, clinical, and pathologic variables were collected. Non-parametric statistics and log-rank tests were used. Cancer specific survival (CSS) was estimated using Kaplan-Meier method according to presentation, tumor size, and presence of metastatic disease, from the time of PN to last follow-up or death. Results: The median age at PN was 57 years (range 32-84). 8 patients presented with bilateral synchronous renal masses; 17 presented with a metachronous contralateral renal mass; and 5 presented with a unilateral renal mass (including 3 in a solitary kidney). Median follow-up after PN was 32 months (range 1-184). Overall, 23 patients (77%) died of disease at a median of 27 months (range 7-86) after PN. Patients who underwent PN for a metachronous contralateral renal mass had a median CSS of 61 months compared to those with bilateral synchronous or unilateral renal masses (CSS 26.5 months, HR 2.98, p =.012 and CSS 31, HR 2.12, p =.069, respectively). Patients who underwent PN for a renal mass ≤4cm and >4cm had a median CSS of 42 and 26.5 months, respectively (HR 2.49, p =.037). Median CSS for patients with and without metastatic disease at original diagnosis was 27 and 61 months, respectively (HR 2.85, p =.013). In this study, patients who became M0 after metastasectomy did not have improved CSS compared to patients who did not (42 and 32 months, p =0.152). Conclusions: Our findings suggest that the burden of disease at initial diagnosis, timing of presentation of the PN index lesion, and the size of the renal mass at PN play an important role in survival. These factors should be taken into consideration when determining which patients would benefit from PN in the setting of mRCC.
Preoperative C-reactive protein combined with SSIGN score as an independent predictor of cancer-specific survival in patients with clear cell renal cell carcinoma.
Authors: Herrel Lindsey Allison , Tai Caroline Gar-Ling , Westby Ruth , Ogan Ken , Canter Daniel , Pattaras John , Nieh Peter , Master Viraj A.
Published: February 2017

451

Background: Renal cell carcinoma (RCC) demonstrates heterogeneous behavior. Approximately 30% to 40% of patients with clinically localized RCC will later metastasize. Current tools are imperfect for predicting who will have distant spread of disease. C-reactive protein (CRP) levels and the Mayo Clinic SSIGN scores are widely use to predict outcomes of clear cell RCC. We investigated the predictive value of the combined use of pre-operative CRP and SSIGN score for cancer specific survival. Methods: Patients undergoing nephrectomy for clinically localized RCC from 2005 to 2010 were studied. Inclusion criteria required clear cell histology, no nodal or metastatic disease at the time of surgery, two years follow-up time, and a recorded preoperative CRP level. SSIGN score was based on postoperative data and was categorized into scores 0-2, 3-5, and ≥ 6. A cut-point of 20 mg/l was used to classify elevated preoperative CRP. Univariate analysis identified variables associated with cancer specific survival (CSS). Variables significant in univariate analysis at p < 0.05 were entered into a multivariate Cox regression model using forward stepwise regression to identify significant predictors of CSS. Results: Study criteria identified 284 patients. Of these patients, 62% were men and 13% had preoperative CRP values ≥ 20 mg/L. No patients had T4 disease, while 22% had T3, 7% had T2, and 70% had T1 disease. SSIGN scores of 0-2, 3-5, and ≥ 6 were assigned to 57%, 30%, and 13% of patients, respectively. On univariate analysis CRP ≥ 20 mg/L was a statistically significant predictor of CSS (p < 0.0004, HR 7.07, CI 95% 2.42, 20.68). Multivariate Cox Regression found preoperative CRP (p = 0.033, HR 3.65, CI 95% 1.11, 11.97) to be an independent predictor of CSS despite controlling for age at surgery (p < 0.05) and SSIGN score (p < 0.05), which were also independent predictors of CSS. Conclusions: In patients with clear cell RCC, pre-operative CRP levels in combination with SSIGN score provides additional information for predicting CSS.
Body mass index and survival of patients with metastastic renal cell carcinoma: Data from the German prospective RCC registry.
Authors: Mueller Lothar , Goebell Peter J. , Von Verschuer Ulla , Hurtz Hans-Juergen , Franzem Melanie , Vogt Michele , Marschner Norbert
Published: February 2017

454

Background: Being overweight is a known risk factor for developing renal cell carcinoma (RCC). On the other hand, overweight patients may harbor a less aggressive type of disease. A recent meta-analysis was able to demonstrate that a high preoperative BMI was an independent prognostic indicator for better overall survival in patients with RCC. We present data on the prognostic impact of the postoperative BMI, at the start of systemic treatment in patients with advanced or metastatic RCC (mRCC). Methods: The German RCC registry is a prospective, longitudinal, multicenter study conducted by a network of 133 office-based medical oncologists in Germany to document treatment of unselected patients with mRCC. Based on the inclusion criteria for this analyses we identified 475 prospectively documented patients who received 1st-line systemic treatment. Patients were grouped by their BMI and overall survival was estimated by Kaplan-Meier analysis. A multivariate cox proportional hazards model was used to determine the impact of potentially prognostic variables at the start of systemic treatment (sex, age, BMI, comorbidity, Motzer’s score, tumor stage [TNMRG], and number of metastatic sites) on overall survival. Results: The mean age of patients at the start of systemic treatment was 68 years and the median follow-up was 23.8 months. 118 (25%) presented with a BMI < 24, 195 (41%) with a BMI 24 - 28 and 162 (34%) with a BMI > 28. Patient characteristics did not differ between groups, except more patients in the low BMI group had a higher prognostic risk according to Motzer-score (11% vs. 5 % vs. 6 %). Median overall survival was 10.0 month, 16.7 month and 23.4 month in the low, medium and high BMI group, respectively. In a multivariate analysis, BMI (HR 0.94, 95% CI 0.91-0.98, p < .001) and Motzer-Score (HR 1.83, 95% CI 1.59-2.12, p < .001) had a significant impact on overall survival. Conclusions: In addition to Motzer’s prognostic score, the BMI at the start of palliative treatment may be used to discriminate mRCC patients with good and poor prognosis. Patients with a higher BMI tend to live longer than patients with low or normal BMI supporting evidence from previous meta-analyses on preoperative BMI and outcome.
Are there geographic differences in the outcome of patients (pts) with metastatic renal cell carcinoma (mRCC) treated with sunitinib (su)?
Authors: Keizman Daniel , Ish-Shalom Maya , Maimon Natalie , Gottfried Maya , Pili Roberto , Hammers Hans J. , Eisenberger Mario A. , Sinibaldi Victoria J. , Boursi Ben , Weitzen Rony , Hayat Henry , Peer Avivit , Neumann Avivit , Kovel Svetlana , Sella Avishay , Mermershtain Wilmosh , Roubinov Keren , Berger Raanan , Carducci Michael Anthony
Published: February 2017

458

Background: Geographic differences in the outcome of pts have been described in various cancers. The VEGFR inhibitor su is a standard treatment (tx) for mRCC. The effect of geographic differences on the outcome of su tx in mRCC is poorly defined. We aimed to study the effect of geographic differences on outcome of su tx in mRCC. Methods: We performed an international multicenter retrospective study of unselected cohort of 275 mRCC pts, who were treated with su from 2004 to 2012 in 7 centers across the United States and Middle East (ME; Israel). Clinicopathologic and prognostic factors, and tx outcome were compared between United States (n=133) and ME (n=142) pts. Chi-square and Fisher's exact tests were used to compare categorical variables, and two-sample t-test was used to compare continuous endpoints. Progression free survival (PFS) and overall survival (OS) were determined by Cox regression. Results: Median age was 61 (United States) vs. 65 (ME, p = 0.01). The groups were balanced regarding gender, Heng risk, past nephrectomy, RCC histology, presence of ≥ 2 metastatic sites, lung/liver/bone metastasis, use of angiotensin system inhibitors (ASI), prior cytokines/ targeted txt, su induced HTN, and su dose reduction/tx interruption secondary to side effects. The incidence of active smokers (28% vs. 15%, p =0.01), bisphosphonates users (23% vs. 13%, p = 0.03) and pts with pre-tx neutrophil to lymphocyte ratio (NLR) ≤ 3 (63% vs. 49%, p = 0.04) was higher among ME pts. In United States vs. ME pts, objective response was partial response/stable disease 77% (n=102) vs. 79% (n=112), and progressive disease at first imaging evaluation within the first 3 months (mos) 23% (n=31) vs. 21% (n=30) (p = 0.77, OR 1.1). Median PFS was 8 vs. 12 mos (HR=1.8, p < 0.0001), and median OS 21 vs. 22 mos (HR=0.94, p = 0.9) in United States vs ME pts. Factors associated with PFS in multivariate analysis of the entire cohort (n=275) were geographic location (United States vs. ME), Heng risk, RCC histology, su induced HTN, ASI use, pre-tx NLR, and smoking status. Conclusions: Geographic differences in clinicopathologic factors and PFS of pts with mRCC treated with su may exist. This should be further investigated, and if validated, applied in clinical practice and clinical trials.
Difference in adverse-event profiles between mTOR inhibitors, temsirolimus, and everolimus for advanced renal cell carcinoma.
Authors: Nozawa Masahiro , Kikuchi Takashi , Nishimoto Mitsutoshi , Kobayashi Yasuyuki , Uemura Hirotsugu
Published: February 2017

461

Background: Everolimus and temsirolimus have proven their efficacy and are used for patients with metastatic renal cell carcinoma (mRCC). They both are rapamycin derivatives and are categorized as mTOR inhibitors. There have been few reports that examined the difference between these two agents regarding adverse events. Our objective was to investigate the difference in the safety of both agents on the basis of our clinical experience. Methods: We identified patients with mRCC who had been treated with everolimus or temsirolimus at our hospital. Treatment duration, relative dose intensity, laboratory data, and adverse events during treatment with each agent were evaluated. Results: A total of 55 patients were evaluable. 43 of those had been treated with everolimus, 22 with temsirolimus, and 10 with both agents. There was no significant difference in age and gender between the two treatment groups. Median treatment durations of the everolimus and temsirolimus groups were 2.4 months and 1.8 months, respectively. Relative dose intensities of the everolimus and temsirolimus groups were 71.6 % and 75.4 %, respectively. Anemia, hyperglycemia, stomatitis, and interstitial lung disease (ILD) were detected with higher frequency in the everolimus group. In the everolimus group, 31 % of patients developed any grade of ILD including 15 % of grade 3, whereas ILD was reported in only one patient treated with temsirolimus with no grade 3 or higher. Frequencies of adverse events of grade 3 or higher were 49 % in the everolimus group and 26 % in the temsirolimus group. Conclusions: Adverse-event profiles of everolimus and temsirolimus may differ from each other. Respiratory disorders may occur more frequently and severely in patients treated with everolimus than temsirolimus. These findings suggest the difference in the pharmacodynamics, pharmacokinetics, and treatment regimen of these two agents may result in different adverse events even though they target the same molecule.
PSA-detected prostate cancer in the United States: A population-based study of 70,345 men with AJCC stage T1cN0M0 disease.
Authors: Zhang Hong , Travis Lois B. , Messing Edward M. , Hyrien Ollivier , Chen Rui , Milano Michael T. , Brasacchio Ralph Anthony , Chen Yuhchyau
Published: February 2017

50

Background: The U.S. Preventive Services Task Force (USPSTF) recently recommended against prostate-specific antigen (PSA)-based screening for prostate cancer. This recommendation has heightened the debate about risks and benefits of prostate cancer screening, and underscored our limited understanding of PSA-detected prostate cancer. The purpose of this study was to determine the frequency of various risks of prostate cancer based on patient characteristics and PSA levels. Methods: This population-based study used the Surveillance, Epidemiology, and End Results (SEER) program to identify men with AJCC stage T1cN0M0 disease diagnosed between 1/2004 and 12/2008. Multivariate logistic regression was conducted to model the probability of developing low (PSA <10 mg/L and Gleason score ≤6), intermediate (PSA between 10 mg/L to 20 mg/L and/or Gleason score 7), and high risk diseases (PSA ≥20 mg/L, and/or Gleason score ≥8). Results: A total of 70,345 men with PSA-detected T1cN0M0 prostate cancer were evaluated. Among them, 47.6%, 35.9% and16.5% had low, intermediate, or high risk disease, respectively. Odds ratios (OR) of having intermediate or high risk disease in patients ≥75 years old were 4.47 (95% confidence interval (CI) 3.81 to 5.26, p<0.01) and 9.39 (95% CI 7.25 to 12.16, p<0.01), respectively, when compared with patients aged <50. Also, black men had increased ORs for intermediate and high risk disease compared with white men (OR 1.50, 95% CI 1.42 to 1.58, p<0.01 for intermediate risk disease; OR 1.84, 95% CI 1.72 to 19.97, p<0.01 for high risk disease). While men aged >75 accounted for 11.8% of the population at risk, they accounted for 24.3% of intermediate and 26.1% of high risk disease. Conclusions: A substantial number of PSA-detected prostate cancer patients have either intermediate or high risk disease at diagnosis. Men age >75 or of black race have the highest risk of presenting with intermediate or high risk disease.
A gene expression signature to predicit overall, prostate cancer, and non–prostate cancer survival.
Authors: Li Chunde , Peng Zhuochun , Skoog Lambert , Hellborg Henrik , Wingmo Inga-lill , Hjelm-Eriksson Marie , Harmenberg Ulrika , Cohn-Cedermark Gabriella , Ährlund-Richter Lars , Pramana Setia , Pawitan Yudi , Nistér Monica , Nilsson Sten
Published: February 2017

51

Background: For prostate cancer patients, prostate cancer specific and non-prostate cancer specific survival have the same importance. This study aimed at identifying expression biomarkers that can predict prostate cancer specific, non-prostate cancer specific and overall survival at diagnosis. Methods: Selected ESCGPs (embryonic stem cell gene predictors) and control genes were analyzed by multiplex quantitative PCR using prostate fine-needle aspiration samples taken at diagnosis from a Swedish cohort of 189 prostate cancer patients diagnosed between 1986 and 2000. Of all patients, 97.9% had overall and cancer-specific survival data and 77.9% were primarily treated only by hormone therapy. The cohort was divided into one discovery and two validation subsets. Univariate and multivariate Cox proportional hazard ratios and Kaplan-Meier plots were used for the survival analysis. A published dataset was used for external validation. Results: An expression signature of F3, VGLL3 and IGFBP3, was sufficient to categorize the patients into high-risk, intermediate-risk and low-risk subtypes. The median overall survival of the subtypes was 3.23, 4.00 and 9.85 years respectively. The difference corresponded to HRs of 5.86 (95% CI 2.91-11.78, P<0.001) for the high-risk and 3.45 (95% CI 1.79-6.66, P<0.001) for the intermediate-risk compared to the low-risk subtype. This signature is significant in correlation to overall, cancer-specific and non-cancer specific survival in both univariate and multivariate analyses including common clinical parameters. Conclusions: These results suggest that these novel expression biomarkers and the expression signature could be used to improve the accuracy of the currently available clinical tools for predicting overall, cancer-specific and non-cancer specific survival and selecting patients with potential survival benefit from hormone treatment.
A genomic classifier independently prognostic of prostate cancer death in a high-risk surgical cohort.
Authors: Cooperberg Matthew R. , Crisan Anamaria , Mitra Anirban Pradip , Ghadessi Mercedeh , Buerki Christine , Davicioni Elai
Published: February 2017

60

Background: Biomarkers may improve ascertainment of progression risk after radical prostatectomy (RP). We compared two validated post-RP classifiers: the Decipher genomic classifier (GC) and CAPRA-S (based on standard clinicopathologic parameters), to predict prostate cancer-specific mortality (CSM) in a contemporary cohort of RP patients. Methods: From a cohort of 1,010 RP patients treated from 2000-06, a case-cohort design was used to analyze a subset of 219 men with one or more high risk features and available paraffin-embedded tissue. Median follow-up was 6 years. The GC, derived from expression levels of 22 biomarkers and dichotomized to denote low- and high-risk, and CAPRA-S, calculated from preoperative PSA and pathologic grade and staging variables, scores were determined. The scores were evaluated individually and in combination using concordance index, decision curve, (DC), re-classification, and Cox analyses for prediction of CSM. Results: 212 men had full data available to calculate the CAPRA-S; 27 experienced CSM. The c-index for GC (0.78) and CAPRA-S (0.76) were similar, although GC showed improved calibration and higher net-benefit on DC analysis. In 103 patients with high-risk CAPRA-S scores (≥6), GC scores were likewise high-risk for 49, among whom 19 had CSM events. The other 54 men were reclassified as low-risk by GC; among these only 1 CSM event was observed. In multivariable Cox analysis both GC and CAPRA-S were independently prognostic of CSM, with hazard ratios of 1.62 (p<0.001) and 1.22 (p=0.01), respectively for unit score increases. A combined model defined based on the Cox model as (0.20*CAPRA-S + 5.68*GC) was more accurate than either score alone (p<0.001 by likelihood ratio test). DC analysis indicated greater net benefit for the combined model than for either score alone. Conclusions: In men treated with RP at high risk of recurrence based on clinical and pathologic variables, both GC and CAPRA-S were significant predictors of CSM. Notably, GC was able to 'down-risk' >50% of men stratified to high risk based on CAPRA-S alone. Thus the GC provides independent prognostic information, and a model integrating GC and CAPRA-S may further improve the prediction of lethal prostate cancer.
Dissecting the therapeutic effects of anti-CTLA-4 and ADT in a murine hormone-sensitive prostate cancer.
Authors: Subudhi Sumit Kumar , Montalvo-Ortiz Welby , Scher Howard I. , Allison James Patrick
Published: February 2017

61

Background: Immune checkpoint blockade with anti-CTLA-4 has emerged as a successful, novel form of cancer immunotherapy that acts directly on activated T cells instead of on cancer cells. CTLA-4 blockade can result in durable, long-term responses, but only a subset of patients treated benefit from this approach. Androgen deprivation therapy (ADT) is the first-line treatment for advanced prostate cancer, and it produces some of the most dramatic responses in clinical oncology. Clinically, the combination of ADT and anti-CTLA-4 was found to be more effective than ADT alone. To optimize the development of combination regimens, we examined the kinetics of the immune effects of ADT ± anti-CTLA-4 in a murine model of hormone-sensitive prostate cancer. Methods: Mice with established Myc-CaP prostate tumors were divided into 4 treatment groups: 1) untreated, 2) degarelix, 3) anti-CTLA-4, or 4) degarelix plus anti-CTLA-4. Tumor growth was measured biweekly. Tumor-infiltrating lymphocytes and T cell cytokine production was determined by flow cytometric analysis and serum IFN-gamma levels were assessed by ELISA. Results: We found that degarelix rapidly induces castrate levels of testosterone within 24 hours in mice and maintains these levels for at least 35 days. The combination of degarelix and anti-CTLA-4 improved median overall survival compared to degarelix alone (P<0.030, Mantel-Cox log-rank test). Tumor regression was associated with the production of the Th1-cytokines, IFN-gamma and TNF-alpha by tumor-infiltrating CD4+ and CD8+ T cells within 1 week of treatment initiation. This response peaked at 2 weeks after treatment initiation and was associated with elevated levels of serum IFN-gamma levels. In this model, anti-CTLA-4 monotherapy had no effect on tumor growth rates or intratumoral/sera cytokine levels. Conclusions: The combination of immune checkpoint blockade with anti-CTLA-4 and medical castration with degarelix is therapeutically effective in a murine model of hormone-sensitive prostate cancer, likely through an IFN-gamma-dependent manner. This model can be used to better identify potential post-treatment biomarkers that can be studied for associations with clinical outcomes.
Evaluating the hypothalamic-pituitary-adrenal axis (HPAA) in men receiving ketoconazole for castrate-resistant prostate cancer (CRPC).
Authors: Aggarwal Rahul Raj , Weinberg Vivian K. , Sosa Eduardo V. , Lin Amy M. , Harzstark Andrea Lynne , Small Eric Jay , Fong Lawrence , Hsieh Andrew Caleb , Formaker Carl , Koepfgen Kathryn M. , Friedlander Terence W. , Ryan Charles J.
Published: February 2017

64

Background: Serum adrenal androgen (AA) levels may be prognostic for survival in men with CRPC treated with androgen synthesis inhibitors (ASIs) including ketoconazole (keto) and abiraterone. We hypothesize that up-regulation of the HPAA and adrenocorticotropic hormone (ACTH) may contribute to therapeutic resistance on ASIs. The current study explores the relationship between ACTH, AA, testosterone (T) and estradiol (E) among CRPC patients (pts) treated with ASI + corticosteroids. Methods: Phase 2 study of keto (400 mg TID) + hydrocortisone (HC) (30 mg/day) in pts with CRPC. Pts who achieved ≥ 30% PSA decline from baseline at week 12 continued keto/HC until progression, at which point HC was replaced by dexamethasone (dex). Serum hormone (H) levels were measured (in AM) at baseline and every 4 weeks using standard assays. Statistical tests include Spearman’s rank test for correlation between baseline H levels; Wilcoxon matched pairs for baseline vs. week 4 distribution; and Fisher’s exact test for associations between H levels (dichotomized at median) with PSA decline. Results: Of 30 pts enrolled and 24 evaluable for PSA response, 13 pts (54%) achieved ≥ 30% PSA decline at 12 weeks. Baseline ACTH was positively correlated with DHEA (r = 0.40; p = 0.04) and cortisol (r = 0.52; p = 0.007). Change from baseline to week 4 in H levels is shown in table. There was a significant increase in pts achieving a PSA decline of ≥ 30% if there was a decrease in E at week 4 vs. no decrease (83% vs. 18%; p = 0.003). Baseline and changes in other H levels were not associated with PSA outcome at week 12. Conclusions: ACTH is positively correlated with DHEA and cortisol in CRPC pts. Declines in E may serve as an additional predictive marker of benefit for ASI therapy. These observations require prospective validation. Analyses exploring changes in ACTH at disease progression and impact of substituting dex for HC are ongoing. Clinical trial information: NCT01036594. [Table: see text]
Quantifying the ki-67 heterogeneity profile in prostate cancer.
Authors: Kamrava Mitchell , Mesko Shane , Banerjee Robyn , Huang Jiaoti , Jeffrey Demanes D. , Marks Leonard S.
Published: February 2017

73

Background: Ki-67 is a robust predictive/prognostic marker in prostate cancer however tumor heterogeneity may compromise its clinical utility when Ki-67 is determined off of prostate biopsy samples. We examined the variation of Ki-67 in prostate biopsy samples by NCCN risk groups and the location of the highest Ki-67 relative to the most dominant lesion on multiparametric (MP) MRI. Methods: An IRB approved retrospective analysis was done on 77 consecutive men whose prostate biopsies revealed cancer. Using a MRI/US fusion device (Artemis), biopsy cores were obtained systematically and when MRI indicated a lesion, by targeting. Ki-67 staining was determined by a manual semi-quantitative method and reported as % of positive cells. The highest Ki-67 per patient was used to determine inter-prostatic variation. Ki-67 range (highest Ki-67 minus lowest Ki-67 value) was used to determine intra-prostatic variation on a subset of 47 patients with ≥2 positive biopsy cores. Ki-67 range was also used to evaluate intra-lesion variation on 31 MP MRI defined lesions with > 1 targeted positive biopsy core. The relationship of the dominant lesion (lesion with the largest tumor diameter) to the highest Ki-67 in the entire prostate was examined for 10 patients with ≥2 distinct lesions on MP MRI. Analysis of variance (ANOVA) was used to evaluate differences between the means of NCCN-defined risk groups. Results: Inter-prostatic Ki-67 mean±standard deviation (SD) values for low, intermediate and high risk patients were 5.1% ± 3.8%, 7.4% ± 6.8%, and 12.0% ± 12.4% (ANOVA p=0.01). Intra-prostatic mean±SD Ki-67 ranges in low, intermediate, and high risk patients were 2.6% ± 3.4%, 4.6% ± 6.4%, 9.5% ± 10.6% (ANOVA p = 0.0246). Intra-lesion mean±SD Ki-67 ranges in low, intermediate and high risk patients were 1.0%±1.0%, 4.0%±4.29%, and 6.7%±11.51% (ANOVA p=0.39). The dominant lesion harbored the highest Ki-67 30% of the time. Conclusions: High risk patients have significantly higher inter- and intra-prostatic Ki-67 heterogeneity profiles than men with low/intermediate risk disease. The highest Ki-67 is often not located in the dominant MRI defined lesion. This data can inform future biopsy strategies when integrating Ki-67 into clinical practice.
Prediction of patient-reported bowel quality of life (QOL) after dose-escalated radiation therapy (RT) for prostate cancer by rectal dosimetry.
Authors: Stenmark Matthew H. , Conlon Anna S.C. , Daignault Stephanie , Bassetti Michael Frederick , Vance Sean , Marsh Robin , Litzenberg Dale , Ritter Timothy , Feng Felix Yi-Chung , Sandler Howard Mark , Sanda Martin G. , Hamstra Daniel A.
Published: February 2017

84

Background: Rectal dose-volume histogram (DVH) parameters and a consensus normal tissue complication probability (NTCP) model predict physician scored toxicity but have not been well studied for patient reported outcomes (PRO) following external beam RT for prostate cancer. Methods: PRO were prospectively collected at baseline and 12 month intervals by expanded prostate cancer index composite (EPIC) for 98 patients from 2004-2009. Linear regression modeling for bowel score at 1 and 2 years was performed using pre-treatment bowel score and DVH parameters [V80 (% of rectal volume >80 Gy), V75, V70, V50, V25, and NTCP]. Results: Median RT dose was 78 Gy with image-guidance in 81%, intensity-modulation in 72%, and pelvic RT in 11%. Rectal DVH parameters are presented in the Table. Pretreatment and 2 year PRO were available for 92% of patients. The mean pretreatment bowel summary score declined from 96.0 (sd 8.0) to 91.8 (13.5) at 2 years. Acute proctitis (grade 1-2) during RT was associated with a decline in 2 year bowel QOL, while acute diarrhea (grade 1-2) was not. At 2 years 63% of patients had a decline <4 points while the remainder had a mean decline of 15.9 (14.2) with 4-6 points having been defined as the minimal clinically significant change. Linear regression modeling, adjusted for pretreatment bowel function, revealed an association between increasing Vdose, NTCP and bowel QOL (Table). Akaike information criterion analysis followed by leave-one-out cross validation, indicated that V75 provided the best predictive model for 2 year bowel QOL followed by NTCP and V70. Conclusions: Most previous studies have highlighted V70 for toxicity (such as rectal bleeding). The association with V75 and rectal QOL has not been previously reported and supports potential changes in how prostate plans are designed to maintain QOL. This is also the first validation of a consensus NTCP model for bowel QOL. [Table: see text]
Association of cross-talk between α1D-adrenergic receptor (α1D -AR) and transient receptor potential vanilloid 1 (TRPV1) with the proliferation of PC3 prostate cancer cells.
Authors: Santoni Giorgio , Farfariello Valerio , Morelli Maria Beatrice , Liberati Sonia , Nabissi Massimo , Santoni Matteo , Piergentili Alessandro , Quaglia Wilma , Amantini Consuelo
Published: February 2017

87

Background: Growing evidence supports the role of α1-ARs in the direct mitogenic effect of catecholamines on prostate cancer (PC) cell growth. The expression of α1D-AR on PC3 prostate cancer cells and the ability of noradrenalin (NA) to stimulate PC3 cell proliferation in a α1D-AR-dependent manner were reported (Quaglia et al., 2005). In addition, TRPV1 expression was also found in prostate cancers (Sanchez et al., 2006). Aim of this study was to investigate the relationship between α1D-AR and TRPV1 receptors and the involvement of TRPV1 in NA-induced proliferation in PC3 cells. Methods: By western blot analysis and confocal microscopy the expression α1D-AR and TRPV1 and localization in PC3 cells were evaluated. PC3 cells were incubated with NA alone or in combination with WS433 and capsazepine (CPZ), α1D-AR and TRPV1 antagonists. Proton release, calcium influx and cell proliferation were assessed in α1D-AR-, TRPV1- or α1D-AR/TRPV1 double-silenced PC3 cells by cytosensor and cytofluorymetric analyses. Finally, lysates from NA-treated PC3 cells alone or in combination with WS433 or CPZ were blotted with anti-phospho ERK, anti-ERK and anti-phospho-(Ser) PKC substrate Abs and Inositol-1,4,5-trisphosphate [3H] radioreceptor assay were performed. Results: α1D-AR and TRPV1 co-localize and are co-immunoprecipitated in PC3 cells. Treatment of PC3 cells with NA strongly stimulated proton release, calcium influx and cell proliferation that were reverted by α1D-AR WS433 and TRPV1 antagonist. NA-induced increase of survival and proliferation was totally abrogated in α1D-AR/TRPV1 silenced cells. In addition, NA stimulates ERK and PKC substrate phosphorylation that was inhibited by WS433 and CPZ. Finally, CPZ treatment inhibited NA-dependent PLC activation, while WS433 had no effect. Conclusions: A functional and structural cross-talk between α1D-AR and TRPV1 receptors control NA-induced proliferation of PC cells. These data strongly suggest the development of new pharmaceutical approaches based on bifunctional antibodies and molecules recognizing both α1D-AR and TRPV1 receptors.
Phase I trial of total androgen blockade, weekly docetaxel, and image-guided intensity-modulated radiotherapy for localized high-risk prostate adenocarcinoma.
Authors: Ramey Stephen J. , Golshayan Ali Reza , Keane Thomas E. , Kraft Andrew S. , Chaudhary Uzair Bashir , Marshall David T.
Published: February 2017

96

Background: High-risk prostate cancer patients have high rates of treatment failure and improved outcomes are needed. Docetaxel has shown efficacy in hormone-resistant prostate cancer and can act as a radiosensitizer. Dose escalation studies with radiation therapy have found improved freedom from failure rates. The addition of androgen deprivation therapy (ADT) improves overall survival. Therefore, this phase I study was designed to find the maximum tolerable dose (MTD) of weekly docetaxel when combined with high-dose image-guided intensity-modulated radiotherapy (IGRT) and ADT in patients with high-risk prostate cancer. Methods: Men with high-risk adenocarcinoma of the prostate (≥T2c, or PSA ≥20ng/ml, or Gleason ≥8) were treated with weekly docetaxel (given at 10-30 mg/m2, increasing by 5 mg/m2until the MTD was reached) concurrently with IGRT of 77.4 Gy in 43 fractions to the prostate and 45 Gy in 25 fractions to the proximal seminal vesicles. ADT consisted of a gonadotropin-releasing hormone agonist (GnRHa) and bicalutamide beginning 2 months before chemoradiation and continuing 2 months concurrently. The GnRHa was then continued for an additional 24 months. Results: 19 patients began combined chemoradiation between April 2006 and December 2010. Median follow-up is 32 months. No dose-limiting toxicities (DLTs) were seen in patients treated with docetaxel doses up to 25 mg/m2. However, at the 30 mg/m2level, 2 of 4 patients experienced DLTs of both grade 3 fatigue and grade 3 upper GI toxicity, indicating the MTD had been exceeded. At last follow-up, 2 patients had died, one from metastatic prostate cancer and the other from heart failure. A second patient demonstrated biochemical failure by the Phoenix criteria at 46 months, giving an actuarial biochemical disease-free survival (bDFS) at 3 years of 94.7%. All patients had ≥grade 2 erectile dysfunction but no other ≥grade 2 long-term toxicities were identified. Conclusions: Weekly docetaxel may be combined with high-dose IGRT and long-term ADT up to a MTD of 25 mg/m2. Long-term side effects with this regimen were minimal, and bDFS rate is encouraging. Clinical trial information: NCT00099086.
Axitinib with or without dose titration for first-line metastatic renal cell carcinoma (mRCC): Unblinded results from a randomized phase II study.
Authors: Rini Brian I. , Gruenwald Viktor , Fishman Mayer N. , Melichar Bohuslav , Ueda Takeshi , Bair A. H. , Chen Ying , Bycott Paul W. , Pavlov Dmitri , Kim Sinil , Jonasch Eric
Published: February 2017

LBA349

Background: Patients receiving the 5-mg twice daily (BID) axitinib starting dose exhibit variable drug exposure; prior pharmacokinetic analyses indicate higher exposure is associated with better outcomes in mRCC. Dose titration based on individual tolerability may optimize exposure and improve efficacy. Methods: Patients (N=213) with treatment-naïve mRCC received axitinib 5 mg BID for a 4-week lead-in period. Then, patients with 2 consecutive weeks of blood pressure ≤150/90 mmHg, no axitinib-related toxicities >grade 2, no dose reductions, and ≤2 antihypertensive medications were randomized (double-blind) to axitinib 5 mg BID + dose titration to 10 mg BID maximum with axitinib or placebo. Those not eligible for randomization continued axitinib 5 mg BID or lower. Primary endpoint was objective response rate (ORR) in randomized arms. Progression-free survival (PFS), overall survival, and safety were secondary endpoints. Assuming response rate under the null hypothesis is 0.15, this study had ≥80% power (1-sided type I error 10%) to detect a ≥25% absolute improvement in ORR with active vs placebo titration. Results: In all, 56 patients each were randomized to active and placebo titration arms, 91 were not randomized, and 10 withdrew during the lead-in period. As of Oct 12, 2012, ORR (95% confidence interval [CI]) was 54% (40–67) in the active titration arm vs 34% (22–48) in the placebo titration arm (1-sided P=0.019), and 59% (49–70) in the non-randomized arm. Median PFS (95% CI) from first dose was 14.5 mo (9.2–24.5) in the active titration arm vs 15.7 mo (8.3–19.4) in the placebo titration arm (hazard ratio favored active titration, 0.85; 95% CI, 0.54–1.35; 1-sided P=0.244), and 16.6 mo (11.2–22.5) in the non-randomized arm. Most frequent all-grade, all-causality adverse events in active titration, placebo titration, and non-randomized arms, respectively, were diarrhea (61% vs 63% vs 63%), hypertension (61% vs 43% vs 82%), and fatigue (45% vs 46% vs 54%). Conclusions: Axitinib is effective and well tolerated in first-line mRCC with prolonged median PFS in all treatment arms compared to historical controls. Axitinib dose titration significantly improved ORR vs placebo. Clinical trial information: NCT00835978.
Overall survival (OS) and safety of dasatinib/docetaxel versus docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC): Results from the randomized phase III READY trial.
Authors: Araujo John C. , Trudel Geralyn C. , Saad Fred , Armstrong Andrew J. , Yu Evan Y. , Bellmunt Joaquim , Wilding George , McCaffrey John , Serrano Sergio V. , Matveev Vsevolod , Efstathiou Eleni , Oudard Stephane , Morris Michael J. , Sizer Bruce , Goebell Peter J. , De Bono Johann Sebastian , Paliwal Prashni , Durham Susan , Cheng Shinta , Logothetis Christopher
Published: February 2017

LBA8

Background: SRC kinases may contribute to androgen independence of mCRPC.Dasatinib (DAS) inhibits tyrosine kinases including SRC kinases with preclinical evidence for antimetastatic activity, inhibition of osteoclast function in tumor microenvironment, and synergistic activity with docetaxel (D). In phase I/II trials of mCRPC patients (pts), DAS in combination with D had an acceptable safety profile with objective response rates (ORR) improved over historical data and decreased levels of bone turnover markers. Methods: READY was a multinational, randomized, double-blinded, placebo-controlled, phase III study. Pts with mCRPC (n = 1,522) were randomized (1:1) to receive either D 75 mg/m2q3wk + prednisone with double-blinded DAS 100 mg qd (DAS/D, n = 762) or placebo (PBO/D, n = 760). Primary endpoint was overall survival (OS). Secondary endpoints were ORR, time to first skeletal-related event (TFSRE), time to prostate-specific antigen progression (TPSAP), urinary N-telopeptide (uNTX) reduction, pain reduction, progression-free survival (PFS), and safety. Results: No OS difference between DAS/D and PBO/D (median, 21.5 vs. 21.2 mos; hazard ratio [HR], 0.99; log-rank P = 0.90) was observed. Results of secondary endpoints for DAS/D vs. PBO/D were: ORR (30.5 vs. 31.9%); TFSRE (median, not reached vs. 31.1 mos; HR, 0.81 [95% CI, 0.64-1.02]); uNTX reduction (66.0 vs. 60.6%); PFS (median, 11.8 vs. 11.1 mos; HR, 0.92); TPSAP (median, 8.0 vs. 7.6 mos; HR, 0.91), and pain reduction (66.6 vs. 71.5%). Twenty-three percent of DAS/D and 14% of PBO/D pts received therapy for <3 mos. Most common AEs in DAS/D arm included diarrhea, fatigue, alopecia, and nausea. Grade 3-4 AEs of interest for DAS/D vs. PBO/D included anemia (8.0 vs.5.9%), neutropenia (6.2 vs. 5.5%), hypocalcemia (3.5 vs.3.1%), GI bleeding (2.6 vs.1.3%), and pleural effusion (1.3 vs. 0.4%). Conclusions: The addition of DAS to standard-of-care chemotherapy in mCRPC pts did not improve OS. There was a modest reduction in the risk of TFSRE with DAS/D vs. PBO/D. With a median follow-up of 19 mos of 761 DAS/D-treated pts, no unexpected toxicities for DAS were observed. Clinical trial information: NCT00744497.
E1308: Reduced-dose IMRT in human papilloma virus (HPV)-associated resectable oropharyngeal squamous carcinomas (OPSCC) after clinical complete response (cCR) to induction chemotherapy (IC).
Authors: Cmelak Anthony , Li Shuli , Marur Shanthi , Zhao Weiqiang , Westra William H. , Chung Christine H. , Gillison Maura L. , Gilbert Jill , Bauman Julie E. , Wagner Lynne I. , Ferris Robert L. , Trevarthen David R. , Colevas A. Dimitrios , Jahagirdar Balkrishna N. , Burtness Barbara
Published: February 2017

LBA6006

Background: HPV+ patients (pts) in E2399 obtained a 2-yr 95% survival and 86% PFS after IC and 70Gy chemoradiation. We hypothesized reduced-dose IMRT (54Gy, 23% reduction) in HPV+ OPSCC pts could maintain high LR control and 85% 2-yr PFS in pts with cCR to IC. Methods: Pts with resectable stage III/IVa,b HPV+ OPSCC received IC q3 weeks x 3 with paclitaxel 90mg/m2 days (D) 1,8,15, cisplatin 75mg/m2 D1, and standard cetuximab (Cetux) weekly schedule. IC response determined IMRT dose independently at primary and involved nodes: IMRT 54Gy/27 if cCR vs. 69.3Gy/33 if <cCR. Cetux was continued during IMRT. Primary endpoint was 2-yr PFS. Results: 90 pts were enrolled (80 analyzable). Med FU is 23.3 months (mo). Tumor and Nodal stage: T4-10%, T3-17%, T2-50%, and T1-23%; N0,1-16%, N2a,b-54%, N2c-31%. Med age 57yrs. 46% never smoked and 84% not current smokers. IC and C-IMRT was well tolerated: 96% received all 3-cycles of IC. 71% had cCR. 62 pts (78%) received reduced-dose Cetux-IMRT. For all reduced IMRT pts, 23mo PFS is 84%, primary site LC 94%, nodal control 95%, and distant 92%. Post-treatment neck dissection was positive for tumor in 4/8 reduced dose IMRT pts compared to 1/3 pts treated with std dose. One late grade 3 toxicity occurred in 1 reduced-dose pt: hypomagnesemia at 30mo. Conclusions: IC + reduced-dose Cetux-IMRT produced high tumor control rates. Late toxicities were minimal. Low dose pts achieved 84% PFS at 23mo and 95% 2-yr survival. Pts with <10yrs smoking, T1-3 and N0-2b disease achieved 96% PFS. Further studies of reduced-dose IMRT in chemoresponsive HPV+ pts are warranted. Clinical trial information: NCT01084083. [Table: see text]