bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pragmatic predictors of response to abiraterone in metastatic castrate resistant-prostate cancer.
Authors: Davies Rhian Sian , Lester Jason Francis , Smith Christian , Casbard Angela Claire 
Published: February 2017

286 Background: In patients with metastatic castrate resistant prostate cancer (mCRPC) there are several treatment options that have been shown to prolong survival. These treatments have not been directly compared in randomized clinical trials. In addition, the optimum sequencing of treatments for an individual patient has not yet been established. There is early evidence there are genetic predictors of response to enzalutamide and abiraterone, but these are likely to be some way off routine clinical application. There is a more urgent need for a practical method of identifying patients who are unlikely to respond to a particular treatment so that a more appropriate therapy can be used. Methods: A retrospective analysis of 47 consecutive patients with mCRPC treated in a single cancer centre was conducted. All patients were treated according to the following treatment sequence: (1) continuous LHRH analogues (LHRHa); (2) antiandrogen therapy and subsequent withdrawal; (3) docetaxel plus prednisolone; (4) abiraterone. Data were collected on patient and disease demographics, treatment received and response. Definitions of relapse and treatment response were as per the Cou-301 trial. Results: 47 patients were identified. Median age was 76 years (range 55-86). Only 1 patient had a Gleason score ≤ 6. Median duration of response to abiraterone in responders versus non-responders of each line of treatment was compared using the unpaired t-test. The results are displayed in Table. Conclusions: Time to progression on LHRHa, no response to bicalutamide and duration of biochemical response to docetaxel were strong predictors of a poor response to abiraterone. Further statistical analysis is planned, and these observations require prospective validation. [Table: see text]
Comparative effectiveness of adjuvant chemotherapy (AC) versus observation in patients with ≥ pT3 and/or pN+ bladder cancer (BCa).
Authors: Galsky Matt D. , Stensland Kristian , Moshier Erin L. , Sfakianos John , McBride Russell Bailey , Tsao Che-Kai , Casey Martin Francis , Hall Simon J , Boffetta Paolo , Oh William K. , Wisnivesky Juan P. 
Published: February 2017

292 Background: Though Level I evidence supports the use of neoadjuvant chemotherapy (NAC) in BCa, the data supporting AC has been mixed. Experience suggests an adequately powered trial to definitively assess the role of AC is unlikely to be completed. Alternative approaches to evidence development are necessary. Methods: Patients who underwent cystectomy for ≥pT3 and/or pN+ M0 BCa were identified from the National Cancer Database. Patients who received NAC and/or diagnosed after 2006 (most recent year with survival data) were excluded. Logistic regression was used to calculate propensity scores representing the predicted probabilities of assignment to AC versus observation based on: age, demographics, year of diagnosis, pT stage, margin status, lymph node density, distance to hospital, hospital cystectomy volume, and hospital type and location. A propensity score-matched cohort of AC versus observation (1:2) patients was created. Stratified Cox proportional hazards regression was used to estimate the hazard ratio (HR) for overall survival for the matched sample while propensity score adjusted and inverse probability of treatment weighted proportional hazards models were used to estimate adjusted HR for the full sample. A sensitivity analysis examined the impact of comorbidities. Results: 3,294 patients undergoing cystectomy alone and 937 patients undergoing cystectomy plus AC met inclusion criteria.Patients receiving AC were significantly more likely to: be younger, have more lymph nodes examined and involved, have higher pT stage, have positive margins, reside in the Northeast and closer to the hospital, and have private insurance. AC was associated with improved overall survival (Table). The results were robust to sensitivity analysis for comorbidities. Conclusions: AC was associated with improved survival in patients with ≥pT3 and/or pN+ BCa in this large comparative effectiveness analysis. [Table: see text]
Phase II clinical trial of intravesical bacillus Calmette-Guerin (BCG) followed by sunitinib for the treatment of high-risk nonmuscle-invasive bladder cancer (NMIBC).
Authors: Helfand Alexander M. , Lee Cheryl T. , Hafez Khaled , Hussain Maha , Liebert Monica , Daignault Stephanie , Montgomery Jeffrey Scott , Miller David Christopher , Drnek Linda , Hollenbeck Brent K. , Weizer Alon Z. 
Published: February 2017

293 Background: We conducted a phase II trial to evaluate combination therapy with intravesical BCG + sunitinib for prevention of recurrence and progression of NMIBC. Methods: Patients with high-grade clinical ≤ T1N0M0 NMIBC without BCG in the past year were eligible and received induction BCG followed 2 weeks later by 28 days of sunitinib (50mg). The primary endpoint was 3 month complete response (CR) by biopsy and cytology. Patients with incomplete response were eligible for a second cycle of BCG + sunitinib. Secondary endpoints included 2-year recurrence and progression-free survival (RFS, PFS). Toxicity was graded according to the NCI CTCAE v.3.0. The Simon Minimax 2-stage study had 80% power with a 5% type I error assuming a 3m CR of 75% with sunitinib + BCG compared to 55% with BCG alone. If ≥ 25/36 evaluable patients achieved a 3m CR, then the treatment would be considered for further study. Binomial proportions, confidence intervals and Kaplan-Meier estimates are reported. Results: Of 36 evaluable patients, median age was 65.9 years (IQR 59-72). Initial stage was T1 (19), Ta (9), and CIS (8). Thirty-six percent completed sunitinib without interruption. Treatment was delayed (median 12 days (IQR 9-16)) and dose was reduced to 37.5 mg in 13 patients. One patient had reduction to 25mg with re-escalation to 37.5mg. One patient completed a 2nd cycle of BCG + sunitinib for incomplete response. BCG maintenance therapy was given to 21 patients. Of 133 adverse events in 34/36 patients, 6 (4.5%) in 5 patients were ≥ grade 3: thrombocytopenia, diarrhea (2), shingles, extremity rash/pain and hand + foot syndrome. CR at 3m included 26/36 (72%, 95% CI[55,86]) reaching the primary endpoint. The patient who completed a 2nd cycle of BCG induction and sunitinib had CR at 6 months. 2y RFS (patients with intact bladder) was 77% (95% CI[58,88]) and 2y PFS was 100%. Conclusions: The primary endpoint of the study of 25 3m CR has been reached. Combined treatment with BCG + sunitinib is associated with low rates of recurrence and progression. Adverse effects were common and frequent but few were serious. BCG + sunitinib may produce outcomes superior to BCG alone. (Study supported by Pfizer, Inc) Clinical trial information: NCT00794950.
Concurrent gemcitabine (GEM) and radiotherapy (XRT) as organ-sparing treatment for muscle-infiltrating bladder cancer (MIBC): Preliminary results of a patient-based cumulative analysis of seven phase I-II trials.
Authors: Caffo Orazio , Thompson Catherine , De Santis Maria , Kragelj Borut , Hamstra Daniel A. , Azria David , Pappagallo Giovanni , Fellin Giovanni , Choudhury Ananya 
Published: February 2017

306 Background: GEM is a highly effective radiosensitiser and has been combined with XRT in MIBC after transurethral resection (TUR) to achieve bladder preservation. Several phase I-II trials confirmed that concurrent GEM and XRT is a feasible treatment able to achieve good disease control and a high rate of organ preservation. We performed a patient-based cumulative analysis of the published trials with concurrent GEM/XRT in MIBC. Methods: Primary data for patients (pts) enrolled in all published studies on GEM/XRT were provided from the institutions. Results: A total of 190 pts were treated in seven phase I-II GEM/XRT trials. The median age was 70 yrs (range 42-87 yrs). The histology was pure transitional in 79% and mixed with squamous features in 21% of the cases. Clinical stage was T2 in 70%, T3 in 21%, and T4 in 8% of the cases, respectively. After TUR, pts received a median XRT dose of 55.5 Gy (range 45-64 Gy) with standard and hypo-fractionated regimes used in 68% and 32% of the cases, respectively. GEM was administered on a weekly or twice-weekly basis, with doses ranging from 10 mg/sqm to 500 mg/sqm; a concurrent administration of cisplatin was planned in 38 pts (20%). Grade ≥ 3 acute and late urinary toxicities were recorded in 7 (4%) and 5 (3%) pts, while grade ≥ 3 acute and late intestinal toxicities were recorded in 20 (10%) and 1 (0.5%) pts, respectively. The complete remission rate was 93.3%. Thirty-six pts (18.9%) experienced a bladder recurrence with 14 pts undergoing cystectomy. The 3- and 5-year survival rates calculated by Kaplan-Meier methods are reported in the table. Conclusions: From this pooled analysis of the clinical outcomes of the pts enrolled in phase I-II studies it appears that GEM/XRT is a treatment with mild toxicity profile, able to achieve a high rate of bladder preservation and producing favorable outcomes compared to other published series for organ-sparing therapy for MIBC. Prospective studies are ongoing to confirm these findings. [Table: see text]
Prospective phase 1 study assessing feasibility of IMRT and IGART to deliver simultaneous integrated high-dose tumor boost (up to 70 Gy) for the radical treatment of localized muscle-invasive bladder cancer.
Authors: Hafeez Shaista , Warren-Oseni Karole , McNair Helen , Hansen Vibeke , McDonald Fiona , Lalondrelle Susan , Thompson Alan , Kumar Pardeep , Harris Victoria , Tan Melissa , Mohammed Kabir , Thomas Karen , Jones Kelly , Dearnaley David Paul , Horwich Alan , Huddart Robert Anthony 
Published: February 2017

307 Background: Advances in IGART offer individualized solutions to improve target coverage and reduce normal tissue irradiation allowing opportunity to increase radiation tumour dose and spare normal bladder. Methods: A library of 3 IMRT plans were created (small, medium and large) from planning CT scans performed at 30 and 60 minutes; treating whole bladder to 52 Gy and tumour to 70 Gy in 32 fractions. Where normal tissue dose constraints were not met consideration was made to boosting tumour to lower dose (68 Gy-64 Gy). Cone beam CT (CBCT) imaging was performed prior to each fraction. Appropriate PTV was selected from the library for treatment delivery. Post treatment CBCT was acquired weekly in order to assess intra-fraction filling and coverage. Results: 22 patients have been planned using this technique. All have met tissue constraints for treatment to 70 Gy. 21 patients have completed radiotherapy, 18 completed treatment to 70 Gy; 1 patient was planned and treated to 68 Gy prior to dose escalation using this technique; 1 patient was treated to a total dose of 65.6 Gy because dose limiting toxicity occurred before dose escalation. 572 CBCTs have been evaluated. Treatment was delivered using small, medium, and large plans in 35%, 52%, and 13% cases respectively. Mean intra-fraction filling was 14 cm3 (SD 16.3, range 0.23-107.9). Mean time between pre- and post-CBCTs was 13 min (SD 2.1, range 9-18). Mean D 98% as assessed on post-radiotherapy CBCT was 98.7% (SD 1.78, range 89.9-100%). At median follow-up of 8 months (range 1-24 months), 18 patients remain alive and disease free. 2 superficial recurrences and 3 deaths from metastatic bladder cancer have occurred. No muscle invasive recurrences have occurred within this cohort. Using this technique one patient has experienced late toxicity (grade 3 cystitis) 5.3 months after radiotherapy (now resolved). Conclusions: IGART using IMRT to delivery a simultaneous integrated tumour boost is feasible with acceptable toxicity. Trial recruitment continues at 70 Gy and will be evaluated in a randomised trial (RAIDER). Clinical trial information: NCT01124682.
Does “low risk” muscle invasive bladder cancer actually exist?
Authors: Pietzak Eugene J. , Malkowicz S. Bruce , Guzzo Thomas J. 
Published: February 2017

308 Background: Despite level one evidence demonstrating improved survival with neoadjuvant chemotherapy (NAC), studies suggest that many eligible patients with muscle invasive bladder cancer (MIBC) never receive it prior to radical cystectomy (RC). Our objective was to determine if the absence of known pre-operative risk factors can indeed stratify for low risk of extravesical disease with RC alone. Methods: We identified consecutive NAC-naive patients with clinical stage cT2N0M0 urothelial type bladder cancer treated with RC at our center. cT2 patients with either hydronephrosis, transurethral resection (TUR) specimens containing lymphovascular invasion (LVI), or mixed variant histology were grouped as high risk. Clinicopathologic and survival outcomes were compared to cT2 patients without these adverse features, who were grouped as low risk. Results: Of 251 cT2 patients, 119 (47.4%) were high risk [LVI=31, hydronephrosis=69, mixed histology=54; ≥2 risk factors=70]. High and low risk cohorts did not differ in age, gender, race, BMI, smoking, co-morbidities, prior intravescial therapy, or treatment delay. At time of RC, high risk patients more often had lymph node metastasis (38.6% v. 26.7% p=0.04) & tumor upstaging to pT3/4 (53.7% v. 40.2 p<0.001), with significantly less achieving pT0 (2.5% v. 12.1% p=0.004). There was no difference in adjuvant chemotherapy rates (26.4% v. 25% p=0.8). Two and five year cancer-specific survival (CSS) was 84.8% and 62.3% for low risk patients, but only 59.5% and 42% for high risk patients (p=0.008), with competing risk analysis revealing worse bladder cancer specific mortality (BCSM) (sub HR=2.08 [95%CI=1.36 – 3.2]). Odds Ratio for BCSM was 1.29 (95%CI=0.68-2.5) if one risk factor was present, & 3.2 (95%CI=1.7-5.8) if two risk factors. Only hydronephrosis (2.2 [95%CI=1.2-4.2]) and mixed histology (2.4 [95%CI=1.2-4.8]) were independently associated with worse BCSM on multi-variable analysis. Conclusions: Good cancer control is provided by RC alone to many patients with cT2 MIBC without adverse risk factors, particularly if hydronephrosis & mixed variant histology is absent. However, tumor upstaging and lymph node involvement is not trivial even in low risk patients, which must be included in informed decision making on NAC.
Improved prognostic classification of patients receiving salvage systemic therapy for advanced urothelial carcinoma.
Authors: Sonpavde Guru , Pond Gregory Russell , Rosenberg Jonathan E. , Bajorin Dean F. , Regazzi Ashley Marie , Choueiri Toni K. , Mullane Stephanie A. , Niegisch Guenter , Albers Peter , Necchi Andrea , di Lorenzo Giuseppe , Fougeray Ronan , Galsky Matt D. , Sridhar Srikala S. , Ko Yoo-Joung , Milowsky Matthew I. , Bellmunt Joaquim 
Published: February 2017

311 Background: Previously identified prognostic factors in patients (pts) receiving salvage systemic therapy for advanced urothelial carcinoma (UC) include performance status (PS), liver metastasis (LM), hemoglobin (Hb) and time from prior chemotherapy (TFPC). Given the prognostic impact of peripheral blood neutrophils (N), lymphocytes (L), thrombocytes (T) and albumin (Alb) in other malignancies, we investigated their impact in the salvage setting of advanced UC. Methods: Phase II trials of salvage systemic therapy were utilized. Data on N, L, T and Alb were required in addition to TFPC, Hb, PS and LM status. N, L, T and Alb were categorized as normal, <lower limit of normal (LLN) and >upper limit of normal (ULN). Cox proportional hazards regression was used to evaluate their association with overall survival (OS). An optimal regression model was constructed using forward stepwise selection and risk groups defined using number of identified adverse risk factors. Trial was a stratification factor. Results: Data was obtained from 10 trials accruing 708 pts. Of these, 682 pts had available TFPC, Hb, PS and LM status, while 631, 554, 649 and 491 had N, L, T and Alb available. Median OS was 6.8 (95% CI: 6.0-7.0) months. Neutrophilia (N>ULN), thrombocytosis (T>ULN) and hypoalbuminemia (Alb <LLN) were significant poor prognostic factors for OS on univariate analyses. After adjustment for TFPC <3 months, Hb <10 g/dl, PS >0 and LM status, only thrombocytosis and hypoalbuminemia remained significant (Table). Risk groups were constructed. Median OS was 8.8, 6.3, 5.0 and 3.8 months for n=290, 220, 123 and 49 patients with 0-1, 2, 3 and ≥4 factors. This 6-factor prognostic model was internally validated with an improvement in the c-index from 0.564 to 0.590. Conclusions: The addition of hypoalbuminemia and thrombocytosis to TFPC, Hb, PS and LM status enhanced the prognostic risk groupings in pts receiving salvage systemic therapy for advanced UC. [Table: see text]
Impact of chemotherapy (CTX) on venous thromboembolism (VTE) and prognostic implications in patients with metastatic urinary tract tumors (UTT).
Authors: Ramos Jorge , Casey Martin Francis , Crabb Simon J. , Bamias Aristotelis , Harshman Lauren Christine , Wong Yu-Ning , Bellmunt Joaquim , De Giorgi Ugo , Ladoire Sylvain , Powles Thomas , Pal Sumanta Kumar , Niegisch Guenter , Sternberg Cora N. , Alva Ajjai Shivaram , Agarwal Neeraj , Necchi Andrea , Vaishampayan Ulka N. , Rosenberg Jonathan E. , Galsky Matt D. , Yu Evan Y. ,   RISC Investigators
Published: February 2017

318 Background: VTE is common in cancer patients (incidence rate estimates 1-10%) and a leading cause of mortality in those receiving CTX. Little is known about the risk of VTE in patients with metastatic UTT. Understanding the frequency of VTE, whether CTX portends higher risk and impact on prognosis is of relevance. Methods: Data was collected via an electronic data capture platform from 25 centers. Patients diagnosed with metastatic UTT were eligible. Patients without a known date of diagnosis, last follow up, or VTE data were excluded. First-line treatment regimen was divided into 6 groups (Table). Cumulative and 90-day from metastatic disease diagnosis unadjusted VTE incidence rates were calculated. The impact of patient, therapy and tumor related factors were analyzed. A multivariate, competing risk regression was utilized to compute subdistribution hazard ratios (HR) of VTE risk for each treatment group. A VTE patient was matched to 4 non-VTE patients to carry out Kaplan-Meier survival analysis. Cases and controls were matched on survival from date of diagnosis of metastatic disease to date of VTE diagnosis and age group. Results: 1,762 patients were eligible. There were 144 (8.2%) and 60 (3.4%) events cumulative and within the first 90 days, respectively. Multivariate analysis revealed that non-urothelial histology and history of vascular disease were associated with increased risk. The HR for VTE based on treatment group, adjusted for covariates, is shown in the table. Overall survival was significantly worse in patients with VTE (p = 0.01). Conclusions: In metastatic UTT patients, there was no difference in VTE risk between CTX regimens. Development of VTE has negative impact on survival. [Table: see text]
Phase I trial of gemcitabine and split-dose cisplatin plus everolimus (RAD001) in patients with advanced urothelial cancer.
Authors: Abida Wassim , Milowsky Matthew I. , Ostrovnaya Irina , Gerst Scott R. , Rosenberg Jonathan E. , Regazzi Ashley Marie , McCoy Asia S. , Boyd Mariel Elena , Bajorin Dean F. 
Published: February 2017

322 Background: Gemcitabine and split-dose cisplatin (GC) is standard first-line therapy for patients with advanced urothelial cancer (UC). Everolimus is an inhibitor of the PI3K/AKT/mTOR pathway, dysregulated in ~35% of UCs. The drug has been shown to have single-agent activity in phase II trials of advanced UC. The safety of combining everolimus with GC in the first-line setting for UC is unknown. Methods: Previously untreated cisplatin-eligible patients with advanced UC were enrolled. Patients received gemcitabine 800 mg/m2 and cisplatin 35mg/m2 on days 1 and 8 with everolimus at dose levels (DL1: 5 mg QOD, DL2: 5 mg daily or DL3: 10 mg daily) for six 21-day cycles. Patients with at least SD continued maintenance everolimus until progression. Restaging evaluations were performed every 2 cycles. The primary objective was to establish the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of the three-drug combination. Results: 12 patients were enrolled, 7 with bladder and 5 with upper tract primaries. 4/12 patients completed at least 6 cycles. 0/3 patients at DL1 had DLTs. 3/3 patients at DL2 had DLTs (pancytopenia, hypersensitivity reaction to everolimus and anemia). Following de-escalation to DL1, 2/6 patients in a new DL1 cohort had DLTs (neutropenia and diarrhea, 1/6 patients inevaluable). Grade 3/4 events included anemia (67%), neutropenia (42%), lymphopenia (42%), thrombocytopenia (25%), urinary tract infection (25%), hypomagnesemia (17%), and hypophosphatemia (17%). Tumor responses included: 4 PR (33%), 5 SD (42%), 1 PD (8%), and 2 inevaluable (17%). 2 patients with PR underwent consolidative surgery but eventually progressed. Responses by MSKCC Risk Scores of 0, 1, and 2 were seen in 3/5 (60%), 1/6 (17%), and 0/1 patients, respectively. Median PFS was 3.9 months (95% CI, 3.7-no reached) and median OS was 10.8 months (95% CI, 6.9-not reached). Conclusions: MTD was reached at DL1 for combination gemcitabine, split-dose cisplatin and everolimus, with 2/8 evaluable patients exhibiting DLTs at this dose level. Clinical trial information: NCT01182168.