bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamic changes of alkaline phosphatase as surrogate for best clinical benefit and overall survival during very early abiraterone therapy compared to PSA-changes in bone metastatic castration resistant prostate cancer.
Authors: Boegemann Martin , Mikah Phillip , Eminaga Okyaz , Herrmann Edwin , Papavassilis Philipp Marius , Hinkelammert Reemt , Semjonow Axel , Schrader Andres Jan , Krabbe Laura-Maria
Published: February 2017

260

Background: Significant progress in treatment of metastatic castration resistant prostate cancer (mCRPC) has been made. Biomarkers to tailor therapy are scarce. To facilitate decision-making we evaluated dynamic changes of alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and prostate specific antigen (PSA) under Abiraterone acetate (AA). ALP-Bouncing can be observed during very early AA-therapy. Methods: Men with bone mCRPC (bmCRPC) on AA 12/2009-01/2014 were analyzed. Dynamic ALP-, LDH- and PSA-changes were analyzed as predictors of best clinical benefit (BCB) and overall survival (OS) with logistic-regression, Cox-regression and Kaplan-Meier-analysis. Results: 39 pre- and 45 post-chemotherapy patients with median follow up of 14.0 months were analyzed. In univariate analysis failure of PSA-reduction ≥50% (PSA-red≥50%) and failure of ALP-Bouncing were the strongest predictors of progressive disease (p=0.003 and 0.021). Rising ALP at 12 weeks (ALP12), no PSA-red≥50% and no ALP-Bouncing were strongest predictors of poor OS, (all p<0.001). Kaplan-Meier-analysis showed worse OS for ALP12, no PSA-red≥50% and no ALP-Bouncing (p<0.001). In subgroup-analysis of oligosymptomatic patients all parameters remained significant predictors of poor OS, no PSA-red≥50% and ALP12 being the strongest (p<0.001). In multivariate analysis PSA-red≥50% remained independent predictor of OS for the whole cohort and for the oligosymptomatic subgroup (p=0.014). No patient with ALP-Bouncing had PD for BCB. Patients with ALP12 had no further benefit of AA. Conclusions: Dynamic changes of ALP, LDH and PSA during AA-therapy are associated with BCB and OS in bmCRPC. ALP-Bouncing occurring earlier than PSA-changes and rising ALP12 under AA may help to decide whether to discontinue AA.
Prostate cancer prognosis via integrative and co-localized glandular morphometry and immunofluorescent protein biomarker expression.
Authors: Donovan Michael J. , Khan Faisal M , Scott Richard , Fernandez Gerardo , Cordon-Cardo Carlos
Published: February 2017

262

Background: Quantitative image analysis of both the prostate needle biopsy (PNB) and the radical prostatectomy sample (RPS) have proven to be robust and predictive for prostate cancer (PCa) prognosis. While metrics assessing morphology and protein biomarker expression separately have been published in prognostic risk prediction models, we sought to determine the performance of novel approaches which combine protein biomarker expression with the morphometry of the gland wherein they express. In order to assess robustness, we evaluated these metrics in both PNB and RPS cohorts. Methods: Novel quantitative biometric features were derived from computerized analysis of morphology and immunofluorescent (IF) biomarker expression in PCa images. A Bayesian probabilistic approach to co-locate and quantify IF biomarker expression within various glandular sub-types was developed. This permitted differentiable analysis of PCa biomarkers such as androgen receptor (AR) in high and low Gleason grade glands of the same patient. Performance in predicting significant clinical disease progression (including metastasis and death-of-disease) was assessed via the concordance index (CI). Performance was evaluated independently in a cohort of 326 PNB samples (median 8-year follow up) and a cohort of 373 RPS (median 5-year follow up). Results: In a univariate analysis, previously published glandular morphology features had a CI of 0.68 (PNB) and 0.76 (RPS). Quantitative AR had a CI of 0.67 (PB) and 0.72 (RPS). Novel metrics of integrative co-localization resulted in a significant increase in prognostic accuracy; CIs of 0.72 (PNB) and 0.83 (RPS). These features separately assessed AR expression depending on the multiple glandular sub-types within the tumor sample. Conclusions: Integrating quantitative image analysis of morphology and IF biomarker expression in the PNB and RPS outperformed previous quantitative metrics. Such robust and reproducible metrics may prove beneficial in improving risk stratification models for future treatment decision making.
Incidence of abiraterone acetate withdrawal response measured by PSA declines.
Authors: Chowdry Rajasree Pia , Lewis Brian E. , Ledet Elisa M. , Silberstein Jonathan L. , Sartor A. Oliver
Published: February 2017

280

Background: The anti-androgen withdrawal effect is a well-described phenomenon occurring in patients with castrate resistant prostate cancer (CRPC) after discontinuing anti-androgen therapy. There is limited data on withdrawal responses after newer hormonal therapies such as Abiraterone Acetate (AA). Discontinuation of AA may lead to PSA declines but the frequency remains unclear. The goal of our study was to assess the incidence and duration of PSA decreases after stopping AA. Methods: We reviewed 51 patients with CRPC who had discontinued AA therapy at a single institution (6/2009-6/2014). PSA values were assessed before, during, and after stopping AA therapy. Response was defined as >50% PSA decline post-AA stoppage, with no additional therapy added. Results: From 51 patients treated with AA, only 22 (43%) were eligible for withdrawal response evaluation. A total of 29 patients (57%) were changed to alternate therapies too soon for withdrawal response evaluation. Of the 22 evaluable patients, AA withdrawal was seen in 2 patients (9%). The first patient had a 72% reduction in PSA upon discontinuation of AA, with PSA dropping from 330 (ng/mL) to 93 over 16 days. Previously administered dexamethasone was continued. He had been on AA therapy for 12 months. Time to next treatment was only 1 month so PFS was not ascertainable. The second patient had a 60% reduction in PSA after simultaneously discontinuing both AA and prednisone. His PSA declined from 25.1 to 9.9 over 2 months. He had received only 2 prior months of AA and prednisone and had a clear PSA rise during this therapy. PFS after AA and prednisone discontinuation was 3 months. Time to next treatment was 6 months. Neither patient who responded to AA withdrawal had a prior bicalutamide withdrawal response. Conclusions: PSA response to AA withdrawal is a known, but poorly understood phenomenon that occurs in a subset of patients. Larger studies with longer follow-up are needed to define the incidence of this observation. The potential role of glucocorticoids in this process needs additional elucidation.
Safety and efficacy of 2-weekly cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Clement-Zhao Alice , Auvray Marie , Verret Benjamin , Vano Yann Alexandre , Angelergues Antoine , Oudard Stephane
Published: February 2017

284

Background: Cabazitaxel (C) administered on a 3-weekly dose schedule has shown a survival benefit in mCRPC patients (pts) pre-treated with docetaxel (D) with concerns about toxicity. We sought to evaluate safety and efficacy of a 2-weekly C schedule. Methods: At the EGP hospital from November 2013 to September 2014, 26 mCRPC pts for whom C was indicated (previously treated with D) received C 16 mg/m² on days 1 and 15 of a 4 weeks-cycle plus daily 10 mg prednisone, until completion of 6 cycles, disease progression, unacceptable toxicity or death. We analyzed safety with toxicity grade ≥ 3 and efficacy, including PSA response, time to biochemical progression (TTBP), radiological progression-free survival (rPFS) and overall survival (OS). Results: 26 pts received C in a 2-weekly schedule; full data are available for 20 pts. Median age was 66.5 years, 34.6% of pts were >70 years; 30.8% had ECOG PS 2; 47.8% had Gleason ≥ 8; 53.8% had lymph node metastases; 96.2% had bone metastases; none had lung or liver metastases. Median D cycles previously received were 6; respectively 80% and 88.4% of pts had received ≥ 2 hormonal manipulations and abiraterone acetate (AA). Median baseline hemoglobin was 12.2 g/dL, median PSA 104.6 ng/mL; 42.9% of pts had ALP ≥ 1.5N, 33.3% had LDH ≥ 1.5N. 4 pts (15%) had grade 1 thrombocytopenia at baseline, 1 (3.8%) had grade 4, reflecting diffuse bone marrow involvement. All pts received G-CSF in primary prophylaxis. Median number of C administration was 7, only 4 pts stopped C because of toxicity (2 for asthenia, 1 for febrile neutroepnia, 1 for thrombocytopenia). Toxicities grade ≥3 were: anemia 33.3%; thrombocytopenia 30%; neutropenia 23.8%; febrile neutropenia 5% (1 pt); no grade ≥3 diarrhea was observed. 45% (9 pts) achieved ≥30% PSA response and 30% (6 pts) ≥50% PSA response. Clinical, biological or radiological response occurred in 50% (10 pts). Median TTBP and rPFS were 3.0 months (2.2-3.6) and 4.2 months (2.8-7.4) respectively. Median OS was not reached at the time of data collection. Conclusions: 2-weekly 16 mg/m² C schedule has a manageable toxicity profile in heavily D and AA pretreated mCRPC pts, and warrants controlled prospective evaluation compared to the standard 3-weekly C schedule.
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

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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, 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.
A comparison of the outcomes after neoadjuvant (NC) or adjuvant chemotherapy (AC) for muscle-invasive urothelial bladder cancer (UC): A French contemporary retrospective multicenter cohort.
Authors: Pouessel Damien , Chevret Sylvie , Roubaud Guilhem , Aarab-Terrisse Safae , Chevreau Christine , Vordos Dimitri , Rolland Frederic , Boudin Laurys , Joly Florence , Joly Charlotte , Beuzeboc Philippe , Boyle Helen Jane , Farneti Delphine , Dauba Jérôme , Moriceau Guillaume , Alexandre Ingrid , Deplanque Gael , Loriot Yohann , Houede Nadine , Culine Stephane
Published: February 2017

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Background: Our aim was to investigate outcome of patients (pts) treated with AC or NC for organ-confined UC, or with NC for clinical lymph node involvement (cN+). Methods: We retrospectively analyzed 482 pts treated in 22 French hospitals between 2000 and 2013 in 3 settings: 226 pts with radical cystectomy (RC) and AC (AC group), 193 cN0 (NC group), and 63 cN+ (cN+ group) pts received NC before a planned RC for cT2-T4, M0 UC. The primary outcome was overall survival (OS). Cancer-related survival (CRS) was also evaluated. Multivariate Cox proportional hazards regression was used to estimate adjusted hazard ratios with 95% confidence interval. Results: Median age was 62, 61.7, and 62.1 in AC, NC, and cN+, respectively. Median time between diagnosis and first treatment (RC or NC) was 2.1, 1.4 and 1.6 months, respectively (p<0.001). In AC, stages were p≤T2 (n=46) or pT≥3 (n=180), pN0 (n=37), pN+ (n=168), or pNx (n=21). Gemcitabine-cisplatin and gemcitabine-carboplatin regimen were mainly delivered as AC in 71.2% and 21.7% of pts. In NC, all pts received methotrexate-vinblastine-doxorubicin-cisplatin (MVAC) or dose-dense MVAC. Median number of cycles was 4 in each group. After NC, RC has been realized in 173 (90%) and 51 pts (82%) in NC and cN+, respectively. In 17 unoperated pts, concomitant chemoradiotherapy was performed. Median follow-up was 24.6 months. Respectively, 133 (59%), 61 (32%), and 22 (35%) pts have relapsed in AC, NC, and cN+; 74%, 63%, and 71% of them received chemotherapy for metastasis. Also 133 (59%), 41 (21%), and 18 (29%) pts died, mostly (90%) due to recurrence. Three-year OS and CRS rates were 54%, 68%, and 56% (p=0.02), and 37%, 53%, and 49% (p=0.038) in AC, NC, and cN+, respectively. In multivariate analysis, only AC (HR: 1.64, 95% CI 1.18-2.30, p=0.001) remained significantly associated with shortened OS. Conclusions: In this large retrospective study reporting real-life survivals, 3-year OS was longer in pts receiving NC, both in cN0 and in cN+ groups, than in pts treated with AC. Although several selection bias can be emphasized preventing us from drawing definitive conclusions, AC appeared to be associated with a poorer prognosis.
Circulating tumor cells (CTC) as potential biomarkers in neoadjuvant chemotherapy of muscle invasive bladder cancer (MIBC).
Authors: Alva Ajjai Shivaram , Daignault-Newton Stephanie , Huebner Tamara , Clark Melanie , Hussain Maha , Ionescu Cristian , Schwartz Mike
Published: February 2017

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Background: Biomarkers to assess early response to cisplatin based neoadjuvant chemotherapy (NAC) in MIBC is a clinical need. We hypothesized that CTC enumeration and genomic profiling using a novel microfluidic immunomagnetic assay IsoFlux (Fluxion Biosciences Inc., CA) could provide novel biomarkers in individual patients during NAC. Methods: Peripheral blood was drawn at baseline and after one cycle (3-4 weeks) of NAC in patients (pts) with locally advanced resectable bladder cancer in an IRB approved prospective study at the University of Michigan. CTCs were enumerated by the CellSearch and IsoFlux assays in parallel and by IsoFlux in duplicate samples. We correlated CTC numbers with pStage at cystectomy, a known prognostic variable for survival. We assessed gene expression by RT-PCR and gene mutational status by Ion Torrent sequencing on CTCs. Results: We analyzed 21 pts with localized muscle invasive bladder cancer (cT2-T4aNx). Mean age was 65 yrs with 84% male. Clinical stage was 71% cT2N0, 14% cT3N0, 10% cT4N0, 5% cT4aN1. NAC was GC in 9 pts and MVAC in 12 pts. The IsoFlux assay detected more CTCs per sample than CellSearch at baseline (median =10 vs. 0, n=5) and after 1 cycle (5.5 vs. 0, n=4). IsoFlux assay in parallel tubes had 80% of samples with <5 CTC difference between the pairs. Baseline CTC concordance with pStage was 75% (12/16) (concordance=either <pT1N0 with <10 CTCs or ≥ pT1N0 with ≥10 CTCs). On the other hand, concordance of cStage with pStage was only 62.5% (10/16). PDGFRA, PIK3CA and MET mutations were detected on CTCs. Interrogation of CTCs for gene expression by RT-PCR and application of next generation sequencing (NGS) to CTCs were feasible. Conclusions: IsoFlux detects more CTCs than CellSearch in patients undergoing NAC. Baseline CTC number is a potential prognostic variable superior to cStage. However, changes in CTC number before and after 1 NAC cycle do not appear to reflect benefit in individual patients. Gene expression and genomic profiling of CTCs are feasible. CTCs are potential liquid biopsies in patients undergoing NAC in bladder cancer.
Impact of first-line cisplatin versus non-cisplatin based chemotherapy on progression-free survival in patients with advanced urothelial carcinoma previously treated with perioperative cisplatin based chemotherapy.
Authors: Locke Jennifer A , Pond Gregory Russell , Sonpavde Guru , Necchi Andrea , Giannatempo Patrizia , Paluri Ravi Kumar , Niegisch Guenter , Albers Peter , Buonerba Carlo , di Lorenzo Giuseppe , Vaishampayan Ulka N. , North Scott A. , Agarwal Neeraj , Hussain Syed A. , Eigl Bernhard J.
Published: February 2017

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Background: Perioperative cisplatin based chemotherapy (PCBC) is a standard of care in the management of muscle invasive urothelial carcinoma (UC). Cisplatin based (C) therapy also represents the historical first line treatment of metastatic disease. There is however no data to guide the optimal choice of first line chemotherapy regimen – C re-treatment vs other second-line or non cisplatin regimens (NC) –in UC patients who relapse after receiving PCBC. This multicenter retrospective study compares C vs NC first line treatment on progression-free survival (PFS) for patients (pts) with advanced UC after PCBC and cystectomy. Methods: Data were collected for patients who received various first-line chemotherapies for advanced UC following previous PCBC therapy. Cox proportional hazards models were used to investigate the prognostic ability of type of peri-operative / first-line chemotherapy, visceral metastasis, ECOG status, time from prior chemotherapy (TFPC), anemia, leukocytosis and albumin on PFS. Results: Data were available for 145 pts from 12 centers. The mean age was 62 years, 113 (77.9%) were men and ECOG-PS was 0 or >0 in 74 (51.0%) and 61 (42.0%) patients. Ninety-one (62.8%) pts received C first line, the median number of cycles was 4 (range 1-17) and the median TFPC was 6.2 months (range 1-154). Median overall survival was 86 weeks (95% CI 70-106) and median PFS was 24 (95% CI 18-27) weeks. Time from perioperative chemotherapy (TFPC) (>52 weeks vs ≤52 weeks; HR 0.63 p=0.027) and ECOG-PS at first line (1+ vs 0; HR 1.73 p=0.010), were prognostic of PFS. No significant effect was noted for C vs NC first line (p=0.70); however, among patients with TFPC >52 weeks, patients with NC had worse PFS (median 4.6 months, 95% CI 1.8-12.2) than those who received C (median 8.1, 95% CI 3.2-16.3). Conclusions: There is no evidence to suggest overall superiority of C vs NC based first line chemotherapy or a second-line regimen in patients with advanced UC who received prior PCBC. However, those with TFPC >52 weeks should probably receive C first line chemotherapy given better PFS with C.
Platinum concentration in bladder tissue treated with neoadjuvant chemotherapy and pathologic response.
Authors: Guancial Elizabeth A. , Kilari Deepak , Messing Edward M. , Kim Eric S.
Published: February 2017

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Background: Platinum (Pt) resistance is a major limitation in the treatment of muscle-invasive bladder cancer (MIBC), for which Pt-based chemotherapy remains the standard of care. Reduced intratumoral drug accumulation is an important mechanism of platinum resistance. Our previous studies in lung cancer demonstrate significant correlation between tissue Pt concentration and tumor response to neoadjuvant chemotherapy (NAC). Tissue Pt concentration was measured in bladder specimens exposed to Pt-based NAC and correlated to pathologic response. Methods: A cohort of 19 clinically annotated, archived frozen bladder specimens from MIBC patients treated with three to four cycles of Pt-based NAC was identified [pT0 (pathologic complete response, pCR), n=4; pTis or pT1 (pathologic partial response, pPR), n=6; >/= pT2 (minimal pathologic response/progression), n=9]. Two cystectomy specimens from MIBC patients treated with Pt-based adjuvant therapy were used as controls. Non-tumor bearing adjacent bladder tissue (“normal”) was identified in cystectomy specimens by a genitourinary pathologist. Total Pt concentration in normal tissue was measured by flameless atomic absorption spectrophotometry. Three group Kruskal-Wallis tests were used to compare the distributions of Pt concentrations by pathologic response (pCR, pPR, minimal response/progression). Mann-Whitney non-parametric two-sided tests were used for two group comparisons. Results: Total Pt concentration in normal adjacent bladder tissue differed by tumor pathologic response (p=0.011). Specimens with a pCR had the highest Pt concentrations compared to those with a pPR (p=0.0095) or no response/progression (p=0.0196). There was no significant difference in Pt levels between PR and no response/progression group (p=0.37). Conclusions: Our findings suggest that enhanced Pt accumulation may be an important determinant of Pt sensitivity. Studies investigating factors that modulate intracellular Pt concentration, such as expression of influx/efflux Pt transporters, may serve as predictive biomarkers and promote increased use of Pt-based NAC.
Long-term effects of Bacilles Calmette-Guerin perfusion therapy for upper urinary tract urothelial carcinoma in situ.
Authors: Yoneyama Takahiro , Tobisawa Yuki , Yoneyama Tohru , Yamamoto Hayato , Imai Atsushi , Mori Kazuyuki , Hatakeyama Shingo , Hashimoto Yasuhiro , Koie Takuya , Ohyama Chikara
Published: February 2017

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Background: Bacillus Calmette-Guerin (BCG) therapy has already been established as a treatment for muscle noninvasive bladder cancer. Although there are several reports indicating the effectiveness of BCG perfusion therapy for the upper urinary tract urothelial carcinoma in situ(CIS), it is not well established yet. We conducted a retrospective study to assess the long-term effects of BCG perfusion therapy for the upper urinary tract CIS. Methods: Thirty-one subjects (24 male, 7 female) who received BCG perfusion therapy for the upper urinary tract CIS from December 1997 to December 2013 were enrolled. 11 subjects had the entire urinary tract CIS, 8 had bilateral, 12 had unilateral CIS of the urinary tract. The average period of observation was 49.9 months (ranging from 5 to 196 months), and the average subject age was 74.8 years (ranging from 56 to 90 years). We used a double-J catheter for 22 cases, a transvesical single-J catheter whose curl was positions in an upper calyx for 8 cases, and a straight ureteral catheter inserted for ureterocutaneostomy for 1 case. We used 80 mg of BCG for the first five cases, 40 mg for the late 26 cases. Urine cytology was performed to assess the treatment validity. Results: Of the 31 cases, the treatment protocol was completed in 27 cases. Urine cytology tests became negative in 25 of the 31 subjects (80.7%) who underwent upper urinary tract perfusion. Among these 22 subjects who had negative tests, 8 subjects had a recurrence in their upper urinary tracts. Side effects were observed in 28 subjects (90.3%), and the most common side effect was bladder irritation. Localized renal tuberculosis, which was successfully treated with conservative therapy, was seen in two cases. Conclusions: BCG perfusion therapy for the upper urinary tract CIS is effective. However, severe side effects are possible, and careful observation is essential while using this therapy.
Complication rates in patients with uncontrolled diabetes undergoing radical cystectomy: A population-based study.
Authors: Faiena Izak , Dombrovskiy Viktor Y. , Sultan Raymond C. , Barbalat Yanina , Salmasi Amirali H. , Singer Eric A. , Weiss Robert E.
Published: February 2017

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Background: Radical cystectomy is known to be associated with a relatively high incidence of postoperative morbidity and mortality. We evaluated the complication rates of a population-based cohort of patients with uncontrolled diabetes who underwent radical cystectomy. Methods: The data for this analysis was captured from the NIS (Nationwide Inpatient Sample) 2002-2009. Among patients who underwent radical cystectomy (ICD-9 diagnosis code 188.x and 57.71), we selected those with uncontrolled diabetes, which is defined by the billing physician (ICD-9 diagnosis code 250.02) and compared to patients without diabetes. We also identified postoperative complications. Patient socio-demographic characteristics, principal and secondary diagnoses, principal and secondary procedures, comorbid diseases, disposition of patient at discharge, hospital length of stay, and hospital cost for our analysis. A chi-square test was employed for categorical variables and Student’s t-test for continuous variables. A multivariable logistic regression analysis was also employed with computing OR and 95% CI. P<0.05 was considered statistically significant. Results: There were significant differences in the postoperative outcomes between groups. In the univariable analysis, patients with uncontrolled diabetes were more likely to have complications (OR=3.21; 95%CI= 2.59-4.00) including infectious complications (OR=2.46; 95%CI= 1.98-3.06) and were more likely to die during the index hospitalization (OR=3.27; 95%CI= 1.41-7.61). Hospital resource utilization was also significantly greater in patients with uncontrolled diabetes. Mean length of stay in this group was 17.3 days compared to 11.4 days in non-diabetic group (P=0.0007); total hospital cost was, respectively, $47,960 and $32,422 (P=0.0009). Conclusions: This study demonstrates a significant association between uncontrolled diabetes and in-hospital post-cystectomy complications, mortality, and hospital resource utilization. This study highlights the recognition of uncontrolled diabetes as a potential modifiable risk factor for patients undergoing cystectomy.
Impact of perioperative blood transfusion on oncologic outcomes in patients treated with radical nephroureterectomy for upper tract urothelial carcinoma.
Authors: Bagrodia Aditya , Kaffenberger Samuel D. , Vacchio Michael J , Murray Katie S , Winer Andrew G. , Cha Eugene K. , Sankin Alexander , Dalbagni Guido , Coleman Jonathan A.
Published: February 2017

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Background: Patients treated for urothelial carcinoma of the urinary bladder treated with radical cystectomy and pelvic lymph node dissection have worse clinical outcomes if they receive perioperative blood transfusion. We evaluated the impact of perioperative blood transfusion on oncologic outcomes in patients with upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU). Methods: We conducted a single-center, retrospective review of 405 patients treated with RNU for UTUC. Clinicopathologic characteristics were recorded. Hospital charts were reviewed to determine if patients received perioperative blood transfusion. Characteristics were compared between groups based on transfusion status using Chi-square analyses. Survival was assessed using the Kaplan-Meier method. Cox regression analysis addressed cancer-specific mortality (CSM). Results: Median age was 71.4 years (IQR 63.7-76.5) and the majority of patients were male (64%). Median follow up was 43.4 months (IQR 16.7-86.6). CSM occurred in 26.2% of patients. Perioperative transfusion was associated with higher rates of invasive T stage (>/=T2), (62% vs. 47%, p=0.019) and lymph node positive disease (23% vs. 10.3%, p=0.029). Three year disease-specific survival (DSS) was 80% for the entire cohort. DSS was significantly shorter (p=0.003) for patients receiving transfusion (66.3%, 95% CI 53.7%-76.3%) than those who did not (83.3%, 95% CI 78.3%-87.3%). Transfusion was an independent predictor of CSM on multivariable analysis including gender, grade, invasive T stage, nodal status, and transfusion (Table 1). Conclusions: Perioperative blood transfusion may be associated with adverse pathologic and oncologic outcomes in patients undergoing RNU for UTUC. [Table: see text]