bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I/II randomized study of panobinostat and bicalutamide in castration-resistant prostate cancer (CRPC) patients progressing on second-line hormone therapy.
Authors: Ferrari A. C. , Stein M. N. , Alumkal J. J. , Gomez-Pinillos A. , Catamero D. D. , Mayer T. M. , Collins F. , Beer T. M. , DiPaola R. S. ,   The Prostate Cancer Clinical Trials Consortium
Published: February 2017

156

Background: Aberrant expression and function of the androgen receptor (AR) is determinant of CRPC progression. We previously demonstrated that the histone-deacetylase inhibitor panobinostat (PAN) decreased AR levels and reversed resistance of androgen-independent AI-LNCaP and Rv1 cells to the antiandrogen bicalutamide (Bic). We designed a ph-I/II study to determine whether PAN would restore the sensitivity to Bic in CRPC patients (pts). We report the ph-I results evaluating safety and maximum tolerated dose (MTD) of Bic combined with oral, intermittent PAN.

Methods: Men with CRPC and limited bone metastasis, ECOG PS 0-2, PSA>2 ng/ml (or <2 + new metastases), adequate organ function and QTc<450 ms progressing on at least two prior hormones including antiandrogens were assigned each to one of 3 cohorts (C) for treatment with Bic 50 mg PO daily with oral PAN at 3 dose levels: C1, 20 mg tri-wkly (60 mg/wk) 2 of 3 wks; C2: 30 mg tri-wkly (90mg/wk) 2 of 3 wks, 40 mg PO tri-wkly (120mg/wk) 3 of 3 wks. Cycles (Cy) repeated every 21 days. Minimum treatment was 3 wks. Treatment could continue if clinical benefit. DLT were: grade (G) 3-4 febrile neutropenia >5 days and/or hospitalization; G3 thrombocytopenia with bleeding; QTcF>500 ms any G4 except nausea, vomiting, or diarrhea.

Results: Nine men, median (m) 65 yrs were treated in cohorts of three. mPSA at entry 9.26 ng/mL (IQR:8.24), mCy number, 6 (IQR: 5). MTD was not reached. All experienced some grade of toxicity attributable to PAN. Toxicity: no G4, only G3 was thrombocytopenia without bleeding in 3 pts (1 in C1, 2 in C3) that resolved spontaneously and controlled by dose reduction; G2: thrombocytopenia in 3, fatigue 2, high cholesterol 2, hypothyroidism 2; G1 thrombocytopenia in 2, fatigue 3, dyspepsia 3, anorexia 2. PSA decline ≥50% was achieved in 2 pts, stable PSA in 3 pts. Ph-II recommended PAN doses: Arm A: 40 mg tri-wkly (120 mg/wk) 2 of 3 wks; Arm B: 20 mg tri-wkly (60 mg/wk) 2 of 3wks with Bic 50 mg/daily.

Conclusions: Oral, intermittent PAN in combination with daily Bic is well tolerated in CRPC pts progressing on second line hormones and shows promising PSA responses suggesting anti-AR activity. Ph-II is ongoing.

[Table: see text]
Elderly patients with metastatic castrate-resistant prostate cancer (mCRPC): Safety and efficacy of docetaxel retreatment.
Authors: Gernone A. , Pagliarulo A. , Calderoni G. , Pagliarulo V.
Published: February 2017

161

Background: Comorbidities are considered a therapeutically limiting problem in elderly patients (pts) with mCRPC. We analysed correlations between comorbidity, toxicity and efficacy of docetaxel re-treatment in pts ≥ 70 years with mCRPC.

Methods: Pts were evaluated according to comprehensive geriatric assessment (CGA). From 2003 to 2010, 70 pts ≥ 70 years with mCRPC received 3-wk first line docetaxel therapy followed by retreatment on biochemical disease progression. Each patient was assessed according the Cumulative Illness Score Rating-Geriatrics (CISR-G) manual. The score was 0-4. The median age was 77 (70-84), ECOG PS 0-2, median baseline PSA 180 ng/ml (15-1200). The more frequent comorbidities were hypertension, diabetes, arrhythmias, chronic obstructive pulmonary disease. The endpoints were: PSA response proportion to first-second-third line chemotherapy, median survival in responding patients and toxicity.

Results: All pts received a standard 3-wk regimen, dose was reduced by 25% for pts score 4. The incidence of adverse events was relatively low and no pts died on therapy. There were no episodes of neutropenic fever. Pts with score 1-2 were 70% (49 pts); pts with score 3 were 20% (14); pts with score 4 were 10% (7). 70 pts (score 0-4) received first line docetaxel chemotherapy with a median no of cycles 14 (6-18), a median survival of 18 months (mos), PSA response 70%. Of these pts 26 (score 0-3) were re-treated with the same regimen with no of cycles 12 (8-18), a median survival of 14 mos, PSA response 45%, duration of first chemotherapy holiday 5 mos (median). Of these pts, 4 (score 0-3) received third line treatment with no of cycles 10 (6-14), a median survival of 10 mos, PSA response 22%, duration of second chemotherapy holiday 4 mos (median). Of these pts only 1 (score 1) received third re-treatment with 8 cycles, PSA response 20%, third chemotherapy holiday 4 mos. 80% of symptomatic pts reported an improvement in symptoms control with docetaxel chemotherapy.

Conclusions: Re-treatment with docetaxel is safe in mCRPC elderly pts despite the association of important comorbidities. Median survival in responding pts was approximately 40 mos from the first to the third line.

No significant financial relationships to disclose.
A randomized phase II study of flutamide with or without PSA-TRICOM in nonmetastatic castration-resistant prostate cancer (CRPC).
Authors: Bilusic M. , Gulley J. L. , Heery C. , Apolo A. B. , Arlen P. M. , Rauckhorst M. , McMahon S. , Dahut W. L. , Schlom J. , Madan R. A.
Published: February 2017

163

Background: PSA-TRICOM is a vector-based, therapeutic cancer vaccine regimen consisting of recombinant poxviruses containing the transgenes for prostate-specific antigen (PSA) and 3 T-cell co-stimulatory molecules (TRICOM). A previous randomized, placebo-controlled phase II study demonstrated an 8.5-month improvement in median survival (25.1 months for PSA-TRICOM group vs. 16.6 months for control group) in men with metastatic CRPC.

Methods: This study is currently enrolling patients with non-metastatic CRPC on testosterone suppression therapy who have a rising PSA. Patients are stratified by PSA doubling time and randomized to androgen receptor antagonist alone (flutamide) or flutamide plus PSA-TRICOM. Flutamide is given at the standard dose of 400 mg TID while PSA-TRICOM is given by monthly subcutaneous injections. The primary endpoint of the study is time to treatment failure (TTF) which is defined as biochemical recurrence (PSA rise) or development of metastatic lesions on scans.

Results: The first 26 patients enrolled are evaluated in this analysis. For flutamide alone (n = 13), the median age at enrollment was 64.7 years and median Gleason Score was 8. For flutamide + PSA-TRICOM (n = 13), the median age at enrollment was 67.1 years and median Gleason score was 8. Median time to progression is 223 days for Fluatmide + PSA- TRICOM (range 70-638) vs. 85 days for Flutamide alone (56-372). Progression for 11/12 flutamide alone patients and 9/10 fluatmide + PSA-TRICOM patients has been by PSA rise only.

Conclusions: Preliminary evidence suggests improvement in time to treatment failure using combination of hormonal therapy with flutamide + PSA-TRICOM vaccine compared to fluatmide alone in patients with non-metastatic CRPC. This trial will continue to accrue a total of 62 patients and also will evaluate immunological responses.

No significant financial relationships to disclose.
Agent orange as a risk factor for positive prostate biopsy.
Authors: Ansbaugh N. J. , Shannon J. , Mori M. , Farris P. E. , Collins L. , Garzotto M.
Published: February 2017

178

Background: Agent Orange (AO), a defoliate contaminated with the known carcinogen dioxin, has become a prominent concern as veterans of the Vietnam War who were exposed to AO are now reaching the age at which prostate cancer is most prevalent. While sufficient evidence has linked AO exposure to many diseases, only limited but suggestive evidence exists to support a positive association between AO and prostate cancer. Despite mixed findings, recent studies have found that the risk of prostate cancer in those exposed to AO was as high as twice the risk in those not exposed. The goal of this study was to examine this association between AO exposure and prostate cancer in a cohort of men referred for a prostate biopsy.

Methods: In this retrospective cohort-design, risk factors were identified using historical clinical data from a population of veterans referred to the Portland VA Hospital for a prostate biopsy between 1993 and 2010. In addition to AO exposure, covariates included prostate specific antigen density (PSAD), results of the digital rectal exam (DRE), age at biopsy, family history, body mass index (BMI), race, and medication use. Outcomes of the biopsies were defined as either positive or negative according to the pathology report and risk factors were compared between individuals found to have prostate cancer and those without cancer. Multiple logistic regression was used to evaluate the effect of AO on risk of prostate cancer after adjustment for confounders.

Results: Of the 2,720 veterans who underwent prostate biopsy, 896 (32.9%) were found to have prostate cancer. After adjustment for significant confounders including PSAD, DRE, age at biopsy, and family history of prostate cancer, veterans with prostate cancer were 49% more likely to have been exposed to AO as compared to those without prostate cancer (odds ratio = 1.49; 95% CI: 1.06-2.11, p=0.022).

Conclusions: Agent Orange exposure was associated with a significant increase in prostate cancer detection in men referred for a prostate biopsy. The limitations in identifying biologically significant levels of AO exposure in this study may suggest potential for underestimation of the true risk. This study supports the findings of recent studies suggesting that AO exposure increases the risk of prostate cancer.

No significant financial relationships to disclose.
Prostate cancer–specific mortality after definitive radiation therapy: Who dies of disease?
Authors: Kim M. M. , Hoffman K. E. , Levy L. B. , Frank S. J. , Choi S. , Nguyen Q. N. , Pugh T. , McGuire S. E. , Lee A. , Kuban D. A.
Published: February 2017

181

Background: A competing risks analysis was undertaken to identify patient subgroups at greatest risk of dying from prostate cancer (CAP) after treatment with definitive external beam radiation therapy (RT) +/− androgen deprivation therapy (ADT) in the PSA era, and to determine which factors predict for survival from disease.

Methods: A total of 2,675 men with localized CAP treated with RT +/− ADT at M. D. Anderson Cancer Center from 1987-2007 were evaluated. Prostate cancer-specific mortality (PCSM) and other cause mortality rates were calculated after stratifying patients according to NCCN risk group, RT dose, use of ADT, and age at treatment. In total, 21% had low-risk, 40% had intermediate-risk, and 39% had high-risk disease. Multivariate analysis (MVA) was performed using Cox regression modeling.

Results: Median age was 68.5 years and median follow-up was 6.4 years. For patients with low-risk disease, only 0.2% died of CAP 10 years after treatment. None of the low-risk patients <70 years old who received ≥72 Gy died of CAP. The majority of deaths in the intermediate-risk group were also due to other causes; men ≥70 years old who received <72 Gy had the highest 10-year PCSM (5%). High-risk patients <70 years old who received <72 Gy without ADT had similar 10-year rates of CAP (15.2%) and non-CAP (18.5%) mortality. Men with high-risk disease <70 years old treated with higher doses >72 Gy were twice as likely to die from non-CAP causes (15.9%) than die from CAP (8.6%). In older men ≥70 years old with high risk disease, dose-escalation with ADT reduced 10-year PCSM from 14% to 4%, and most deaths were due to other causes (41% and 20%). On MVA, dose (p=0.002), ADT (p=0.007), PSA (p<0.0001) and Gleason score (p<0.0001) were predictive of PCSM in the high-risk group.

Conclusions: Men with low- and intermediate-risk CAP treated with definitive RT are unlikely to die of disease. PCSM is higher in men with high-risk disease but can be reduced with dose escalation and ADT, although patients are still twice as likely to die of other causes.

No significant financial relationships to disclose.
Prostate cancer screening and incidence among men younger than age 50.
Authors: Li J. , German R. , King J. , Joseph D. , Thompson T. , Wu X. , Tai E. , Ajani U.
Published: February 2017

183

Background: Prostate cancer has long been considered as a disease of older men. However, age at diagnosis with prostate cancer has continued to decline. Since the introduction of prostate-specific antigen (PSA) test in 1986, the prostate cancer incidence rate has steadily and dramatically increased in men under age 50. This study aims to better understand demographic variations in prostate cancer screening and incidence, and clinical characteristics of prostate cancers in men under age 50.

Methods: We examined prostate cancer testing data from the Behavioral Risk Factor Surveillance System (2002, 2004, 2006, and 2008) and prostate cancer incidence data from the CDC's National Program of Cancer Registries and the NCI's Surveillance, Epidemiology, and End Results programs (2001-2006). We estimated the weighted percentage of self-reported cancer testing using SUDAAN and age-adjusted cancer incidence rates and trends using SEER-STAT. Statistical significance for trends was determined by the annual percentage change (APC) differing form zero.

Results: A total of 29,176 prostate cancer cases were identified from 2001-2006 among men under age 50. Of these, 551 (1.9%) were among men under age 40. Incidence rates remained stable from 2001-2006; however the incidence of well-differentiated tumors decreased significantly (APC=−24.7) during this time period. About 44% of men aged 40-49 years old reported having a prostate cancer test in the past two years. Prostate cancer testing and incidence rates were highest among men who were black, non-Hispanic, or lived in the northeast. Black men had more than a 2-fold increase in cancer incidence than white men.

Conclusions: The magnitude of prostate cancer testing and incidence in men under age 50 reveals significant health/public health problems in this younger population. This study demonstrates substantial regional differences in prostate cancer testing and incidence in men under age 50. It also confirms that prostate cancer testing and incidence varies by race and ethnicity. We observed a large disparity in prostate cancer incidence between blacks and whites. The incidence rate remained stable over time; the dramatic decrease occurred in well-differentiated cancers.

No significant financial relationships to disclose.
Prostate cancer hypoxia as a predictor of early biochemical and local failure after radiotherapy.
Authors: Milosevic M. , Bristow R. G. , Menard C. , Chung P. W. , Bayley A. , McLean M. , Toi A. , Gospodarowicz M. K. , Catton C. , Warde P. R.
Published: February 2017

20

Background: Tumor hypoxia is an important determinant of patient outcome in many human malignancies, and has been associated with radioresistance and the development of metastases. The aim of this study was to determine the predictive effect of hypoxia in prostate cancer patients treated with RT.

Methods: A total of 256 patients with clinically localized prostate cancer underwent pre-treatment, transrectal, ultrasound-guided measurement of tumor oxygen using a needle electrode. The median pO2 (mpO2) was 6.7 mm Hg and the median hypoxic proportion <10 mm Hg (HP10) was 0.63. Most patients were treated with IMRT to the prostate alone using doses in the range of 75.6-79.8 Gy. Sixty-one received neoadjuvant and concurrent hormonal therapy. The Phoenix definition of biochemical relapse was used, and the median follow-up was 5.4 years.

Results: The 5-year bRFR was 78%. High PSA and Gleason score were independently associated with biochemical relapse, and formed the baseline clinical multivariate model. The effect of hypoxia was found to vary with the duration of patient follow- up. HP10, when added to the clinical multivariate model as a time-dependent variable, was a significant, independent predictor of early bRFR (p=0.015). The predictive effect of hypoxia diminished with increasing follow-up and was lost by 36 to 48 months. The relationship between hypoxia and early biochemical recurrence was more pronounced when the analysis was restricted to 144 patients with bulk tumor at the site of the oxygen measurements (p=0.008). Prostate biopsy was performed in 73 patients a median of 36 months after completing RT. Hypoxia was the only factor predictive of local recurrence in this sub-group, with the effect being greatest early in follow-up (p=0.038).

Conclusions: This is the largest clinical study of prostate cancer hypoxia with direct measurement of tumor oxygen levels. It suggests that hypoxia in the index tumor increases the risk of recurrence early after completing RT but not at longer times. The results imply a complex interaction between hypoxia and local vs. distant failure, which may be better elucidated with longer follow-up.

No significant financial relationships to disclose.
Primary genitourinary small cell carcinoma: Clinicopathologic and survival outcomes from SEER database.
Authors: Thota R. , Birdsong S. , Subbiah S.
Published: February 2017

200

Background: Small cell carcinoma of genitourinary system (SCC) is a highly aggressive and rare entity. The aim of the study is to characterize the clinicopathologic characteristics and evaluate the treatment outcomes of SCC in adult patients.

Methods: Retrospective analysis of 732 patents diagnosed with small cell carcinoma of bladder from 1973 to 2007 was done via SEER database. Demographics, stage, type of treatment received and cancer-specific mortality were examined.

Results: 732 patients were identified with SCC of genitourinary tract of which 341 were small cell bladder cancer, 336 were small cell prostate cancer and 55 were small cell renal cancer. Of these 644 patients were males and 88 were females. Median age of diagnosis is 73 years for bladder, 72 years for prostate and 70 years for renal cancer. Majority of the patients were Caucasians (89%) followed by African Americans (6%) and other races (4.98%). Grading of the tumor revealed that 12 patients had well differentiated tumor, 18 patients had moderately differentiated tumor, 191 patients had poorly differentiated, 292 patients had undifferentiated tumor and 219 patients had unknown grade. Pathological T-stages were as follows: T1= 34 (4.6%), T2= 102 (14%), T3= 43 (9%), T4= 41 (5.6%), 38.4% unknown T stage and 67 (9%) patients had metastatic disease. In majority of the patients the treatment received was unknown (565), 90 patients received external beam radiation, and 76 patients received surgery. Cancer-specific mortality was 54% in bladder cancer, 71% in prostate cancer and 78.6% in renal cancer. Median overall survival for all stages was 15.8 months in bladder cancer, 11.3 months in prostate cancer and 8 months in renal cancer.

Conclusions: Results show that SCC is a highly aggressive tumor with poor prognosis. Clinical trials involving multiple institutes are needed to accrue enough patients so that treatment paradigms for this uncommon disease can be developed.

No significant financial relationships to disclose.
Significant interaction between testosterone recovery (TR) and biochemical progression-free survival (BPFS) in intermediate- and high-risk patients with prostate cancer treated with radiation therapy (RT) and androgen deprivation therapy (ADT).
Authors: Shasha D. , Nabhani T. , Rauth S. J. , Salant R. , Harrison L. B.
Published: February 2017

202

Background: To examine the interaction testosterone-recovery-free survival (TRFS) and BPFS in patients with intermediate and high-risk prostate cancer treated with combined external beam radiation therapy (EBRT), prostate implant (PI), and ADT.

Methods: We prospectively collected data between 1998 and 2010 from 1,564 patients with clinically localized prostate cancer treated by a single physician (DS). 294 patients with NCCN intermediate or high-risk prostate cancer were treated with EBRT, PI, and ADT. 60% of these patients had intermediate-risk disease. Initial prostate-specifc antigen (PSA), Gleason Score (GS), AJCC tumor stage (TStage), and RT parameters were recorded. PSA, and testosterone (T) were measured at each follow-up visit. BPFS was scored using the Phoenix definition. Testosterone recovery occurred when the serum T level rose above 150ng/ml. TR was dichotomized at 2 years. Survival was evaluated using Cox-regression analysis.

Results: Median age was 66 yrs-old, intraquartile range (IQR) was 60-71. Median ADT duration (ADTD) was 1.31 years (IQR 0.25-2.35). Testosterone recovery (TR) was seen in 73% of patients. Median TRFS was 3.1 years (IQR 1.94-4.12). Median BPFS was 4.96 years (IQR 3.39-9.12). Overall BPFS was 90% in this patient population. Three patients experienced metastatic failure. There were no prostate cancer deaths. On univariate analysis ADTD (p=0.05), TRFS (p=0.04), GS (p=0.02), and PSA (p=0.05) were significantly associated with BPFS. On multivariable analysis TRFS (p=0.009), TStage (p=0.02), GS (p=0.02), and PSA (p=0.04) were significantly associated with BPFS.

Conclusions: Prolonged testosterone suppression after combination EBRT/PI/ADT is strongly associated with improved BPFS. The physiological implications of this finding warrant further study.

No significant financial relationships to disclose.
Prognostic clinical parameters to predict the necessity of reconstructive vascular surgery for patients who undergo postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) for advanced nonseminatous germ cell tumors (NSGCT).
Authors: Heidenreich A. , Schrader M. , Dieckmann K. , Winter C. , Pfister D. A. ,   German Testicular Cancer Study Group
Published: February 2017

229

Background: PC-RPLND remains an integral part of the multimodality treatment for advanced NSGCT. The need to resect and to replace the major retroperitoneal vessels must be known preoperatively to enable complete resection of the residual masses.

Methods: PC-RPLND was performed in 411 patients with NSGCT and normalized (81%) or plateauing (19%) tumor markers following 3-4 cycles PEB/PEI. PC-RPLND was performed in 5 institutions with a variable surgical frequency of 14 to 158 PC-RPLNDs. Good, intermediate, and poor prognosis according to the IGCCCG criteria was identified in in 59.8%, 21.2%, and 19% respectively.

Results: Resection of the inferior vena cava was performed in 28 (6.81%), resection of the abdominal aorta was necessary in 13 (3.16%) patients. In 29/41 (70.7%) adjunctive surgical procedures such as nephrectomy, small bowel resection, ureteral resection had to be performed to ensure complete resection of the residual masses. Histologically vital cancer or mature teratoma was identified in 78.1% of the resected vascular specimens. Mean time of surgery was 295 (243-615) Min., mean blood loss was 690 (350 – 3400) ml. Good prognosis was identified in 15.4%, intermediate and poor prognosis was present in 41%and 43.6%, resp. Of all 411 patients involvement of the major retroperitoneal vessels was found in 3.2%, 18.4% and 21.8% with good, intermediate, and poor prognosis, resp. The mean tumor diameter was 5.9 (1.0 – 32) cm for the entire cohort and 9.8 (4-32) cm for the cohort of patients with vascular surgery. Significant prognosticators to predict vascular involvement were identified by multivariate analysis: intermediate/poor prognosis, number of cycles of chemotherapy, tumor diameter > 14cm, circumferential encasement of > 50% of the vessel diameter.

Conclusions: Complete resection of the inferior vena cava or the abdominal aorta during PC-RPLND is necessary in about 10% of patients. The identified predictors enable already preoperatively a risk adapted interdisciplinary approach for complete resection of the residual masses in an experienced centre.

No significant financial relationships to disclose.
Multi-institutional quality-of-care initiative for nonmetastatic, muscle-invasive, transitional cell carcinoma of the bladder: Phase I.
Authors: Feifer A. , Taylor J. M. , Shouery M. , Steinberg G. D. , Stadler W. M. , Schoenberg M. , Zlotta A. , Lerner S. P. , Bajorin D. F. , Bochner B. ,   B.C.A.N. Muscle-invasive Bladder Cancer Quality of Care Consortium
Published: February 2017

240

Background: Evidence supports multimodality treatment for muscle invasive bladder cancer [MIBC] with the strongest evidence (level 1) existing for cisplatin-based neoadjuvant chemotherapy. Although reflected in guidelines for the management of MIBC, little is known about the variation of actual practice patterns among academic institutions. We thus evaluated treatment variation among 14 academic centers in the management of patients with MIBC.

Methods: Retrospective data were collected for centralized analysis. All patients who underwent radical cystectomy for clinical T2-4 N0M0 MIBC from 2003–2008 were eligible for inclusion. Specific endpoints for analysis included: rates of neoadjuvant and adjuvant therapy, cisplatin use, number of cycles and rates of pelvic lymphadenectomy.

Results: 14 institutions participated and data on 4,541 patients who met inclusion criteria were tabulated. Overall 34% of patients received perioperative chemotherapy. The overall use of neoadjuvant and adjuvant therapy was 12% and 22%, respectively. In a subset analysis of those patients with specific chemotherapy agent information provided (n=3,120), 59% of patients managed with perioperative chemotherapy received cisplatin. Of those who received treatment in the neoadjuvant setting, cisplatinum was received in 65% of cases (supported by level 1 evidence). 80% of patients who received perioperative chemotherapy received at least 3 cycles. At radical cystectomy 95% of patients received a bilateral PLND.

Conclusions: In this cohort of academic North American centers, 66% of potentially eligible bladder cancer patients undergoing radical cystectomy did not receive perioperative chemotherapy. Only 12% of patients received neoadjuvant chemotherapy, and 35% of those patients received a non-cisplatin based regimens. Despite level 1 evidence that cisplatin based neoadjuvant chemotherapy is associated with a survival advantage, only a small percentage of eligible patients undergoing radical cystectomy for muscle invasive, resectable disease receive combined treatment. Further study is needed clarify specific reasons for the treatment variation observed in academic centers.

No significant financial relationships to disclose.
Phase II study of everolimus (RAD001) in metastatic transitional cell carcinoma (TCC) of the urothelium.
Authors: Milowsky M. I. , Regazzi A. M. , Garcia-Grossman I. R. , Trout A. , Flaherty A. , Gerst S. , Bajorin D. F.
Published: February 2017

245

Background: Second-line chemotherapy has limited activity in advanced TCC with a median progression free survival (PFS) of 2-3 months. We have previously demonstrated the overexpression of activated mTOR pathway markers in invasive TCC specimens (BJU Int. 2010 Jul 26). Everolimus selectively inhibits mTOR, a central regulator of cell growth, proliferation, survival, and angiogenesis. This trial was designed to assess the efficacy of everolimus in patients (pts) with advanced TCC.

Methods: The primary objectives of this single-institution phase II trial of everolimus in pts with TCC who have failed prior chemotherapy are 1) to measure PFS as determined by RECIST and 2) to evaluate toxicity. Prior therapy is restricted to ≤ 4 chemotherapy drugs. Pts receive everolimus 10 mg oral daily continuously (1 cycle = 4 weeks). A Simon 2-stage design requires ≥13 of 23 pts to be progression free at 2 months to proceed to maximal accrual of 37.

Results: 43 pts (31 M, 12 F) with a median age of 65 yrs (32-84) and median KPS of 90 (70-90) were enrolled between 02/16/2009 and 09/30/2010. Primary tumor sites include bladder (32 pts) and ureter/renal pelvis (11 pts). Prior therapy included 28 pts with 2 drugs, 13 with 3 and 2 with 4. 34 pts have visceral metastases including lung (21), liver (19), and bone (5), and 9 pts have lymph node only disease. 8 pts who received ≤ 1 cycle secondary to rapid progression or toxicity unrelated to everolimus were deemed inevaluable for PFS endpoint and were replaced. To date, 33 pts are evaluable for the primary PFS endpoint; 2 pts are too early for PFS assessment. 22 of 33 pts are progression-free at 2 months. The median PFS for 33 evaluable pts is 2.9 months (1.4-9). One partial response has been seen. The most common grade 3-4 toxicities at least possibly related to everolimus include: anemia (7), infection (6), hyperglycemia (5), lymphopenia (4), hypophosphatemia (4), fatigue (3), hyponatremia (3), mucositis (2), dehydration (2), renal (2) and liver (2).

Conclusions: Everolimus has clinical activity in pts with advanced TCC. An ongoing analysis of pretreatment tumor tissue specimens for markers of activated mTOR pathway will be correlated with PFS.

[Table: see text]
Phase II trial of gemcitabine, carboplatin, and bevacizumab in chemotherapy-naive patients (Pts) with advanced/metastatic urothelial carcinoma (UC).
Authors: Balar A. V. , Milowsky M. I. , Apolo A. B. , Ostrovnaya I. , Iasonos A. , Trout A. , Regazzi A. M. , Garcia-Grossman I. R. , Gallagher D. J. , Bajorin D. F.
Published: February 2017

248

Background: Effective treatment for pts with advanced UC unfit to receive cisplatin-based therapy remains an unmet need. A recent phase III study showed limited benefit of gemcitabine-carboplatin (GC) alone (median OS 9.3 months) (DeSantis ASCO 2010). We recently identified the VEGF-axis as a viable pathway for UC treatment (JCO 2010;Mar 10). We propose that bevacizumab, a monoclonal antibody against VEGFR, may be safely added to GC and improve time to progression (TTP) in pts with advanced UC.

Methods: Primary endpoints (N=47 planned enrollment) were median TTP, to test an improvement of 50% over a 4.8 months median TTP seen with GC alone (Urology 2004;64:479), and safety. Secondary endpoints were response rate (RR) and overall survival (OS). Pts first received a single dose of bevacizumab 10 mg/kg. 2 weeks later they received 6 cycles of gemcitabine 1,000 mg/m2 on day(D) 1 and D 8, and both carboplatin AUC 4.5 and bevacizumab 15 mg/kg on D1 every 21 days. Pts who achieved at least stable disease were eligible to receive maintenance bevacizumab at 15 mg/kg q21 days for 18 additional doses. Restaging evaluations were performed after every 3 cycles of therapy.

Results: 51 pts (37 M, 14 F; median age 67 (Range 42-83)) were enrolled from 6/06 to 6/10. Primary tumor sites include bladder (31), renal pelvis (17) and ureter (2). 38 pts (74.5%) had visceral disease including lung (22), liver (13), bone (9) and adrenal (2). 13 pts had LN only disease. 46 of 51 pts were evaluable for response rate (RR) and TTP, 51 for toxicity. RR by RECIST was 46% (21 pts; PR 18, CR 3). 12 achieved stable disease; 1 too early to assess. Responses by MSKCC Risk Scores of 0, 1 and 2 were seen in 8/11(73%), 10/29 (35%), and 3/6 (50%) pts, respectively. 39% of pts had grade 3/4 toxicity, notably vascular thromboembolic events (VTE) in 18%.

Conclusions: Bevacizumab can be safely added to GC in the treatment of advanced UC. The 16% VTE rate is similar to the 17% rate seen at MSKCC with GC alone. (JCO 2009;27:15s). Addition of bevacizumab does not improve the RR seen with GC alone in phase II and III studies (Bellmunt Eur J Cancer 2001; DeSantis ASCO 2010). Analysis of bevacizumab's impact on TTP and OS is ongoing and will be updated.

[Table: see text]
Patterns of utilization of urine-based markers in non-muscle-invasive bladder cancer: Results from the BCAN/SUO/AUA/LUGPA electronic survey.
Authors: Smith A. , Nielsen M. E. , Ferguson J. , Manvar A. , Pruthi R. , Wallen E. , Lotan Y.
Published: February 2017

261

Background: In addition to cytologic evaluation, there are currently four urine-based tests approved by the FDA for bladder cancer detection. At this point, the Guidelines panels from the AUA and EAU do not make specific recommendations about the ideal role of these tests. Furthermore, there is a paucity of data on current patterns of care in this area of practice.

Methods: An electronic survey was developed by the Bladder Cancer Advocacy Network (BCAN) to elicit self-reported practices of the use of cytology and urine-based markers in the settings of general use, surveillance, and assessment of response after intravesical therapy for patients with NMIBC. The survey was circulated to urologists via the AUA, SUO and LUGPA distribution lists. 512 respondents completed the survey.

Results: Among all respondents, 93% report sending cytology routinely (25% via barbotage) in general use. In contrast, 37% report using NMP22 in this setting, 54% report using FISH, and 32% (45% of SUO respondents vs. 31% of AUA respondents, p=0.04) responded that there is “no role for urine-based markers in this setting.” Similar proportions were reported in the specific settings of routine surveillance and post-BCG assessment. When presented with the vignette of a positive marker test and negative cytology and cystoscopy, 36% chose to proceed to the OR for biopsy, 37% chose to repeat cystoscopy and cytology in 3 months, 21% chose “no role for markers in this setting” and 13% chose “other.”

Conclusions: In the absence of more specific guidance, the results of this survey suggest considerable variation in the use and interpretation of urine-based markers in NMIBC. FISH is the marker reported to be used most commonly in multiple settings, however 31-45% of respondents report “no role” for any of the tests in their practice. Greater than one out of three respondents reported taking patients for biopsy under anesthesia in the setting of an isolated positive marker. These preliminary data underscore the need for prospective studies to validate the optimal role of urine-based markers in the setting of NMIBC.

No significant financial relationships to disclose.
Sunitinib in BCG-refractory non-muscle-invasive transitional cell carcinoma of the bladder.
Authors: Garcia J. A. , Stephenson A. J. , Ireland J. , Finke J. , Elson P. , Schaaf L. , Gong M. C. , Campbell S. , Dreicer R.
Published: February 2017

262

Background: Treatment options for pts with BCG-refractory NMITCC are limited and there is no established role for systemic chemotherapy in this setting. While cystectomy remains the gold standard, the vast majority of pts are unable or unwilling to have surgery. Sunitinib is an oral tyrosine kinase inhibitor of VEGFR-2, PDGFR, KIT and FLT3 with demonstrated antitumor activity in advanced TCC. To determine the clinical and biologic effects of sunitinib in BCG-refractory NMITCC pts a prospective phase II study was conducted.

Methods: Pts with biopsy proven BCG- refractory NMITCC received three 28-day cycles of continuous sunitinib (37.5 mg PO). Subsequently, pts underwent cystoscopic evaluation. If no tumor was found, pts continued with standard cystoscopic surveillance. A single stage design was employed to test the hypothesis of a 25% improvement in the 12-month CR rate over the 20% CR historically observed in this setting. Overall response rate (ORR), disease-free recurrence (DFR) and safety were recorded. Exploratory endpoints included treatment effect on CTCs, type-1 response and immunosuppressive Treg cells.

Results: To date 17 of a planned 31 pts are enrolled. Median age is 72 years (range, 54-82); 94% of pts were ECOG 0; 6 pts had received additional intravesical therapy other than BCG. Fourteen pts have already completed 3 cycles of treatment and 13 pts had at least once cystoscopic assessment. Among these, 8 pts (62%) were NED in their first cystoscopic evaluation. Most common treatment-related toxicity observed in both studies included fatigue, HTN, stomatitis, PPE, diarrhea and thrombocytopenia. Treatment with sunitinib also resulted in a sustained increase (compared to pre-treatment) in CD3+ and CD4+ IFN-g producing T-cells (p < 0.07). In addition there was a significant decrease in CD33+ MDSC following 2 and 3 cycles of therapy (p < 0.04). There was also a significant decrease in T regulatory cells following 2 cycles of therapy (p = 0.04); however it was not maintained during cycle 3 (p = 0.36).

Conclusions: Sunitinib has modest clinical activity in pts with BCG-refractory NMITCC. Early immune studies also denote the ability of sunitinib to restore the balance of type-1 and type-2 immune response in bladder cancer.

[Table: see text]
Reported patterns of utilization of intravesical therapy in non-muscle-invasive bladder cancer: Results from the BCAN/SUO/AUA/LUGPA electronic survey.
Authors: Smith A. , Nielsen M. E. , Manvar A. , Ferguson J. , Pruthi R. , Wallen E. , Lotan Y.
Published: February 2017

267

Background: Guidelines recommend intravesical chemotherapy and immunotherapy in the management of non-muscle-invasive bladder cancer (NMIBC) to reduce the risks of recurrence and potentially progression. Nevertheless, recent claims-based analyses have suggested exceedingly low rates of utilization of some of these therapies in practice. In general, there is a paucity of data to inform our understanding of current patterns of care.

Methods: An electronic survey was developed by the Bladder Cancer Advocacy Network (BCAN) to elicit self-reported practices of utilization of intravesical chemo- and immuno-therapy for patients with NMIBC. The survey was circulated to urologists via the AUA, SUO and LUGPA distribution lists. 512 respondents completed the survey.

Results: Overall, 63% of respondents reported routine administration of perioperative mitomycin-c (MMC) after TURBT [80% of SUO respondents vs. 55% of AUA/LUGPA respondents (p<0.001)]. Whereas 5% of respondents reported routine induction therapy with all new low-grade (LG) diagnoses, 99% reported routinely doing so in new high-grade (HG) cases; most commonly with single- agent BCG (94%; vs. 9% BCG/IFN and 5% MMC). Reported induction therapy was higher in the setting of high-volume (77%) or frequently recurrent LG (44%) disease. 89% reported routinely using maintenance therapy for HG, vs. 29% for LG. Reduced strength BCG was most commonly endorsed only in the settings of poor tolerance of full strength (84%) or maintenance (11%), with only 3% endorsing routine use. Routine post-BCG biopsy, even with normal cystoscopy, was endorsed by 28% of respondents, and 64% of respondents used urine-based markers to assess response to intravesical therapy.

Conclusions: Urologists report grade-specific patterns of utilization of intravesical therapy for NMIBC, at rates higher than suggested in some claims-based analyses. Variation exists in post-treatment followup practices. Further study is needed to rectify these self-reported patterns of care with results from claims-based analyses.

No significant financial relationships to disclose.
The neoadjuvant management of bladder cancer in Canada: A survey of genitourinary medical oncologists.
Authors: Hsu T. , North S. , Eigl B. J. , Chi K. N. , Canil C. M. , Wood L. , Lau A. , Panzarella T. , Sridhar S. S.
Published: February 2017

285

Background: The uptake of neoadjuvant chemotherapy (NC) for the treatment of stage II/III bladder cancer remains variable despite evidence supporting its use. The aim of this study is to better understand the use of NC in Canada to facilitate standardization of practice and develop a platform for clinical trials.

Methods: The survey was initially tested on a subset of medical oncologists. It was then e-mailed to 30 medical oncologists across Canada who primarily treat bladder cancer.

Results: In total, 25 (83%) surveys were completed. Respondents were 92% academic based, 100% full time, and 52% in practice for >10 years. The majority of referrals for all stages came from urologists with 4 respondents (16%) seeing 5-10 cases/yr, 10 (40%) seeing 11-15/yr, 5 (20%) seeing 16- 20/yr and 6 (24%) seeing >20/yr. Of these 8 reported having only 1-2 referrals for NC; 7 had 3-4 NC referrals; 7 had 5-6 NC referrals; and 2 reported seeing >6 referrals/year. Patients referred for NC tended to be younger (50-65); Performance Status (PS) 0/1; T-stage T3a/T3b; or nodal status N1/N2. 96% indicated they do offer NC to selected patients as both standard of care and to downsize tumors. Key factors cited for not offering NC were: Age >85, PS 3/4; T-stage T2a or T4a; Nodal status: N3; GFR <40ml/min. Main baseline staging modalities included CT chest/abdomen/pelvis, bone scan and cystoscopy. Gemcitabine/cisplatin was most commonly used with 20% using high-dose MVAC. Six (27%) reported doing midway staging with CT abdomen/pelvis and cystoscopy; 36% report staging after completion of chemo. Average time from last chemotherapy to cystectomy was 4-6 wks, with no patients being offered adjuvant chemotherapy postoperatively.

Conclusions: The majority of GU MO in Canada would offer NC. Stage, PS, renal function, and comorbidities were the biggest determinants of offering NC, while age played a lesser role. The number of overall referrals for NC, however, remains relatively low. We plan to survey urologists in Canada to determine if differences in attitudes about NC or barriers to referrals account for the low number of referrals.

No significant financial relationships to disclose.
Sequential FDG-PET/CT as a surrogate marker of response to sunitinib in metastatic clear cell renal cancer.
Authors: Powles T. , Chowdhury S. , Avril N. , Bomanji J. , Shamash J. , Sarwar N. , Rockall A. , Sahdev A. , Nathan P. D. , Kayani I.
Published: February 2017

301

Background: The purpose of this study was to investigate sequential FDG PET-CT as a correlative marker in metastatic clear cell renal cancer (mRCC) patients treated with first line sunitinib. Three sequential scans were performed to determine the importance of the timing of scans.

Methods: Forty-four untreated mRCC patients with MSKCC intermediate risk and poor risk disease were enrolled into a prospective study. FDG PET-CT scans were performed before (n=44), after 4 weeks (n=43) and 16 weeks (n=40) of sunitinib given at standard doses as the translational aspect of this trial ( NCT01024205 ). The primary endpoint was to determine whether 18F-FDG PET-CT response (defined as a 20% reduction in SUVmax) correlated with survival.

Results: Forty-three (98%) patients had FDG PET-CT avid lesions at diagnosis (median SUVmax 6.8 range: <2.5–18.4). In multivariate analysis a high SUVmax and increased number of PET positive lesions correlated with worse overall survival (OS) (HR: 3.30 (95%CI: 1.36–8.45) and 3.67 (95%CI: 1.43–9.39) respectively[p<0.05]). After 4 weeks of sunitinib, metabolic responses occurred in 24 (57%) patients at 4 weeks, but this did not correlate with progression-free survival [PFS] (HR for responders= 0.87 [95%CI: 0.40–1.99]) or OS (HR for responders= 0.80 [95%CI: 0.34–1.85]) (p>0.05 for both). After 16 weeks of treatment, FDG PET-CT demonstrated disease progression in 28% (n=12) patients. At this time point, the FDG PET-CT correlated with both OS and PFS (HR 5.96 [95%CI: 2.43–19.02] and HR 12.13 [95%CI: 3.72–46.45] respectively).

Conclusions: Baseline FDG PET prior to sunitinib yields prognostically significant data. FDG PET response at 16 weeks predicts outcome, which is not the case at 4 weeks. This subsets of patients with a poor prognosis at 16 weeks could be investigated within the context of a randomized clinical trial.

[Table: see text]
Hand–foot syndrome (HFS) as a potential biomarker of efficacy in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with sunitinib (SU).
Authors: Michaelson M. D. , Cohen D. P. , Li S. , Motzer R. J. , Escudier B. , Barrios C. H. , Burnett P. E. , Puzanov I.
Published: February 2017

320

Background: HFS and related skin toxicities are common side effects of tyrosine kinase inhibitors such as SU, a multitargeted inhibitor of VEGF and PDGF receptors plus other receptor tyrosine kinases. In a randomized phase III trial of treatment-naïve mRCC pts, SU showed superior progression-free survival (PFS) and objective response rate (ORR) over interferon-alfa, with a median PFS of 11 mo and median overall survival (OS) of 26.4 mo, establishing SU as a reference standard of care (Motzer et al, 2009). In this retrospective analysis, correlations between SU-associated HFS and efficacy endpoints were investigated in mRCC pts from 5 clinical trials in the first- and second-line treatment settings.

Methods: Analyses included pooled data from 770 pts who received single-agent SU as 50 mg/d on a 4-week-on/2-week-off schedule (n=544; 71%) or 37.5 mg continuous once-daily dosing (n=226; 29%). Median PFS and OS were estimated by Kaplan–Meier methods and compared between pts with vs without HFS using a log-rank test. ORR was compared by Pearson's chi-square test. Tumor response was assessed by investigators and adverse events were recorded regularly. Multivariate and time-dependent covariate analyses were performed.

Results: Of 770 pts, 179 (23%) developed any-grade HFS, compared with 591 (77%) who did not. Most instances of HFS (63%) initially occurred during the first 3 treatment cycles. Pts who developed HFS had significantly better ORR (55.6% vs. 32.7%), PFS (14.3 vs. 8.3 mo), and OS (38.3 vs. 18.9 mo) than pts who did not develop HFS (p<0.0001). In a multivariate analysis, SU-associated HFS remained a significant independent predictor of both PFS and OS (and of OS by time-dependent covariate analysis).

Conclusions: In mRCC pts, SU-associated HFS was significantly and independently associated with improved clinical outcomes. Overall, pts who did not develop HFS still had substantial benefit from SU. However, the presence of HFS identified a subset of pts that manifested highly favorable efficacy results with SU. These findings suggest that development of HFS may serve as a predictive biomarker of SU efficacy, although prospective validation is warranted.

[Table: see text]
Phase II trial of bevacizumab monotherapy in nonmetastatic castrate-resistant prostate cancer (CRPC).
Authors: Ogita S. , Tejwani S. , Heilbrun L. K. , Fontana J. A. , Heath E. I. , Freeman S. , Smith D. W. , Baranowski K. , Vaishampayan U. N.
Published: February 2017

33

Background: To this day, no therapy has proven efficacy in the clinical management of PSA relapse non-metastatic CRPC. Investigating novel therapeutic agents that will induce a PSA response, and delay progression to overt metastases is of paramount importance.

Methods: A single arm multi-center phase II clinical trial is being conducted. Inclusion criteria are PSA only progression despite androgen deprivation therapy, defined as three rising PSA levels with a measurement interval of at least 2 weeks, and minimum PSA level ≥ 1 ng/mL. Patients with radiologic evidence of bone metastases were excluded. Bevacizumab single agent was administered at 10 mg/kg every 14 days. PSA was evaluated at least every 6 weeks and bevacizumab was continued until PSA progression or new metastasis.

Results: 15 patients (see Table ) have been enrolled on this ongoing trial. Toxicities observed were grade 4 pulmonary embolism, grade 3 hypertension, and grade 3 proteinuria in one patient each, but no treatment related mortality. Median treatment duration was 12.6 weeks (range 11–33.1 wks). 12 patients are evaluable for PSA response. Four patients had PSA decline of 14, 20.9, 24, and 45% respectively. Median PSA doubling time during bevacizumab increased to 5.93 months (range 0.81–27.09 months) from pretherapy median of 4.08 months, a 45% improvement. Five patients have progressed to develop bone metastases at median of 7.7 months (range 2.8–18.2) after protocol registration.

Conclusions: Bevacizumab was well tolerated, and impacted PSA kinetics in non-metastatic CRPC. Further investigations are warranted. Supported in part by Genentech Inc. (clinicaltrials.gov NCT00478413 ).

[Table: see text]

[Table: see text]