bluuebunny/crossref_metadata_2025 huggingface dataset:
inSIRT trial: Single-center phase II study of yttrium-90 radioactive resin microspheres in the treatment of liver-predominant metastatic colorectal adenocarcinoma after failure of first-line combination chemotherapy.
Authors: Roeland Eric , Shimabukuro Kelly Anne , Fanta Paul Timothy , Rose Steven C. , Reid Tony R.
Published: February 2017

685

Background: Liver metastases develop in half of colorectal cancer (CRC) cases and once metastatic ~90% die due to consequences from the hepatic metastases. We are evaluating the aggressive management of liver metastases through the incorporation of selective internal radiation therapy (SIRT) using yttrium-90 radioactive microspheres after evidence of progressive disease following first-line FOLFOX ± bevacizumab. Optimal timing for microsphere treatment relative to chemotherapy is not clearly established. We present preliminary data of a phase II study evaluating tumor response rates to SIRT following FOLFOX ± bevacizumab and prior to FOLFIRI.

Methods: Subjects with predominant hepatic metastatic CRC despite first-line FOLFOX based therapy ± bevacizumab are eligible. Interventional radiology and nuclear medicine assess the liver lesions and the subject receives SIRT followed by second-line FOLFIRI (without bevacizumab) 4-6 weeks after the final SIRT. The primary objective is PFS at 6 mos and secondary objectives include: OS, tumor response rates, and toxicity.

Results: To date, 8 metastatic CRC subjects have been treated and 9 subjects enrolled (goal 30 subjects). One subject was withdrawn due to progressive lung metastases. 4 of 8 subjects (50%) achieved PFS at 6 mos and average TTP is 6.7 mos (0.7-17.3 mos). Overall treatment has been well tolerated, but one possible study related SAE of liver failure occurred (subject 8). The OS endpoint has not been achieved.

Conclusions: Historically, second-line FOLFIRI has achieved a 2.5 mos median PFS. In 8 subjects with liver predominant metastatic CRC, we have observed 50% PFS at 6 mos. These encouraging results demonstrate the utility of an innovative direct approach to metastatic CRC after failure of first-line combination chemotherapy.

[Table: see text]
What care is appropriate and necessary for metastatic gastric cancer patients? Results of a RAND/UCLA expert panel.
Authors: Mahar Alyson L. , Helyer Lucy K. , Swallow Carol Jane , Law Calvin , Paszat Lawrence Frank , Seevaratnam Rajini , Cardoso Roberta , McLeod Robin S. , Bocicariu Alina , Coburn Natalie G. ,   The Gastric Cancer Processes of Care Expert Panel
Published: February 2017

70

Background: Most gastric cancer patients present with advanced stage disease precluding curative surgical treatment. The utility of surgical and non-surgical options for non-curative, advanced disease is debated and the appropriate treatment strategy unclear.

Methods: A multi-disciplinary expert panel of 16 physicians from 6 countries, scored 47 scenarios using the RAND/UCLA Appropriateness Methodology. Appropriateness was scored from 1 (highly inappropriate) to 9 (highly appropriate). Median appropriateness scores (AS) from 1-3 were considered inappropriate, 4-6 uncertain, and 7-9, appropriate. Agreement was reached when 11 of 16 panelists scored the statement similarly. If a statement was agreed to be appropriate, it was then given a necessity score (NS) in the same manner.

Results: Surgical resection and bypass were agreed to be inappropriate in patients with minor symptoms and visible carcinomatosis, liver metastases or more than one site of metastatic disease for cardia and distal lesions (AS 1.0-3.5). The expert panel disagreed on the role for surgical resection in patients who were cytology positive only (AS 4-6). The role of resection for patients with major symptoms if they had visible carcinomatosis, liver metastases or more than one site of metastatic disease (AS 2-5) was indeterminate. Patients with distal tumours and major symptoms and multiple liver metastases or more than one site of metastatic disease were considered indeterminate for surgical resection (AS 2). Best supportive care was agreed to be appropriate for patients with minor symptoms and multiple liver metastases or more than one site of metastatic disease (AS 8, NS 5-6).

Conclusions: The role of surgery in metastatic gastric cancer treatment decision-making is not supported by experts for the majority of scenarios. Continued uncertainty in appropriate and necessary treatment decision-making for advanced patients with a minimal burden metastatic disease exists and underscores the need for randomized controlled trials.
Population-based outcome of stages IA-IIA resected gastric adenocarcinoma: Who should get adjuvant treatment?
Authors: Gold Jason S. , Al Natour Riad H. , Saund Mandeep S. , Yoon Charles H. , Sharma Ashish M. , Huang Qin , Boosalis Valia A. , Whang Edward E.
Published: February 2017

75

Background: The benefit of adjuvant treatment in gastric adenocarcinoma was demonstrated by randomized controlled studies that predominantly enrolled patients with locally advanced tumors. Thus its role for stage IIB – IIIC disease is widely accepted. Our aim was to identify patients with stage IA – IIA gastric adenocarcinoma who have a poor prognosis and therefore may benefit from adjuvant treatment.

Methods: Patients with local or local-regional gastric adenocarcinoma who underwent surgical resection with pathological evaluation of ≥15 lymph nodes and had available disease-specific survival (DSS) data were identified from the Surveillance Epidemiology and End Results Registry. AJCC 7th edition gastric cancer staging was used. Kaplan-Meier survival was estimated. Survival differences were evaluated with the logrank test and Cox multivariate analysis.

Results: TN grouping strongly predicted DSS (p<0.001, n=8515 patients). Stage IA (T1N0) (n=887) tumors had a distinctly excellent outcome, 91±1.2% DSS at 5 years, and thus were excluded from further analysis. The 5 TN groups of stages IB and IIA (n=1544) had the next best outcomes with DSS ranging from 66±4.6% to 81±2.3% at 5 years. Older age (p<0.001), higher grade (p=0.004), larger size (p<0.001), and proximal tumor location (p<0.001) were independent predictors of worse DSS in stage IB and IIA tumors. Interestingly, T and N stages did not independently predict outcome (p=0.07, p=0.41 respectively). We devised a risk stratification scheme for stage IB and IIA tumors where 1 point was assigned for each of the following variables: age >60 years, tumor size >5 cm, proximal tumor location, and grade other than well differentiated. DSS was 100% at 5 years for patients with no points (n=2); 86±4.3% for those with 1 point (n=92); 76±3.0%, 2 points (n=325); 72±2.8%, 3 points (n=372); and 48±4.9%, 4 points (n=136) (p<0.001).

Conclusions: Patients with stage IB and IIA gastric adenocarcinomas with at least 2 adverse features (age >60 years, tumor size >5 cm, proximal tumor location, and grade other than well differentiated) have 5 year DSS ≤76%. Adjuvant therapy may be warranted for these patients.
Prevalence and characteristics of patients with metastatic prostate cancer who receive no anticancer therapy.
Authors: Small Alexander C. , Tsao Che-Kai , Moshier Erin , Godbold James , Sonpavde Guru , Oh William K. , Galsky Matt D.
Published: February 2017

101

Background: Clinical experience reveals that a subset of patients presenting with advanced solid tumors, including prostate cancer, never receive anticancer therapy due to a variety of factors including poor functional status, comorbidities, and patient preference. We sought to determine the prevalence, and characteristics, of this patient population.

Methods: The National Cancer Database (NCDB) was queried to identify patients diagnosed with stage IV prostate cancer between 2000 and 2008. Patients who received no anticancer therapy (including chemotherapy, hormonal therapy, radiation, and surgery) were identified and were further categorized by age, race, insurance status, and income. For these subcategories, prevalence ratios were generated using the proportion of untreated metastatic prostate cancer (uMPC) to metastatic prostate cancer (MPC).

Results: Of the 1,201,732 patients with prostate cancer diagnosed between 2000-2008, 59,074 (4.9%) had MPC. Of those patients presenting with MPC, 6582 (11.1%) received no anticancer therapy. With every 10-year increase in age, the prevalence of uMPC increased 43% (PR=1.43; p<0.0001). Blacks (PR=1.32, p<0.0001) and Hispanics (PR=1.41, p<0.0001) were more likely than Caucasians to have uMPC. With every $10,000 increase in income the prevalence of uMPC decreased by 7% (PR=0.93; p<0.0001). Patients with Medicaid were 57% more likely to be untreated, patients with Medicare were 82% more likely to be untreated, and uninsured patients were 96% more likely to be untreated than those patients with private insurance (p<0.0001).

Conclusions: A large subset of patients presenting with MPC never receive anticancer therapy. While tumor biology likely plays a role with regard to rapid disease onset and progression, these data suggest that age, racial and socioeconomic disparities exist in the treatment of MPC.
The influence of regional radiation oncologist and urologist capacities on treatment choice for prostate cancer management.
Authors: Yu James B. , Aneja Sanjay , Makarov Danil V. , Roberts Kenneth B , Gross Cary P.
Published: February 2017

108

Background: Our study investigates the influence of regional variations of radiation oncology and urology services on the treatment modality chosen for prostate cancer (PCa) management.

Methods: PCa treatment choice and patient data from 2004-2007 were obtained from the NCI Surveillance, Epidemiology, and End Results (SEER) database and combined with the health system data from the Area Resource File. The health system characteristics analyzed were radiation oncologist (RO) density, urologist (U) density, primary care provider (PCP) density, IMRT equipped hospital density, general radiation therapy (RT) equipped hospital density, and median household income. Patient factors analyzed included race, marital status, and age. Separate logistic regression models were built to test the association between health system characteristics and whether patients received any form of RT (EBRT, brachytherapy, or a combination) or just surgical treatment.

Results: Overall of the 108,612 patients in our sample, 43.7% received some form of RT. Patients residing in Health Service Areas (HSAs) with increased RO densities were more likely to receive some form of radiation to treat PCa (OR 1.07 [SE 0.02, p<.001]). Conversely increased U density was associated decreased use of RT (OR .95 [SE .01, p<.001]). Presence of IMRT equipped and general RT equipped hospitals were both associated with increased use of radiation therapy (OR 1.53 [SE .05, p<.001] and OR 1.13 [SE .03, p<.001] respectively). Alternatively, 39.3% of patients in our sample received just surgical interventions. Patients residing in HSAs with increased RO densities were less likely to receive only surgical treatment for PCa (OR .91 [SE .01, p<.001]). Increased U density was associated with increased likelihood of only surgical treatment for PCa (OR 1.09 [SE 0.01, p<.001]). Presence of IMRT equipped and general RT hospitals were both associated with decreased use of only surgical treatment for PCa (OR .82 [SE .03, p<.001] and OR .82 [SE .02, p<.001] respectively).

Conclusions: Radiation oncologist and urologist capacities influence the regional variations in the treatment choice for prostate cancer.
Impact of different definitions of high-risk prostate cancer on survival after radical prostatectomy.
Authors: Nepple Kenneth Gerard , Sandhu Gurdarshan S , Kallogjeri Dorina , Strope Seth A. , Grubb Robert L. , Klein Eric A. , Stephenson Andrew J. , Kibel Adam Stuart
Published: February 2017

113

Background: Multiple definitions of high risk prostate cancer exist. Studies have primarily correlated these definitions with biochemical recurrence and not with survival. We applied six previously described high risk definitions to men treated with radical prostatectomy and evaluated their ability to predict survival outcomes in a multi-institutional cohort.

Methods: The study population included 6477 men treated with radical prostatectomy between 1995 and 2005 and followed for a median of 67 months. The six high risk definitions were 1) preoperative PSA≥20ng/ml, 2) biopsy Gleason score 8-10, 3) clinical stage≥T2c, 4) clinical stage T3, 5) D’Amico definition, or 6) National Comprehensive Cancer Network definition. Survival was evaluated with the Kaplan-Meier method to generate unadjusted prostate cancer survival estimates. To control for the competing risks of age and comorbidity, multivariable Cox proportional hazard regression models were used to estimate the hazard ratio for prostate cancer specific mortality (PCSM) and overall mortality (OM) in high risk patients compared to low/intermediate risk.

Results: High risk patients comprised between 0.7% (cT3) and 8.2% (D’Amico) of the study population. The 10-year Kaplan Meier prostate cancer survival estimates varied from 89.7% for PSA≥20 to 69.7% for cT3. On multivariable analysis controlling for age and comorbidity, high risk prostate cancer (of all definitions) had an increased risk of PCSM compared to low/intermediate risk with a hazard ratio (HR) ranging from 4.38 for PSA≥20 to 19.97 for cT3 (all p<0.0001). For OM, again controlling for age and comorbidity, high risk patients of all definitions except preoperative PSA≥20 (HR=0.98, p=0.99) were associated with increased risk of OM (HR range: 1.72 for D’Amico, 1.73 for stage≥T2c, 1.88 for NCCN, 2.63 for Gleason 8-10, 3.31 for cT3; all p<0.01).

Conclusions: In a contemporary cohort of men with high risk prostate cancer treated with radical prostatectomy, the majority of men experienced long term prostate cancer survival. However, heterogeneity in survival outcomes existed based on the definition of high risk used. Clinical stage T3 and high Gleason score were most strongly associated with PCSM and OM.
Centralized revision of diagnostic pathologic slides for prostate cancer patients on active surveillance: Is it just time- and resource-consuming?
Authors: Colecchia Maurizio , Alvisi MariaFrancesca , Paolini Biagio , Nicolai Nicola , Villa Sergio , Salvioni Roberto , Marenghi Cristina , Rancati Tiziana , Valdagni Riccardo
Published: February 2017

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Background: Active Surveillance (AS) is offered to prostate cancer (PCa) patients (pts) with very low risk disease, with well defined diagnostic biopsy details. For this reason, in order to standardize diagnostic inclusion criteria, we requested pathologic review before AS enrollment. We here report on second opinion of PCa needle biopsies to determine how often the expert opinion of a uro-pathologist resulted in a different diagnosis, in the group of pts who were proposed for AS.

Methods: AS institutional protocol (SAINT) started in Mar 05. Entry criteria: initial PSA≤10ng/ml, Tstage≤T2a, GPS≤3+3, positive biopsy cores≤20%, max core length containing cancer≤50%. In Nov 07 PRIAS started. PRIAS vs SAINT differs on: max 2 positive cores and PSA density<0.2ng/ml/cc. A second opinion on biopsy was requested in 248 cases (Oct 05 - Jul 10), due to outside diagnosis. We analyzed differences between outside diagnosis and institutional expert opinion. We considered two classes of differences: minor differences (which did not prevent AS enrollment) and significant changes (which resulted in a change in prognosis and closed the possibility of AS enrollment).

Results: 40/248 (16.1%) cases had minor differences (18 SAINT and 22 PRIAS). In SAINT pts, 12/18 (66.7%) biopsies were increased in the max core length containing cancer (but still≤50%) and 6/18 (33.3%) had a change in the number of positive cores (but still≤20% of total cores). In PRIAS pts 10/22 (45.5%) changes were related to upsizing (from 1 to 2 positive cores) and 5/12 to downsizing (from 2 to 1 positive core). 7/22 changes were related to differences in core length containing cancer (from below to above 50%). Significant differences were observed in 30/248 (12.1%). 20/30 were related to upgrading, 10/30 pts had an upsizing: 1 SAINT pt exceeded 20% of positive cores, 5 SAINT pts exceeded 50% of max tumor length of positive cores, while 4 PRIAS pts increased from 2 to 3 or 4 positive cores.

Conclusions: Central pathology review reduces population heterogeneity in the specific setting of AS programs, significant reclassification of risk category involved 12% of pts. Current clinical consequences of central review cannot be determined.
The effect of the diagnosis and treatment of lower urinary tract symptoms (LUTS) on the diagnosis of prostate cancer in a population cohort with 20-year follow-up.
Authors: Weight Christopher J. , Kim Simon P. , Boorjian Stephen A. , Karnes R. Jeffrey , Jacobson Debra , McGree Michaela , St. Sauver Jennifer
Published: February 2017

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Background: LUTS are one of the most common reasons patients visit urologists. These symptoms have not been typically associated with the development of prostate cancer (CaP). However, we hypothesized that visiting a physician for LUTS may modify the diagnostic intensity for CaP compared to population controls.

Methods: We examined data from a longitudinal, population-based cohort of 2,447 men between 40 and 79 years old who were followed prospectively from 1990 to 2010. Participants completed the American Urological Association Symptom Index (AUASI) every two years. Self-reported moderate/severe LUTS were defined as an AUASI score >7 (n=1627). Data including the treatment for LUTS (n=874), prostate biopsy (PBx), family history of CaP and diagnosis of CaP were obtained through self-report and review of medical records. Associations between self-reported LUTS, treatment for LUTS, and risk of PBx or CaP were estimated using multivariate Cox proportional hazard models.

Results: An interaction was noted between age and LUTS and PBx and CaP diagnosis. In younger men, the diagnosis and treatment of LUTS was associated with increased risk of PBx (HR 2.39: 95% CI 1.83, 3.13) and CaP (HR 3.47: 95% CI 2.38, 5.07). Conversely in older men, treatment for LUTS was associated with a decreased risk of PBx and CaP (Table). Self reported LUTS was not significantly associated with CaP diagnosis in younger men and was protective in older men (Table).

Conclusions: There is a differential effect of LUTS on prostate cancer testing and diagnosis when stratified by age. The reason for this difference is unclear, but appears to be due largely to diagnostic intensity rather than a true biologic association between LUTS and CaP.

[Table: see text]
Safety and efficacy of maintenance therapy (MT) with a nonspecific cytochrome-P 17 inhibitor (CYP17i) after response/stabilization to docetaxel in metastatic castratation-resistant prostate cancer (mCRPC) patients.
Authors: Gil-Bazo Ignacio , Castillo Ainhoa , Zudaire Maria E. , Arevalo Estefania , Carranza Omar Esteban , Fusco Juan Pablo , Castanon Eduardo , Perez-Gracia Jose Luis , López-Picazo José María , Gurpide Alfonso , Garcia-Foncillas Jesus
Published: February 2017

145

Background: ACRPC causes >30,000 deaths/year in the USA. The front-line treatment consists of docetaxel-based chemotherapy (D). 50% of patients (pts) show at least a 50% PSA decline during D and >15% show a partial response (R) in measurable disease. However, most of these pts present progression (P) after a median of 6-8 months (m). mCRPC remains driven by ligand-dependent androgen (A) receptor signaling. Ketoconazole (K) is a nonspecific cytochrome-P 17 inhibitor (CYP17i) able to block adrenal A synthesis. Low-dose K (LDK), (200 mg, t.d.s) has shown interesting activity in mCRPC after P to androgen deprivation therapy (ADT). The FDA recently granted approval to Abiraterone acetate, a selective CYP17i showing a survival benefit after P to D. The role of a CYP17i in the maintenance setting after response/stabilization to D has never been studied.

Methods: 38 mCRPC pts starting D after P to ADT maintained LHRHa and additionally received a median of 7 cycles (3-12) of front-line three-weekly D (75 mg/m2) plus daily prednisone (10 mg). 20/38 pts showing no progression to D were enrolled. One month after the last D cycle 10 pts were assigned to MT with LDK plus prednisone (10 mg daily) and continued to receive LHRHa while the 10 pts in the control arm continued on LHRHa alone. Progression-free survival (PFS) was the primary endpoint of the study.

Results: After a median follow-up of 27 m, all pts in the control arm progressed after D treatment while 8/10 pts progressed to MT. PFS from D initiation was 11.4 m for MT and 8.9 m for control arm (p=0.025). Toxicity profiles showed no significant differences between both arms. No pts discontinued LDK for toxicity reasons.

Conclusions: To our knowledge, this is the first study testing a CYP17i for MT after response/stabilization to D in mCRPC. Although this is a small cohort of pts and a longer follow-up is needed, these preliminary data show a significant benefit in PFS of more than 2 months with LDK MT compared to no MT after D with a favorable toxicity profile. Thus, a further analysis in a larger series and the potential impact of this PFS benefit on the overall survival is warranted.
An ambispective observational study in the safety and efficacy of abiraterone acetate in the French temporary authorizations for use (ATU): Predictive parameters of response.
Authors: Azria David , Massard Christophe , Tosi Diego , Houede Nadine , Joly Florence , Gravis Gwenaelle , Delva Remy , Le Moulec Sylvestre , Latorzeff Igor , Ferrero Jean-Marc , Culine Stephane , Ladoire Sylvain , Tartas Sophie , Oudard Stephane , Rodier Jean-Michel Pierre , Laguerre Brigitte , Alexandre Jerome , Topart Delphine , Beuzeboc Philippe
Published: February 2017

149

Background: The Temporary Authorizations for Use (ATU) procedure is an exceptional measure making available medicinal products that have not yet been granted a Marketing Authorisation. Abiraterone acetate (AA) was available for ATU since December 2010 in France. We then decided to evaluate the tolerance and efficacy of this treatment and identify predictive factors of response.

Methods: 82 centers were contacted and clinical data were reported in two months (15th July-19th September 2011). Patients were defined as non-responders in case of interruption of AA due to disease progression or death. PSA values were recorded at each medical visit. Reported toxicities were also recorded. Statistical analyses were descriptive and predictive factors were determined.

Results: A total of 18 centers accepted to participate in this study including 381 patients. Median age at diagnosis was 63 years. The Gleason score (n=320) were 4-6, 7, and 8-10 in 13.4%, 36.9% and 49.7%, respectively. Before AA, the type of metastasis was bone only, organs only, and bone+organs in 45.4%, 7.9% and 46.7%, respectively. Median PSA before CT and before AA was 58.1 and 137.5 ng/ml, respectively. Median duration of hormonotherapy (HT) before any CT was 34 months. Median duration of CT before AA was 6.1 months with a median number of CT lines of one. Median duration of AA was 117 days. In the non-responders group (n=114), median duration of AA was significantly shorter than in the responders group (n=267), 87 days vs 147 days, respectively (p<0.0001). One third of the patients in the responders group presented a PSA increase over time but continued AA as they clinically improved. Only 13 patients stopped AA for grade 3-4 toxicities. GIeason 8-10 and the number of CT lines (>1) before AA were identified as independent predictive factors of non response.

Conclusions: This report is the largest ambispective observational study of AA in an ATU process. PSA values during AA treatment were used as a good indicator of progression. GIeason 8-10 and the number of CT lines (>1) before AA were identified as independent predictive factors and therefore could be used for further strategies in this setting.
Exploratory analysis of survival benefit and prior docetaxel (D) treatment in COU-AA-301, a phase III study of abiraterone acetate (AA) plus prednisone (P) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Chi Kim N. , Scher Howard I. , Molina Arturo , Logothetis Christopher , Jones Robert J. , Staffurth John , North Scott A. , Vogelzang Nicholas J. , Saad Fred , Mainwaring Paul N. , Harland Stephen John , Li Jinhui , Kheoh Thian San , Haqq Christopher M. , Fizazi Karim
Published: February 2017

15

Background: AA, a selective androgen biosynthesis inhibitor, blocks the action of CYP17, thereby inhibiting adrenal and intratumoral androgen synthesis. AA has demonstrated improved overall survival (OS) by 4.6 months (mos) vs placebo (HR=0.74) in patients (pts) previously treated with D.

Methods: COU-AA-301 is a randomized double-blind study of AA (1 g) + P (5 mg po BID) vs placebo + P administered to mCRPC pts post-D with a primary endpoint of OS. To evaluate the robustness of the primary survival results, we performed post hoc exploratory analyses to assess whether the timing of first and last dose of D and reason for D discontinuation impacted OS.

Results: At the time of randomization, treatment arms were balanced with respect to baseline characteristics, prior D use, and reasons for discontinuation. In both arms, almost half (45%) discontinued D due to progressive disease (PD); the remainder discontinued D as part of planned treatment (37%), toxicity (12%), or for other reasons (5%) per investigator reporting. Median OS from first and last dose of D were longer with AA vs placebo (Table). Median OS was longer with AA vs placebo in pts who discontinued D for PD or for all other reasons.

Conclusions: These exploratory analyses suggest that the survival benefit of AA in mCRPC was maintained when calculated from first or last dose of prior D, and whether or not pts discontinued D for PD. Pts in the AA arm of this study had a prolonged median OS of > 32 mos from the time of initial D therapy. Congruity among these analyses demonstrates the robustness of the primary survival result.

[Table: see text]
Use of elevated insulin-like growth factor binding protein-1 (IGFBP-1) to predict outcomes in men with metastatic prostate cancer treated with androgen-deprivation therapy (ADT).
Authors: Sharma Jaya , Gray Kathryn P. , Nakabayashi Mari , Petrozziello Gillian , Evan Carolyn , Fichorova Raina , Kantoff Philip W. , Sweeney Christopher
Published: February 2017

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Background: IGF-1 has been shown to promote cancer growth by activation of PI3 kinase and downregulation of AMPK. IGFBP-1 shuttles IGF-1 across blood vessel membranes. Elevated IGFBP-1 blood levels may be indicative of tissue IGF-1 levels and has been associated with prostate cancer risk. We hypothesized that IGF-1 and IGFBP-1 blood levels might effect ADT efficacy.

Methods: A retrospective analysis of IGF-1 and IGFBP-1 was undertaken in men commencing ADT for metastatic prostate cancer. Blood was drawn within one month of initiating ADT and stored. Proteins were measured using multiplex electrochemiluminescence assays. A cohort of 122 patients was compiled from a prospective trial (50 patients) and chart review (72 patients). A multivariate analysis (MVA) using a COX model was performed to identify associations between blood levels of the markers and time to the development of castration resistant prostate cancer (CRPC) and overall survival (OS). The covariates analyzed were age at time of ADT, ECOG score, race, baseline PSA, and extent of disease.

Results: At time of initiating ADT the cohort had a median age of 67 years, PSA of 27.4 and 82% had ECOG 0. 91% were Caucasian. 62% had extensive metastatic disease. Median OS was 42.2 months. The median (med) baseline levels for IGF-1 was 75.6 ng/ml and for IGFBP-1 was 1844 pg/ml. As detailed in the table, patients with IGFBP-1 levels above the median had significantly shorter time to development of CRPC and OS on MVA. There was no association between IGF-1 levels and time to CRPC development or OS.

Conclusions: Elevated levels of IGFBP-1 are associated with shorter duration of ADT efficacy in men with metastatic prostate cancer. This correlative data supports the ongoing SWOG trial assessing whether IGF signaling blockade improves ADT efficacy, as has been seen in preclinical models.

[Table: see text]
Preliminary results of a factorial phase II randomized trial of continuous (C) or intermittent (I) docetaxel (DOC) with or without estramustine (E) as first-line treatment for castration-resistant prostate cancer (CRPC) (HOPLITE trial).
Authors: Caffo Orazio , Lo Re Giovanni , Sava Teodoro , Buti Sebastiano , Sacco Cosimo , Basso Umberto , Zustovich Fable , Martini Thomas , Perin Alessandra , Veccia Antonello , Russo Lucianna , Facchini Gaetano , Barile Carmen , Gernone Angela , De Vivo Rocco , Pappagallo Giovanni L. , Galligioni Enzo
Published: February 2017

220

Background: DOC given for 8 consecutive courses is considered a standard first line treatment for CRPC pts and I administration could reduce its impact on quality of life (QL). E is considered synergistic with DOC. Aim of this study was to evaluate in a 2 × 2 factorial design, if I DOC could improve QL compared to C DOC and whether E added to DOC could improve its activity.

Methods: CRPC pts were randomized to: C DOC 70 mg/m2 i.v. q 3 wks for 8 courses, alone (arm A) or with E 280 mg/TID p.o. for 5 days starting on -1 day (arm B), or the same treatments given with a 3-month rest period after the first 4 courses (arm C and D, respectively). The primary end points were QL (EORTC QLQ C30 and BPI) of A+B vs C+D and 1-y PFS (according to PCWG2) of A+C vs B+D.

Results: From 11/06 to 10/10, 148 CRPC pts were enrolled and 124 pts are presently evaluable (24 too early). The median age was 69 (range 42–81) and the median baseline PSA was 55.6 (range 0.33–4212). The major hematological toxicities were: anemia G3 (3 pts), neutropenia G3 (4 pts) – G4 (5 pts), febrile neutropenia (5 pts). QL outcomes of C and I groups, were not statistically different in terms of general QL items. 1-y PFS was also superimposable (10% and 13.5%, respectively) for DOC and DOC+E groups. The 2-y overall survival was also evaluated with no differences between I and C groups (42.5% and 53.7% respectively) and between DOC and DOC+E groups (42.8% and 53.5% respectively).

Conclusions: These preliminary results seem to indicate that I treatment may not improve QL compared to C treatment. Moreover, the addition of E to DOC did not improve 1-y PFS of CRPC pts. Updated data with the complete sample analysis will be presented.
Pilot study of veliparib (ABT-888) with temozolomide (TMZ) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Hussain Maha , Carducci Michael Anthony , Slovin Susan F. , Cetnar Jeremy Paul , Qian Jiang , McKeegan Evelyn Mary , Litvinovich Elizabeth , Chyla Brenda , Hetman Robert , Desai Bhardwaj , Giranda Vincent L. , Alumkal Joshi J.
Published: February 2017

224

Background: Castration-resistant PC tumors exhibit increased PARP activity (critical enzymes for DNA damage repair). Veliparib is a novel, oral, potent inhibitor of PARP-1 and PARP-2. Preclinically, resistance to oral TMZ treatment in the PC3-Luc prostate cancer mouse model was reversed when mice were treated with veliparib. Based on the synergistic interaction, we evaluated the efficacy and safety of veliparib + TMZ in mCRPC pts.

Methods: Eligible pts had mCRPC, PSA>2 ng/mL, progressed on at least one docetaxel based therapy and adequate organ function. Pts received veliparib 40 mg BID Days (D) 1-7 and TMZ D1-5 in 28D cycle (C) until disease progression (PD) or unacceptable toxicities. Tumor response was assessed every 8 weeks. Primary objective: Efficacy based on rate of PSA decline of 30% or greater. Secondary objectives: safety, RECIST objective response rate, progression-free survival (PFS), overall survival (OS) and biomarker analyses. A sample size of 25 pts provided 76% power to differentiate between PSA response rates of 5 and 20% at 1-sided type I error rate of 0.1.

Results: 26 pts were enrolled; median age 67 years [55, 81]; median baseline PSA 107 ng/ml (6.9, 4584.4); 7/26 (27%) had 2 prior therapies. Median Cs of veliparib + TMZ received were 2 (range 1–9). Most frequent treatment related adverse events (AE) were fatigue (50%), nausea (38%) and constipation (23%). Grade 3/4 AEs in >10% of pts was thrombocytopenia (15%). All pts are off therapy. 25 pts were PSA response evaluable; 2 pts had a confirmed PSA response; 1 pt had a 37% decrease in PSA while the other pt had a 96% decrease in PSA and a 40% reduction in tumor size. 4/25 pts had stable disease for a minimum of 4 months (m). Median PFS was 2.1 m [95% CI: 1.8, 3.9]; 11/26 pts have died with median OS of 9.1 m [95% CI: 5.5, 11.7]. There was a negative correlation between change from baseline in circulating tumor cells and PFS.

Conclusions: Veliparib + TMZ were well tolerated with evidence of some activity. Due to lack of activity of TMZ in CRPC,veliparib-induced potentiation of TMZ may not be clinically significant. Other combinations will be explored with higher doses of veliparib. Biomarker data will be presented.
Predicting clinical outcomes after radical nephroureterectomy for upper tract urothelial carcinoma.
Authors: Cha Eugene K. , Shariat Shahrokh F. , Kormaksson Matthias , Novara Giacomo , Rink Michael , Lotan Yair , Scherr Douglas , Raman Jay D. , Kassouf Wassim , Zigeuner Richard , Bensalah Karim , Weizer Alon Z. , Bolenz Christian , Roscigno Marco , Koppie Theresa M. , Fristche Hans-Martin , Ficarra Vincenzo , Langner Cord , Wood Christopher G. , Margulis Vitaly ,   Upper Tract Urothelial Carcinoma Collaborative Group
Published: February 2017

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Background: Novel prognostic factors for patients after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) have recently been described. We tested the prognostic value of pathologic characteristics and developed models to predict the individual probabilities of recurrence-free survival (RFS) and cancer-specific survival (CSS) after RNU.

Methods: Our study included 2,244 patients treated with RNU without neoadjuvant or adjuvant therapy at 23 international institutions. Tumor characteristics included T classification, grade, lymph node status, lymphovascular invasion, tumor architecture, location, and concomitant CIS. The cohort was split for development (12 centers, n=1273) and external validation (11 centers, n=971).

Results: At a median follow-up of 45 months, 501 patients (22.3%) experienced disease recurrence and 418 patients (18.6%) died of UTUC. On multivariable analysis, T classification (p-for-trend <0.001), lymph node metastasis (HR:1.98, p=0.002), lymphovascular invasion (HR:1.66, p<0.001), sessile tumor architecture (HR:1.76, p<0.001), and concomitant CIS (HR:1.33, p=0.035) were associated with disease recurrence. Similarly, T classification (p-for-trend <0.001), lymph node metastasis (HR:2.23, p=0.001), lymphovascular invasion (HR:1.81, p<0.001), and sessile tumor architecture (HR:1.72, p=0.001) were independently associated with cancer-specific mortality. Our models achieved 76.8% and 81.5% accuracy for predicting RFS and CSS, respectively. In contrast to these well-calibrated models, stratification based upon AJCC stage grouping resulted in a large degree of heterogeneity and did not improve discrimination.

Conclusions: Using standard pathologic features, we developed highly accurate prognostic models for the prediction of RFS and CSS after RNU for UTUC. These models offer improvements in calibration over AJCC stage grouping and can be utilized for individualized patient counseling, follow-up scheduling, risk stratification for adjuvant therapies, and inclusion criteria for clinical trials.
Association between variants on 8q24 and prostate cancer: A review and meta-analysis.
Authors: Troutman Sarah M. , Sissung Tristan M. , Cropp Cheryl D. , Venzon David J. , Spencer Shawn D. , Price Douglas K. , Figg William Douglas
Published: February 2017

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Background: Racial disparities in the incidence prostate cancer exist but remain unexplained. Recent studies implicate single nucleotide polymorphisms (SNPs) within the 8q24 region as a risk factor for prostate cancer (PCa) and the frequency of variant alleles at these SNPs appear to differ by race. To determine the association between 8q24 polymorphisms and PCa among men of different races, we performed meta-analyses, stratified by race.

Methods: Twenty-nine studies of seven SNPs and one microsatellite marker located within the 8q24 region were included in the meta-analyses. Allelic odds ratio (OR) values and confidence intervals were calculated using the Mantel-Haenszel test. This test assumes homogeneity so we first used the Breslow-Day test to determine whether or not the assumption of homogeneity was valid in each population.

Results: PCa risk was associated with the following SNPs in all included races: rs6983267, rs1447295, rs6983561, rs7837688, rs16901979, and DG8S737(-8). PCa risk in Caucasians was conferred by rs6983267 (OR = 1.22 (1.17-1.27)), rs1447295 (OR = 1.43 (1.45-1.49)), rs6983561 (OR = 1.45 (1.30-1.61), rs7837688 (OR = 1.55 (1.39-1.73)), rs16902979 (OR = 1.39 (1.29-1.49)), and DG8S737(-8) (OR = 1.32 (1.12-1.56)). In African American men, a significant association was found for rs1447295 (OR = 1.1 (1.02-1.18)), rs6983561 (OR = 1.43 (1.29-1.59)), rs16901979 (OR = 1.39 (1.29-1.49)), and DG8S737(-8) (OR =1.34 (1.19-1.50)). Alleles associated with PCa risk in Asians were rs6983267 (OR = 1.15 (1.04-1.26)), rs1447295 (OR = 1.39 (1.25-1.54)), rs6983561 (OR = 1.68 (1.51-1.88)), and rs16901979 (OR = 1.65 (1.48-1.85)). The risk allele at rs1447295 was also associated with PCa risk among Hispanic men.

Conclusions: 8q24 contains SNPs that are associated with PCa risk, but the strength of this association depended on race. Racial disparities in the incidence of PCa may in part be accounted for by 8q24 variants.
Phase II study of gemcitabine, cisplatin, and sunitinib (S) in patients with advanced urothelial carcinoma (UC).
Authors: Galsky Matt D. , Hellerstedt Beth A. , O'Rourke Mark Allen , Vogelzang Nicholas J. , Kocs Darren M. , McKenney Scott A. , Melnyk Anton M. , Hutson Thomas E. , Rauch Mary Ann , Wang Yunfei , Asmar Lina , Sonpavde Guru
Published: February 2017

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Background: Sunitinib (S) has single-agent activity in patients with advanced urothelial carcinoma (UC). Preclinical studies in UC demonstrate at least additive antitumor activity combining S with gemcitabine (G) or cisplatin (C).

Methods: Patients with chemonaïve metastatic UC were enrolled in a multicenter phase II trial with overall response rate (ORR) as the primary endpoint. The initial dosing regimen, based on a phase I trial (Reck, 2010), was G 1000 mg/m2 IV (Days 1 & 8), C 70 mg/m2 IV (Day 1), and S 37.5 mg PO daily (Days 1-14)/each 21-day cycle (up to 6 cycles), followed by S 37.5 mg daily until progression.

Results: From December 2008 to August 2009, 15 eligible patients enrolled. Seven of 15 patients discontinued treatment early (median: 3 cycles) due to toxicity, most often due to recurrent neutropenia and thrombocytopenia. Intrapatient dose reductions were required for G (12/15), C (8/15), and S (10/15). Eight of 15 patients experienced serious adverse events. Based on the toxicity profile, enrollment was held and the dosing regimen was revised to G 800 mg/m2 IV (Days 1 and 8), C 60 mg/m2 IV (Day 1), S 37.5 mg PO daily (Days 1-14). From December 2009 to April 2011, 18 additional patients were enrolled. Despite the reduced starting doses, intrapatient dose reductions were required for G (13/18), C (9/18), and S (15/18). The most frequent Grade 3-4 toxicities for both groups were neutropenia (70%), thrombocytopenia (58%), and anemia (30%). Antitumor activity is shown in the Table. Median PFS was 7.9 and median OS was 13.8 months.

Conclusions: Combination G+C+S is poorly tolerated and results in activity comparable to historical results with G+C alone. Supported in part by a grant from Pfizer Inc.

[Table: see text]
A phase I trial of intravesical antisense oligonucleotide targeting heat shock protein 27 (OGX-427) for the treatment of non-muscle-invasive bladder cancer.
Authors: So Alan I. , Black Peter C. , Chi Kim N. , Hurtado-Col Antonio , Gleave Martin E.
Published: February 2017

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Background: The treatment options to prevent recurrence and progression in patients with non-muscle invasive bladder cancer (NMIBC) are limited. Heat Shock Protein 27 (Hsp27) is a cytoprotective protein that has been shown to be important in a variety of malignancies, including bladder cancer (BCa), where it has been linked to therapeutic resistance and disease progression. OGX-427 is a 2nd generation (2’-MOE) antisense oligonucleotide that potently inhibits Hsp27 expression in vitro and in vivo.

Methods: We initiated a phase I clinical study to assess the safety, pharmacokinetic (pk), pharmacodynamic (pd) and biologic effects of intravesical treatments of OGX-427 using a presurgical dose-escalating design for patients with BCa. Eligible patients include patients with Ta, T1 or carcinoma-in-situ and candidates for transurethral resection of the bladder tumor (TURBT), or patients with muscle invasive BCa (>cT2) and candidates for radical cystectomy (RC). Patients are treated with intravesical OGX-427 on days 1,3,5, and 8 and then undergo surgery on day 9-12. Dose is escalated after tolerability and safety assessment for each cohort at 20uM, 50 uM, 100uM, 250uM, 500uM, and 750uM.

Results: To date, we have enrolled 13 patients in the trial and have completed the 250uM cohort. 12 patients had NMIBC and one had cT2 disease and underwent a cystectomy. No significant drug-related adverse events have been reported; no dose limiting toxicity was observed and only one patient developed gross hematuria (grade 1) within 24 hours of administration of drug that spontaneously resolved. Pathological staging of surgical specimens revealed that five patients (38%) had complete responses (p0). The remaining NMIBC patients had pTa tumors that ranged from G1-G2; the sole patient undergoing cystectomy had pT2aG3 bladder cancer. Accrual of the two remaining cohorts will be complete shortly and the pd and pk analysis will be performed once all specimens are available.

Conclusions: OGX-427 is well tolerated intravesically with minimal toxicity. Our results indicate early evidence of activity of OGX-427 against bladder cancer that requires confirmation in phase II/III studies.
Extended lymphadenectomy and adjuvant chemotherapy in muscle-invasive bladder cancer treated by radical cystectomy.
Authors: Bostrom Peter J. , Mirtti Tuomas , Nurmi Martti , Laato Matti , Van Rhijn Bas W.G. , Fleshner Neil Eric , Finelli Antonio , Jewett Michael A. S. , Moore Malcolm J. , Sridhar Srikala S. , Tannock Ian , Zlotta Alexandre
Published: February 2017

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Background: Level 1 evidence is weak for adjuvant chemotherapy (AC) after cystectomy, but surveys indicate physicians refer patients for AC more frequently than for neoadjuvant chemotherapy (NC). The exact benefit of an extended pelvic lymph node dissection (ePLND) remains debated. We addressed the issue of AC and ePLND analyzing two academic centers RC databases with opposite approaches, one using ePLND and AC, the other performing a limited lymph node dissection and no AC.

Methods: Two ethics approved RC databases including consecutive BC patients undergoing RC at the University Health Network, Canada and the University of Turku, Finland were studied. Excluding non-urothelial cases and patients receiving NC, 563 patients were available for analysis. Clinicopathological variables, rate and extent of PLND and rate of adjuvant cisplatin-based chemotherapy were analyzed using the χ2-test. Kaplan-Meier method and multivariate Cox regression analysis were used to analyze survival.

Results: In Toronto, patients had more extensive PLNDs (>10 nodes removed, 58% vs. 8%, p<0.001), higher rate of nodal metastases (26% vs. 7%, p<0.001), and received more often AC (21% vs. 1%, p<0.001). Positive margin rates were similar (4% in both centers). No BC specific survival difference was demonstrated in ≤ pT2a or in pT4a tumors. There was a trend for improved survival in pT2b tumors (10y BC specific survival 65% vs. 42%, p=0.23) and a significant difference favouring the Toronto cohort in pT3a and pT3b tumors (55% vs. 31%, p=0.025; 43% vs. 28% p=0.06, respectively). In multivariate analysis, N-stage (HR 2.5, 95% CI 1.5-4.1; p<0001) and ePLND (HR 0.53, 95% CI 0.31-0.93, p=0.026) significantly affected disease specific survival. The benefit of AC did not reach significance (HR 0.61, 95% CI 0.36-1.05, p=0.072). An interaction model combining ePLND and AC was significantly related to improved outcome (HR 0.49, 95% CI 0.26-0.92, p=0.026).

Conclusions: Despite not being randomized, using 2 study cohorts that received completely opposite managements in terms of ePLND and AC, our results support that ePLND and AC may offer a survival advantage in T2b and especially in T3 BC treated with RC.
Influence of vascular comorbities and race on erectile dysfunction after prostate cancer radiotherapy.
Authors: Wang Yuefeng , Liu Tian , Rossi Peter J. , Cooper Sherrie , Jani Ashesh B.
Published: February 2017

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Background: Vascular comorbidities (VC’s) [hypertension (HTN), diabetes (DM) and/or hyperlipidemia (HL)] are known factors related to erectile dysfunction (ED) prior to radiotherapy (XRT). We have undertaken this study to understand the influence of VC’s on post-XRT ED incidence, and to further characterize ED incidence by racial groups.

Methods: We reviewed the charts of 732 prostate cancer patients [267 white (W) and 465 African American (AA)] who received XRT [external beam radiotherapy (EBRT) and/or brachytherapy (BT)] with or without use of hormone therapy between 1999 and 2010. The number of pre-XRT VC’s (0, 1, 2, or 3) was determined by medical history and medication list. ED (defined by use of erectile aids or by documentation of moderate or high sexual dysfunction on patient history) was determined pre-XRT as well as 1, 6, and 12 months post-XRT and compared by follow-up interval since XRT, by number of VC’s, and by race in each case using the two sample proportion test.

Results: ED incidence progressively increased with time from 22% pre-XRT to 52% 12 months post-XRT (p<0.001). Additionally, ED incidence increased with increasing of number of VC’s – 12-month incidences between patients with 0 vs 2 (p=0.024), 0 vs 3 (p<0.001), 1 vs 3 (p<0.001), and 2 vs 3 (p=0.004) VC’s were statistically significant (0 vs 1 and 1 vs 2 were non-significant). Pre-XRT ED incidence was 20% vs 23% (for W vs AA patients, p=0.156) due to higher incidence of VC’s in the AA group. At 12 month follow-up, ED incidences for W vs AA patients were 38% vs 45%, 46% vs 49%, 52% vs 57%, and 71% vs 75% with 0, 1, 2 and 3 co-morbidities, respectively (all p-values non-significant).

Conclusions: Our analysis represents the first effort exploring post-XRT ED as determined by the number VC’s and by race. Our results suggest that number of VC’s have a significant effect on development of post-XRT ED. Pre- and post-XRT ED appear to be independent of race when number of VC’s are considered. Our results can be used to guide physicians in counseling patients on the incidence of ED by number of VC’s and as preliminary data for prospective efforts aimed at reducing post-XRT ED.