bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I/II study of the MEK inhibitor BAY 86-9766 (BAY) in combination with gemcitabine (GEM) in patients with nonresectable, locally advanced or metastatic pancreatic cancer (PC): Phase I dose-escalation results.
Authors: Van Laethem Jean-Luc , Heinemann Volker , Martens Uwe Marc , Jassem Jacek , Michl Patrick , Peeters Marc , Weekes Colin D. , Maréchal Raphael , Stieler Jens , Giurescu Marius , Rajagopalan Prabhu , Garosi Vittorio Luigi , Riess Hanno
Published: March 2020

4050

Background: Targeting the RAS–RAF–MEK–ERK pathway may be useful in the treatment of PC, as 75–90% of PCs have KRAS mutation. BAY is an orally bioavailable, potent, allosteric MEK 1/2 inhibitor that showed single-agent activity, and synergistic activity with GEM, in ectopic, orthotopic, syngenic and patient-derived xenograft PC models. Methods: The phase I part aimed to determine the maximum tolerated dose (MTD) of BAY in combination with GEM, and the pharmacokinetics of BAY and GEM. 3+3 study design was used. After informed consent, eligible patients with advanced PC received GEM 1000 mg/m2 (30-min, once-weekly IV infusion for 7 out of 8 weeks in cycle 1 [C1], and 3 out of 4 weeks in subsequent cycles) and oral BAY 30 mg BID (dose level 1 [DL1]) or 50 mg BID (DL2). No escalation beyond DL2 was planned. MTD was the highest dose at which maximum 1 out of 6 evaluable patients displayed dose-limiting toxicities (DLT) during C1. Results: As of 6 Jan 2012, 17 patients were enrolled and treated (10 at DL1, 7 at DL2). DL1 cohort has completed; DL2 evaluation is ongoing. At DL1, DLTs occurred in 1/6 evaluable patients: a patient with extensive liver metastasis developed chemotherapy-associated steatohepatitis (CASH) and died of hepatic failure. Rare CASH cases have been reported to be associated with GEM alone, but co-involvement of BAY currently cannot be ruled out. To date, 3 patients have completed C1 at DL2 without DLTs. DL2 completion is expected in March 2012. BAY+GEM showed a manageable tolerability profile. The most frequent treatment-related grade 3–4 adverse event (AE) at any DL was neutropenia (n=6). The most frequent clinically relevant BAY-related AE was acneiform rash (n=11), which was mostly grade 1–2 (one case grade 3) and manageable. BAY+GEM showed evidence of clinical efficacy: partial responses were seen in 4/10 patients at DL1 and 1/3 patients at DL2. No pharmacokinetic interaction between BAY and GEM was seen at DL1. Conclusions: In patients with advanced PC, BAY 30 mg BID in combination with GEM had a manageable safety profile, with acneiform rash as the clinically most relevant toxicity attributable to BAY.
Inequal benefits from regionalization of cancer care: The pancreatic cancer surgery paradigm.
Authors: McDade Theodore P. , Smith Jillian K , Chau Zeling , Witkowski Elan R. , West James K. , Tseng Jennifer F.
Published: March 2020

4059

Background: Regionalization has been proposed for high-level care, including multidisciplinary cancer treatment and complex procedures. Pancreatic resections can serve as a marker for both. Using Massachusetts Division of Health Care Finance and Policy (DHCFP) data, we investigated regionalization of surgery for pancreatic cancer (PCa), its potential effect on perioperative outcomes, and disparities in access to high-volume PCa surgery centers. Methods: Using MA DHCFP Hospital Inpatient Discharge Data, 2005-2009, 10,524 discharges for PCa were identified, of which 746 were associated with pancreatic resection. Discharges with missing or out-of-state residence were excluded (n=704). Using geodetic methods and ZIP codes, center-to-center distances were calculated between patient (pt) and treating hospital. Median ZIP income was estimated from 2009 census data. High volume hospitals (4 of 25 performing pancreatic resections in MA) were defined using Leapfrog Criteria (> 11 per year (87th percentile for MA). Chi-square and logistic regression analyses were performed using SAS software. Results: Median age was 65. Pts were predominantly White (87.2%), with median ZIP income of $54,677. Pts travelled in-state up to 112 miles (median 15.4), with the majority resected at high volume hospitals (76%). Median length of stay (LOS) was 8.0 days, with LOS>1 week associated with low volume hospitals (p=0.0002). Of 14 in-hospital deaths, 7 were at low volume hospitals (4.14% of 169 pts) compared to 7 at high volume hospitals (1.31% of 535 pts) (p=0.0214). Predictors of shorter travel distance were: Black race (OR 4.45 (95% CI 1.66-11.93)), operation at low volume hospital (OR 2.62 (95% CI 1.81-3.77), and increased age (per year) (OR 1.02 (95% CI 1.00-1.03), but not sex or median income. Conclusions: Using MA statewide discharge data, regionalization of pancreatic cancer surgery to high-volume, better-outcome centers is seen to be occurring. However, it is not uniform, and disparities exist between groups of cancer pts that do and do not travel for their care. In the current era of scrutiny on cost, quality, and access to cancer care, further study into predictors of pts receiving optimal care is warranted.
Customization of treatment for patients with esophageal adenocarcinoma (EAC) who achieve clinical complete response (cCR) after chemoradiation using initial standardized uptake value (iSUV) of 18f-fluorodeoxyglucose PET.
Authors: Suzuki Akihiro , Xiao Lianchun , Taketa Takashi , Blum Mariela A. , Welsh James , Lin Steven H. , Weston Brian , Lee Jeffrey H , Bhutani Manoop S. , Rice David C. , Mehran Reza J. , Maru Dipen M , Erasmus Jeremy J. , Hofstetter Wayne Lewis , Swisher Stephen , Ajani Jaffer A.
Published: March 2020

4069

Background: Patients with localized esophageal adenocarcinoma (EAC) receive preoperative chemoradiation followed by surgery (trimodality [TM] therapy) or definitive chemoradiotherapy (bimodality [BM] therapy) based on comorbidities and tumor geography. However, we cannot individualize recommendations beyond these parameters. We hypothesized that iSUV could customize therapy. Methods: Data source was our prospective database of fully staged EAC patients (2002-2010). All patients had a cCR (post-chemoradiation negative biopsy and post-chemoradiation physiologic uptake on PET). iSUV cut-point was derived by recursive partitioning. Results: For 323 cCR patients, the median follow-up was 40.8 months. 206 (63.8%) patients had TM and 117 (36.2%) had BM therapy. Median OS of TM patients and BM patients were 94.8 months (95 % CI; NA-NA) and 36.5 months (95% CI; 30.5-42.4; p<0.001), respectively. Similar differences were observed in RFS (p<0.001). The median iSUV was 9.4 (range, 0-58.0). Intriguingly, TM patients with iSUV of >6 had a better OS (94.8 months; 95% CI; 39.1-150.5) and RFS (94.8 months; 95% CI; 18.2-171.4) compared to BM patients with iSUV of >6 OS (31.4 months; 95% CI; 21.0-41.9; p=<0.001) and RFS (17.2 months; 95% CI; 14.5-19.8; p<0.001). However, the prognosis of TM and BM cCR patients with iSUV <6 was similar (OS, p=0.62 and RFS, p=0.46). The pathological CR (pathCR) rate in TM patients was similar irrespective of iSUV of ≥6 (27.1%) vs. iSUV <6 (28.6%; p=0.85). Conclusions: Our unique data provide an insight into the fate of cCR EAC patients by iSUV. Patient with iSUV ≥6 dramatically benefit from surgery and TM therapy is encouraged. iSUV and pathCR do not correlate. iSUV can customize therapy of localized EAC patients.
Efficacy and safety of bevacizumab combined with capecitabine in progressive, metastatic well-differentiated digestive endocrine tumors (BETTER study).
Authors: Mitry Emmanuel , Walter Thomas , Baudin Eric , Kurtz Jean-Emmanuel , Ruszniewski Philippe , Dominguez Sophie , Bengrine-Lefevre Leila , Cadiot Guilaume , Kraemer Sandrine , Ducreux Michel
Published: March 2020

4071

Background: Neuroendocrine digestive tumors are highly vascularized neoplasms known to express the vascular endothelial growth factor (VEGF). We assessed the activity of bevacizumab (Bv), a monoclonal antibody directed against VEGF combined with capecitabine (CAP). Methods: In this multicenter, open-label, non-randomized, two-group phase II trial, one group assessed Bv (7.5 mg/m² on d1/3 weeks) combined with CAP (1,000 mg/m2 twice daily, orally d1-14, resumed on day 22). Eligible patients (pts) had progressive, metastatic well-differentiateddigestive tract endocrine tumors (WHO 2000 classification), ECOG-PS ≤2, Ki 67 index < 15%, no prior systemic chemotherapy and acceptable organ functions. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival, response rate, safety and quality of life. Pts were treated for a minimum of 6 months and study duration was 24 months. Results: From Jun 2007 to Oct 2009, 49 pts were enrolled, 26 (53.1%) were men; median age 60.3 years (41.2-82.3); ECOG-PS was 0/1 in 46 (93.9%) pts. Primary tumor site was: small intestine 40 (81.6%) pts, caecum 3 (6.1%), rectum 4 (8.2%) and stomach 2 (4.1%). Ki-67 proliferative index was 0-2% in 17 (35.4%) pts, 3-4% in 14 (29.2%), 5-9% in 13 (27.1%), 10-14% in 4 (8.3%) Metastatic sites were liver: 46 (93.9%) pts, lymph nodes: 24 (49.0%), peritoneum 23 (46.9%). Median treatment duration was 13.8 months; median number of cycles was 19. At 24 months, median PFS was 23.4 months [95%CI: 13.2; not reached] based on 26 events. PFS rate at 18 months was 55%. Tumor control rate was 87.8% (n=43) including partial response in 9 (18.4%) pts and stable disease in 34 (69.4%) pts. Survival rate at 24 months was 85%, median overall survival was not reached, 8 patients died. CTC grade 3/4 Adverse Events (AEs) occurred in 41 (83.7%) pts, mainly digestive 14 (28.6%) pts. Main G3/4 Bv targeted AE was hypertension in 15 (30.6%) pts. Conclusions: In this chemotherapy resistant tumor, the combination of capecitabine and bevacizumab, assessed in a phase II study, shows such encouraging results that this combination may become a reference in the medical treatment of ileal NET.
Outcome of 58 trimodality-eligible esophagogastric cancer (EC) patients who achieved clinical complete response (cCR) after preoperative chemoradiation but then declined surgery.
Authors: Taketa Takashi , Correa Arlene M , Suzuki Akihiro , Blum Mariela A. , Lee Jeffrey H , Welsh James , Lin Steven H. , Maru Dipen M , Erasmus Jeremy J. , Bhutani Manoop S. , Weston Brian , Rice David C. , Swisher Stephen , Hofstetter Wayne Lewis , Ajani Jaffer A.
Published: March 2020

4078

Background: For patients with EC who can withstand surgery, the preferred therapy is trimodality. However, after achieving a cCR (defined as post-chemoradiation negative endoscopic biopsy for cancer and post-chemoradiation physiologic FDG uptake by PET), some patients are tempted to decline surgery. Literature is sparse on the outcome of such patients. Methods: Between 2002 and 2011, we identified 621 trimodality-eligible EC patients in our prospective database. All patients had to be trimodality-elgible and must have received preoperative chemoradiation and completed preoperative staging that included a repeat endoscopic biopsy and PET-CT prior to surgery among other routine tests. Results: Of 621 trimodality-eligible patients identified, 58 patients declined surgery after completing chemoradiation. All patients had a cCR. The median age was 69 (range, 47-85). Male (84.5%) and Caucasian (91.4%) were dominant. Baseline stage was II (44.8%) or III (51.7%) and histology was adenocarcinoma (67.2%) or squamous cell carcinoma (29.3%). 40 patients remain alive at a median follow up of 50.4 months (95% CI, 38.6-62.1). 5-year OS and relapse-free survival were 56.7±9.0% and 32.9±7.7%. Of 12 patients with local recurrence during surveillance, 11 had salvage resection. Conclusions: Although, the outcome of EC patients with cCR who declined surgery appears reasonable, in the absence of a validated prediction/prognosis model, only trimodality therapy must be encouraged for trimodality-eligible patients. Supported by UT M. D. Anderson Cancer Center grants and generous donors.
Phase I trial of temsirolimus (TEM) plus sorafenib (SOR) in advanced hepatocellular carcinoma (HCC) with pharmacokinetic (PK) and biomarker correlates.
Authors: Kelley Robin Katie , Nimeiri Halla Sayed , Munster Pamela N. , Mulcahy Mary Frances , Vergo Maxwell Thomas , DeSon Amanda , Murphy Christi , Yeh Benjamin M. , Ko Andrew H. , Korn Wolfgang Michael , Hwang Jimmy , Luttgen Madelyn , Kuhn Peter , Huang Yong , Benson Al Bowen , Venook Alan Paul
Published: March 2020

4102

Background: Mammalian target of rapamycin inhibitors added to SOR augment antitumor effect in HCC models. We developed a phase 1 trial to determine maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of TEM plus SOR in HCC patients (pts). The study was approved and funded by the National Comprehensive Cancer Network (NCCN) from general research support from Pfizer, Inc., and conducted at 2 NCCN centers. Methods: Eligibility: ≥1 measurable site. No prior systemic therapy (Tx). ECOG ≤2, Child Pugh ≤7, bilirubin ≤2 mg/dL, platelets (PLT) ≥75,000/mcL. Design: 3+3 escalation. Dose-limiting toxicity (DLT) window 28 days. MTD expansion cohort of 9 pts for PK and biomarkers. Endpoints: 1°: MTD, RP2D. 2°: Safety, toxicity, PK for TEM. Exploratory: Tumor necrosis, alpha fetoprotein (AFP)-L3, des-γ-carboxyprothrombin, and circulating tumor cells (CTC) by slide-based assay. Results: 21 pts enrolled. Median age: 60 (47-77). Male/Female: 15/6. Etiology: HCV 9 (43%), HBV 4 (19%), HBV+HCV 2 (10%), ETOH 2 (10%), unknown 4 (19%). Toxicity: DL1: 1 DLT Grade (Gr) 3 PLT. All pts required reductions for adverse events (AE); de-escalated to DL-1 for intolerability. DL-1: 1 DLT Gr3 hand-foot syndrome (HFS). Most common related ≥Gr 3 AE: HypoPO4 (52%); PLT (24%); transaminitis (19%); diarrhea, fatigue, HFS (10% each). Possibly related serious AE (SAE): Gr4 tumor rupture, Gr4 urosepsis, Gr3 dental infection with Gr2 ANC, Gr2 pneumonia (1 pt, 5% each). Best response: Confirmed partial response (PR) 2/21 (10%), stable disease (SD) 11/21 (52%), progression 1/21 (5%), 7/21 (33%) not evaluable. Time on study: Range <1 to 19+ months; median 3+ months for pts who completed ≥1 cycle (16/21). 16/21 (76%) had baseline elevated AFP ≥20; 8/16 (50%) had >50% decline. CTC were detected in 5/5 of tested samples. Decreased tumor enhancement on Tx was seen. Conclusions: DL-1 is MTD and RP2D, lower than a prior trial in pts without HCC; tolerability may be impacted by cirrhosis. Encouraging durable radiographic and AFP responses occurred. [Table: see text]
Clinical activity and safety of anti-PD-1 (BMS-936558, MDX-1106) in patients with previously treated metastatic renal cell carcinoma (mRCC).
Authors: McDermott David F. , Drake Charles G. , Sznol Mario , Choueiri Toni K. , Powderly John , Smith David C. , Wigginton Jon , McDonald Dan , Kollia Georgia , Gupta Ashok Kumar , Atkins Michael B.
Published: March 2020

4505

Background: BMS-936558 is a fully human monoclonal antibody that blocks the programmed death-1 co-inhibitory receptor (PD-1) expressed by activated T cells. In the initial portion of a phase I study, BMS-936558 showed promising activity in patients (pts) with various solid tumors, including mRCC. We expanded accrual in order to better characterize antitumor and dose effects. Methods: RCC pts were treated with BMS-936558 administered IV Q2WK at 10 mg/kg initially, followed by additional pts at 1 mg/kg. Pts received up to 12 cycles (4 doses/cycle) of treatment or until PD or CR. Clinical activity was assessed by RECIST 1.0. Results: Of 240 pts treated as of July 1 2011, 33 had mRCC and were treated at 1 (n=17) or 10 mg/kg (n=16). ECOG performance status was 0/1 in 13/19 pts. The number of prior therapies was 1 (n=10), 2 (n=9), or ≥3 (n=14), and included prior immunotherapy (n=20) or antiangiogenic therapy (n=24); 31 pts had prior nephrectomy. Sites of metastatic disease included lymph node (n=26), liver (n=7), lung (n=28), and bone (n=10). Median duration of therapy was 19 wk (max 96 wk). The incidence of grade 3-4 related AEs was 12% and included hypophosphatemia (6%), elevated ALT (3%), and cough (3%). Clinical activity was observed at both dose levels (Table). Some pts had a persistent reduction in overall tumor burden in the presence of new lesions and were not categorized as responders. Responses were noted in pts with visceral and bone metastases. Among the responders who were first treated ≥1 yr prior to data lock, 4 of 5 pts treated at 10 mg/kg had OR duration ≥1 yr, and 1 of 2 pts treated at 1 mg/kg was still on study with OR duration of 17.5 mo. Although the data for pts treated at 1mg/kg are not mature, the estimated progression-free survival (PFS) rate at 24 wk in pts receiving 10 mg/kg was 67% (Table). Conclusions: BMS-936558 is well tolerated and has durable clinical activity in pts with previously treated mRCC. Further development of BMS-936558 in pts with mRCC is ongoing. [Table: see text]
Prostate-specific antigen decline (PSA) as a surrogate for overall survival (OS) in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) who failed first-line chemotherapy.
Authors: Halabi Susan , Armstrong Andrew J. , Sartor A. Oliver , De Bono Johann Sebastian , Kaplan Ellen B , Small Eric Jay
Published: March 2020

4515

Background: PSA kinetics, and more specifically a 30% decline in PSA following initiation of first-line chemotherapy with docetaxel, has been reported to be a surrogate endpoint for OS in mCRPC pts. The objective of this analysis was to evaluate PSA kinetics as surrogate endpoints for overall survival (OS) in patients who were receiving second line chemotherapy following progression after docetaxel front line therapy. Methods: Data from a phase III trial of 755 mCRPC pts randomized to treatment with cabazitaxel in combination with prednisone (C+P) every 3 weeks or mitoxantrone in combination with prednisone (M+P) were used. All pts were previously treated with a docetaxel-containing regimen. PSA decline (≥30% and ≥50% ) and PSA velocity within the first three months of treatment were evaluated as potential surrogate endpoints for OS. The proportional hazards (PH) model was used to test for Prentice’s criteria and the proportion of treatment explained (PTE) was computed as a second test of surrogacy. PTE was defined as one minus the ratio of the treatment coefficient in the adjusted PH model (includes PSA decline or velocity) to the treatment coefficient in the unadjusted PH model. Results: Of 755 men, 654 had sufficient PSA data to be included in the analysis. Treatment arm (C+P vs. M+P) was prognostic of OS with a hazard ratio (HR) of 0.65 (95% CI=0.54-0.79, p<0.001). A 30% PSA decline within three months of treatment was associated with a HR of 0.46 (95% CI 0.37-0.57, p-value<0.001) for OS. After adjusting for treatment effect, the HR for 30% PSA decline was 0.50 (95% CI= 0.40-0.62, p<0.001) but treatment arm remained statistically significant thus failing Prentice’s third criterion. The PTE for ≥30% decline in PSA within three months was 0.39 (95% CI= 0.36-0.42) indicating a lack of surrogacy for OS. Similar results were observed for pts who experienced ≥50% decline in PSA and PSA velocity. Conclusions: Neither PSA decline (≥30% and ≥50%) nor PSA velocity within the first three months of therapy are surrogate endpoints for OS in pts receiving second line chemotherapy.
Association of long-term exposure to circulating platinum with adverse late effects in testicular cancer survivors.
Authors: Boer Hink , Proost Johannes H , Nuver Janine , Bunskoek Sophie , Gietema Joyce Q. , Geubels Barbara M. , Altena Renske , Zwart Nynke , Oosting Sjoukje , Uges Donald R.A. , Meijer Coby , De Vries Elisabeth , Gietema Jourik A.
Published: March 2020

4528

Background: Successful platinum(Pt)-based chemotherapy for testicular cancer (TC) comes at the price of late cardiovascular morbidity and neurotoxicity. Damage induced by circulating Pt could be an etiological mechanism. We investigated the relation between circulating Pt and late effects. Methods: In 96 consecutive TC patients (med age 29 [17-53] at chemotherapy), 3 serum samples and a 24h-urine sample were collected on several time-points med 5 yrs (1-13) after treatment. Pt concentrations ([Pt]) were measured with a sensitive voltammetric method (Lancet 2000, 355:1075). Measured [Pt] combined with cisplatin dose, age, weight and height were analyzed simultaneously to construct a population pharmacokinetic (PK) model using NONMEM. Based on the PK parameters of each patient, individual [Pt] at 1, 3, 5, 10 yrs after start and AUC were calculated. Cardiovascular status, paresthesia and markers of vascular damage were assessed after a med follow-up (FU) of 9 yrs (3-15). Results: Decay of [Pt] was best described by a two compartment model. Mean terminal T1/2 was 3.7 (±0.3) yrs. At all time-points [Pt] correlated with cisplatin dose and renal function during treatment. [Pt] at 3 yrs correlated with systolic blood pressure (BP) (r=.32, p<0.01) and creatinine clearance (CRCL) (r=-.25, p=0.02) at FU. Patients with increased BP had higher Pt AUCs than patients with normal BP (table). Pt AUCs were higher in patients with paresthesia (table). Conclusions: Known late effects of cisplatin-based chemotherapy such as hypertension and paresthesia are related to higher circulating [Pt]. Long-term exposure to Pt is involved in healthy tissue damage in TC survivors. [Table: see text]
Phase III AXIS trial of axitinib versus sorafenib in metastatic renal cell carcinoma: Updated results among cytokine-treated patients.
Authors: Michaelson M. Dror , Rini Brian I. , Escudier Bernard J. , Clark Joseph , Redman Bruce , Tarazi Jamal Christo , Rosbrook Brad , Kim Sinil , Motzer Robert John
Published: March 2020

4546

Background: Axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors, improved progression-free survival (PFS) compared to sorafenib in patients with metastatic renal cell carcinoma (mRCC) in the phase III AXIS trial. In patients previously treated with cytokines, median PFS (mPFS) was 12.1 mo. In a prior phase II study of axitinib for cytokine-refractory mRCC, mPFS was 13.7 mo and the 5-yr overall survival (OS) rate was 20.6%. We report updated PFS and OS for cytokine-treated patients from the AXIS trial. Methods: 723 patients with clear-cell mRCC and progressive disease after 1 systemic therapy were enrolled, of whom 251 received prior interleukin-2 (IL-2) or interferon-α (IFN-α). Patients were randomized 1:1 to axitinib (5 mg twice daily [BID] starting dose) or sorafenib (400 mg BID). Results: As of Jun 3, 2011, mPFS (95% confidence interval [CI]) for cytokine-treated patients was 12.0 mo (10.1, 13.9) with axitinib (n=126) vs 6.6 mo (6.4, 8.3) with sorafenib (n=125): hazard ratio [HR] (95% CI) 0.519 (0.375, 0.720); p<0.0001. For those treated with an IL-2-containing regimen, mPFS (95% CI) was 15.7 mo (8.3, 19.4) with axitinib (n=37) vs 8.3 mo (4.7, 15.7) with sorafenib (n=38). For those treated with IFN-α alone, mPFS (95% CI) was 12.0 mo (10.0, 13.8) with axitinib (n=89) vs 6.5 mo (6.4, 8.2) with sorafenib (n=87). As of Nov 1, 2011, median OS (95% CI) in the cytokine-treated subgroup was 29.4 mo (24.5, not estimable) with axitinib vs 27.8 mo (23.1, 34.5) with sorafenib: HR (95% CI) 0.813 (0.555, 1.191); p=0.144. Adverse event (AE) profiles were similar in both arms. Few cytokine-treated patients (5.6%) discontinued axitinib due to toxicity. AEs reported in >25% of cytokine-treated patients receiving axitinib were diarrhea (49.2%), hypertension (47.6%), fatigue (35.7%), dysphonia (29.4%), and hand–foot syndrome (28.6%). Conclusions: Axitinib showed median PFS and OS of 1 and 2.5 yr, respectively, in cytokine-treated patients, confirming prior phase II study results, and was well tolerated. PFS was superior to that of sorafenib in second-line mRCC and compares favorably with historical results of other agents in second-line mRCC.
Radium-223 chloride (Ra-223) impact on skeletal-related events (SREs) and ECOG performance status (PS) in patients with castration-resistant prostate cancer (CRPC) with bone metastases: Interim results of a phase III trial (ALSYMPCA).
Authors: Sartor A. Oliver , Heinrich Daniel , O'Sullivan Joe M. , Fossa Sophie D. , Chodacki Ales , Wiechno Pawel J. , Logue John P. , Seke Mihalj , Widmark Anders , Johannessen Dag Clement , Nilsson Sten , Hoskin Peter , Bottomley David , Coleman Robert Edward , Vogelzang Nicholas J. , O'Bryan-Tear C. Gillies , Garcia-Vargas Jose E. , Shan Minghua , Parker Chris
Published: March 2020

4551

Background: Ra-223, a 1st-in-class alpha-pharmaceutical, targets bone metastases (mets) with high-energy alpha-particles of short range (<100 μm). ALSYMPCA, a phase III, double-blind, randomized, multinational study, compared Ra-223 plus best standard of care (BSC) v placebo (pbo) plus BSC in patients (pts) with bone mets in CRPC. The primary endpoint was OS; secondary endpoints included SREs and ECOG PS. Methods: Eligible pts had progressive, symptomatic CRPC with ≥ 2 bone mets on scintigraphy and no known visceral mets; were receiving BSC; and either previously received docetaxel, were docetaxel ineligible, or refused docetaxel. Pts were randomized 2:1 to 6 injections of Ra‑223 (50 kBq/kg IV) q4 wks or matching pbo and stratified by prior docetaxel use, baseline ALP level, and current bisphosphonate use. Results: 921 pts were randomized from 6/2008-2/2011. In a planned interim analysis (n = 809), Ra-223 significantly improved OS v pbo (median OS 14.0 v 11.2 mo, respectively; two-sided P = .00185; HR = .695; 95% CI, .552-.875).SREs were lower in the Ra-223 v pbo group, and time to 1st SRE was significantly delayed (median time to SRE 13.6 mo v 8.4 mo, respectively; P = .00046; HR = .610; 95% CI, .461-.807). The proportion of pts with ECOG PS deterioration (≥ 2 points) was less in Ra-223 v pbo group at Wk 12 and Wk 24 (4%, 15/389 v 9%, 16/180 and 7%, 16/236 v 12%, 10/83, respectively). Time to ECOG PS deterioration (≥ 2 points) was significantly delayed by Ra-223 v pbo (P = .003; HR = .62; 95% CI, .46-.85). Conclusions: Ra-233 significantly delayed time to 1st SRE and SRE components, notably SCC. Fewer pts in the Ra-223 group had ECOG PS deterioration. Ra-223 improves OS with excellent safety and may provide a new standard of care for CRPC pts with bone mets. [Table: see text]
Development of a nomogram model using a very large sample of patients (pts) to predict the risk of 99mTc-bone scan (BS) positivity in pts receiving androgen deprivation therapy (ADT) for prostate cancer (PCa).
Authors: Gotto Geoffrey , Yu Changhong , Bernstein Melanie , Eastham James Andrew , Kattan Michael W.
Published: March 2020

4552

Background: Decisions to start imaging pts with PCa can be difficult due to the heterogeneous nature of the disease. Nomograms can combine information on multiple disease factors to improve predictive accuracy and are not influenced by subjective confounders that may affect clinical judgment. However, currently available nomograms for PCa predict current or future risk of positive BS in ADT-naive pts only. We have developed a new nomogram to predict current BS positivity in ADT-treated pts with PCa using a very large pt sample. Methods: All BS records from 1650 ADT-treated pts who received treatment at the Memorial Sloan-Kettering Cancer Center from 2000 to 2011 were analyzed. Pts were followed up from the start of ADT until the first positive BS or last hospital visit. Multivariate logistic regression analysis was used to model the variables that could be used for predicting likelihood of metastases and the variables were incorporated into the nomogram model. The current probability of bone metastasis was generated by the nomogram using the pt variables at each BS and the predictive accuracy was quantified by calculating the concordance index (C-index). Results: In total, 3949 BS records were analyzed and 950 pts had a positive scan. There was an average of 1.1 prior negative scans before a positive result was recorded. Median prostate-specific antigen (PSA) was 2.5 ng/mL and mean PSA doubling time (PSADT) was 7.8 months. At the same time of the positive scans, 49.4% of pts had a PSA <10 ng/mL. Based on clinical relevance and data availability, 13 variables were included in the nomogram model: number of previous negative BSs, PSA, PSADT, prostatectomy, radiotherapy, brachytherapy, chemotherapy, immunotherapy, estrogen therapy, cryotherapy, clinical trial enrollment, and most recent primary and secondary Gleason grades. C-index for the nomogram was 0.76. Conclusions: This is the first nomogram to predict current BS positivity in pts with PCa following ADT. The nomogram was devised from a very large data set from a single center and provides high predictive accuracy.
Development of a needle biopsy-based genomic test to improve discrimination of clinically aggressive from indolent prostate cancer.
Authors: Klein Eric A. , Maddala Tara , Millward Carl , Cherbavaz Diana B. , Falzarano Sara Moscovita , Knezevic Dejan , Novotny William F. , Lee Mark , Magi-Galluzzi Cristina
Published: March 2020

4560

Background: Standardized, quantitative tools are needed to improve discrimination of clinically aggressive from indolent prostate cancer at diagnosis. We previously identified multiple genes and biological pathways in radical prostatectomy (RP) specimens associated with clinical recurrence and adverse pathology. We evaluated whether measurement of these genes in prostate needle biopsy (Bx) specimens predicts adverse pathology - high grade (GS ≥ 4+3) and/or non-organ-confined disease (pT3) - in a separate study of AUA low-intermed risk pts treated w/ RP. Methods: All AUA low-intermed risk (cT1-T2a, GS 3+3/3+4) pts treated w/ RP <6 mos from Bx at Cleveland Clinic (1999-2007) w/ available Bx tissue and <3 pos cores were evaluated. Expression of 81 prognostic genes identified in previous RP studies and 5 reference genes was quantitated by RT-PCR in 60 µm manually microdissected FPE prostate needle Bx tissue. Association of gene expression w/ adverse pathology was analyzed by logistic regression controlling false discovery rate (FDR) using Storey’s method. Results: RT-PCR was successful for 167 of 171 (98%) pts (92 AUA low, 75 intermed). At RP, 58 pts (35%) had high-grade and/or non-organ confined disease. 58 of 81(72%) genes predicted high grade and/or non-organ-confined disease (FDR<10%), including all stromal response and androgen genes and the majority of cellular organization genes (82%). Proportionately fewer proliferation (40%), stress response (29%), and basal epithelial (25%) genes were associated w/ adverse path. Androgen and cellular organization genes consistently predicted lower risk; stromal response and proliferation genes predicted higher risk; (majority of std odds ratios >1.5, comparable to the prognostic strength of ER in breast cancer). Conclusions: Genes and biological pathways associated w/ clinically aggressive prostate cancer in RP specimens can be reliably measured by RT-PCR from fixed prostate needle biopsies and predict high-grade, non-organ-confined disease. These results support the potential value of a Bx-based assay to inform selection of immediate treatment or active surveillance for pts diagnosed with prostate cancer on needle Bx.
Validation of a genomic-clinical classifier for predicting clinical progression in high-risk prostate cancer.
Authors: Buerki Christine , Mitra Anirban Pradip , Black Peter C. , Ghadessi Mercedeh , Bergstralh Eric J. , Erho Nicholas , Carlson Rachel , Crisan Anamaria , Sierocinski Thomas , Zimmermann Benedikt , Haddad Zaid , Vergara Ismael A. , Ballman Karla V. , Klee George G. , Fink Stephanie , Kollmeyer Thomas M. , Triche Timothy J. , Davicioni Elai , Karnes R. Jeffrey , Jenkins Robert B.
Published: March 2020

4565

Background: The efficient delivery of adjuvant therapy after radical prostatectomy (RP) in patients with prostate cancer is limited by the lack of biomarkers, beyond clinicopathologic factors, that are able to assess the risk of clinically significant disease progression. Previously, routine FFPE patient specimens from the Mayo Clinic Radical Prostatectomy Registry with long term follow-up were selected to develop a genomic classifier (GC) to predict clinical progression. Here, we present the validation of a GC in a cohort of patients at high risk of disease progression. Methods: A case-cohort study of high-risk RP patients from the Mayo Clinic (N=219) was used to validate the genomic classifier (GC) for predicting clinical progression (defined by positive bone or CT scan post-RP). Its performance was compared to a multivariable clinical classifier (CC) and a genomic-clinical classifier (GCC) which combines GC with established clinicopathologic variables. Concordance index, Cox modeling and decision curve analysis were used to compare the different models. Results: GC and GCC were predictive of clinical progression in the high-risk cohort with c-indices of 0.79 and 0.82, respectively, compared to the clinical classifier (0.70). Multivariable survival analysis showed that the majority of prognostic information of GCC came from the GC with a minor contribution from Gleason score. Decision curve analysis showed that GCC had a higher overall net benefit compared to CC over a wide range of ‘decision-to-treat’ thresholds for the risk of progression. Conclusions: In this high-risk cohort, GC and GCC classifiers showed improved performance over CC in prediction of clinical progression. GC is an independent prognostic factor in this cohort and captures the majority of prognostic information. GC and GCC’s prognostic performance and their usefulness in guiding decision-making in the adjuvant setting after RP need further testing in studies of additional prostate cancer risk groups.
Dual antiangiogenic therapy using lenalidomide and bevacizumab with docetaxel and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Adesunloye Bamidele , Huang Xuan , Ning Yangmin M. , Madan Ravi A. , Gulley James L. , Beatson Melony , Kluetz Paul Gustav , Adelberg David E. , Arlen Philip M. , Parnes Howard L. , Mulquin Marcia , Steinberg Seth M. , Wright John Joseph , Trepel Jane B. , Dawson Nancy Ann , Chen Clara , Bassim Carol , Apolo Andrea Borghese , Figg William Douglas , Dahut William L.
Published: March 2020

4569

Background: Previously, we had shown the potent anti−tumor activity of dual anti-angiogenic therapy by combining bevacizumab (B) and thalidomide (T) with docetaxel (D) and prednisone (P) in mCRPC (Ning JCO 2010). We hypothesized that combining lenalidomide (L), an analogue of T, with B, D, and P would have a more favorable efficacy/toxicity profile. Methods: All patients (pts) had chemotherapy−naïve mCRPC. Among the first 52 pts, 3 received L 15 mg daily, 3 had 20 mg daily, and the rest had 25 mg daily for 14 days of every 21−day cycle (C). The protocol was recently amended to enroll 11 more pts at L 15 mg; 2 pts have now been enrolled in this expansion cohort. All pts received D 75 mg/m2 and B 15 mg/kg on day 1 with P 10 mg and enoxaparin daily throughout each C. Pegfilgrastim was given on day 2. PSA each C with imaging after C2 and after every 3C. Dental exams with mandible CT scan at baseline, after C5, and every 6C. Results: 54 of 62 pts have been enrolled. Median age 65.5 (51−82), Gleason score 8 (5−10), on−study PSA 85.2 ng/ml (0.15−3520), and pre−study PSA doubling time 1.49 months (0.52−6.73). Median number of Cs was 16 (3−38). PFS was 22 months and probability of survival at 12 months was 90%. Forty-six (85.2%) and 42 (77.8%) pts had PSA declines of ≥50% and ≥75%, respectively. Of 30 pts with measurable disease there were 1 CR and 25 PR (86.7% overall RR). 17/54 pts were off study for radiographic disease progression and 8/54 for other reasons. Grade ≥2 toxicities included neutropenia (34/54), anemia (23/54), thrombocytopenia (7/54), hypertension (12/54), perianal fistula (3/54), rectal fissure (1/54), myocardial infarction (1/54), and osteonecrosis of the jaw (ONJ) (12/54, 22.0%). At the time of diagnosis of ONJ, 7/12pts were on bisphosphonates (BP), 2/12 had used BP previously, and 3/12 never used BP. The incidence of ONJ was comparable to 18.3% reported by Ning et al. A recent study of carboplatin plus weekly docetaxel reported an incidence of 29.3%. Conclusions: Dual anti-angiogenic therapy with, B and L, plus D and P was associated with high PSA (85.2%) and tumor (86.7%) responses in mCRPC, with manageable toxicities. The incidence of ONJ is comparable to other studies.
Preliminary quality-of-life outcomes for SWOG-9346: Intermittent androgen deprivation in patients with hormone-sensitive metastatic prostate cancer (HSM1PC)—Phase III.
Authors: Moinpour Carol , Berry Donna Lynn , Ely Benjamin , Tangen Catherine M. , Higano Celestia S. , Picus Joel , Schellhammer Paul F. , Skinner Eila C. , Cher Michael L. , Thompson Ian Murchie , Hussain Maha
Published: March 2020

4571

Background: The relative quality of life (QOL) for patients with newly diagnosed, metastatic prostate cancer, treated with intermittent androgen deprivation (IAD) has been assumed and hypothesized, yet never compared in a well-powered randomized trial (RT) to continuous androgen deprivation (CAD). SWOG-9346 provided such a RT in which to test QOL differences between CAD and IAD in men with metastatic prostate cancer. Methods: Patients were randomized to CAD or IAD. Patients completed the SWOG QOL Questionnaire (SF-20/SF-36, Symptom Distress Scale, treatment-specific symptoms, global QOL) at randomization and months (mo) 3, 9, and 15 post-randomization. Five QOL change scores at one time point (mo 3) were designated as primary for the QOL endpoint and are reported in this abstract: impotence, libido, energy/vitality (E/V), physical function (PF), and emotional function (EF). Significance level was adjusted for 5 comparisons (used p=0.01). Results: 615 patients in the CAD arm and 633 in the IAD arm completed the QOL questionnaire at baseline. Change between baseline and 3 months differed for the two arms with CAD reporting statistically significantly more impotence and less libido than IAD. EF was also slightly better for the IAD arm. Conclusions: These results indicate better sexual function in men receiving IAD versus CAD through post-randomization month 3. Additional benefits for IAD may include better PF, E/V and EF. Ongoing analyses will address the role of missing data, additional follow-up assessments, and resumption of therapy in the IAD arm. [Table: see text]
Defining a nine-biomarker panel for predicting bladder cancer outcome in combination with smoking intensity: A report from the Los Angeles Cancer Surveillance Program.
Authors: Mitra Anirban Pradip , Castelao Jose E , Hawes Debra , Tsao-Wei Denice D , Jiang Xuejuan , Shi Shan Rong , Young Lillian L , Datar Ram H , Skinner Eila C , Stein John Peter , Groshen Susan G. , Yu Mimi C , Ross Ronald K , Skinner Donald G , Cortessis Victoria K , Cote Richard J
Published: March 2020

4575

Background: Urothelial carcinoma of the bladder (UCB) is a disease of alterations in several cellular pathways. Routine molecular profiling studies do not account for smoking, a well established risk factor for UCB, and its influence on outcome. This study assessed the prognostic potential of a multi-pathway protein panel across all UCB stages in a population-based cohort after accounting for clinicopathologic factors and smoking history. Methods: 212 UCB patients from the LA CSP, part of the NCI/SEER cancer registry, were included. "Smoking intensity" analyzed biologic and molecular impact of smoking by combining smoking status, duration of smoking and number of cigarettes smoked daily into a composite covariate. Tumors were profiled for Bax, caspase-3, Apaf-1, Bcl-2, p53, p21, COX2, VEGF and E-cadherin alterations by IHC. Univariate analyses and multivariable modeling examined associations with outcome. Results: Median follow up was 13.2 years. Age, pathologic stage, adjuvant therapy (all p< 0.001) and surgical modality (p = 0.05) were associated with survival. Increasing smoking intensity was associated with worse outcome (P < 0.001). Apaf-1 (p = 0.005), E-cadherin (p = 0.014) and p53 (p = 0.032) were univariately prognostic; E-cadherin remained prognostic after multivariate analysis (p = 0.04). Combined alterations in all 9 biomarkers were prognostic by univariate (p < 0.001) and multivariate (p = 0.006) analysis. A multivariate model that included all 9 biomarkers and smoking intensity was more accurate in predicting prognosis than models comprising of standard clinicopathologic covariates without (p < 0.001) or with (p = 0.018) smoking intensity. Conclusions: The study confirms detrimental effects of smoking on UCB prognosis. Apaf-1, E-cadherin and p53 individually predicted UCB survival. Increasing number of biomarker alterations was significantly associated with worsening survival, although markers contained in the panel were not necessarily prognostic individually. Predictive value of the nine-biomarker panel with smoking intensity was significantly higher than that of routine clinicopathologic parameters alone.
FGFR3 protein expression and gene mutation in primary and metastatic urothelial carcinoma (UC) tumors.
Authors: Rosenberg Jonathan E. , Werner Lillian , Bamias Aristotelis , Choueiri Toni K. , Schutz Fabio A. B. , Park Rachel S. , O'Brien Robert , Guancial Elizabeth Ann , Ross Robert W , Berman David M. , Riester Markus , Lis Rosina , Loda Massimo F. , Stack Edward C. , Michor Franziska , Chehab Nabil , Molins Joaquim Bellmunt
Published: March 2020

4577

Background: FGFR3 protein expression may represent a valid therapeutic target in metastatic UC. The prevalence of both mutation and overexpression is unknown in metastatic UC. Methods: Tissue microarrays of formalin fixed paraffin-embedded urothelial carcinomas (UC) were stained for FGFR3 by immunohistochemistry (IHC) [primary (n=250); metastatic (n=31); of which (n=14) were paired]. FGFR3 immunostaining was scored as negative or positive based on previously reported scoring systems. FGFR3 mutation in primary tumors was assessed by iPlex and confirmed by hME sequencing (n=141) or Affymetrix OncoScan FFPE Express 2.0 (primary: n=17; metastases n=31). Results: FGFR3 IHC positivity was present in 48% of metastases (95% CI=32-65%) and 26% of primary tumors, (95%=CI 21-32%), though strong staining was rare (<1%). Paired primary and metastatic tumors were both negative in 50% of cases, with 14% positive only in the metastasis, 14% positive only in the primary tumor, and 21% positive in both. If the primary tumor showed staining, 71% of the metastases showed staining. FGFR3 IHC staining did not impact overall survival (p=0.8). FGFR3 mutations were observed in 9.6% of metastatic tumors (95% CI=3.3-25%), compared to 3.5% of primary tumors (95% CI=1.5%-8%). Co-occurrence of mutation and FGFR3 DNA copy number gain was observed in one specimen. Conclusions: FGFR3 IHC staining is present 26 % of primary tumors of patients who go on to develop metastatic disease, and nearly half of metastatic tumor sites. FGFR3 mutation frequency in primary and metastatic tumor specimens is low. Further investigation of the frequency of FGFR3 protein expression in metastases is needed. The presence of FGFR3 protein by IHC staining in primary and metastatic specimens suggests that FGFR3 may represent a therapeutic target even in the absence of mutation. Further functional studies are needed.
BRCA1, RAP80, and AEG-1 mRNA expression in resectable muscle-invasive bladder cancer (MIBC) patients (p) treated with neoadjuvant cisplatin-based chemotherapy.
Authors: Font Pous Albert , Celiz Pamela , Taron Miquel , Chaib Iman , Gago Jose Luis , Mendez Pedro , Sanchez Jose Javier , Etxaniz Olatz , Cechini Luis , Pardo Nuria , Sanchez Belen , Cuadra Jose Luis , Valverde Ivana , Buisan Oscar , Ibarz Luis , Rosell Rafael
Published: March 2020

4579

Background: Cystectomy remains the standard treatment in MIBC and only a minority of p are treated with neoadjuvant chemotherapy, suggesting that predictive markers of chemotherapy outcome are needed. Low BRCA1 mRNA expression is associated with an improvement in survival in bladder cancer p treated with cisplatin-based chemotherapy. However, BRCA1 function can be modulated by other DNA repair genes. RAP80 is required for the accumulation of BRCA1 to sites of DNA breaks, and cells depleted of RAP80 exhibit hypersensitivity to irradiation. AEG-1 can induce BRCA1 expression and cause chemoresistance. Methods: Paraffin-embedded pre-treatment tumor samples were collected by transurethral resection from 65 p with resectable MIBC stage T2-4N0M0 treated with neoadjuvant cisplatin-based chemotherapy. Gene expression levels of BRCA1, RAP80 and AEG-1 were quantified by real-time quantitative PCR. Expression levels were divided into terciles and correlated with median survival (MS). Results: 33 p were treated with cisplatin, methotrexate and vinblastine (CMV) and 32 p with cisplatin and gemcitabine. Chemotherapy was followed by cystectomy in 60 p. Overall MS was not reached and 5-year survival was 51%. MS was 45 months (m) and 5-year survival was 27% in 21 p with high BRCA1 mRNA levels vs 168 m and 59% in 44 p with low and intermediate levels (p=0.05). MS was 50 m in 15 p with high AEG-1 levels, 45 m in 15 p with intermediate levels, and was not reached in 18 p with low levels, although these differences were not statistically significant (p=0.3). No differences in MS were observed according to RAP80 mRNA levels. Conclusions: BRCA1 can be a useful marker to predict the efficacy of neoadjuvant chemotherapy. Cisplatin-based chemotherapy should be recommended in p with low/intermediate BRCA1 expression. Further studies with larger numbers of p are warranted to elucidate the role of AEG-1 in this setting.
Phase II trial of neoadjuvant gemcitabine (G) and cisplatin (C) with sunitinib in patients (pts) with muscle-invasive bladder cancer (MIBC).
Authors: Balar Arjun Vasant , Iyer Gopa , Apolo Andrea Borghese , Regazzi Ashley Marie , Garcia-Grossman Ilana Rebecca , Pendse Deepa , Ostrovnaya Irina , Chou Joanne F. , Bochner Bernard , Dalbagni Guido , Herr Harry W. , Milowsky Matthew I. , Bajorin Dean F.
Published: March 2020

4581^

Background: Response to neoadjuvant chemotherapy (NC) prior to radical cystectomy (RC) predicts improved overall survival (OS) in MIBC. Associations with enhanced survival include complete pathologic response (pT0; Grossman, NEJM 2003) and eradication of the muscle-invasive component (<pT2; Splinter, J Urol 1992). Sunitinib (S) is active in pretreated pts with advanced disease. We tested if S added to GC was safe, improved the rate of pT0, and improved the rate of <pT2. Methods: Cisplatin-eligible pts with cT2-4aN0 bladder cancer received G 1000 mg/m2 and C 35 mg/m2 on day (D) 1 and D8 with S 25 mg orally daily D1-14 of a 21D cycle for 4 cycles. RC plus pelvic lymph node dissection was required to assess response of pT0 or <pT2. A Simon’s Minimax 2-stage design was used to test a null (H0) pT0 rate ≤ 20% against alternative (H1) pT0 rate ≥ 40% with Type I and II error rates of 0.05 and 0.10 respectively. Enrollment to the 2nd stage of 45 patients was planned if ≥ 6 of the initial 24 evaluable pts achieved pT0. Primary endpoint was pT0N0 and secondary endpoints were: response defined as <pT2N0; safety; time to progression (TTP), and OS. Results: 18 pts (15M, 3F), median age 63 (54-76) were enrolled from 6/09 and 10/11 after which financial support was withdrawn. 3 pts were inevaluable for response endpoints due to: 1.) withdrawal of consent, 2.) declining any surgery, 3.) partial cystectomy instead of RC. All 18 were evaluable for safety, TTP and OS. 1 of 15 pts had pT0N0 (6.6%; 95% CI 0.34 – 29.8%) and 5 had <pT2N0 (33%; 95% CI 15-58%). 4 of 5 pts with status <pT2N0 were pTisN0. Median TTP was 10 months (95% CI 3.5-NR). 3 pts were deceased at time of analysis; median OS not reached. Neutropenia due to the 3 drug combination required routine GCSF support on day 8 of each cycle. Grade 3/4 toxicities were anemia (11 pts), neutropenia (6), thromboembolic events (2), febrile neutropenia (2) and infection (2). Conclusions: Despite incomplete accrual, the pT0 rate was low suggesting that S does not add to GC. Residual non-invasive disease (<pT2) was common, including a large proportion of pts with pTisN0. Given these findings, response criteria for future NC studies should consider either <pT2 or < pTis as the primary endpoint.