bluuebunny/crossref_metadata_2025 huggingface dataset:
Androgen deprivation therapy (ADT) plus docetaxel (D) versus ADT alone for hormone-naïve metastatic prostate cancer (PCa): Long-term analysis of the GETUG-AFU 15 phase III trial.
Authors: Gravis Gwenaelle , Boher Jean-Marie , Joly Florence , Oudard Stephane , Albiges Laurence , Priou Franck , Latorzeff Igor , Delva Remy , Krakowski Ivan , Laguerre Brigitte , Rolland Frederic , Theodore Christine , Deplanque Gael , Ferrero Jean-Marc , Pouessel Damien , Mourey Loic , Beuzeboc Philippe , Habibian Muriel , Soulie Michel , Fizazi Karim
Published: February 2017

140

Background: ADT is standard treatment for metastatic PCa. Recently, the E3805 trial reported a survival benefit for (ADT+D) in high volume disease (HVD) patients, whereas the GETUG-15 trial did not demonstrate a survival improvement among a less selected group of patients (pts) with hormone-naïve metastatic PCa. We report an updated analysis of overall survival (OS) of the GETUG 15 trial and aligned the definition of HVD and low volume disease (LVD) subgroups. Methods: Long-termOS was analyzed in the intention-to-treat population (n=385 pts). Additionally, we retrospectively assessed the tumor volume as defined per E3805criteria in all patients enrolled in GETUG 15. Results: See Table. With a median follow-up of 82.9 months (95%CI [80.5-84.3]) (vs 50 months (95%CI [80.5-84.3] in the original analysis), 212 patients (55%) have died. The median OS is 46.5 [39.1-60.6] and 60.9 months [46.1-71.4] in the ADT and in the ADT + D arms, respectively (HR: 0.9 [95%CI: 0.7-1.2]). In HVD patients (n=183, 47.5%), median OS rates were 35.1 months [29.9-44.2] in the ADT alone arm and 39 months [28-52.6] in the ADT+D arm (HR: 0.8 [0.6-1.2]). Conclusions: With longer follow-up, the addition of docetaxel to ADT did not significantly improve OS in patients with hormone-naïve metastatic prostate cancer. In the retrospective analysis using aligned definition of volume of metastasis as E3805, the HVD outcomes were similar to E3805 for ADT alone and there was a non-significant 4 months increase in OS with ADT+D, in this underpowered subset. Clinical trial information: 00104715. [Table: see text]
Final analysis of COMET-2: Cabozantinib (Cabo) versus mitoxantrone/prednisone (MP) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) with moderate to severe pain who were previously treated with docetaxel (D) and abiraterone (A) and/or enzalutamide (E).
Authors: Basch Ethan M. , Scholz Mark C. , De Bono Johann Sebastian , Vogelzang Nicholas J. , De Souza Paul L. , Marx Gavin M. , Vaishampayan Ulka N. , George Saby , Schwarz James K. , Antonarakis Emmanuel S. , O'Sullivan Joe M. , Rezazadeh Kalebasty Arash , Chi Kim N. , Dreicer Robert , Hutson Thomas E. , Mangeshkar Milan , Holland Jaymes S. , Weitzman Aaron , Scher Howard I.
Published: February 2017

141

Background: Cabo inhibits tyrosine kinases including MET and VEGFRs. In a phase 2 study in mCRPC pts, Cabo was associated with improvements in pain, bone scans, measurable disease, and circulating tumor cells. COMET-2 compared the effects of Cabo versus MP on pain palliation in men with progressive mCRPC. Methods: In this double-blind, controlled phase 3 study (NCT01522443), pts with moderate to severe pain and disease progression following D, and A and/or E were randomized 1:1 to receive Cabo (60 mg qd) or MP (12 mg/m2 q3wk and 5 mg bid, resp). All pts were required to have a 7-day average of 4+ pain per Brief Pain Inventory (BPI) item 3 while on an optimized narcotics regimen at baseline. Randomization was stratified by prior cabazitaxel and ECOG performance status. The primary endpoint was pain response (≥30% reduction in BPI item 3) at week 6, confirmed at week 12, without increase in narcotics. The original sample size (N = 246) was selected to achieve at least 90% power to detect an increase in pain response with Cabo (25%) vs. MP (8%) using a two-sided α = 0.05 chi-squared test. The secondary efficacy endpoints were bone scan response (BSR) and overall survival (OS). Results: 119 pts were randomized between March 2012 and July 2014. Randomization was concluded prior to reaching the planned sample size because the companion study COMET-1 did not show a significant OS benefit compared to P in a similar population. Pain response rates were 15% for Cabo vs 17% for MP (P = 0.773). BSR rates were 31% for Cabo vs 5.2% for MP. Median OS was 9 months for Cabo vs 7.9 months for MP. Most frequent G3/4 AEs in the Cabo arm were anemia (22% vs 26% MP), hypertension (22% vs 0% MP), fatigue (18% vs 8.8% MP), and AST increased (10% vs 1.8% MP), with fewer pts discontinuing study treatment for AEs in the Cabo arm (16% vs 26% MP). Conclusions: The primary endpoint of improving pain response was not achieved in this heavily pretreated population. The key secondary endpoints of BSR and OS showed trends favoring the Cabo arm, and no new safety signals were observed at the dose of 60 mg. Clinical trial information: NCT01522443.
Antigen-specific immune responses through 24 months in the STAND trial: A randomized phase 2 study evaluating optimal sequencing of sipuleucel-T (sip-T) and androgen deprivation therapy (ADT) in biochemically-recurrent prostate cancer (BRPC).
Authors: Antonarakis Emmanuel S. , Kibel Adam S. , Adams George W. , Karsh Lawrence Ivan , Elfiky Aymen , Shore Neal D. , Vogelzang Nicholas J. , Corman John M. , Tyler Robert Claude , McCoy Candice , DeVries Todd , Sheikh Nadeem A. , Drake Charles G.
Published: February 2017

171

Background: Sip-T is an autologous cellular immunotherapy targeting prostatic acid phosphatase (PAP), approved for treatment of asymptomatic/minimally symptomatic metastatic castration-resistant prostate cancer. STAND evaluates sequencing of sip-T and ADT in men with BRPC at high risk of metastases. Here we report interim assessments of cellular and humoral responses through 24 mos. Methods: Men (n=68)were randomized 1:1 to sip-T followed by ADT (2 wks after 3rd infusion; Arm 1) or ADT (3-mo lead-in) followed by sip-T (Arm 2). Product parameters (total nucleated cell [TNC] count, antigen presenting cell [APC] count, APC activation) were determined with each product manufacture. Cellular and humoral immune responses were analyzed through 24 mos with a repeated measures statistical model. Results: Sample size ranged 8–28 for cellular responses and 34–64 for humoral responses. PA2024 ELISPOT count increased vs baseline at most timepoints (p<0.05) and was lower in Arm 2 vs Arm 1 (p=0.015). PA2024 antigen-specific T-cell proliferation increased from baseline at all timepoints (p≤0.001) and was lower in Arm 2 vs Arm 1 (p<0.001). PA2024 antibody titers were similar between treatment arms (p=0.976). PA2024 antibody titer was significantly higher at the 3rd sip-T infusion visit and remained elevated at 24 mos (23 times higher on average vs baseline; p<0.001). A similar antibody titer profile was reported for PAP but of lesser magnitude. The number of immune responders (post-baseline antibody titer ≥25,600) was similar at any timepoint between arms (Arm 1: 30/34, 88.1%; Arm 2: 32/34, 94.1%; p=0.673). Higher cumulative TNC and baseline hemoglobin positively correlated with maximum PA2024 antibody titer response (p<0.05). Conclusions: Sip-T induced a robust immune response sustained to 24 mos in men with BRPC. Cellular response appeared to differ according to treatment sequence; humoral response was similar between treatment arms. Given its consistent association with the humoral response, cumulative TNC count may be a potential biomarker of response to sip-T. Clinical trial information: NCT01431391.
Development of intermediate and high-risk prostate cancer after testicular cancer.
Authors: Riggin Andrew John , Siddiqui Mohummad Minhaj
Published: February 2017

177

Background: Men with a history of testicular cancer are known to have an increased risk of developing prostate cancer (PCa) in epidemiologic studies. We hypothesized they may also have an increased risk of developing intermediate to high-risk PCa. Herein, we present a case-control study to assess the association of a history of testicular cancer and intermediate to high-risk PCa. Methods: We used the eighteen Surveillance, Epidemiology and End Results (SEER) registries to compare men with a history of testicular cancer to a control population of men with a history of melanoma. Melanoma was used as a control group because, to our knowledge, there is no association of melanoma and PCa. Men were excluded if they were not 60 years of age or older to allow for sufficient PCa diagnosis. PCa incidence was only counted if it occurred at least 5 years after the diagnosis of their primary cancer to allow for possible temporal effect of the primary malignancy. Incidence of total and intermediate to high-risk PCa(Gleason score ≥ 7) was compared using Kaplan-Meier (KM) curves. Cox proportional hazards models were utilized to assess for associations of PCa (JMP 10, SAS Inc). Results: 119,781 men with melanoma and 10,365 men with testicular cancer were identified. The incidence of all PCa by age 80 was 2.7% in the control melanoma cohort and 12.3% in the case cohort of men with history of testicular cancer (p<0.0001 for KM survival curves). For intermediate/high-risk disease, the incidence was 1.1% versus 5.7% for each cohort respectively (p<0.0001 for KM survival curves). Testis cancer (versus the control melanoma cohort) was associated with an increased risk of all PCa (HR 4.7, p<0.0001) and intermediate/high-risk PCa (HR 5.5, p<0.0001). These associations persisted even when controlling for race. Conclusions: A history of testicular cancer is associated with a significantly increased risk of developing both PCa and intermediate/high risk PCa.
Contemporary use of radium-223 (Ra-223) in men with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC): Feasibility and safety.
Authors: Emamekhoo Hamid , Chowdry Rajasree Pia , Elson Paul , Ledet Elisa M. , Martin Allison , Cotogno Patrick , Beach Jennifer , Steinberger Allie E. , Allman Kimberly D , Stolten Michael , Garcia Jorge A. , Sartor Oliver
Published: February 2017

210

Background: Ra-223 is an α-emitter that binds to the newly formed bone matrix and targets osteoblastic metastatic lesions. Treatment with Ra-223 delays symptomatic skeletal-related events (SREs) and improves overall survival (OS) in men with mCRPC. Concerns about the efficacy and safety of Ra-223 in the pre-chemotherapy space, given alone or in combination with Abiraterone Acetate (AA) or enzalutamide (ENZ), have been raised. Methods: To determine the feasibility, efficacy and safety profile of Ra-223 given alone or in combination with AA or ENZ to men with docetaxel-naïve mCRPC a retrospective study was conducted. PSA decline, rPFS and safety data for patients (pts) treated at Cleveland Clinic (CC) and Tulane University (TU) were analyzed. Results: Fifty-one (27 CC and 24 TU) chemo-naïve mCRPC pts with bone metastases were identified. The median age was 63 (46-87). Testosterone suppression was maintained during treatment. Pre-treatment alkaline phosphatase (ALP) was elevated in 16 pts (33%). In addition to bone, 24 pts (47%) had soft-tissue metastases. While 23 pts received Ra-223 alone, 22 pts (43%) received concomitant AA or ENZ therapy. To date, the median number of Ra-223 cycles received is 5 (1-6) with 39% of pts (20/51) receiving all 6 cycles. PSA declines >30% were observed in 31% of pts. All but one pt had at least some decline in ALP. ALP decline >30% was observed in 68% of pts. Reasons for treatment discontinuation included; completion of 6 cycles 39% (20/51); PD 35% (18/51); AEs 8% (4/51) and pt choice 4% (2/51). Grade (G) 3/4 AEs were observed in 4 pts; G3 anemia (n=3) and G4 thrombocytopenia (n=1). The vast majority of pts had PSA progression (81%) and 42% of pts have died. Estimated median time to PSA progression and OS are 3.9 (95% C.I. 1.84-4.82) and 11.0 months (95% C.I. 7.5-16.4), respectively. Pts with normal baseline hemoglobin levels and those who received concomitant AA tended to have better PSA progression-free and OS (p<.06). Conclusions: Treatment with Ra-223 in combination with AA or ENZ in chemo-naïve mCRPC pts is feasible with no new safety signals of concern. Further evaluation of the combination of AA or ENZ with Ra-223 in this setting is warranted.
Clinical activity, safety, and biomarkers of MPDL3280A in metastatic urothelial bladder cancer: Additional analysis from phase IA study.
Authors: Kim Joseph W. , Bellmunt Joaquim , Powles Thomas , Loriot Yohann , Vogelzang Nicholas J. , Cruz Zambrano Cristina , Burris Howard A. , Teng Siew-leng Melinda , Shen Xiaodong , Bruey Jean-Marie , Boyd Zachary , Hegde Priti S. , Petrylak Daniel Peter
Published: February 2017

297

Background: Metastatic urothelial bladder cancer (UBC) is a mutationally-complex disease in which PD-L1 expression in the tumor microenvironment may inhibit immune-mediated antitumor responses. MPDL3280A is a PD-L1-targeting antibody with an engineered Fc domain that disrupts PD-L1/PD-1 and PD-L1/B7.1 signaling. Methods: MPDL3280A was studied in a phase Ia metastatic UBC expansion cohort. UBC pts received MPDL3280A 15 mg/kg IV q3w for ≤16 cycles. Efficacy-evaluable pts were dosed by January 27, 2014 (≥12 week follow-up) with a data cutoff of April 21, 2014. RECIST v1.1 was used to assess ORR. PD-L1 expression (by immune cell IHC) was centrally evaluated from archival biopsies. In-tumor gene expression and peripheral biomarker analyses were done on pts dosed by Nov 20, 2013, with a cutoff of January 1, 2014. Results: In the UBC cohort, 33 IHC 2/3 pts, 36 IHC 0/1 pts, and 1 PD-L1 pt with unknown IHC were efficacy-evaluable. Median pt age was 65 y (36-89), and 73% were male. Visceral and liver metastases were present in 74% and 33% of pts, respectively. 73% had ≥2 prior therapies, and 91% had prior platinum. The unconfirmed ORR was 52% (95% CI, 34-69; 3 CRs, 14 PRs) in IHC 2/3 pts and 14% (95% CI, 6-28; 5 PRs) in IHC 0/1 pts. The median DOR was not yet reached (0.1+ to 42+ w in IHC 2/3 pts, n=17; 6+ to 19+ w in IHC 0/1 pts, n=5). 19/22 responding pts had ongoing responses. Median PFS was 24 w in IHC 2/3 pts (5 to 50+ w, n=33) and 8 w in IHC 0/1 pts (0.1+ to 30+ w, n=36). Of 74 pts evaluable for safety, all grade treatment-related AEs occurred in 65%, most often fatigue, decreased appetite and nausea. 5% had treatment-related G3-4 AEs. No treatment-related deaths were seen. The median follow-up was 5.4 mos (1+ to 12 mos, n=70). IHC 2/3 tumors had low expression of a baseline myeloid marker gene signature, including IL8 and IL1B, which was associated with MPLD3280A response. Additionally, circulating inflammatory markers (e.g., CRP) and tumor burden markers (e.g., HCG) decreased in responders by cycle 2. Updated data will be presented. Conclusions: MPDL3280A was well tolerated in UBC pts. Rapid and durable responses were seen and correlated with PD-L1 IHC status on immune cells. Biomarkers suggest a potential role for myeloid biology in primary resistance to MPDL3280A. Clinical trial information: NCT01375842.
A randomized trial of 79.2Gy versus 70.2Gy radiation therapy (RT) for localized prostate cancer.
Authors: Michalski Jeff M. , Moughan Jennifer , Purdy James , Bosch Walter , Bahary Jean-Paul , Lau Harold Y. , Duclos Marie , Parliament Matthew , Morton Gerard , Hamstra Daniel A. , Seider Michael J. , Lock Michael , Patel Malti , Gay Hiram Alberto , Vigneault Eric , Dignam James , Sandler Howard Mark
Published: February 2017

4

Background: RTOG 0126 is a phase III trial for localized prostate cancer (PC) testing whether dose escalation to 79.2Gy with 3DCRT or IMRT will improve overall survival (OS). Methods: Stage cT1b-T2b with Gleason Score (GS) 2-6 and PSA ≥ 10 and <20 or GS 7 and PSA <15 were eligible and randomized to receive 79.2Gy or 70.2Gy. No androgen withdrawal was used. Treatment was 3DCRT or IMRT to 79.2Gy in 44 fractions or 70.2Gy in 39 fractions. The objective was to detect a 23% reduction in mortality hazard (HR=0.77) for 79.2Gy. ASTRO and Phoenix definition was used for biochemical failure (BF). Time to local progression (LP), distant metastases (DM), PC death, and late GI/GU toxicity was calculated from date of registration. OS was estimated by Kaplan Meier and arms compared with log rank test. BF, LP, DM, time to late GI/GU, and PC death were estimated by cumulative incidence method and arms compared with Gray’s test. Results: 1,532 men were randomized, 763 to 79.2Gy and 769 to 70.2Gy. 1,499 were eligible, 751 and 748 in the 79.2Gy and 70.2Gy arms respectively. Median age was 69, 70% had PSA < 10 ng/ml, 84% with GS 7, 57% had T1 disease, and 66% used 3D-CRT. With a median of 7.0 years follow up, the 5 and 10-yr rates of OS are 88% and 67% with 79.2Gy and 89% and 66% with 70.2Gy (p=0.87; HR (95%CI)=0.98 (0.79,1.21)). The ASTRO (Phoenix) BF rates at 5 and 10 yr are 25% (16%) and 30% (26%) with 79.2Gy and 40% (21%) and 45% (43%) with 70.2Gy (both p<0.0001). The 5 and 10-yr rates of LP are 1% and 4% with 79.2Gy and 2% and 8% with 70.2Gy (p=0.0059; HR (95%CI)=0.46 (0.27,0.81)). The 5 and 10 yr rates of DM are 2% and 5% with 79.2Gy and 3% and 8% with 70.2Gy (p=0.026; HR (95%CI)=0.57 (0.35,0.94)). The high dose arm had lower rate of salvage therapy, 13.5% vs 21%, p=0.0002. The 10 yr rates for time to late grade ≥ 2 GI/GU are 22%/15% with 79.2Gy and 16%/10% with 70.2Gy (p=0.0063/p=0.001). Time to late grade ≥ 3 GI was higher for the 79.2Gy arm (p=0.035) but time to late grade ≥ 3 GU toxicity was not (p=0.14). Conclusions: Despite significant improvement in BF, DM, and LP rates, dose escalation did not improve OS. Patients receiving high dose radiation experience more late toxicity. Clinical trial information: NCT00033631.
Comparison of simultaneous high dose stereotactic radiotherapy with normofractionated radiotherapy in patients with metastatic renal cell carcinoma under systemic therapy.
Authors: Staehler Michael D. , Lisa Behr , Nuhn Philipp , Schlenker Boris , Wilkowski Ralf
Published: February 2017

467

Background: Conventional radiation therapy (RT) is considered ineffective in metastatic renal cell carcinoma (mRCC). There are data suggesting that this might be related to low doses per fraction and that higher doses could be more effective. We introduced hypofracationated high-dose radiation therapy in patients with an indication for radiotherapy an retrospectively compared the results to patients with a conventional radiation therapy. Methods: We identified 97 pts with mRCC and an indication for radiotherapy of metastatic lesions between 2007 and 2013. All pts underwent simultaneous systemic therapy based on targeted agents and systemic therapy. 83 pts had a hypofractionated high dose stereotactic radiation (HDRT) (5 Gy per fraction, 3 fractions per week, total 45 Gy) while 14 pts underwent conventional normo-fractionated radiotherapy (NDR) (1.8 Gy per fraction) as described elsewhere. Results: Median age was 64.1 years (27-86). 189 metastatic lesions were irradiated. 64% of the pts had clear cell histology, with 14% harboring papillary RCC type II and 11% other subentities. Median overall survival was significantly longer for pts after HDRT was 9.4 months (+/-9.4 months) and 4.5 months (+/- 3.4 months) after NDR (p=0.01). The multivariate cox regression analysis revealed the MSKCC risk score, HDR therapy and the disease free survival as positive predictors for survival. No grade III toxicities were found, with 24% of the patients experiencing grade 1 or 2 side effects, mainly diarrhea and fatigue. Conclusions: In mRCC HDRT with simultaneous systemic therapy is related to a better overall survival than NRT. HDRT in combination with targeted therapy should be regarded the standard of care if RT is indicated.
cMet: Results in papillary renal cell carcinoma of a phase I study of AZD6094/volitinib leading to a phase 2 clinical trial with AZD6094/volitinib in patients with advanced papillary renal cell cancer (PRCC).
Authors: Gan Hui Kong , Lickliter Jason , Millward Michael , Gu Yi , Weiguo SU , Qi Chuan , MU Hua , Frigault Melanie , Morgan Shethah , Gardner Humphrey Athelstan , Albiges Laurence , Pal Sumanta Kumar , Burris Howard A. , Choueiri Toni K.
Published: February 2017

487

Background: Met is a receptor tyrosine kinase that is deregulated across multiple cancer types, leading to uncontrolled tumor cell growth, invasion and survival. MET is frequently dysregulated in PRCC. Activating Met mutations are present in hereditary and a subset of sporadic PRCC cases (up to 21% of type I PRCC, Albiges et al, 2014). Trisomy of chromosome 7 (containing both MET and HGF genes) has been reported in 45-75% of sporadic PRCC cases; 81% of type I and 46% of type II PRCC have copy number alterations of MET (Albiges et al, 2014). Methods: AZD6094 (HMPL-504/volitinib) is a potent, selective Met inhibitor. Preclinically, AZD6094 inhibits in vitro growth of MET-amplified gastric and lung cell lines. In vivo AZD6094 induces regressions in PRCC explant models. Results: In phase I, AZD6094 was well tolerated, with good exposure and low accumulation (Gan et al, 2014). Two PRCC pts in the 600 mg QD cohort (one with ongoing treatment at 19 months) and 1 PRCC in the 1,000 mg QD cohort (ongoing treatment at 13 months) achieved PR. A fourth patient, on 300 mg BD, showed a best tumor response of 25% decrease from baseline. Analysis of tumor samples showed that all the responders had MET copy number increase. Conclusions: These encouraging findings have triggered a phase II trial. This is an open label non-randomised multi-centre study to assess the efficacy of AZD6094 monotherapy in treatment naive and previously treated PRCC patients. Eligibility includes PRCC histopathology, ECOG status 0 or 1, ability to comply with the collection of tumor samples, adequate haematological, liver, and kidney function, and measurable disease (RECIST 1.1). The study is ongoing in collaboration with Sarah Cannon Research Institute in the United States, Canadian, EU centres. This study is sponsored by AstraZeneca, clinical trial information: NCT02127710. Clinical trial information: NCT01773018.
High concordance of BAP1 and PBRM1 expression in patient-matched primary and metastatic ccRCC tumors.
Authors: Shreders Amanda , Joseph Richard Wayne , Serie Daniel , Kapur Payal , Ho Thai Huu , Eckel-Passow Jeanette , Brugarolas James , Parker Alexander S.
Published: February 2017

507

Background: Clear cell renal cell carcinoma (ccRCC) is a well-described molecularly heterogeneous tumor. Herein, we assessed the concordance of two of the most commonly mutated genes in ccRCC, PBRM1 (~50%), and BAP1 (~15%), in patient-matched primary and metastatic tumors. Methods: One pathologist (PK) assessed PBRM1 and BAP1 protein expression using immunohistochemistry (IHC) in 99 patients with a primary and at least one metastatic ccRCC tumor available for analysis. All available metastatic tumors were analyzed. Results: A total of 99 patients (48 M0 and 51 M1) had both a primary tumor and at least one metastatic tumor available for analysis. There were a total of 158 metastases with one patient having up to 7 metastases available for analysis. The concordance between primary and patient-matched metastasis was 87% for PBRM1 and 99% for BAP1. We observed a similar concordance between patients with M0 versus M1 disease. Conclusions: While ccRCC is molecularly heterogeneous, PRBM1, and BAP1 are largely concordant between primary and metastatic lesions suggesting that PBRM1 and BAP1 are genetically truncal events in the molecular pathogenesis of ccRCC.
Effectiveness of massage therapy (MT) as a treatment strategy and preventive modality for chemotherapy-induced peripheral neuropathy (CIPN) symptoms.
Authors: Menendez Alvaro G. , Cobb Regina , Carvajal Alejandro Ramon , Healey Kathi , D'Ambra Diane , Espat N. Joseph
Published: February 2017

193

Background: CIPN has a known negative impact on quality of life (QoL) and can be a dose-limiting side effect of cytotoxic drugs with no generally agreed upon therapeutic intervention. In this study MT was assessed as a primary and secondary preventive modality of CIPN symptoms under the hypothesis that it can be used as an effective prophylactic and therapeutic option. Methods: A single arm 10-week prospective study (n = 62) with pre/post intervention assessment using a validated survey instrument adapted from “Peripheral neuropathy associated with novel therapies […]”. (Clin J Onc Nur. 2008; (12)3:9-12) Results: 97% (60/62) had at least 2 CIPN-related symptoms. (Table 1) After a single MT session, at least 50% of pts (range 52-100%) reported improvement in all CIPN-related symptom categories. These observations were maintained until 2nd MT session except for vestibulocochlear related symptoms. Initially, 25/60 were on analgesics. Of these, 14 (56%) had no progression of symptoms after 1st MT session. 13/25 presented for 2nd session. 5/13 (38%) reported no progression, 4/13 (31%) reported complete resolution of symptoms and 4/13 (31%) had progression. Conclusions: With the exception of vestibulocochlear symptoms associated with CIPN, study participants reported 50% or greater improvement, which was maintained after 1st MT session. The data suggests that pts on analgesics may also benefit from MT as at least 66% (17/25) reported lack of progression or resolution of symptoms after MT intervention. Consideration for an MT-inclusive treatment strategy is supported by this study. [Table: see text]
Implementing innovative, learner-centered methods to teach oncology fellows how to face difficult conversations.
Authors: Shaw Andrew , Reilley Matthew , McQuade Jennifer Leigh , Baile Walter F. , Epner Daniel E.
Published: February 2017

27

Background: Oncologists engage in emotionally charged conversations with patients and families about prognosis, goals of care, and end of life transitions. Many oncologists lack key skills for guiding patients through such conversations. Key skills include posing open ended questions to elicit the patient’s perspective, using silence effectively, and responding to emotion with empathy. We previously described a communication skills curriculum for first year medical oncology fellows consisting of a series of one hour monthly seminars (Epner and Baile, Academic Medicine, 2014). We now describe improvements in the curriculum based on extensive feedback from learners and teaching assistants. Methods: Anonymous feedback from first year fellows indicated longer sessions would allow for sufficient warm up and more in depth reflection and opportunity to practice. We therefore consolidated the sessions into quarterly 4 hour workshops. Several fellows also expressed discomfort with participating in role play of clinical scenarios in front of colleagues, so we implemented small group learning in which 3-4 fellows practiced communication skills in facilitated role play scenarios. We also replaced large group role play with narrative medicine techniques, such as reading and discussing medically-themed short stories and reflective writing exercises to allow the greatest amount of participation among learners. Results: Fellows completed anonymous surveys on which they rated items on a 4 point scale, with 1 being best and 4 worst. The average score of the two survey items pertaining to large group role play was 2.6. After changes in the curriculum, items pertaining to narrative medicine averaged 1.3, which was very favorable. Items pertaining to relevance and value of the curriculum also averaged less than 1.5 for all years. Attendance was 100% with the exception of fellows who were on vacation. Conclusions: Learner-centered, interactive innovations to our previous communication skills curriculum were highly rated by fellows and addressed issues of enhanced participation in a learning environment in which fellows felt safe to actively participate, reflect, and interact extensively with their peers.
A novel scoring system to predict survival in patients with advanced pancreatic adenocarcinoma: The Memorial Prognostic Score (MPS).
Authors: Yang Andrew Chung , Wiesenthal Alison , Epstein Andrew S. , Zheng Junting , Goldberg Jessica , Meadows Jason , O'Reilly Eileen Mary , Glare Paul A.
Published: February 2017

36

Background: A major limitation of prognostic tools such as the Eastern Cooperative Oncology Group (ECOG), Karnofsky, and Palliative Performance Scale is a reliance on subjective clinical assessment. An objective tool, the Glasgow Prognostic Score (GPS) is derived from C-reactive Protein (CRP) and albumin and has been validated in patients with operable and inoperable malignancies. One disadvantage of this tool is that CRP is not routinely measured in the United States. We examined if the Neutrophil-Lymphocyte Ratios (NLR) (Ahn, H.K., et al., Neutrophil-Lymphocyte Ratio Predicts Survival in Terminal Cancer Patients. J Palliat Med, 2016) could be substituted for CRP in the GPS to predict survival in patients with advanced pancreatic adenocarcinoma. Methods: A retrospective chart review identified patients at MSKCC with pathology-confirmed stage IV pancreatic adenocarcinoma diagnosed between 2011 to 2014. Pre-treatment absolute neutrophil count, absolute lymphocyte count, and albumin were extracted. The NLR for each patient was calculated and assigned: NLR ≤ 4 g/dl = 0, NLR > 4 g/dl = 1; serum albumin > 4 g/dl = 0, and serum albumin < 4 g/dl = 1. Combining NLR and albumin scores resulted in a composite MPS score of 0-2, similar to GPS. We evaluated the association of the MPS with overall survival. Results: N = 833 patients were identified with median survivals summarized in the table below. A log-rank test showed statistically significant differences in survival between MPS groups (p<0.00005). The MPS on univariate analysis had a HR of 1.36 (95% CI 1.23 – 1.50, p<0.0005) associated with overall survival. Conclusions: The MPS, a novel composite of NLR and albumin, is an objective prognostic tool that divided this sample of patients into three clinically distinct subgroups. Further interrogation will control for performance status, disease characteristics and anti-cancer therapy. [Table: see text]
Symptom burden to predict health care utilization in hospitalized patients with incurable cancer.
Authors: Nipp Ryan David , El-Jawahri Areej , Moran Samantha M.C. , D'Arpino Sara , Johnson Connor , Lage Daniel E. , Wong Risa , Xiao Yian , VanDusen Harry , Pirl William F. , Traeger Lara , Lennes Inga Tolin , Cashavelly Barbara J. , Martinson Holly S. , Jackson Vicki A. , Greer Joseph A. , Ryan David P. , Hochberg Ephraim P. , Temel Jennifer S.
Published: February 2017

98

Background: Patients with incurable cancer are often hospitalized and have frequent readmissions after discharge. Considering the high physical and psychological symptom burden in this population, we sought to investigate symptoms as predictors of hospital length of stay (LOS) and time to first unplanned readmission. Methods: We consecutively enrolled incurable cancer patients with unplanned hospital admissions from 9/2014-4/2016. Within the first 5 days of admission, we assessed physical (Edmonton Symptom Assessment System [ESAS]; scored 0-10) and mood symptoms (Patient Health Questionnaire 4 [PHQ-4]; scored categorically). We created summated ESAS total and physical symptom variables. To identify predictors of LOS we used linear regression and for time to readmission we used Cox regression, with all models adjusted for age, sex, marital status, comorbidity, education, cancer type and time since incurable diagnosis. Results: We enrolled 1,000 of 1,227 (81%) eligible patients (mean age = 63.4; 50% female; 66% married). Gastrointestinal (33%) and lung (18%) cancers were the most common. Mean hospital LOS was 6.2 days and 30-day readmission rate was 25%. Over half of patients reported moderate/severe fatigue, drowsiness, lack of appetite, pain and poor well-being. Over one-fourth screened positive for PHQ depression and anxiety. All physical and mood symptoms individually predicted for longer LOS. Pain, nausea, poor well-being, ESAS total, ESAS physical and PHQ anxiety predicted for shorter time to readmission. Conclusions: Hospitalized patients with incurable cancer experience a high symptom burden, which correlates with their health care utilization. Both physical and psychological symptoms predict for longer hospital LOS and shorter time to readmission. These findings can inform interventions targeting patients’ symptoms during hospital admissions in an effort to improve health care delivery and utilization. [Table: see text]
ProCAID: A phase I clinical trial to combine the AKT inhibitor AZD5363 with docetaxel and prednisolone (DP) chemotherapy for metastatic castration resistant prostate cancer (mCRPC).
Authors: Crabb Simon J. , Birtle Alison J. , Martin Karen , Downs Nichola , Bowers Megan , Ratcliffe Ian , Ellis Mary , Griffiths Gareth , Thompson Stuart , Khoo Vincent , Jones Robert J.
Published: February 2017

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Background: DP extends survival in mCRPC. However emergent clinical resistance is effectively inevitable. Serine/threonine protein kinase AKT (protein kinase B) pathway activation is highly prevalent in mCRPC contributing to disease progression and DP therapeutic resistance. AZD5363 is a potent oral pan-AKT inhibitor. Pre-clinical data suggest activity in mCRPC and synergy with docetaxel. This phase I trial was to develop a DP/AZD5363 combination in mCRPC. Methods: Eligibility included chemotherapy naive histologically/cytologically proven measurable/evaluable mCRPC, PSA or radiographic disease progression, ECOG performance status 0 or 1, serum testosterone <1.7 nmol/L. Treatment comprised DP up to 10 cycles (75 mg/m2, IV, day 1; prednisolone 5 mg BID, PO, day 1–21) and AZD5363 to disease progression. Planned AZD5363 dose levels were 320 mg (DL1), 400 mg (DL2) and 480 mg (DL3), BID, PO, 4 days on/3 days off, from cycle 1, day 2. We utilised a conventional 3+3 dose escalation to determine a recommended phase II dose (RP2D) for AZD5363 combined with DP according to defined dose limiting toxicity (DLT) using CTCAEv4. Results: 10 patients were recruited (4 DL1, 6 DL2), median age 67.5 (Range: 56-72). A median of 6.5 cycles (Range: 3-10) of DP and 4 cycles (Range: 1-13) of AZD5363 were administered. No DLTs were seen in DL1. 2 patients in DL2 experienced DLTs (G3 rash, G3 diarrhoea). 7 pts (70%) had at least one G3/4 IMP-related AE with neutropenia (n=3) and maculo-papular rash (n=3) the most common. G3/4 AEs considered related to AZD5363 occurred in 3 patients (0 DL1, 3 DL2) including maculo-papular rash, diarrhoea and neutropenia. Transient hyperglycaemia occurred in all patients (Random glucose C1D2 pre dose mean 6.0 mmol/L, 2 hour mean 8.7 mmol/L, 4 hour mean 9.5 mmol/L, 8 hour mean 6.5 mmol/L). Conclusions:The RP2D for AZD5363 is 320 mg bd 4 days on/3 days off in combination with full dose DP for mCRPC. A placebo controlled randomised phase II trial for this approach has commenced recruitment. This work was supported by CRUK [C9317/A16029]. CRUK Reference: CRUK/12/042. This research was conducted with support from the Investigator-Sponsored Study Collaboration between AstraZeneca and the National Cancer Research Network. Clinical trial information: NCT02121639.
A phase 2 study of BIND-014 (PSMA-targeted docetaxel nanoparticle) administered to patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC).
Authors: Autio Karen A. , Garcia Jorge A. , Alva Ajjai Shivaram , Hart Lowell L. , Milowsky Matthew I. , Posadas Edwin M. , Ryan Charles J. , Summa Jason Mark , Youssoufian Hagop , Scher Howard I. , Dreicer Robert
Published: February 2017

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Background: BIND-014 is a novel PSMA-targeted Accurin (polymeric nanoparticle) that contains docetaxel (D). BIND-014 is anticipated to improve the therapeutic index of D by increasing its intratumoral concentration and duration of exposure. In a phase 1 study, BIND-014 was generally well-tolerated and displayed anti-tumor effects, including in two patients with chemotherapy-naïve mCRPC. Methods: A phase 2 study was conducted of BIND-014 administered by a 60-min IV infusion at 60 mg/m² on day 1 of a 21-day cycle in combination with 5 mg of prednisone twice per day to patients with chemotherapy-naïve mCRPC. Prior treatment included abiraterone acetate (AA, 48%), enzalutamide (E, 12%) or both (14%). Of these 31 patients 19% progressed within ≤ 6 months on prior AA and/or E. The primary endpoint was radiographic progression-free survival (rPFS) using PCWG2 for bone and RECIST v1.1. Other endpoints included prostate specific antigen (PSA) and circulating tumor cell count (CTC) conversions, objective response rate (ORR), and overall survival (OS). Results: Forty-two patients were enrolled and received a median of 6 doses (range 1 – 21). Median rPFS was 7.1 months (95% CI: 2.6 – 9.9) with 4 patients (10%) censored. PSA response ( ≥ 50% reduction from baseline) was observed in 12 of 40 patients (30%). CTC conversions (from ≥ 5 CTCs/7.5 mL of blood at baseline to < 5 CTCs) occurred in 13 of 26 patients (50%). ORR was 32% with 3 confirmed responses (1 complete response and 2 partial responses) and 3 unconfirmed responses out of 19 patients with measurable disease. Estimated median OS was 13.4 months (95% CI: 9.9 – 18.6) with 14 patients (33%) censored. The most common hematological treatment-related adverse events (TRAEs) observed were lymphopenia (26%), and anemia (19%).Fatigue (69%), nausea (55%), diarrhea (45%), dyspnea (36%), and neuropathy (33%) were the most common non-hematological TRAEs. The most common TRAEs were generally grade 1 and 2. Conclusions: BIND-014 administered at 60 mg/m² on day 1 of a 21-day cycle is clinically active and well-tolerated when administered to patients with chemotherapy-naïve mCRPC including those with prior AA and/or E. Clinical trial information: NCT01812746.
Elevated HOXC6/DLX1 mRNA biomarker levels in urine to help select patients at increased risk for high-grade prostate cancer detection upon prostate biopsy.
Authors: Hendriks Rianne , Dijkstra Siebren , Cornel Erik Bastiaan , Jannink Sander , de Jong Hans , Hessels Daphne , Melchers Willem , Smit Frank , Leyten Gisele , De Reijke Theo , Vergunst Henk , Kil Paul , Knipscheer Ben , Hulsbergen-van de Kaa Christina , Mulders Peter , Van Oort Inge , Schalken Jack
Published: February 2017

31

Background: The major challenge in prostate cancer (PCa) diagnostics is to improve the early detection of clinically significant or high-grade PCa, especially in the sPSA "grey-zone" (4-10 ng/ml). Ideally, PCa-specific biomarkers would be obtained non-invasively, for example derived from urine. The aim of this study was to evaluate the expression levels and clinical utility of the recently identified urinary HOXC6-DLX1 mRNA biomarker combination in men at risk of having high-grade PCa. Methods: From two prospective, multicenter studies, a total of 863 post-DRE urine samples were collected from men with elevated sPSA levels before undergoing a prostate biopsy procedure. The HOXC6-DLX1 mRNA biomarkers were measured in urine using RT-qPCR and results were quantified using the Delta DeltaCt method (ΔΔCT), normalized and expressed in a score from 1 to 1421. Results: The HOXC6-DLX1 risk score was significantly higher in urine from patients with high-grade PCa upon prostate biopsy compared to no PCa and PCa Gleason score ≤6. In the sPSA "grey-zone", the HOXC6-DLX1 combination had the highest area-under-the-curve (AUC) of 0.67 (95% confidence interval (CI): 0.58-0.75) for prediction of high-grade PCa upon prostate biopsy in cohort A and 0.68 (95% CI: 0.59-0.76) in cohort B; as compared to sPSA with an AUC of 0.60 (95% CI: 0.51-0.70) and 0.62 (95% CI: 0.52-0.73) respectively. Overall, elevated HOXC6-DLX1 risk scores correlated with an increased risk of high-grade PCa detected on biopsy; 47% of men with a score >108 had significant cancer as compared to 6% with a risk score <17. Using a HOXC6-DLX1 risk score cut-off of 27.5 in the sPSA "grey-zone", 165 biopsies (31%) could have been avoided, and only 4% of patients with high-grade PCa would have been missed. Conclusions: The urine-based HOXC6-DLX1 assay provides a non-invasive solution to improve the selection of patients at increased risk for high-grade PCa who would benefit most from a prostate biopsy procedure, while reducing the number of unnecessary biopsies, particularly in the sPSA "grey-zone".
A randomized clinical trial comparing adjuvant radiation versus chemo-RT versus chemotherapy alone after radical cystectomy for locally advanced bladder cancer.
Authors: Zaghloul Mohamed S. , Christodouleas John Paul , Smith Andrew , Abdalla Ahmed , William Hany , Khaled Hussein Mustafa , Hwang Wei-Ting , Baumann Brian Christopher
Published: February 2017

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Background: There is growing interest in using adjuvant radiation therapy (RT) to reduce local failures (LF) after radical cystectomy (RC) for locally advanced bladder cancer. A previous RCT demonstrated significantly improved LF & OS with adjuvant RT vs. RC alone. An RCT was performed to compare the efficacy of adjuvant RT vs chemo-RT vs chemo alone after RC. The primary endpoint was disease-free survival (DFS). Secondary endpoints were OS, LRFS, DMFS and toxicity. Methods: Patients ≤ 70 yrs with ECOG PS ≤ 2 with locally advanced bladder cancer and ≥ 1 high-risk feature who underwent RC with negative margins at the Egyptian National Cancer Institute from 2002 – 2008 were enrolled. High risk features included stage ≥ pT3b, grade 3, or positive nodes. Patients were randomized following RC to RT (45 Gy in 1.5 Gy/fx given BID with 3D-conformal RT), chemo-RT with 2 cycles of gemcitabine/cisplatin before and after RT, or 4 cycles of chemo alone. The chemo alone arm was added as a 2nd randomization in 2007. Patients were followed regularly with CT scans q 6 months in the first 2 years & then yearly. Results: 198 patients were enrolled. 78 received RT, 75 chemo-RT and 45 received chemo alone. Median age was 54 (range 27 – 70) and the M:F ratio was 4:1. 53% had urothelial carcinoma, 41% had SCC and 6% other. Median follow-up was 19 mo (range 1 – 127 mo). The RT, chemo-RT and chemo alone arms had similar characteristics except for age (median 55, 52 and 55, respectively, p = 0.03) and tumor size (p = 0.02). There was no significant difference in DFS, DMFS or OS, although there was a trend toward improved DFS favoring the RT-containing arms with 3 yr rates of 63%, 68% and 56% in the RT, chemo-RT and chemo arms (p = 0.25). LRFS was significantly improved for the RT arms vs. chemo alone, with 3 yr rates of 87%, 96% and 69% (p < 0.01), regardless of histology. Treatment was reasonably well-tolerated with late grade ≥ 3 GI toxicity of 8%, 7% & 2%, respectively. Conclusions: This is the first RCT comparing adjuvant RT (+/- chemo) vs. adjuvant chemo following cystectomy for bladder cancer. RT was associated with significantly improved local control compared to chemo alone. There was no significant difference in DFS, DMFS, or OS. Clinical trial information: NCT01734798.
Phase II trial of gemcitabine + cisplatin + ipilimumab in patients with metastatic urothelial cancer.
Authors: Galsky Matt D. , Hahn Noah M. , Albany Costantine , Fleming Mark T. , Starodub Alexander , Twardowski Przemyslaw , Pal Sumanta K. , Hauke Ralph J. , Sonpavde Guru , Oh William K. , Bhardwaj Nina , Gnjatic Sacha , Kim-Schulze Seunghee , Liu Ziyue
Published: February 2017

357

Background: Immune checkpoint blockade, with anti-PD-1/PD-L1 antibodies, has shown striking results in patients (pts) with mUC. While CTLA4 blockade has demonstrated pharmacodynamic effects in localized bladder cancer (Carthon, Clin Can Res, 2010), the role of CTLA4 blockade in mUC remains undefined. We hypothesized that chemotherapy may lead to immunogenic cell death, and other immunomodulatory effects, which could subsequently be exploited with the addition of ipilimumab. Methods: Pts with mUC received 2 cycles of gemcitabine + cisplatin (GC) alone followed by 4 cycles of GC + ipilimumab (GCIpi). The primary endpoint was % of patients alive at 1 year. Secondary endpoints included safety, objective response rate, and progression-free survival. Immune monitoring was performed at baseline, after GC alone, and after GCIpi. Results: 36 pts with mUC (median age 60; range: 33-80) were enrolled; KPS was 80%, 90% and 100% in 30%, 45%, and 25%; 58% had visceral metastases and 20% had liver metastases. Pts received a median of 5 cycles of GC (range: 1-6) and 3 doses of Ipi (range: 1-8). The most common grade 3-4 adverse events were neutropenia (36%), thrombocytopenia (19%), anemia (25%), hyponatremia (31%), thromboembolism (11%), and renal insufficiency (19%). The most common grade 3-4 immune-related adverse events were colitis (6%), hypophysitis (3%), hyperthyroidism (1%), and rash (1%). The objective response rate is shown in the Table. Median progression-free survival is 8 months (95% CI 6.2-9.8 months). Median follow-up is 10.4 months (range: 2.8-35.3 months). The primary endpoint analysis will be mature for the meeting. GC alone had no significant impact on circulating immune cell subsets; Ipi significantly expanded circulating CD4 and CD8 T cells. Conclusions: A phased schedule of GC plus immune checkpoint blockade was feasible in pts with mUC. Ipi induced immunomodulatory effects despite concurrent chemotherapy. Survival data are not yet mature. Ongoing analyses are exploring the impact of GC alone, and GCIpi, on antigen-specific T cell immunity and correlating such findings with “outlier” survival times. Clinical trial information: NCT01524991. [Table: see text]
The hotspot mutational landscape of upper tract and bladder urothelial cancers and correlation to survival.
Authors: Campbell Matthew T. , McConkey David James , Matin Surena F. , Kamat Ashish M. , Dinney Colin P. N. , Wang Jennifer , Gao Jianjun , Siefker-Radtke Arlene O.
Published: February 2017

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Background: The prevalence of potentially targetable molecular mutations in urothelial carcinoma of the upper tract and bladder carcinoma are beginning to emerge. Important differences of molecular alterations may exist between upper tract and bladder primary tumors necessitating different treatment approaches and drug development strategies for these patients. Methods: All patients with urothelial carcinoma at UT MD Anderson who had undergone the CLIA-certified 50 gene panel utilizing next generation sequencing for detection of hotspot mutations were retrospectively reviewed. The prevalence of mutations was tabulated and compared between upper tract and bladder primary tumor locations using the Fisher’s exact test. Survival comparisons were calculated using the Kaplan-Meier technique and the Log Rank Test. Results: 136 patients with urothelial carcinoma were included in the analysis of which 41 were upper tract and 95 had bladder primary tumors. Of the 136 patients, 132 had de novo or developed metastatic/recurrent disease. The most prevalent mutations in the upper tract primary cohort included FGFR3, TP53, EGFR, FBXW7, PIK3CA, and KRAS. The most prevalent mutations in the bladder primary tumors were TP53, PIK3CA, RB1, FGFR3, HRAS, KRAS, BRAF, and FBXW7. In both upper tract and bladder tumors, a mutation in FGFR3 was nearly mutually exclusive for having a TP53 mutation. Compared to bladder primary tumors, upper tract tumors were more likely to have an FGFR3 mutation (36.5% vs. 7.4%, p < 0.0001), while the prevalence of TP53 (34% vs. 49%) and or a mutation in PIK3CA, HRAS, or KRAS (12.2% vs. 20.8%) was not significantly different. In the 132 patients with metastatic disease, the presence of a mutation in PIK3CA, HRAS, or KRAS was associated with inferior survival (HR 2.342, 95% CI: 1.32-8.67, p = 0.012), while the presence of an FGFR3 or TP53 mutation was not associated with a statistically different survival when compared to patients with wild type mutational status. Conclusions: Patients with upper tract and bladder primary sites have different molecular mutation rates. Understanding how these mutations in differing sites affect tumor biology may have important clinical implications.