bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I dose-finding study of vorinostat (V) combined with capecitabine (X) and cisplatin (P) as first-line therapy in patients with advanced gastric cancer.
Authors: Yoo Changhoon , Ryu Min-Hee , Ryoo Baek-Yeol , Koo Dong Hoe , Park Inkeun , Kang Yoon-Koo
Published: February 2017

73

Background: The purpose of this trial is to determine the recommended dose (RD) of vorinostat (V), a histone deacetylase inhibitor, in combination with capecitabine (X) and cisplatin (P) and to explore feasibility of V-XP at the RD in advanced gastric cancer. Methods: The standard 3+3 method was used to determine the RD of 3-weekly V-XP during the first cycle. The doses of X (days 1-14, p.o.), P (day 1, i.v.), and V (days 1-14, p.o.) were escalated as following scheme; X 1,600 mg/m2/day, P 60 mg/m2, V 300 mg/day in level 1; X 1,600 mg/m2/day, P 60 mg/m2, V 400 mg/day in level 2A; X 2,000 mg/m2/day, P 60 mg/m2, V 300 mg/day in level 2B; X 2,000 mg/m2/day, P 60 mg/m2, V 400 mg/day in level 3; X 2,000 mg/m2/day, P 80 mg/m2, V 400 mg/day in level 4. Results: A total of 24 patients were enrolled. Median age was 50 years (range, 25-66), and 11 (46%) were male. Dose limiting toxicity (DLT) was noted in 1 of 6 in level 1 (Grade 4 thrombocytopenia), 0 of 3 in level 2A, 1 of 6 in level 2B (Grade 3 fatigue), 1 of 6 in level 3 (Grade 3 stomatitis) and 2 of 3 in level 4 (Grade 4 thrombocytopenia, and discontinuation of X or V more than 25% of prescribed dosage due to Grade 3 anorexia and Grade 3 fatigue). Level 4 was maximal tolerated dose, and RD was determined as level 3. Six additional patients were enrolled at level 3 to confirm the feasibility, and DLT was not occurred. In 12 patients who received dose level 3, median 6 cycles (range, 3-10) of chemotherapy were given and most frequent Grade 3/4 toxicities were neutropenia (n=5, 42%) and anorexia (n=3, 25%). In overall, the objective responses were confirmed in 9 (47%) out of 19 patients with measurable lesions. With a median follow-up of 9 months, median progression-free survival was 7 months (95% confidence interval, 4 to 10 months), and median overall survival was not reached. Conclusions: Major DLTs of V-XP were thrombocytopenia, fatigue, anorexia and stomatitis. The 3-weekly schedule of X (2,000 mg/m2/day on day 1-14), P (60 mg/m2 on day 1), and V (400 mg/day on day 1-14) is recommended for further development of this regimen in patients with advanced gastric cancer. Clinical trial information: NCT01045538.
Comparative outcomes for 3D conformal versus intensity modulated radiation therapy for esophageal cancer.
Authors: Freilich Jessica , Chuong Michael , Yue Binglin , Fulp William J. , Abuodeh Yazan Asad , Almhanna Khaldoun , Meredith Kenneth , Karl Richard C. , Hoffe Sarah , Shridhar Ravi
Published: February 2017

76

Background: Emerging data suggests a benefit for using intensity modulated radiation therapy (IMRT) for the management of esophageal cancer. Methods: We retrospectively reviewed patients treated at our institution who received definitive or preoperative chemoradiation with either IMRT or 3D conformal radiation therapy (3DCRT) between October 2000 and January 2012. Kaplan Meier analysis and the Cox proportional hazard model were used to evaluate survival outcomes. Results: We evaluated a total of 232 patients (138 IMRT, 94 3DCRT) who received a median dose of 50.4 Gy (range, 44-64.8) to gross disease. Median follow up for all patients, IMRT patients alone, and 3DCRT patients alone was 18.5 (range, 2.5-124.2), 16.5 (range, 3-59), and 25.9 months (range, 2.5-124.2), respectively. We observed no significant difference based on radiation technique (3DCRT vs. IMRT) with respect to median overall survival (OS) (29 vs. 32 months; p=0.78) or median relapse free survival (RFS) (20 vs. 25 months; p=0.74). On multivariable analysis (MVA), not undergoing surgical resection resulted in worse OS (HR 2.255; p <0.0001) and RFS (HR 1.893; p<0.0001). Superior OS was associated on MVA with stage I/II disease (HR 0.523; p=0.010) and tumor length ≤5 cm (HR 0.567; p=0.006). Improved RFS on MVA was associated with stage I/II disease (HR 0.663; p=0.070), tumor length ≤5 cm (HR 0.611; p=0.011), adenocarcinoma histology (HR 0.532; p=0.055), and 3DCRT(HR 0.524; p=0.002). IMRT was also associated on univariate analysis with a significant decrease in acute weight loss (mean 6%+4.3% vs 9%+7.4%, p=0.0001) and on MVA with a decrease in objective grade ≥ 3 toxicity, defined as any hospitalization, feeding tube, or >20% weight loss (OR 0.51; p=0.050). Conclusions: Our data suggest that while IMRT-based chemoradiation for esophageal cancer does not impact survival there was significantly less toxicity. In the IMRT group there was significant decrease in weight loss and grade ≥3 toxicity compared to 3DCRT.
Reporting of subgroup analyses (SGA) in phase III randomized trials in gastrointestinal (GI) cancer.
Authors: Barton Sarah Rachel , Chau Ian , Peckitt Clare , Sclafani Francesco , Cunningham David
Published: February 2017

78

Background: Correct interpretation of SGA is important as it influences selection of therapeutic interventions for patient subsets. We aimed to evaluate the association of prospectively determined study characteristics with reporting of SGA and claims of subgroup effects in GI cancer trials. Methods: We performed a systematic literature review and extracted data from all articles meeting the following criteria: published 01/01/2003-01/09/2012 in peer-reviewed journal; reporting results of phase III randomised controlled trial; n≥150; testing investigational medicinal product in GI cancer. The primary aim was to compare reporting of SGA between industry and nonindustry sponsored trials. Results: 145 trials were identified. SGA were reported in 100 (69%). A significantly larger median number of SGA were reported in industry than in non-industry sponsored trials (6 vs 2, p=0.004). In the 52 trials claiming subgroup effects, significant test of interaction was evident in only 25%, with no difference between industry and non-industry trials (Table). There was an association between larger number of trial subjects and more SGA reported (p<0.001). Trials of targeted therapy compared to cytotoxic (median 6 vs 2, p=0.004) and trials with significant primary endpoint (median 6 vs 2, p=0.006) reported more SGA. Industry sponsored trials with a significant primary endpoint reported more SGA (median 8) than others (p<0.001). Conclusions: Industry sponsored trials with positive result and trials of targeted therapy appear to report SGA more frequently. Since only quarter of trials claiming subgroup effects had evidence of significant test of interaction, circumspection should be adopted when using SGA as the basis for variance in GI cancer treatment. Conference abstracts may contain more SGA, and these will be incorporated into further analyses. [Table: see text]
Association of low serum levels of transforming growth factor β1 (TGF-β1) and high levels of vascular endothelial growth factor-A (VEGF-A) following neoadjuvant chemoradiotherapy with poor outcome in esophageal cancer patients receiving combined modality therapy: A preliminary analysis using proximity ligation assay.
Authors: Graber Madeline S , Cheng Jason C. , Hsu Feng-Ming , Koong Albert
Published: February 2017

80

Background: Currently, serum biomarkers do not influence the treatment of esophageal cancer. The purpose of this project is to investigate, using the proximity ligation assay (PLA), serum biomarkers that predict treatment response and survival outcome for patients with locally advanced esophageal cancer (LAEC) undergoing neoadjuvant concurrent chemoradiotherapy (CCRT) followed by radical esophagectomy. Methods: From 2004 to 2011, 79 patients with LAEC receiving CCRT of taxane-based chemotherapy and 40 Gy followed by curative surgery were enrolled in this study. Serum samples were collected before and within one month after CCRT. Fifteen biomarkers (Axl, BMP2/4, EGFR, FAM84B, Gas6, Her2, IGFBP3, MMP1, MMP13, OPN, PDGFR-α, Periostin, SPARC, TGF-β1, VEGF-A) were analyzed using PLA. Pathological responses were classified into complete response (CR), microscopic residual (MicroR), or macroscopic residual (MacroR). Associations between serum level of each biomarker and pathological response, disease-free survival (DFS), and overall survival (OS) were evaluated by ANOVA and Log-rank tests. Results: Of 79 patients, 30 had CR (38%), 37 had MicroR (47%) and 12 had MacroR (15%). With a median follow-up of 54.5 months, the median OS and DFS were 34 and 43 months, respectively. Among evaluated biomarkers, TGF-β1 was the most significant one associated with pathological response (p=0.009, two-way ANOVA), with higher post-CCRT TGF-β1 levels predicting better response (p=0.035, one-way ANOVA). Patients with higher post-CCRT TGF-β1 levels (≥3rd quartile) had significantly better DFS (median not reached vs. 27 months, p=0.03). Patients with both lower levels of post-CCRT TGF-β1 and higher levels of VEGF-A had significantly worse DFS (13 months, p=0.001) and OS (18 months, p=0.035). Conclusions: Post-CCRT serum TGF-β1 and VEGF-A levels by PLA may be used to predict pathological response and survival outcome for esophageal cancer patients receiving combined modality therapy.
The impact of race on gastric cancer outcomes in the United States.
Authors: Powers Benjamin Daniel , Daly Maureen Patricia , Davey Adam , Taghavi Sharven , Jayarajan Senthil N. , Willis Alliric Isaac
Published: February 2017

83

Background: Disparities in gastric cancer outcomes are well-documented. We evaluate the association of race with gastric cancer outcomes using a diverse database of patients in the U.S. Methods: SEER was queried for gastric adenocarcinoma cases from 2004-2008, excluding cardia. Logistic (LR) and Cox regressions were used for analyses. Results: 9,440 cases were analyzed: 4,134 (43.8%) Whites (W), 2,015 (21.3%) Asian-American Pacific Islanders (AP), 1,826 (19.3%) Hispanics (H), and 1,465 (15.5%) Blacks (B). Presentation: Average age was 70.1. B, H, and AP were more likely than W to present younger. AP were more likely and H less likely than W to present at a lower stage. B were more likely to have a lower grade. No differences in gender were seen. Treatment: Compared to W, AP were more likely to have surgery. AP, H, and B were more likely to receive radiation (XRT). AP and H had increased odds of ≥15 lymph nodes examined (LNE). Survival: AP and H had improved but B had worse survival compared to W when stratified by receipt of surgery, XRT, and stage and adjusted for age, gender, LNE, anatomic site, and grade. Conclusions: AP were more likely to present with lower stage, have surgery, XRT, ≥15 LNE, and highly significantly better survival than W. H were more likely to present younger but with higher stage, have ≥15 LNE, XRT, and better survival. For B there were no differences in stage or receipt of surgery, though there were increased odds of XRT but had worse survival. These racial disparities in gastric cancer suggest potential differences in tumor or host biology and quality of treatment that impact outcomes and merit further study. [Table: see text]
A phase I dose-finding study of everolimus in combination with capecitabine and oxaliplatin (XELOX) as the first-line chemotherapy for patients with advanced gastric cancer.
Authors: Park Inkeun , Ryu Min-Hee , Ryoo Baek-Yeol , Kang Myoung Joo , Lee Changsuk , Park Young Soo , Kang Yoon-Koo
Published: February 2017

86

Background: The purpose of this phase I study is to determine the recommended dose (RD) of everolimus (E), an mTOR inhibitor, in combination with capecitabine (XEL) and oxaliplatin (OX) and to explore feasibility of EXELOX at the RD in advanced gastric cancer (AGC). Methods: The standard 3+3 method was used to determine the RD of 3-weekly EXELOX during the first cycle. The doses of each drug [E (mg/day, D1-D21)/XEL (mg/m2/day, D1-D14)/OX (mg/m2, D1)] were as follows: level 1, 7.5/1600/100; level 2A, 7.5/1,600/130; level 2B, 7.5/2,000/100; level 3A, 10/1,600/130; level 3B, 10/2,000/100; level 4, 7.5/2,000/130. Results: During the first cycle of chemotherapy, no dose limiting toxicity (DLT) was noted in each cohort of 3 patients (pts) at dose levels 1-3A. At dose level 3B, 1 DLT (delay of the next cycle over 3 weeks because of Gr2 thrombocytopenia and Gr2 AST) was observed out of 6 pts. At dose level 4, DLTs (Gr3 fatigue and Gr4 thrombocytopenia) were found in 2 out of 3 pts. However, with frequent dose delay or reduction in subsequent cycles, the actual dose intensity of XELOX during the first 3 cycles was not higher at dose levels 2 or 3 than at dose level 1. Accordingly, dose level 1 was finally considered more suitable to maintain the actual dose intensity over chemotherapy cycles. At dose level 1, with no DLT during the first 3 cycles in 3 more pts accrued to confirm the safety, 12 additional pts were enrolled in the extension cohort to explore feasibility of EXELOX in the aspect of efficacy. Among 16 patients with measurable disease at dose level 1, 8 (50%) pts achieved a confirmed PR, 7 (44%) had SD, and 1 (6%) showed PD as a best response. With a median follow-up period of 12 months (range 4.9–12.8 months), the median progression-free survival and overall survival were 5.5 and 8.1 months, respectively at dose level 1. Conclusions: In this study, the doses of XEL (1,600 mg/m2/day), OX (100 mg/m2), and E (7.5 mg/day) were recommended with good tolerability for the 3 weekly EXELOX combination as the 1st line chemotherapy for AGC. The efficacy of this combination needs to be evaluated in future trials. Clinical trial information: NCT01049620.
Does radiation therapy increase late cardiac death in patients with esophageal cancer?
Authors: Lin Chi , Denniston Kyle A.
Published: February 2017

90

Background: The objective of this study was to evaluate the effect of radiation therapy (RT) on late cardiac death in patients with esophageal cancer. Methods: A total of 35,618 patients diagnosed with esophageal squamous cell carcinoma (SCC) or adenocarcinoma (ADE) between 1973 and 2008 were identified from the SEER database. After excluding records with missing data, 24983 patients remained. Patients who survived ≥ 5 years (2075) were identified for this analysis. Examined risk factors for cardiac death include age (≤55/56-65/66-75/>75), gender, race (white/non-white), stage (local/regional/distant), histology (SCC/ADE), esophageal subsite (<18cm/18-24cm/25-32cm/33-40cm), diagnosis year (1973-1983/1984-1993/1994-2003), and treatment with surgery or RT. Time to cardiac death was evaluated using the Kaplan-Meier method. A multivariate logistic regression model with backward elimination and the Cox Proportional Hazards model were used to evaluate risk factors for cardiac death. Results: Patients who received RT tended to be younger, white, diagnosed more recently, have more advanced disease, SCC histology and not undergo surgery. RT group had a higher risk of cardiac death than no-RT group (Log-Rank p < 0.0001). Median time to cardiac death in RT group was 251 months (95% CI 223-367) and was not reached in no-RT group. The probability of cardiac death increased with age and decreased with diagnosis year. This trend was more pronounced in RT group. Multivariate analysis found RT to be associated with higher probability of cardiac death (OR 1.45, 95% CI 1.10-1.93), after adjusting for age and diagnosis year. Gender, race, histology, stage, esophageal subsite and surgery status were not associated with cardiac death. After adjusting for age, Cox model showed that patients who received RT were more likely to die of cardiac causes than those who did not receive RT (HR 1.91, 95% CI 1.47-2.47). Diagnosis year was not a risk factor in the Cox model. Conclusions: Patients with esophageal cancer who received RT and survived ≥ 5 years had a higher risk of cardiac death than those who did not receive RT. Further study of cardiac outcome in long term survivors of esophageal cancer treated with RT, and accounting for comorbidity, is warranted.
Phase II trial of sorafenib in esophageal (E) and gastroesophageal junction (GEJ) cancer: Response and prolonged stable disease observed in adenocarcinoma.
Authors: Ku Geoffrey Y. , Janjigian Yelena Yuriy , Shah Manish A. , Herrera Jessica , Tang Laura H. , Fuqua Louis , Capanu Marinela , Ilson David
Published: February 2017

91

Background: Sorafenib is a tyrosine kinase inhibitor targeting VEGFr, PDGFr, Raf and other pathways. Encouraging response and survival were observed in a phase II trial of sorafenib with chemotherapy in GE cancer (J Clin Oncol 27:2947;2010). We performed a phase II trial of single-agent sorafenib with the primary endpoint of progression-free survival (PFS). Secondary endpoints include response and toxicity. Methods: Patients (Pts) with measurable metastatic E and GEJ cancer with ≤3 prior chemotherapy regimens were treated with sorafenib 400 mg BID. CT scans were performed monthly for the first 2 months, then every 2 months. Results: Thirty-five patients have been accrued, with 34 evaluable; median age 62, 31 male, 4 female, median KPS 80%, E 25, GEJ 10, adenocarcinoma (AC) 30 squamous 5, median no. of prior therapies 2. Of 31 response-evaluable Pts, 1 (3%) ongoing complete response was noted (34+ months) in a Pt with E AC with biopsy-proven lymph node recurrence after chemoradiation and surgery; 23 Pts (74%) had stable disease. Median PFS is 3.7 months (95% CI 1.9 to 4 months), with median overall survival 8.9 months (95% CI 6.9 to 11.6 months). Four patients remain on treatment. Significant grade 3 toxicities included hand foot reaction (3 Pts), rash (1 Pt), dehydration (3 Pts) and fatigue (2 Pts). Twenty-seven of 33 tumors (82%) tested positive for phospho-ERK by immunohistochemistry. Conclusions: Encouraging activity in terms of PFS has been noted in this heavily pre-treated population. Updated data will be presented. Supported by a grant from Bayer. Clinical trial information: NCT00917462.
Patterns of locoregional relapses for patients with esophageal cancer for whom exclusive chemoradiotherapy failed: A plea for dose escalation and elective nodal irradiation.
Authors: Chevalier Cedric , Vulquin Noemie , Gauthier Mélanie , Petitfils Aurelie , Martin Etienne , Truc Gilles , Peignaux-Casasnovas Karine , Khoury Cedric , Wiazzane Nadia , Maingon Philippe , Crehange Gilles
Published: February 2017

99

Background: Nearly half of the patients (pts) with an esophageal cancer (EC) have a locoregional failure (LRF) after exclusive chemoradiation (eCRT). eCRT delivering 50Gy remains the standard of care for non operable pts. We aim to evaluate the patterns of LRF with respect to planned dose and/or the incidental (unplanned) dose that covered LRF. Methods: Twenty-two pts with EC who failed locally and/or regionally in their follow-up were exclusively reviewed. All the pts have been initially treated (t0) in a curative intent with eCRT. Co-image registration of CT or PET-CT at time of failure and planning CT at t0 was used for image fusion. Each nodal failure (Nf) and each local failure of the primary tumor (Lf) has been outlined, as well as each nodal station (NS) including Nf according to the RTOG classification. Dosimetric parameters in relation with Lf, Nf and involved NS were derived from the initial dosimetric plan. Results: All the patients underwent eCRT including a 5-FU based chemotherapy regimen. Eighteen patients were treated with elective nodal irradiation (ENI) whereas 4 pts did not. The median dose delivered was 50Gy [50Gy-64Gy]. In the follow-up period, 14 pts were in complete response, 3 pts in partial response, 4 pts had a progressive disease (1pt unknown). The median delay between the start of radiotherapy and LRF was 14.3 months [4.27-48.46]. 13 pts had a Lf (included in “planned-dose”), 9 pts had a Nf, 2 pts had a Lf with Nf and 7 pts had a concomittant distant failure. Among pts with Nf, 8 failures were in-field whereas 3 pts had an out-field relapse. Re-calculated doses for NS delineated on the CT performed at t0 were significantly less important than the planned dose (see Table). Conclusions: Our results suggest that an inadequate dose to both the primary tumor and NS could explain high LRF rates observed in EC. A French randomized phase III trial (NCT 01348217) is currently testing a higher dose to the primary tumor and/or ENI with IMRT in an attempt to improve locoregional control. [Table: see text]
Ex vivo prostate cancer explant organ culture model system for targeted drug development in prostate cancer
Authors: Gupta Shilpa , Gu Lei , Liao Zhiyong , McCue Peter , Trabulsi Edouard John , Nevalainen Marja T.
Published: February 2017

110

Background: Effective drug development does not always occur successfully in prostate cancer despite discovery of pathways and targeted agents due to lack of pre-clinical models that effectively mimic prostate cancer in humans. We optimized a novel Ex vivo organ-culture model system using clinical human prostate cancers to test novel therapeutic agents targeting the Jak2/Stat5a/b pathway in prostate cancer; this pre-clinical model may be useful to test novel drugs in prostate cancer for target validation and efficacy. Methods: Organ explant cultures of prostate cancers from 16 patients undergoing radical prostatectomy were performed within 2 hours of surgery, 1-2 mm fresh tissue explants were cultured in a medium containing different doses of pharmacologic inhibitor of Stat5a/b (IST5-002) or a small molecule Jak2 inhibitor with appropriate controls and treated with the drug daily for 7 days. Explants were fixed and analyzed for viability by hematoxylin-eosin staining and “in situ DNA end-labeling” assays, Stat5 activation was analyzed by immunohistochemistry for phosphorylated Stat5a/b. Results: Morphology of prostate cancer was well maintained and dose-dependent tumor responsesoccurred with the Stat5a/b and Jak2 inhibitors. The minimum effective dose of each drug was 25 micromoles and considerable effects on morphology and apoptosis were seen at 50 micromoles. Conclusions: Inhibition of the /Stat5a/b pathway showed promising preclinical activity in prostate cancer as demonstrated by our 3D-ex vivo explant organ culture model system using clinical human prostate cancers, corroborating the data from prostate cancer cell lines and xenograft prostate tumors. This model system may also serve as an effective pre-clinical tool to explore new targets and analyze the effects of different targeted therapies in prostate cancer. Finally, since this uses Ex vivo prostate cancer explants from individual prostate cancer patients, once could test different targeted agents in parallel and based on the efficacy of individual drugs, select patients who would best respond to a particular drug, thus providing an effective personalized medicine approach.
A randomized phase II trial of dexamethasone versus prednisolone as secondary hormonal therapy in CRPC.
Authors: Venkitaraman Ramachandran , Thomas Karen , Murthy Vedang , Woode-Amissah Ruth , Dearnaley David Paul , Horwich Alan , Huddart Robert Anthony , De Bono Johann Sebastian , Parker Chris
Published: February 2017

123

Background: Dexamethasone and prednisolone are glucocorticosteroids used as second line hormonal treatment for castration refractory prostate cancer (CRPC). The biochemical response rates in cohort studies suggest that dexamethasone may be the more active agent. We conducted an open label, randomised phase II trial of dexamethasone versus prednisolone. Methods: Patients with castration resistant prostate cancer with progressive disease on androgen deprivation therapy were eligible. They were randomized to receive either prednisolone 10mg daily or dexamethasone 0.5mg daily. The main endpoint was confirmed PSA response rate according to the PSA Working Group 2 criteria. Patients with PSA progression on prednisolone crossed over to dexamethasone. Secondary endpoints included time to PSA progression, radiologic response rate using RECIST criteria, and safety. Results: Seventy-five patients were randomized. Confirmed PSA response was achieved in 12/39 patients (31%) on dexamethasone compared to 6/36 (17%) on prednisolone (p = 0.153). Median time to PSA progression was 9.7 months on dexamethasone compared to 5.1 months on prednisolone (HR 1.57, 95% CI 0.90 -2.75). In 43 patients with measurable disease, the response rate by RECIST criteria was 15% and 6% for dexamethasone and prednisolone, respectively (p = 0.606). Clinically significant toxicities were rare. Of 23 patients who crossed over at progression on prednisolone to dexamethasone, 19 patients were evaluable for PSA response. Seven of the 19 patients (37%) had a confirmed PSA response to dexamethasone after progression on prednisolone. Conclusions: The data are consistent with the hypothesis that dexamethasone is more active than prednisolone in the treatment of CRPC. In the absence of definitive, larger trials, dexamethasone should be used in preference to prednisolone in this setting. Clinical trial information: 2005-006018-16.
Use of supportive measures to improve outcome and decrease toxicity in docetaxel-based antiangiogenesis combinations.
Authors: Karzai Fatima H. , Adesunloye Bamidele , Ning Yangmin M. , Madan Ravi Amrit , Gulley James L. , Apolo Andrea Borghese , Beatson Melony A. , Couvillon Anna , Harold Nancy , Parnes Howard L. , Arlen Philip M. , Wright John Joseph , Chen Clara , Dawson Nancy Ann , Figg William Douglas , Dahut William L.
Published: February 2017

128

Background: We have recently completed accrual of 63 patients (pts) to our study combining lenalidomide (L), with bevacizumab (B), docetaxel (D), and prednisone (P) (ART-P). Due to the lack of improved survival and the increased toxicity of anti-angiogenic docetaxel combinations in the MAINSAIL and CALGB 90410 trials we attempted to contrast and compare our studies with the failed phase III trials. Methods: Among the first 52 pts on the ART-P, 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). We later enrolled 11 more pts at L 15 mg. 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. Patients on CALGB 90410 received D 75 mg/m2 and B 15 mg/kg on day 1 with P 10 mg and on MAINSAIL received D 75 mg/m2, L 25 mg daily for 14 days of every 21−day cycle with daily P. Patients on CALGB 90410 and MAINSAIL did not receive enoxaparin or pegfilgrastim prophylactically. Results: Median number of Cs in ART-P was 16 (3−38). PFS was 22 months and median OS has not been reached. Pts with measurable disease had 1 CR and 25 PR (86.7% RR). Two patients (3%) had deep vein thromboses. Of 1,219 cycles given, 14 cycles were complicated by febrile neutropenia (FN) (1.1%). There were no treatment related deaths. In comparison, median number of Cs in MAINSAIL L+DP arm was 6, with a PFS of 45 weeks and an OS of 77 weeks. Thirty-four pts (6.5%) developed pulmonary emboli and there were 2 deaths due to toxicity in the experimental arm. Nearly 12% of Cs were complicated by FN. In the experimental arm of CALGB 90410 trial, median OS was 22.6 months with median PFS of 9.9 months. Median number of Cs was 8, and 19 pts developed thromboses/emboli (3.6%). In addition, 7% of patients developed FN and treatment related deaths were reported at 4%. Conclusions: The use of supportive care allows the ART-P combination to be given for more cycles than were given in MAINSAIL and CALGB 90401 potentiating a longer PFS, RR and possibly OS with an improved toxicity profile. This data demonstrates the potential importance of supportive measures and is hypothesis generating for future combination studies. Clinical trial information: NCT00942578.
Analysis of putative resistance mechanisms in recent treatments targeting the androgen receptor in castration-resistant prostate cancer (CRPC).
Authors: Thelen Paul , Walleck Eiko , Bremmer Felix , Trojan Lutz , Strauß Arne
Published: February 2017

130

Background: Recent breakthrough therapies targeting androgen receptor signalling in CRPC involve multifunctional androgen receptor (AR) blockade and exhaustive androgen deprivation. Nevertheless, limitations to an enduring effectiveness of new drugs are anticipated in resistance mechanisms occurring under such treatments. Here we specify the origin of CYP17A1 up-regulation under abiraterone acetate treatment in CRPC cell models. Methods: CRPC cell models VCaP and LNCaP as well as AR-negative PC-3- and non-neoplastic epithelial BPH-1-cells were treated with various concentrations of abiraterone hydrolyzed from abiraterone acetate (AA, Janssen-Cilag, Germany). Functional analyses by RNA interference were done with AR- and CYP17A1-siRNA. Expression of androgen regulated genes and CYP17A1, AKR1C3 was quantitated by real time PCR. Protein analyses were performed by western blots and PSA secretion was assessed by ELISA kits. Results: AA treatments (5 to 25 µM) of AR positive CRPC cell models led to decreased expression of androgen regulated genes such as PSA. In these cells diminished expression of androgen regulated genes was accompanied by an up-regulation of CYP17A1 expression (>2-fold at 25µM AA) within short treatments of 24 hours. No such effects became evident in AR-negative PC-3 cells. AR directed siRNA (siAR) used in VCaP cells significantly reduced mRNA expression and AR protein abundance. Such interference with AR signalling in the absence of AA also caused an (up to 8-fold) up-regulation of CYP17A1 expression. Conclusions: In AR-positive cells AA treatments cause a down-regulation of androgen regulated genes in spite of an elevated expression of CYP17A1, the very target enzyme for this drug. CYP17A1 up-regulation already occurs within 24 hour treatments of AA and does not require adaptation events over several cell cycles. CYP17A1 is also up-regulated in the absence of AA when AR signalling is physically eliminated by siAR. These results reveal an immediate counter-regulation of CYP17A1 expression whenever AR-signalling is inhibited adequately but not a persisting adaptation yielding drug resistance.
Long-term immune responses elicited by a DNA vaccine encoding prostatic acid phosphatase (PAP) in patients with nonmetastatic castrate-resistant prostate cancer.
Authors: McNeel Douglas G. , Becker Jordan T. , Eickhoff Jens C. , Johnson Laura E. , Liu Glenn , Olson Brian M.
Published: February 2017

135

Background: We have previously reported a phase I/II trial with a DNA vaccine encoding PAP in patients with stage M0 CaP. Vaccination was found to be safe and immunologically active. Th1-biased PAP-specific immune responses were associated with increases in PSA doubling time (DT). In the current trial, we sought to evaluate the immunological efficacy of immunizations performed over a 1-2-year period of time, with the goal of identifying a preferred schedule. Methods: Patients (pts) were randomized to a schedule of 6 immunizations at 2-wk intervals followed by quarterly booster immunizations, or a schedule determined by frequent immune monitoring. Immune monitoring was by IFNγ and granzyme B ELISPOT and antigen-specific T-cell proliferation. Pts continued immunization until evidence of radiographic progression, toxicity, two years, or 24 total immunizations, whichever occurred first. Results: 17 pts were enrolled, of whom 11 completed at least 1 year on treatment, and 4 completed 2 years. 3 pts remain on study. 1 pt experienced a grade 3 allergic reaction (angioedema) after 11 immunizations; no other events > grade 2 were observed. 6/16 evaluable pts developed durable immune responses, defined as statistically significant PAP-specific T-cell responses by at least two separate measures that were at least 3-fold the baseline response and detectable at >1 post-treatment time point. 2 pts in the immune-monitoring arm developed immune responses after 6 immunizations that were detectable at each quarterly time point up to 2 years. 5/15 evaluable pts were observed to have a >3-fold increase in PSA DT; the 2 with the greatest increase in PSA DT developed PAP-specific IFNγ-secreting T cells detectable at multiple time points after immunization. Conclusions: Repetitive immunization with this vaccine appears safe and immunologically active. Presence of durable Th1-biased antigen-specific immune responses is a mechanistically rational biomarker, and may be associated with favorable increases in PSA DT observed in 2 separate trials. Impact of vaccination on time to radiographic disease progression awaits results from an ongoing randomized clinical trial. Clinical trial information: NCT00849121.
Value of NADiA ProsVue on the CAPRA-S nomogram for predicting postprostatectomy clinical recurrence.
Authors: Moul Judd W. , Lilja Hans , Lance Raymond , Vessella Robert , McDermed Jonathan E. , Sarno Mark J. , Adams Thomas H.
Published: February 2017

139

Background: The post-radical prostatectomy (RP) CAPRA-S nomogram stratifies men into low, intermediate and high risk groups for biochemical recurrence (BCR) and proved accurate for predicting 3 and 5 year BCR rates in a large study cohort. NADiA ProsVue is a prognostic test that identifies men at reduced risk of clinically recurrent prostate cancer when used with traditional risk factors. We assessed ProsVue, a prognostic test for identifying post-RP clinical recurrence, in an independent population of men classified into low, intermediate and high CAPRA-S risk groups. Methods: The 304 men in the ProsVue 510(k) study were categorized into low (scores 0-2), intermediate (3-5) and high (≥6) CAPRA-S risk groups. Men were categorized as “at reduced risk” or “not at reduced risk” using a 2.0 pg/mL/month ProsVue cutpoint. Clinical recurrence was defined by positive biopsy or imaging results or death due to prostate cancer. Clinical progression-free survival (cPFS) was determined between subgroups using univariate Cox regression and Kaplan-Meier survival analyses and Wilcoxon and log-rank p values were reported. Results: Recurrence occurred in 8/156 (5.1%), 20/93 (21.5%) and 32/55 (58.2%) of men in the low, intermediate, and high CAPRA-S risk groups, respectively (P<0.0001). After 3, 5, 8 and 15 year followup, men in all CAPRA-S risk groups with ProsVue results ≤2.0 had significantly longer cPFS compared to men with results >2.0. The differences are marked as early as 3 years post-RP in the intermediate and high risk groups. Conclusions: ProsVue added significant prognostic value for identifying risk of clinical recurrence within low, intermediate and high CAPRA-S risk groups. ProsVue is the strongest independent predictor of clinical recurrence of prostate cancer post-RP. [Table: see text]
Overtreatment of prostate cancer in Florida.
Authors: Gilbert Scott Michael , Henriksen Carl
Published: February 2017

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Background: Although most evidence suggests that older men with localized prostate cancer do not benefit from treatment, many men with relatively limited (<10 years) life expectancy continue to seek and receive treatment. Given mounting concerns regarding overtreatment, we sought to better understand geographic differences in the potential overtreatment of prostate cancer. Methods: We used the Florida Cancer Data System (FCDS) to identify treated and untreated cases of prostate cancer between 2004-2007. The FCDS is a large statewide cancer registry that collects clinical, demographic and treatment information for incident cancers. We defined potential overtreatment according to risk of disease (Gleason <=7, stage T2 and less) and age ( >75 years). We used Geographic Information Systems (GIS) to map differences in overtreatment across Health Service Areas (HSAs) in Florida. We then examined the relationship between the number of urologists and radiation oncologists reported in the Area Resource File and potential overtreatment using linear regression models. All analyses were performed using standard statistical software (SAS and ArcGIS). Results: Among men older than 75 years (n=10,411), 9.2% received surgery, 38.7% received external radiation therapy, 15% received brachytherapy and 10.5% received primary androgen deprivation therapy; only 26.6% of patients were managed expectantly. Overtreatment varied significantly across Florida. Among some HSA clusters in Central and Panhandle Florida, overtreatment was estimated in less than 21.6 % of cases. Much higher rates of overtreatment (36-52% of cases) was observed among other HSAs, particularly in South Florida. Although the number of urologists (per 100,000 male population) was not associated with an increased propensity for overtreatment in regression models, the concentration of radiation oncologists was associated with an increase of 0.64 cases of overtreatment (per 100,000 men) for each additional radiation oncologist (p<0.0001). Conclusions: Treatment among older men with low- and intermediate-risk localized prostate cancer is more common than expectant management. The propensity for overtreatment varies considerably according to geographic and healthcare market factors.
Dose-escalated adaptive image-guided radiotherapy versus high-dose-rate brachytherapy monotherapy for low-risk prostate cancer.
Authors: Marina Ovidiu , Krauss Daniel J. , Brabbins Donald , Wallace Michelle , Martinez Alvaro A , Ye Hong , Gustafson Gary S.
Published: February 2017

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Background: Both IGRT and HDR are used for definitive treatment of low-risk prostate. No comparative study of these contemporary modalities exists. Methods: Charts for patients with low-risk prostate cancer by NCCN criteria treated 1999-2012 were reviewed. For IGRT, the clinical target volume (CTV) included the prostate and proximal seminal vesicles. A CT-based, off-line adaptive treatment plan was made with a patient-specific confidence-limited planning target volume (cl-PTV) based on the planning plus four additional daily CT scans. Overall survival (OS) was calculated by the Kaplan-Meier method (log-rank test), with Cox regression for uni- and multi-variate analysis. Cumulative incidence (Gray’s test), with competing risks analysis (Fine and Gray) were used for biochemical control (BC) and freedom from local recurrence (FFLR). Results: There were 598 IGRT and 399 HDR patients (see Table), with a median follow-up of 6.1 and 3.6 years, respectively (p<0.001). The median prescribed IGRT dose was 75.6 Gy (range 73.8-79.2). HDR doses were 24 Gy (n=126) or 27 Gy (n=151) in 2 fractions, or 36 Gy (n=3) or 38 Gy (n=335) in 4 fractions. Five- and 10-year BC was 99% and 94% for IGRT and 98% and 95% for HDR (p=0.77); FFLR was 100% and 99% for both (p=0.89); and OS was 95% and 75% for IGRT and 97% and 85% for HDR (p=0.04). On multivariate analysis, predictors (p<0.10) for OS were age (p<0.001) and PNI (p=0.04); for LR, PPC (p=0.01); and for BC, a trend for PSA (p=0.08). Treatment type was not a predictor of OS, BC or FFLR (p>0.5). Conclusions: Both dose- escalated IGRT and HDR monotherapy yield similarly excellent outcomes for low-risk prostate cancer. Our experience supports the continued use of brachytherapy as monotherapy in low-risk prostate cancer. [Table: see text]
Immune response with sipuleucel-T in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Phase II ProACT study.
Authors: Gardner Thomas A. , Petrylak Daniel Peter , Corman John M. , Hall Simon , Weinstein Ralph , Keyser Robert , Sims Robert Brownell , Sanders Amanda , Sheikh Nadeem A. , Higano Celestia S.
Published: February 2017

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Background: Sipuleucel-T is an autologous cellular immunotherapy for asymptomatic or minimally symptomatic mCRPC. Sipuleucel-T prepared using 10μg/mL PA2024 (PAP-GM-CSF antigen) stimulates immune responses and prolongs overall survival (OS). ProACT is an ongoing phase 2 study to evaluate immune responses and OS of sipuleucel-T when manufactured using 3 different concentrations of PA2024. Here we report data from the FDA-approved concentration, 10μg/mL PA2024 (n=40). Methods: Pts with asymptomatic or minimally symptomatic mCRPC (n=120) received sipuleucel-T manufactured using 2, 5 or 10μg/mL PA2024 for a total of 3 infusions with 2-wk intervals. Peripheral immune responses were evaluated 2, 4 and 6 mo after 1st infusion by serum ELISA (n=40), and B cell activation phenotype was characterized during the manufacture of the product by flow cytometry (n=19). Results: During product manufacture both mature and memory B cells were activated; the percentage of B cells that had a mature phenotype (defined as CD20+ IgD+ CD27+ CD86+) was increased only after culture of each successive treatment. Activated memory B cells (defined as CD20+ IgD- CD27+ CD86+) were also increased after culture of each successive treatment and in pre-culture cells at the 3rd treatment. At mo 2, median serum anti-PA2024 and anti-PAP titers (IgG and IgM combined) were 128 and 32-fold higher vs baseline respectively, compared to median serum anti-GM-CSF titers, which were 16-fold higher vs baseline. Median serum anti-PA2024 titers (IgG and IgM combined) were significantly higher than those for anti-GM-CSF (p<0.001) at all timepoints and correlated with anti-PAP titers (r=0.840). PA2024 and PAP responder frequencies (IgG and IgM titers combined >12,800) were 79% and 47% of pts, respectively. Anti-tetanus titers were predominantly IgG and did not differ between timepoints. Conclusions: These data indicate that sipuleucel-T induces an activated memory phenotype, evident after each culture in vivo after the first two treatments. Sipuleucel-T also appears to generate robust, long lasting anti-PA2024 and anti-PAP responses. Analyses comparing the 3 dosing cohorts will be reported in future publications. Clinical trial information: NCT00715078.
Does the diagnosing urologist influence choice of initial active treatment versus observation in older men with favorable prostate cancer?
Authors: Hoffman Karen Elizabeth , Niu Jiangong , Shen Yu , Jiang Jing , Shah Jay Bakul , Smith Grace L. , Davis John W. , Kim Jeri , Volk Robert , Kuban Deborah A. , Giordano Sharon Hermes , Smith Benjamin D.
Published: February 2017

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Background: Upfront treatment of older men with favorable prostate cancer yields substantial morbidity but does not improve survival. Deferring treatment in favor of observation promises to reduce morbidity without compromising survival, yet few patients select observation. Prior literature focuses on patient factors contributing to active treatment but the influence of the patient’s urologist on treatment choice remains uncertain. Methods: We identified men age 66 and older with favorable prostate cancer (cT1c or cT2; Gleason 6) diagnosed from 2004-2007 in the SEER-Medicare and Texas Cancer Registry-Medicare databases whose catchments include 34% of the United States (US). Diagnosing urologist, practice setting and cancer-directed treatment within 12 month of diagnosis (prostatectomy, radiotherapy, cryotherapy or androgen deprivation) were determined from claims data. Physician characteristics were obtained from the AMA Master File. Fixed effect and random effect hierarchical multivariate models evaluated physician variation and factors associated with observation. Results: 17,468 patients received care from 2,613 urologists. 64% of patients had T1c cancer. 85% received active treatment and 15% had observation. Even among men 80 and older, 67% received active treatment. The diagnosing urologist accounted for 10% of the variance in choice of active treatment versus observation. After adjusting for patient factors, urologists practicing in an office setting (vs. hospital; p<0.001) and not trained in the US (vs. US-trained; p=0.006) were less likely to manage patients with observation. With adjustment for case mix, only 3.5% of urologists demonstrated a higher than average likelihood of managing their patients with observation; 34% of men diagnosed by these urologists were observed. Conclusions: The vast majority of older men, even those over 80, received active treatment for favorable prostate cancer. The diagnosing urologist contributed to variation in the choice of treatment versus observation. Less than 5% of urologists demonstrated higher than average use of observation suggesting widespread bias against observation during the study era.
Phase II trial of combination therapy with intravenous carboplatin (C) and oral everolimus (EVE) and prednisone (P) in docetaxel-pretreated (DP) metastatic castrate-resistant prostate cancer (mCRPC): A Prostate Cancer Clinical Trial Consortium study.
Authors: Veeraputhiran Muthu Kumaran , Shevrin Daniel H. , Heilbrun Lance K. , Smith Daryn , Li Jing , Dickow Brenda , Heath Elisabeth I. , Vaishampayan Ulka N.
Published: February 2017

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Background: Platinum based therapies have demonstrated efficacy in DP mCRPC. EVE demonstrated preclinical efficacy in chemotherapy resistant prostate cancer models. Clinical synergy was noted between C and EVE, hence a phase II trial of the combination was conducted. Methods: Primary endpoint was time to progression (TTP). Progression was defined per RECIST criteria for measurable disease (MD), or skeletal event, or > 2 new areas of bone metastases. DP mCRPC patients with adequate renal and liver function, and performance status of 0 or 1 were eligible. Intravenous C at target AUC of 5 on day 1, and oral EVE 5mg once daily and P 5mg twice daily were administered in 21 day cycles. PSA was assessed every 21 days and radiologic response was assessed every 3 cycles. Secondary endpoints included overall survival (OS), correlation of TTP and PSA response, with markers such as phopho mTOR, pAKT, p70S6 and circulating tumor cells (CTC). Results: 26 patients (pts) enrolled, including 8 African Americans, and accrual is complete. Median age was 69 years (range 54-86). Median pretherapy PSA was 190 ng/ml (range 13 - 2174). 18 pts (69%) had bone pain. Gleason score was > 8 in 18 pts. 19 pts had measurable disease of which 15 had MD progression, 18 had bone scan progression, and 2 had PSA-only progression. 124 cycles have been administered; median 3 cycles (range 1 - 16). The predominant grade 3 or 4 toxicities were thrombocytopenia in 8 pts, pulmonary embolism in 2 and neutropenia in 3. No treatment related deaths occurred. Of 26 pts who are response evaluable, 4 (15%) had a > 30% PSA decline and 1 had a >90% PSA decline. Of 19 pts with MD, 8 had stable disease and no objective responses were observed. The median TTP and OS were 2.5 months (90% CI: 1.8 - 4.3), and 12.5 months (90% CI: 6.7 - 16.1), respectively. Correlative studies including pharmacokinetic and pharmacodynamic evaluations are ongoing, and will be reported. Conclusions: The combination was tolerable but revealed modest clinical efficacy. Biomarker evaluation may help identify a subset likely to benefit from mTOR inhibition strategy in mCRPC. Clinical trial information: NCT01051570.