bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of toxicity, efficacy, and dose modifications in obese and non-obese patients receiving modified FOLFOX6 (mFOLFOX) for metastatic colorectal cancer (mCRC).
Authors: Wojenski Daniel Jerzy , Finnes Heidi D. , Dierkhising Ross A. , McCullough Kristen Beth , Alberts Steven R.
Published: February 2017

572

Background: There is limited data regarding chemotherapy dosing in obese mCRC patients. Methods: A retrospective, single institution, cohort study of mCRC patients receiving mFOLFOX6 (fluorouracil (5-FU) bolus omitted) was conducted between January 2002 and January 2011. Patients were stratified into: obese (BMI > 30) full dose, obese dose reduced (oxaliplatin (OX) and/or 5-FU), non-obese (BMI 18-29.9) full dose, and non-obese dose reduced. The primary endpoint was incidence of grade 3/4 myelosuppression within the first 12 wks of therapy. Secondary endpoints included incidence of any grade diarrhea and neuropathy, progression free (PFS) and overall survival (OS). Results: Of the 236 patients (72 obese, 164 non-obese), 15 obese and 37 non-obese received a dose reduction. Grade 3/4 myelosuppression occurred in 0 obese OX dose reduced, 3 (7.5%) obese full dose, 1 (8.3%) non-obese dose reduced, and 7 (7.8%) non-obese full dose patients (p=0.93). Grade 3/4 myelosuppression occurred in 0 obese 5-FU dose reduced, 3 (7.5%) obese full dose, 2 (12.5%) non-obese dose reduced, and 6 (7%) non-obese full dose patients (p=0.8). There were no statistically significant differences in the incidence of neuropathy or diarrhea between groups. PFS was longer in OX full dose patients (obese dose reduced, 8.8 mos; obese full dose, 10 mos; non-obese dose reduced, 3.7 mos; non-obese full dose, 10.4 mos; p=0.0094). No difference in PFS was found with 5-FU dosing (p=0.0615). OS favored OX full dose patients (obese dose reduced, 1.6 yrs; obese full dose, 2.4 yrs; non-obese dose reduced, 0.7 yrs; non-obese full dose, 2 yrs; p=0.0006) and 5-FU full dose patients (obese dose reduced, 1.6 yrs; obese full dose, 2.2 yrs; non-obese dose reduced, 1.6 yrs; non-obese full dose, 1.9 yrs; p=0.0287). Conclusions: There is no difference in the incidence of grade 3/4 myelosuppression, diarrhea or neuropathy in obese versus non-obese patients, dose reduced or not. OX dose reductions were associated with reduced PFS and OS. 5-FU dose reductions were associated with reduced OS. Our study supports ASCO recommendations against dose reductions in obese patients receiving chemotherapy.
A prospective study of XELOX plus bevacizumab as first-line therapy in Japanese patients with metastatic colorectal cancer (KSCC0902).
Authors: Takeuchi Masaaki , Ogata Yutaka , Tanaka Takaho , Kaibara Atsushi , Emi Yasunori , Saeki Hiroshi , Oki Eiji , Sadanaga Noriaki , Kusumoto Tetsuya , Touyama Tetsuo , Matsushita Hiroo , Shimokawa Mototugu , Baba Hideo , Shirouzu Kazuo , Maehara Yoshihiko ,   Kyushu Study Group of Clinical Cancer
Published: February 2017

583

Background: XELOX plus bevacizumab (Bev) is one of the standard therapies for metastatic colorectal cancer (mCRC). However there was no clinical practice date in Japan. This study was designed to evaluate the efficacy and safety of XELOX plus Bev in the clinical practice in Japanese mCRC patients (pts) including the elderly. Methods: The study design was multicenter, single-arm, open-label prospective study. The major inclusion criteria were previously untreated mCRC; presence of measurable lesions; age 20 years; ECOG performance status (PS) 0–2; and adequate organ function. Pts received Bev 7.5 mg/kg d1 and XELOX (oxaliplatin 130 mg/m2 d1 plus capecitabine 1,000 mg/m2 bid d1-14) q3w. This schedule was repeated until unacceptable toxicity or disease progression occurred. The primary endpoint was RECIST-confirmed objective response rate (ORR). A sample size of 41 was planned for a threshold ORR of 30% and expected value of 50%, with one-sided alpha of 0.05 and beta of approximately 0.2. Results: Of the 47 pts (male/female, 29/18; median age, 66 years (range 38-81); PS 0/1/2, 40/5/2) enrolled from May 2010 to Mar 2011. One patient did not fulfill the eligibility criteria. 46 pts were assessed for response; CR 1 pts, PR 23 pts, SD 15 pts, PD 2 pts, and NE 5 pts. The confirmed ORR was 52.2% (90% CI, 39.2-65.0%). The response rate across all time points without confirmation was 67.4% (95% CI, 52.0-80.5%). Median PFS and OS have not yet been reached. The most common grade 3/4 adverse events were anorexia 12.8%, neutropenia 10.6%, fatigue 8.5%, hypertension 4.3%, thrombocytopenia 4.3%, hand-foot syndrome 2.1% and bleeding 2.1%. Grade 3/4 peripheral neuropathy did not occur. Conclusions: First-line treatment of XELOX + Bev showed a promising response rate and an acceptable tolerability profile in the clinical practice in Japanese mCRC pts including the elderly. Clinical trial information: UMIN000003915.
Final results of RTOG 0246: A phase II study of selective surgical resection for locoregionally advanced esophageal cancer treated with a paclitaxel-based chemoradiation regimen.
Authors: Swisher Stephen , Moughan Jennifer , Komaki Ritsuko , Ajani Jaffer A. , Wu Tsung-Teh , Hofstetter Wayne Lewis , Konski Andre A. , Willett Christopher
Published: February 2017

7

Background: The organ preserving strategy of selective esophageal resection after definitive chemoradiation was evaluated in a multi-center, prospective Phase II trial. Methods: Treatment involved induction chemotherapy with 5-FU (650 mg/mg2/d), cisplatin (15 mg/mg2/d) and paclitaxel (200 mg/mg2/d) for 2 cycles followed by concurrent chemoradiation with 50.4 Gy (1.8 Gy/fx) and daily 5-FU (300 mg/mg2/d) with cisplatin (15 mg/mg2/d) over the first 5 days. Following definitive chemoradiation, pts were evaluated for residual locoregional disease with chest and abdominal CT scans, EUS and optional PET scans. If there was no suspected residual disease patients were observed and monitored serially for recurrent disease at 3 mos x 2, 6 mos x 3 and then yrly. Esophageal resection was considered only for pts with suspected residual or recurrent locoregional esophageal cancer that did not have systemic disease. Results: 43 pts from Sept 2003 to March 2006 with non-metastatic resectable esophageal cancer were entered from 19 sites to RTOG 0246. 41 pts were eligible for analysis. 29 pts (73%) were adenocarcinoma histology with pretreatment clinical stage T3 or greater in 31 pts (76%) and N1 in 29 pts (71%). Following induction chemotherapy and chemoradiation 3 pts (7.3%) died of treatment related deaths and 1 pt died of disease progression. 21 pts (51%) underwent surgical resection following chemoradiation because of suspected residual disease 17 pts (41%), pt choice (1) or recurrent locoregional disease 3 pts (7%). 1 pt died postoperatively from esophageal anastomotic leak. 11 pts (27%) are alive and free of disease 70 to 90 months after chemoradiation, of which 5 (12%) did not have esophagectomy. With a median follow-up of 6.7 yrs (for 16 alive pts), the estimated overall 2.5 and 5-year survival rates (95% CI) are 46.3% (30.7%-60.6%) and 36.6% (22.3%-51.0%). Conclusions: The long-term results from this multi-center, prospective Phase II trial demonstrates the efficacy of a selective surgical resection approach following definitive chemoradiation in a predominantly adenocarcinoma population of locoregionally advanced esophageal cancer. Clinical trial information: NCT00081289.
Comparative outcomes of oncologic therapy in gastric extranodal marginal zone (MALT) lymphoma: Analysis of the Surveillance, Epidemiology and End Results (SEER)-Medicare database.
Authors: Olszewski Adam J.
Published: February 2017

75

Background: Therapy for H. pylori (HPy)-negative or recurrent gastric MALT lymphoma is largely based on single-arm trials. The aim of this observational study was to compare outcomes after surgery, radiation (XRT) or chemotherapy (CT) in the SEER-Medicare dataset. Methods: Gastric MALT lymphoma cases diagnosed between 1997 and 2007 were selected, excluding patients without adequate Medicare coverage at diagnosis or follow up. Outcomes of XRT and CT were compared in stage IE group balanced by a propensity score. Flexible parametric models were used to study overall (OS) and lymphoma-specific survival (LSS). Treatments were evaluated with competing risk models, reporting hazard ratios (HR) and 95% confidence intervals (95%CI). Results: Among 1134 patients (median age: 77 years, median follow-up data: 4.3 years), 50% had no recorded oncologic treatment, 5% underwent surgery, 21% XRT and 24% CT as initial therapy, at a median of 3.4 months from diagnosis. HPyinfection was recorded in 19%. Oncologic therapy was more frequent in patients who were younger, diagnosed after 2000, with stage >IE and no poor performance status (PS) indicator. Worse LSS was associated with increasing age, male sex, poor PS, gastrointestinal hemorrhage/perforation, stage >IE, B-symptoms, being widowed or prior malignancy. In the 347 stage IE patients who received XRT or CT within 2 years of diagnosis, XRT alone as initial therapy was associated with better CSS than CT (HR 0.27, 95%CI 0.13-0.55, P<0.001). OS did not differ. Among the 321 patients treated with CT, 45% received rituximab (R) alone, 43% cyclophosphamide-based and 10% fludarabine-based regimens. The median OS after CT was 5.8 years without significant difference between these groups. Compared with patients receiving R alone, LSS was worse for those treated with CT alone (HR=2.31, 95%CI 1.2-4.26, P=.007), but did not significantly differ for those treated with R+CT (HR=1.63, 95%CI 0.84-31.17, P=0.15). Conclusions: XRT may be a preferable choice in elderly patients with stage IE gastric MALT lymphoma. In those requiring CT, addition of CT to rituximab alone is not associated with improved LSS.
Association of trimodality therapy (TMT) with rate of local-regional relapse and rare luminal-only relapse for patients with esophageal and esophagogastric junction (E-EGJ) cancer: Implications for the surveillance strategy.
Authors: Sudo Kazuki , Taketa Takashi , Correa Arlene M. , Campagna Maria-Claudia , Wadhwa Roopma , Blum Mariela A. , Komaki Ritsuko , Lee Jeffrey H. , Bhutani Manoop S. , Weston Brian , Liao Zhongxing X. , Rice David C. , Swisher Stephen , Hofstetter Wayne Lewis , Ajani Jaffer A.
Published: February 2017

79

Background: For local-regional E-EGJ cancer patients, the preferred therapy is chemoradiation (CTRT) followed by surgery (TMT). Following TMT, esophagogastroduodenoscopy (EGD) and imaging studies are routinely performed but the literature lacks guidance for an evidence-based surveillance strategy. Methods: Between 2000 and 2010, 579 patients with local-regional E-EGJ cancer underwent TMT. We reviewed the patterns of relapse over time. Local-regional relapse was classified as regional or luminal-only. Overall survival was estimated by the Kaplan-Meier method. Results: For 579 patients, the median follow-up time was 57.4 months (95% confidence interval [CI]: 51.5-63.3 months). First relapses were as follows: 199 patients (34.4%) with distant metastases and 33 (5.7%) with local-regional relapse (of these only 10 [or 1.7% of 579] had a luminal-only relapse). 3 out of 33 patients underwent salvage surgery and survived >2 years from relapse. Sixteen out of 33 patients received CTRT and only 4 survived >2 years. Therefore, 7 (21% of patients with local-regional relapse or 1.2% of 579 patients) survived >2 years. For the 33 patients with local-regional relapse, the median overall survival from relapse was 15.3 months (95% CI: 11.0-19.6). Conclusions: After TMT therapy, local-regional relapses are uncommon (<6%) and luminal-only relapses are even rare (<2%). 91% of local-regional relapses occur within 3 years of surgery. Only 7 (1.2% of 579) patients survived > 2 years despite therapy. These data can contribute to an evidence-based surveillance strategy for E-EGJ cancer patients after TMT. Supported by UTMDACC and generous donors.
IMAGE, a randomized phase Ib/II study of elisidepsin (E) as a single agent in pretreated advanced gastroesophageal (GE) cancer.
Authors: Salazar Ramon , Metges Jean Philippe , Anthoney David Alan , Laus Gianluca , Alsina Maqueda Maria , Goncalves Anthony , Montagut Clara , Brown Jennifer , Gunzer Katharina , Szyldergemajn Sergio A. , Petty Russell D.
Published: February 2017

92

Background: E is a new marine compound with broad in vitro/in vivo antitumor activity. Low μM concentrations lead to cell-death through membrane permeabilization. E has shown evidence of activity in pre-treated GE patients (pts) in phase I trials. Methods: The primary objective was to determine the tolerability and efficacy of E in pts with GE cancer after 1-2 prior chemotherapy (CT) lines. Initially, dose was optimized (Phase Ib) in two different schedules: a fixed flat dose (FD) of intravenous (i.v) E (8 and 10 mg), in 24h, biweekly (Arm A) and i.v E (3.0 and 3.75mg), in 3h, weekly (Arm B). After dose optimization patients were included and stratified by histology to each optimal dose (Phase II) to determine the rate of progression-free survival at week 16 ± 1 (PFS4) in an intention to treat analysis. If at least two out of 15 pts reached PFS4, recruitment would continue to a maximum of 40 pts per arm. Results: A total of 45 pts were recruited, 12 pts into Phase Ib (Arm A/B: 6/6 pts) and 33 pts into Phase II (Arm A/B: 15/18 pts). Median age was 60 years (35–81 years), 39 were males and ECOG PS was 1 in 75% of pts. Tumour sites were gastric (32% pts), esophageal (39% pts) and esophago-gastric junction (30% pts). Ninety percent of pts had metastatic disease, 31.8% of which had liver metastasis; 55% of pts had two prior lines of CT . No DLTs occurred during the first cycle in the Phase Ib. The optimal dose for Arm A was 10 mg FD, 24h, biweekly; the optimal dose for Arm B was 3.75mg FD, 3h, weekly. Two patients reached PFS4 in Phase Ib (Arm A). Only one patient reached PFS4 in Phase II (Arm A). No objective responses were observed. Therefore, protocol criteria for further recruitment were not met. The safety profile showed grade 1-2 toxicity pruritus (29.5%), nausea (15.9%), vomiting (6.8%) and fatigue (25%). Grade 3-4 toxicity consisted of asymptomatic reversible liver enzyme increases in 20.5% of patients. Conclusions: E is a very tolerable drug with a unique mechanism of action. In the current setting of non-stratified advanced GE patients, E has insufficient antitumor activity to warrant further investigation. Clinical trial information: 2010-020325-40.
SCOPE 1: A phase II/III trial of chemoradiotherapy in esophageal cancer plus or minus cetuximab.
Authors: Crosby Thomas , Hurt Chris , Falk Stephen , Gollins Simon , Mukherjee Somnath , Staffurth John , Ray Ruby , Bridgewater John A. , Geh Ian , Cunningham David , Maughan Tim , Griffiths Gareth
Published: February 2017

LBA3

Background: SCOPE 1 is the largest multicentre trial of definitive chemo-radiotherapy (dCRT) in localised oesophageal cancer (LOC) in the UK and investigated adding cetuximab to standard cisplatin and fluoropyrimidine treatment. Methods: Patients in this phase II/III trial had LOC and been selected to receive dCRT and were randomised to receive cisplatin 60mg/m2 D1 and capecitabine 625mg/m2 daily D1-21 for 4 cycles, cycles 3 and 4 given concurrently with 50Gy in 25 fractions of RT with or without cetuximab 400mg/m2 D1 followed by 250mg/m2weekly. Recruitment continued from 02/2008 until analysis of the phase II endpoint (24 week failure free survival in the cetuximab arm, overall sample size 180: p1=0.60 and p2=0.75, α=0.05, β=0.9) in 01/2012. The phase II endpoint was not met and the IDMC recommended trial closure on the basis of futility. Results: 258 patients were recruited. Median age 67; morphology(%) SCC:ACA 73:27; tumour location(%) upper:middle:lower 11:45:44; stage(%) I:II:III 3:37:60; reason not for surgery(%) disease extent:patient choice:comorbidity 47:38:16. Patients who received cetuximab had: higher non-haematologic toxicity (78 vs 62.8%, p=0.004; primarily dermatological (22 vs 4%) and metabolic (24% vs 11%)); a lower rate of completion of standard therapy (capecitabine 69 vs 85%, p=0.002; cisplatin 77 vs 90%, p=0.005 and radiotherapy (75 vs 86%, p=0.027); reduced failure free survival at 24 weeks (66 vs 77%), median survival (22 vs 25 months, log rank p=0.043) and 2-yr survival (41 vs 56%). Conclusions: In SCOPE 1, disease control and survival in the standard dCRT arm is superior to any previous published multi-centre studies. The use of cetuximab was associated with greater toxicity, lower doses of dCRT and worse survival. Cetuximab cannot be recommended in combination with standard dCRT for unselected patients with oesophageal cancer. Strategies to build on these results should incorporate biomarker driven treatment and latest radiotherapy technologies to safely intensify treatment. This trial was sponsored by Velindre NHS Trust, conducted by Wales Cancer Trials Unit at Cardiff University and supported by CR-UK [grant number C20177/A7256]. Clinical trial information: 47718479.
COUGAR-02: A randomized phase III study of docetaxel versus active symptom control in advanced esophagogastric adenocarcinoma.
Authors: Ford Hugo , Marshall Andrea , Wadsley Jonathan , Coxon Fareeda Y. , Mansoor Wasat , Bridgewater John A. , Madhusudan Srinivasan , Falk Stephen , Middleton Gary William , Swinson Daniel , Chau Ian , Thompson Joyce , Blazeby Jane M. , Cunningham David , Kareclas Paula , Dunn Janet A. ,   National Cancer Research Institute, Upper GI Clinical Studies Group
Published: February 2017

LBA4

Background: Survival in patients who relapse after first-line chemotherapy for advanced esophagogastric adenocarcinoma (OGC) is poor though recently randomized trials have suggested a small survival benefit for second-line chemotherapy with taxanes or irinotecan. There is very little data on quality of life or survival, particularly in patients who progress shortly after first-line therapy. Methods: COUGAR-02 was a multicenter open-label, randomized controlled phase III trial for patients with locally advanced or metastatic OGC of performance status (PS) 0-2 who had progressed within 6 months of previous platinum/fluoropyrimidine (PF) chemotherapy (CT). Patients were randomized (1:1) to receive either docetaxel 75mg/m2every 3 weeks for up to 6 cycles or active symptom control (ASC), which could include any treatment thought by the treating clinician to be appropriate for the management of symptoms including radiotherapy, steroids and supportive medications. The primary endpoint was overall survival. Secondary endpoints were response rate, toxicity, health related quality of life (HRQL) and healthcare resource use. Results: Between April 2008 and April 2012, 168 patients were recruited (84 patients in each arm). Median age was 65 years (range 28-84), 81% were male. PS at randomisation was 0 for 27%, 1 for 57% and 2 for 15%. Site of disease was stomach in 46%, esophagogastric junction in 34% and esophagus in 20%. 86% had metastatic disease. 43% progressed during previous CT, 28% progressed within 3 months of end of previous CT and 29% progressed between 3 and 6 months. 19 (23%) patients completed 6 CT cycles (median 3 cycles per patient). The main reasons for not completing treatment were progression and toxicity. Docetaxel significantly improved overall survival over ASC alone (median 5.2 months (95% CI 4.1-5.9 months) for docetaxel; 3.6 months (95% CI 3.3-4.4 months) for ASC, HR=0.67 (95% CI 0.49-0.92); p=0.01). 7% had a partial response and 46% had stable disease after CT. 21% on docetaxel had grade 4 toxicity. Conclusions: The addition of docetaxel to ASC significantly improved overall survival. Docetaxel can be considered a standard of care in this setting. Clinical trial information: 13366390.
Effect of inhibition of the PI3K/Akt/mTOR pathway on AR splicing and downstream targets.
Authors: Liu XiaoMei , Gomez-Pinillos Alejandro , Shah Payal , Lavilla Carmencita , Ferrari Anna C.
Published: February 2017

101

Background: Increased androgen receptor (AR) and PI3K/Akt/mTOR signaling drive androgen-independent (AI) prostate cancer (PC) progression. AR splice variants (SV) lacking the ligand-binding domain activate ligand-independent transcriptional programs that support castration resistant proliferation and survival. Treatment of the androgen-dependent PTEN null LNCaP (AD-cells), its AI derivative (AI-cells) and wt PTEN RV1 cells with the dual PI3K/mTOR inhibitor BEZ235 (E) combined with the histone deacetylase inhibitor Panobinostat (PAN) induced synergistic growth inhibition and cell death in vitro and in vivo. The effect of these treatments on AR splicing is unknown. Methods: LNCaP AD, AI and RV1 cells were treated with PAN 20nM, E 350nM, rapamycin (Rapa) 20nM and PI3Ki BKM120 (K) 1.5µM for 24h. Total (t) AR, SV’s and AR targets mRNA were measured by qtPCR and western. RV1 xenografts received 3 weeks E 35mg/kg/d or PAN 10mg/kg/QOD or PAN+E. Results: Baseline levels of tAR mRNA in AI were higher than AD and RV1 cells while SV1, SV7 and SV5-7 were higher in RV1 than AD and AI cells. Treatment with E, Rapa and K increased both tAR and SV’s mRNA’s and AR and PSA proteins. In contrast, treatment with PAN reduced tAR and SV’s levels in AD and AI with no effect on RV1. PAN reduced the induction of tAR by Rapa or K in AD, AI and RV1 but did not abrogate induction of SV’s. PAN inhibition was sufficient to abrogate the effect of E and decrease tAR and SV’s levels as well as AR protein and AR canonical and non-canonical targets (PSA, TMPRSS2 and UBE2C) and PSA protein below baseline levels in all cells treated with PAN+E. Similarly, RV1 tumors treated with E had a 50% increase in tAR and 20% in SV5-7 but no induction of CDK1 or UBE2C and a 35% reduction in PSA while RV1 tumors treated with PAN+E showed 40% reduction in both SV’s 1 and 7 and downstream targets CDK1 and UBE2C. Conclusions: Inhibition of PI3K/mTOR with E increases overall levels of AR transcription that is more pronounced on SV’s and uncouples AR’s transcriptional activity on canonical downstream targets in vivo. PAN can abrogate the stimulation of E by decreasing both SV’s expression and AR transcriptional activity on non-canonical targets. These effects may underlie their synergistic growth inhibition.
A phase II trial of temsirolimus in men with castration-resistant metastatic prostate cancer.
Authors: Armstrong Andrew J. , Shen Tong , Halabi Susan , Kemeny Gabor , Bitting Rhonda Lynn , Kartcheske Patricia , Embree Elizabeth , Morris Karla , Winters Carolyn , Jaffe Tracy , Fleming Mark T. , George Daniel J.
Published: February 2017

105

Background: PTEN loss is common in advanced prostate cancer, leading to constitutive activation of the PI3 Kinase pathway. Temsirolimus blocks mTOR/TORC1, a key signaling node in this pathway; its activity in men with advanced castration-resistant metastatic prostate cancer is unknown. Methods: We conducted a single arm trial of weekly IV temsirolimus in men with chemorefractory metastatic CRPC who had >=5 circulating tumor cells (CTCs) at baseline (Cellsearch). The primary endpoint was change in CTCs at 8 weeks; secondary endpoints were composite progression-free survival (excluding PSA), PSA and radiographic response rates, safety, and survival. At PSA/CTC progression, an anti-androgen could be added while continuing temsirolimus. Results: Eleven patients were accrued out of a planned 20; the trial was stopped prematurely due to lack of efficacy/feasibility. Median age was 61, with 55% African-Americans and 36% Caucasians. Median baseline PSA was 390 ng/dl, median baseline CTC was 14 cells, 50% had significant pain, and 63% had >2 prior chemotherapy regimens. The median decline in CTC enumeration at week 8 was 48% and three patients experienced a decline in CTCs to <5. However, 73% of men had persistently unfavorable CTCs (>=5) over time and only 1 patient had a >=30% PSA decline. Median PFS was 1.9 months (95% CI 0.9-3.1) and median OS was 8.8 months (95% CI 3.1-15.6). Toxicities included grade 4 hypophosphatemia and grade 4 CNS hemorrhage, and frequent grade 3 fatigue, anemia, stomatitis, hypokalemia, weakness, and hyperglycemia. Persistently high N-cadherin expression on longitudinal CTC analysis was observed as a marker of epithelial plasticity and treatment resistance. Conclusions: Temsirolimus lacked sufficient clinical activity in men with metastatic CRPC, despite transient CTC improvements in some men. Future studies should focus on combination approaches or novel PI3K pathway inhibitors. Clinical trial information: NCT00887640.
Activity of gemcitabine-oxalipaltin (GemOx) plus prednisolone in patients with castration-resistant prostate cancer (CRPC) for whom docetaxel-based chemotherapy failed.
Authors: Lee Jae-Lyun , Kim Yesul , Ahn Jin-Hee , Choi MeeKyung , Hong Seung-Woo , Jeong In Gab , Song Cheryn , Hong Bum-Sik , Hong Jun Hyuk , Kim Choung-Soo , Ahn Hanjong
Published: February 2017

108

Background: We assessed the cytotoxic effects of the gemcitabine in combination with oxaliplatin (GemOx) in prostate cancer cell lines and evaluated the efficacy and safety of GemOx in patients with metastatic castration-resistant prostate cancer (CRPC) who failed docetaxel based chemotherapy. Methods: Gemcitabine and oxaliplatin were preclinically tested for their cytotoxic activity in LNCaP, PC3 and DU145 cell lines. The combined drug effects were evaluated using the Chou and Taladay analysis. Clinically, patients with CRPC who failed prior docetaxel chemotherapy were treated with gemcitabine 1,000 mg/m2 at fixed-dose rate (10 mg/m2/min) and oxaliplatin 100 mg/m2 intravenously every 2 weeks and prednisolone 5 mg orally twice daily. Unless disease progression or intolerability develops, treatment could be continued until 12 cycles. Primary endpoint was PSA response rate (PCWG 1.0 criteria). Results: The IC50of gemcitabine and oxaliplatin were, respectively, 1.25 μM and 0.69 μM for LNCaP cells; 50.00+ μM and 12.81 μM for PC3 cells; and 11.23 μM and 11.04 μM for DU145 cells. The GemOx combination displayed synergistic effects in all 3 cell lines. In phase II study, 31 patients were accrued. At the time of this analysis 7 patients were still continuing treatment. The median age was 67 years (range 57 ~ 81) and the median dose of docetaxel exposure was 525 mg/m2. A total of 231 cycles administered with a median of 9 cycles per patient. PSA responses were observed in 52% (95% CI, 34~69) and partial responses were observed in 7 of 10 patients with measurable disease. Out of 23 patients, 10 patients achieved pain response (44%). With a median FU duration of 8.0 months, the median time to PSA progression was 6.4 months (95% CI, 3.5~9.2). Peripheral neuropathy developed in 78% of patients but remained of grade 1 ~2 intensities. Frequently observed grade 3 or 4 toxicities were neutropenia (10%), thrombocytopenia (10%), anemia (3%), and diarrhea (3%). Conclusions: GemOx is active and well tolerated in patients with CPRC after docetaxel failure and deserves further investigation in this setting (NCT 01487720). Clinical trial information: NCT01487720.
Study of the impact of Charlson comorbidity index and hypertension on survival in patients with metastatic castration-resistant prostate cancer.
Authors: Goyal Jatinder , Pond Gregory Russell , Galsky Matt D. , Hendricks Ryan , Small Alexander C. , Tsao Che-Kai , Sonpavde Guru
Published: February 2017

111

Background: Clinical and laboratory factors, i.e. visceral metastasis, anemia, LDH, PSA, PSA-doubling time, bone scan progression, pain, performance status (PS), are recognized to be prognostic factors for overall survival (OS) in metastatic castration resistant prostate cancer (mCRPC). We sought to determine if the Charlson comorbidity Index (CCI) and hypertension (HTN) provide prognostic information independent of these known factors. Methods: We retrospectively evaluated 221 patients with mCRPC treated with docetaxel plus prednisone (DP) combined with AT-101 (bcl-2 antagonist) or placebo on a randomized phase II trial. Both arms of the trial were combined since no differences in outcomes or toxicities were observed. Wilcoxon rank sum test and Fisher’s exact tests were used to compare data by comorbidity groups (CCI as a continuous variable, CCI = 6 vs. CCI ≥7 and HTN vs. no HTN). Cox regression analysis was done to identify whether CCI or HTN independently predicted OS after adjusting for trial stratification factors (pain, performance status), nomogram, risk-groups and PCWG-2 clinical sub-types. Results: CCI was 6 in 116 patients (52.7%) whereas it was 7 in 70 (31.8%), 8 in 23 (10.5%), 9 in (1.8%) and 10 in 7 patients (3.2%) respectively. HTN was present in 107 (48.6%) patients. Patients with HTN had increased CCI (mean CCI 7.0 vs. 6.43, p < 0.001). Patients with CCI of ≥7 were older and exhibited worse ECOG-PS and anemia than patients with CCI of 6 (p<0.05). CCI was not found to be independently predictive of OS on univariable and multivariable analyses. HTN alone or in combination with CCI was borderline significantly associated with OS (p~0.08) on both univariable and multivariable analyses. Conclusions: CCI did not predict OS independent of known prognostic factors in mCRPC. Age, performance status and anemia may adequately capture comorbidities in the context of mCRPC, given their association with higher CCI. Further analysis of HTN in a larger dataset may be warranted given its borderline independent association with OS.
A multicenter population-based experience with abiraterone acetate (AA) in patients with metastatic castration resistant prostate cancer (mCRPC).
Authors: Clayton Ravinder , Heng Daniel Yick Chin , Wu Jackson S.Y. , Zielinski Rob , North Scott A. , Emmenegger Urban , Hotte Sebastien J. , Al-Shamsi Humaid Obaid , Chen Leo , Eigl Bernhard J.
Published: February 2017

113

Background: The COU-AA-301 trial showed that abiraterone (AA), an oral cytochrome p450 CYP17 inhibitor, improved survival for men with mCRPC progressing after docetaxel. AA is now a standard treatment in this setting. In order to better understand the non-clinical trial experience with AA, we undertook a multicenter retrospective analysis of patients (pts) treated with AA. Methods: Consecutive pts with mCRPC from 5 tertiary cancer centers in Canada who had received AA post-docetaxel were identified using centralized pharmacy records for each center. Pts who received AA for approved indications or within expanded access programs were included. Demographics, prognostic factors, treatment outcomes and toxicity profiles were collected. Results: One hundred and eighty seven pts, who initiated AA between Jan-2011 and Jun-2012, were included. Median age at diagnosis and AA start was 65 and 73 years. 73 (39%) pts had M1 disease at diagnosis. ECOG 0/1/2/3 was noted in 17/96/39/8 pts. Median PSA at AA start was 132 with a median PSAdt of 2.8 months. 54 (29%) pts received more than 1 prior course of chemotherapy. Median follow up was 20.5 months. Median survival from start of AA was 9.3 months (95% CI, 7.9-12.6). Regional results were: Alberta 14 months (95% CI, 13-18); BC 8.2 months (95% CI, 5.4-9.6); and Ontario 7.3 months (95% CI, 5.7-8.1). Median overall survival from date of mCRPC was 36 months (95% CI, 29-40); in Alberta this was 39 months (95% CI, 29-47); BC 26 months (95% CI, 18-41); and Ontario 33 months (95% CI, 25-41). AA was well tolerated with toxicities comparable to those seen in the trial population, with anemia and fatigue being the most common reported toxicity. Conclusions: This is one of the largest cohorts of men with mCRPC treated with AA in the non-clinical trial setting. Treatment outcomes corroborate with results reported in clinical trials, supporting the effectiveness of AA in an unselected population. A difference in survival outcomes between the different cancer regions can be attributed to differences in time to AA start. Future analyses to evaluate potential prognostic/predictive factors will be undertaken.
Epigenetic field effect markers as indicative of occult high-grade prostate cancer.
Authors: Gaston Sandra Marlene , Hayek Jihad E , Otto Gaetan , Yen James , Bigley Joseph , Van Neste Leander , Kearney Gary P
Published: February 2017

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Background: Epigenetic changes through DNA methylation can serve as biomarkers for the presence of prostate cancer (PCa). Gene methylation in histologically benign tissue adjacent to PCa can provide “field effect" biomarkers to detect cancer missed due to sampling errors. Such errors may also result in underestimates of PCa stage or grade, complicating decisions about Active Surveillance. We previously showed increased field effect methylation in GS 7 over GS 6 subjects in a small patient cohort. Here, established methylation markers of PCa (GSTP1, APC and RASSF1) were tested in a larger cohort to compare histologically benign biopsy cores from patients diagnosed with no cancer, low volume GS 6 cancer and GS 7 cancer. The objective was to confirm that epigenetic field effects may be useful for detecting occult high grade malignancies in diagnostic and prognostic settings. Methods: DNA was extracted from prostate biopsy tissue prints and used for multiplex methylation-specific PCR (MSP) assays of the 3 genes. All testing was done blinded. Each of 12 tissue cores was tested from a series of 76 biopsy patients: 34 diagnosed with GS 6 PCa, 22 with GS 7 PCa, and 20 no-cancer controls. Results: In 19 of the 22 GS 7 cases (86%), epigenetic markers were positive for field effects in one or more adjacent benign cores; 12 (54%) were positive for all 3 epigenetic markers. In contrast, only 9 of 34 cases (26%) GS 6 cases were positive for all 3 markers. We again observed that robust marker expression in histologically benign cores from cases diagnosed with low volume GS 6 PCa was associated with higher grade cancer at radical prostatectomy (upgrading). APC showed the best performance as a single marker “field effect” test for adjacent high grade PCa. Conclusions: GSTP1, APC and/or RASSF1 gene promoter methylation was observed to be more prevalent in histologically benign cores from biopsy patients diagnosed with GS 7 PCa, as compared with low volume GS 6. This study confirms previous findings in a larger cohort of subjects that these “field effect” biomarkers can be useful for detecting cancer adjacent to histologically negative biopsies and may be indicative of occult aggressive PCa.
Patient-reported sexual and urinary function after open and robotic radical prostatectomy.
Authors: Klink Joseph C. , Li Jianbo , Klein Eric A. , Kaouk Jihad , Jones J. Stephen , Stephenson Andrew J.
Published: February 2017

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Background: Urinary continence (UC) and sexual function (SF) may be impacted differently after robotic-assisted laparoscopic (RALRP) versus open (ORP) radical prostatectomy. We compared UC and SF among patients treated by RALRP and ORP at a high-volume hospital who were enrolled in a prospective, longitudinal quality-of-life (QOL) protocol. Methods: Between 2007 and 2012, 516 patients treated by active surveillance, brachytherapy, cryotherapy, RALRP, and ORP were enrolled in a QOL protocol at our institution. The focus of this study is 361 patients who were treated by RALRP (N=190) and ORP (N=171). Functional outcomes were assessed at baseline and at 1, 3, 6, 12, and 24 months using a validated QOL instrument (Giesler RB et al. Qual Life Res 2000). SF was assessed by adding the scores from questions on the quality and frequency of erections. UC was assessed by adding the scores from three questions about the frequency and quantity of incontinence and pad usage. Wilcoxon rank sum test and linear regression multivariable analysis were used to assess SF and UC at each time point. Results: Treatment groups were similar in age, PSA, clinical stage, Gleason grade, BMI, baseline UC and SF scores and baseline PDE-5 inhibitor use (all P > 0.05), but the RALRP patients were slightly older (60 vs 61 years, p=0.04) and had larger prostates (38 vs 44 grams, p=0.001). On multivariate analysis, UC was worse in the RALRP cohort at 1 month (12.0 vs 10.9, P = 0.02), 3 months (9.9 vs 8.5, P = 0.01), and 6 months (8.1 vs 6.8, P=0.01) but was similar at 12 and 24 months (all P > 0.2). SF was similar between both RALRP and ORP at all time points (all P > 0.3). At 24 months, UC for RALRP and ORP was 7.1 vs. 6.4, respectively which was not significant in multivariable analysis (P = 0.5). Likewise, SF for RALRP and ORP was 5.3 vs. 6.2 (multivariable P = 0.9). On repeated measures analysis there was no difference between the groups in UC or SF (P=0.4 and 0.5, respectively). Conclusions: Prospectively collected, patient reported QOL endpoints for SF are similar after RALRP and ORP at all time points in a high-volume hospital. Final UC is similar between both techniques, although RALRP patients may experience a slightly slower return to continence.
Aflibercept versus placebo in combination with docetaxel/prednisone for first-line treatment of men with metastatic castration-resistant prostate cancer (mCRPC): Results from the multinational phase III trial (VENICE).
Authors: Tannock Ian , Fizazi Karim , Ivanov Sergei , Karlsson Camilla Thellenberg , Flechon Aude , Skoneczna Iwona Anna , Orlandi Francisco Jorquera , Gravis Gwenaelle , Matveev Vsevolod B. , Bavbek Sevil E. , Gil Thierry , Viana Luciano S. , Aren Osvaldo Rudy , Karyakin Oleg , Elliott Tony , Birtle Alison J. , Magherini Emmanuelle , Hatteville Laurence , Tombal Bertrand , Rosenthal Mark ,   The VENICE Investigators
Published: February 2017

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Background: Docetaxel/prednisone is standard first-line chemotherapy for mCRPC. Aflibercept (known as ziv-aflibercept in the US) is a recombinant human fusion protein that binds VEGF-A, VEGF-B and Placental Growth Factor (PlGF), thereby inhibiting angiogenesis. Methods: VENICE was a double-blind, randomized phase III study with overall survival (OS) as primary endpoint. Men with mCRPC, ECOG PS 0-2, adequate organ function and no prior cytotoxic therapy were treated with docetaxel (75 mg/m² iv q3w) and oral prednisone (5mg bid) and randomized double blind 1:1 to receive aflibercept (A) 6 mg/kg or placebo (Pbo), IV every 3 weeks. Pts were stratified by ECOG PS (0-1 vs 2). For final OS analysis, 873 deaths were required to detect a hazard ratio (HR) of 0.8 with 90% power (overall 2-sided α = 0.05). Results: From Aug 2007 to Feb 2010, 1224 patients (median age 68 yr, PS 0-1 96%) were randomized. Baseline characteristics were well balanced between arms. Median number of cycles was 8 (A) and 9 (Pbo). Median relative dose intensity was >0.93 for A, Pbo and docetaxel. At final cut-off, median follow-up was 35.4 mos and 873 pts had died. Results for primary and key secondary endpoints with confidence intervals are in the table. Higher incidence of all grade hypertension, stomatitis, appetite disorders, diarrhea, dehydration, epistaxis, dysphonia, cough, headache and infections was observed in the aflibercept arm. Conclusions: Aflibercept in combination with docetaxel/prednisone given as first line chemotherapy for mCRPC did not lead to a statistically significant improvement in OS and added toxicity. (NCT00519285 sponsored by Sanofi and Regeneron Pharmaceuticals, Inc.) Clinical trial information: NCT00519285. [Table: see text]
Real-world experience with sipuleucel-T in patients (pts) ≥80 years old with metastatic castration-resistant prostate cancer (mCRPC): Data from PROCEED.
Authors: Nabhan Chadi , Sartor A. Oliver , Cooperberg Matthew R. , Vacirca Jeffrey L. , Concepcion Raoul S. , Berry William R. , Dhawan Manish , Tutrone Ronald , Sandler Andrew , McCoy Candice , Whitmore James Boyd , Tyler Robert Claude , Higano Celestia S.
Published: February 2017

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Background: Sipuleucel-T is an autologous cellular immunotherapy indicated for asymptomatic or minimally symptomatic mCRPC based on data from the phase III IMPACT pivotal trial that showed a significant improvement in overall survival (OS) compared to control (HR: 0.78 [95% CI: 0.61, 0.98]; P=0.03; median OS difference 4.1 mos). Analysis of IMPACT demonstrated evidence of a positive sipuleucel-T treatment effect in men above and below the median age of 71. We sought to understand the disease characteristics and product parameters in pts ≥80 years (yrs) given the high prevalence of older men in the mCRPC pt population. Methods: PROCEED is an ongoing, multicenter (>190 sites), phase 4 registry enrolling pts receiving sipuleucel-T. Information on antigen presenting cell (APC) activation and total nucleated cell (TNC) count were obtained during product manufacture. Results: Of 560 subjects who completed sipuleucel-T treatment to date: 110 (20%) pts were ≥80 yrs-old. Disease characteristics in pts ≥80 yrs vs <80 yrs are detailed in the table below. Product parameters were similar between groups. Conclusions: Pts ≥80 exhibit similar product parameters compared with their younger counterparts. Future follow-up will explore OS and correlations with immune parameters in both groups. Clinical trial information: NCT01306890. [Table: see text]
Predictors and prognostic implication of pathologic fracture (PF), spinal cord compression (SCC), and bone surgery (BS) following diagnosis of metastatic prostate cancer (PCa).
Authors: Onukwugha Ebere , Yong Candice , Mullins C. Daniel , Seal Brian S. , Hussain Arif
Published: February 2017

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Background: Information is limited about the predictors of PF, SCC, or BS and their relationship with PCa mortality in older men diagnosed with metastatic PCa. Methods: We analyzed patients aged 66 or older from the linked Surveillance, Epidemiology, and End Results & Medicare (SEER-Medicare) database. Cases were diagnosed with M1 PCa between 2000 and 2007. Patients surviving at least 30 days post-diagnosis were identified and followed until death or censoring in December, 2009. Post-diagnosis occurrence of PF, SCC, and BS was identified using Medicare claims. (Multinomial) logistic and Cox proportional hazards regression models controlled for demographic characteristics, preventive service use, comorbidity status, and performance status proxies. Survival models were estimated in the full sample (FS) and in a propensity-score matched sample (PSMS). The survival requirement was relaxed and patients diagnosed with stage M1b were considered in sensitivity analyses. Results: Application of inclusion criteria resulted in 7,062 patients in FS (2,398 in PSMS). PCa-specific and all-cause mortality were 54% and 80% at a median (mean; min; max) follow up of 609 days (837; 30; 3,653). The average age for the sample was 78 yrs and 14% were non-Hispanic African American. The proportion with any event, SCC, PF, and BS were: 17%; 10%; 5%; 3%. Race, marital status, comorbid conditions, and health services use related to bone metastases were correlated with the likelihood of sustaining a PF, SCC, or BS, with differences based on the type of event. In the PCa mortality model the HR associated with each event was as follows using FS: [SCC] HR 1.12, 1.01 – 1.24; [PF] HR 1.14, 1.00 – 1.31; [BS] 0.61, 0.50 – 0.75. Results using PSMS were: [SCC] HR 1.04, 0.92 – 1.17; [PF] HR 1.11, 0.96 – 1.28; [BS] 0.58, 0.47 – 0.72. Relaxing the assumption of a minimum survival requirement did not change qualitative results. Conclusions: Patient demographics and clinical comorbid conditions correlate with the likelihood of sustaining PF, SCC or BS. Compared to fractures and spinal cord compression, the relationship between bone surgery and PCa-specific survival is more favorable.
Are PSA baseline levels an indicator for suitability of intermittent androgen deprivation in patients with PSA relapse after radical prostatectomy?
Authors: Tunn Ulf W. , Canepa Giorgio , Kienle Erika
Published: February 2017

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Background: Intermittent androgen deprivation (IAD) for prostate cancer patients is currently discussed as a treatment option to improve quality of life and to delay hormone resistance. So far only limited data are available indicating whether certain subgroups of patients with PSA relapse without local recurrence after radical prostatectomy are best suited for this therapy. Methods: In a prospective randomized phase III trial, men with unfavourable prognostic factors and a systemic PSA progression (PSA ≥ 1ng/ml) following an initial fall to < 0.5 ng/ml within 3 months after radical prostatectomy were enrolled. They underwent a 6-months androgen deprivation (AD) induction phase with a microencapsulated leuprorelin acetate 3-month depot formulation plus an overlapping antiandrogen to prevent tumor flare-up. Achieving a PSA level < 0.5 ng/ml, they were randomized to either an IAD treatment arm or to continuous AD. In the IAD arm, retreatment was started when PSA rose to ≥ 3 ng/ml. During Off-Treatment-Time (OTT) PSA and Testosterone were controlled on a monthly basis. Results: Analysis of the first IAD cycle, confined as induction phase + OTT, revealed two subgroups of patients with a cycle length ≤ 15 months (group 1) and ≥ 20 months (group 2) respectively. This was due to a significant difference in the time from testosterone normalization (≥ 2.3 ng/ml, TN) to an increased PSA-value ≥ 3 ng/ml. See Table. Conclusions: Our data show a significant (p=0.001) relationship of low PSA baseline levels to delayed biochemical PSA progression during OTT. Thus IAD might be most suitable for patients with low PSA baseline levels leading to a slow increase of PSA after TN during OTT, providing time to improve quality of life and delay potential hormone resistance. Further large scale studies will be necessary to confirm our findings. Clinical trial information: AP 06/95.[Table: see text]
Exploratory analysis of the visceral disease (VD) patient subset in COU-AA-301, a phase III study of abiraterone acetate (AA) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Goodman Oscar B. , Flaig Thomas W. , Molina Arturo , Mulders Peter , Suttmann Henrik , Li Jinhui , Kheoh Thian San , De Bono Johann Sebastian , Scher Howard I.
Published: February 2017

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Background: VD is a negative prognostic factor in mCRPC patients (pts) and may be less responsive to hormonal therapy. AA, a selective androgen biosynthesis inhibitor, inhibits androgen synthesis from adrenal and intratumoral sources. Improved overall survival (OS) with AA vs prednisone (P) was demonstrated in a randomized trial of pts with mCRPC post-docetaxel (D). Here we further assess the effect of AA on OS and other clinical outcomes in post-D mCRPC pts with VD (liver or lung, but not nodal-only metastases). Methods: In COU-AA-301, pts with mCRPC previously treated with D were randomized 2:1 to AA (1000 mg) + P (5 mg BID) (n=797) or placebo + P (n=398). The primary end point was OS. Data shown herein represent the updated analysis (775 events) of patients with (n=352) or without (n=843) VD. Results: The OS benefit of AA was similarly improved in patients with VD (4.6 m) and without VD (4.8 m) (Table). Treatment with AA led to significant 40% and 32% reductions in the risk of radiographic progression or death in patients with VD or without VD, respectively. Soft-tissue objective response rates were superior with AA in both groups. PSA response rates (50% reduction) were significantly improved by AA in both groups. Grade 3/4 adverse events (AEs) were similar in both groups. Hypertension, hypokalemia, and LFT abnormalities were observed with AA in pts with and without VD. Conclusions: AA has substantial anti-tumor activity and provides clinical benefit including improvements in OS and rPFS in post-D mCRPC pts with VD indicating it is a therapeutically active treatment option for CRPC pts. Safety/tolerability of AA in pts with VD was similar to that reported previously in mCRPC. Clinical trial information: NCT00638690. [Table: see text]