bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II study of bevacizumab and cetuximab as neoadjuvant treatment in locally advanced rectal cancer: A preliminary security report.
Authors: Elvira G. , Torrecillas L. , Cervantes G. , Erzao Valle Solis A. A.
Published: February 2017

627

Background: Concurrent chemoradiotherapy is the standard treatment in locally advanced rectal cancer. Bevacizumab and cetuximab are accepted today in the treatment of metastatic colorrectal cancer. We evaluate the activity and security of these drugs in the neoadyuvante setting.

Methods: Ten patients have been included so far. Treatment consists in a first phase with induction treatment with capecitabine 2,000 mg/m2 D1-14, oxaliplatin 130 mg/m2 and bevacizumab 7.5 mg/kg every 3 weeks for two cycles. In sequential form a second phase that consist in external beam radiation therapy that was given at 50.4 Gy in 28 sesions concurrently with capecitabine 1,300 mg/m2 /d continuous during radiotherapy with cetuximab 400 mg/m2 every two weeks in patients with k-ras wild type.

Results: 10 patients completed induction treatment and eight patients completed the concurrent phase. As of today, two patients are still on treatment. At this point, four patients have been operated; three patients are still waiting for surgery, and one avoided surgery. During induction treatment the main toxicity was disesthesias in eight patients, four patient presented grade 2 emesis, two presented grade 2 altered liver function test, two had grade 2 hand foot syndrome. One patient presented grade 3 hemorrhage. During the second phase, eight patients received cetuximab and presented rash grade 1-2, diarrhea grade 1 in five patients, emesis grade 1 in four patients, anemia grade 2 in two patients, proctitis grade 2 in four patients, and grade 3 in one patient. From four patients who were operated two presented complete pathological response and two have tumor persistence.

Conclusions: The combination of chemoradiation with bevacizumab and cetuximab seems to be secure with no increment in toxicity and those presented are acceptable and manageable.

No significant financial relationships to disclose.
Preoperative chemoradiation with S-1 plus oxaliplatin in patients with locally advanced rectal cancer: Results of a phase II study and the role of apparent diffusion coefficient (ADC) by diffusion-weighted magnetic resonance imaging (DW MRI) for prediction of pathologic responses.
Authors: Lee E. M. , Hong J. L. , Lee J. L. , Kim S. Y. , Park Y. S. , Kim J. H. , Yu C. S. , Kim J. C. , Kim A. Y. , Kim T. W.
Published: February 2017

629

Background: We conducted a phase II study of preoperative chemoradiation (CRT) with S-1, a novel oral fluoropyrimidine, plus oxaliplatin in patients (pts) with locally advanced rectal cancer. Tumor ADCs were measured by DW-MRI and were evaluated as a predictive marker for pathologic responses.

Methods: Radiotherapy was delivered to a total 50.4 Gy. The recommended doses were determined by a previous phase I study; oxaliplatin 50 mg/m2/week on D1, 8, 22 and 29, and S-1 80 mg/m2/day on D1-14 and D22-35. Total mesorectal excision was performed within 6 ± 2 weeks. Primary endpoint was pathologic complete response (pCR) rate. The value of tumor ADCs by DW-MRI was measured before and after CRT, and was correlated with pathologic responses after surgery.

Results: A total of 38 patients were enrolled; 22 (57.9%) were men and the median age was 54 years (range, 28-67). Of 35 patients who underwent curative surgery, 28 patients underwent sphincter-saving operations. There was no grade 4 toxicity, and grade 3 toxicities included leukopenia (2.7%), neutropenia (2.7%), anorexia (2.7%), nausea (2.7%) and diarrhea (8.8%). The pCR rate was 25.7% (8/35, 95% CI [10.9-42.1]) and additional 10 patients (28.6%) showed near total regressions of tumor. Tumor ADCs by DW-MRI were calculated in 38 patients (including phase I part). The post-CRT ADC and the ADC changes (ΔADC) were significantly correlated with pCR rate (post-CRT ADC: 1.52±0.46 vs. 1.07±0.58, p=0.037, ΔADC: 44.5% vs. -7.6%, p=0.026).

Conclusions: Preoperative CRT with S-1 plus oxaliplatin showed promising results in pathologic responses and favorable toxicities profiles. Tumor ADC by DW-MRI seems to be a useful method for predicting responses.

No significant financial relationships to disclose.
Randomized, double-blind, placebo-controlled phase II study of AMG 386 in combination with cisplatin and capecitabine (CX) in patients (pts) with metastatic gastroesophageal adenocarcinoma.
Authors: Eatock M. M. , Szanto J. , Tebbutt N. C. , Bampton C. L. , Strickland A. H. , Valladares Ayerbes M. , Nanayakkara N. , Sun Y. , Adewoye A. H. , Bodoky G.
Published: February 2017

66

Background: AMG 386, a first-in-class investigational peptide-Fc fusion protein (peptibody), blocks angiogenesis via inhibiting the interaction between angiopoietins-1 and -2 and the Tie2 receptor. We evaluated the efficacy and tolerability of AMG 386 or placebo plus CX in the first-line treatment of metastatic gastroesophageal adenocarcinoma.

Methods: Pts with confirmed metastatic adenocarcinoma of the stomach, gastroesophageal junction or distal esophagus were randomized 1:1:1 to receive CX (cisplatin, 80 mg/m2 IV Q3W; capecitabine, 1,000 mg/m2 orally BID for 14 days Q3W) plus AMG 386 10 mg/kg (Arm A), 3 mg/kg (Arm B), or placebo (Arm C) IV QW. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR; in pts with measurable disease), adverse events (AEs), and pharmacokinetics (PK).

Results: 171 pts were randomized (Arm A/B/C, n = 56/59/56). Efficacy results are summarized in the table. The incidence of grade ≥ 3 AEs in Arms A/B/C was 80/84/75%. Serious AEs occurred in 73/60/47% and serious AEs grade ≥ 3 in 66/60/43% of pts. AEs in Arms A/B/C included abdominal pain (30/40/17%; grade ≥ 3, 18/3/4%), peripheral edema (13/29/6%; grade ≥ 3, 0/2/0%), venous thromboembolic events (20/22/19%; grade ≥ 3, 20/19/17%), and pulmonary embolism (9/3/15%; grade ≥ 3, 9/2/13%). Median AMG 386 Cmax and Cmin values at steady state after CX coadministration were dose-proportional. Coadministration with CX did not markedly affect AMG 386 exposure.

Conclusions: In this study, AMG 386 plus CX did not significantly improve PFS or ORR over placebo plus CX in this patient population. The toxicity of the combination of AMG 386 plus CX, compared with placebo, was greater but manageable. No unexpected AEs occurred.

[Table: see text]

[Table: see text]
A randomized controlled phase III trial to evaluate the effect of preoperative enteral immunonutrition on the surgical site infection after total gastrectomy (OGSG0507).
Authors: Kimura Y. , Tsujinaka T. , Fujitani K. , Fujita J. , Miyashiro I. , Imamura H. , Kobayashi K. , Kurokawa Y. , Shimokawa T. , Furukawa H. ,   Osaka Gastrointestinal Cancer Chemotherapy Study Group (OGSG)
Published: February 2017

74

Background: To investigate the effect of preoperative enteral immunonutrion on the incidence of surgical site infection (SSI) after total gastrectomy for gastric cancer, we conducted a prospective randomized controlled trial.

Methods: Eligibility criteria included: (1) histologically proven adenocarcinoma of stomach, (2) scheduled total gastrectomy, (3) aged less than 80 years, (4) not malnourished, (5) possible to ingest liquid diet, (6) written informed consent. Eligible patients (pts) wereassigned to the immunonutrition (I) group or the control (C) group. In the C group pts freely accessed to regular diet until surgery. In the I group, pts were supplemented with 1,000 ml/day of immunonutrient enriched with arginine, omega-3 fatty acids and RNA (Impact) in addition to the regular diet for 5 days before surgery. The primary endpoint was the incidence of SSI and the secondary endpoints were other infectious complications and serum CRP level on POD 3 or 4.

Results: From 02/2004 to 12/2009, 240 gastric cancer patients (pts) who underwent gastric surgery were enrolled. 125 pts assigned to the I group and 115 pts assigned to the C group. Age, sex, body weight, serum albumin and general nutritional status were well balanced between the two groups. 223 pts underwent total gastrectomy, 6 pts proximal gastrectomy, 4 pts distal gastrectomy, and 7 pts simple laparotomy. In terms of tumor status, there were no significant difference between the groups in histological type, T stage, and lymph node metastasis. 104 of 125 pts assigned to the I group tolerated a daily intake 1,000 ml of Impact for 5 days. The incidence of SSI was 26 (20.8%) in the I group and 24 (20.9%) in the C group (R.R: 1.00, 95% C.I: 0.61-1.63). Postoperative morbidity was 36 (28.8%) in the I group and 30 (26.1%) in the C group. There was no difference in days of hospital stay after surgery between the groups.

Conclusions: The oral administration of immunonutrient for 5 days before surgery did not contributed to the reduction of infectious complications after total gastrectomy in gastric cancer pts.

No significant financial relationships to disclose.
Patterns of radiotherapy practice in the management of gastric cancer: Preliminary findings from the Quality Research in Radiation Oncology (QRRO) GI Committee process surveys.
Authors: Goodman K. A. , Khalid N. , Kachnic L. A. , Minsky B. D. , Crozier C. , Owen J. B. , Wilson J. F. , Thomas C. R.
Published: February 2017

77

Background: The specific aim of the ACR QRRO survey was to determine the national patterns of radiotherapy (RT) practice in patients (pts) treated for stage IB–IV (non-metastatic) gastric cancer (GC).

Methods: A National Process Survey was conducted from randomly selected U.S. RT facilities to assess demographics, staging, geographic region, practice setting, and treatment through retrospective on-site record review of eligible GC cases treated from 2005-2007. Three clinical performance measures (CPMs): 1) use of CT-based treatment planning; 2) use of dose volume histograms (DVHs) to evaluate RT dose to the kidneys and liver; 3) completion of RT within the prescribed time frame were assessed. Three emerging quality indicators: 1) use of intensity modulated RT (IMRT); 2) use of image-guided tools (IGRT), other than CT, for RT target delineation; 3) use of preop RT were also assessed.

Results: CPMs were computed on data collected through Aug, 2010 for 250 eligible pts at 45 institutions. Median age was 62 years; 66% male; 60% Caucasian. 13% were AJCC 2002 stage I, 29% II, 32% IIIA, 10% IIIB and 12% IV. Most pts (43%) were treated at academic centers with 32% at large non-academic centers and 25% medium-small facilities. Almost all (99.5%) pts underwent CT-based planning and 75% had DVHs to evaluate normal tissue doses to the kidneys and liver. 70% completed RT within the prescribed time frame. IMRT and IGRT were used in 22% and 17% of pts, respectively. IGRT techniques included: PET (n = 20), MRI (n = 1), respiratory gating and/or 4D-CT (n = 22) and on-board imaging (n = 10). 19% of pts received preop RT.

Conclusions: Preliminary findings from QRRO's analysis of radiation practice patterns for non-metastatic gastric cancer indicate widespread adoption of CT-based planning with the use of DVHs to evaluate normal tissue doses. Moreover, most pts completed adjuvant RT in the prescribed time frame. Emerging RT techniques such as IMRT and IGRT were not routinely incorporated into clinical practice during the evaluated time period. These data will serve as a benchmark for future QRRO gastric cancer surveys.

No significant financial relationships to disclose.
Onset of CT scan morphological changes in metastatic lesions and associated responses in gastric patients treated with telatinib.
Authors: Bhosale P. , Ajani J. A. , Baker J. S. , Whiteside M. , Castillo J. , Kunkel L. A.
Published: February 2017

81

Background: Response to the antiangiogenic agent, bevacizumab, by CT has been associated with a unique morphologic change in liver metastasis (mets) where heterogeneous attenuation, variable degree of enhancement and ill-defined borders before treatment transform into homogeneous, hypoattenuating lesions with well defined borders, mimicking a cyst. CT-based morphologic criteria in colorectal cancer (CRC) had a statistically significant association with pathologic response and overall survival, (Chun, JAMA 2009). The CT changes likely reflect the replacement of mets by fibroconnective tissue rather than tumor necrosis. Telatinib (tel) is a novel orally available kinase inhibitor that is highly selective for the VEGFR, PDGFR, and KIT tyrosine kinases at nanomolar concentrations with potent antiangiogenic activity.

Methods: TEL0805, a Phase 2 study administered tel with capecitabine (X) and cisplatin (P) in previously untreated metastatic or unresectable gastric or GEJ adenocarcinoma pts. Response assessments were every 2 cycles (6 weeks). The ORR in response evaluable pts was 69% (1 CR, 21 PR in 32 pts). CT films from 16/32 response evaluable pts were analyzed and reviewed by a radiologist at a single institution, 10 pts had liver mets.

Results: The median onset of response was 49 days. CT changes of mets at week 6 scans included: decreased attenuation and/or a sharp interface with rapid reduction of mets (n=6); mixed response, with decreased attenuation but persistent borders, and/or slight increase in mets followed by onset of response week 12 (n=3), and PD (n=1). CT changes correlate with durable responses.

Conclusions: Telatinib + XP produces rapid onset of tumor response with morphologic CT changes in gastric cancer liver mets similar to those observed in CRC pts with bevacizumab, consistent with antiangiogenic activity. Further analyses in a randomized setting to correlate CT morphologic response with survival are planned.

[Table: see text]
Efficacy of adjuvant chemotherapy with S-1 in patients with positive peritoneal cytology (CY1) who underwent R1 surgery.
Authors: Terashima M. , Bando E. , Tokunaga M. , Tanizawa Y. , Kawamura T. , Kondo J. , Kinugasa Y. , Kanemoto H. , Uesaka K.
Published: February 2017

84

Background: In recent TNM classification, positive peritoneal cytology (CY1) is regarded as M1 disease and classified into stage IV. However, the prognosis of the CY1 patients underwent R1 surgery (microscopic residual tumor) is considered to be relatively better than those underwent R2 surgery (macroscopic residual tumor). Adjuvant chemotherapy with S-1 had demonstrated significant survival benefit in stage II and III gastric cancer in Japan. However, the efficacy of adjuvant S-1 in patients with relatively more advanced stage had not been investigated. Therefore, we investigated the efficacy of adjuvant chemotherapy with S-1 in CY1 patients underwent R1 surgery.

Methods: Among the 2,202 patients with gastric cancer treated at our department between September 2002 and July 2009, a total of 105 patients with CY1 and underwent R1 surgery were included in this study. Clinocopathological features and survival were retrospectively analyzed using prospectively registered data base system.

Results: There were 64 male and 41 female patients. The median age was 61 years old. Eighty-five patients had T4a or T4b tumor and 96 patients had lymph node metastasis. Seventy-eight patients had undifferentiated type of tumor. In 83 patients, adjuvant chemotherapy with S-1 had been performed. In the uni-variate analysis, only the extent of lymph node dissection (D2) and the adjuvant chemotherapy with S-1 demonstrated significant survival benefit. In multi-variable analysis using Cox proportional hazarded model, N-factor, extent of lymph node dissection (D2 vs D1), and adjuvant chemotherapy with S-1 were selected as independent prognostic factors. The median survival time and 5-year survival rate in patients underwent R1 resection with D2 lymphadenectomy and adjuvant S-1 treatment were 42 months and 46%, respectively.

Conclusions: In patients with CY1 and underwent R1 surgery, adjuvant chemotherapy with S-1 demonstrated significant survival benefit. In patients with positive peritoneal cytology without other non-curative factors, D2 lymph node dissection and adjuvant chemotherapy using S-1 is recommended.

No significant financial relationships to disclose.
A global, multicenter phase II trial of lapatinib plus capecitabine in gastric cancer.
Authors: Pishvaian M. , Sakaeva D. , Hsieh R. K. , Rha S. Y. , Caderillo-Ruiz G. , Miller W. H. , Kemner A. M. , Nagarwala Y. M. , Zhang W. , Lenz H.
Published: February 2017

88

Background: Advanced gastric cancer (GC) is an incurable disease. HER2 overexpression has been reportedin 6%–35% of gastric and gastroesophageal tumors, whereas the EGFR is upregulated in about 18%–28%. Clinical studies confirm that targeting HER2 in combination with chemotherapy is an effective strategy, achieving a median survival of ∼13.5 mos. Lapatinib, a dual tyrosine kinase inhibitor of HER2 and the EGFR, inhibits tumor growth and modulates expression of fluoropyrimidine-targeting genes. LPT109747 is an international, multicenter phase II study investigating the combination of lapatinib + capecitabine in patients with advanced gastric or gastroesophageal junction adenocarcinoma.

Methods: Primary endpoints of the study included clinical response rate, 5 mo PFS and mRNA and protein expression levels of genes involved in the 5-FU and HER2 pathway. HER2 overexpression was not required at study entry. Oral lapatinib was administered (1,250 mg/d, continuously) during a monotherapy run-in period (day -7 to 0) and in combination with oral capecitabine (1,000 mg/m2 BID, 14 of 21 days). Patients were treated until disease progression (PD) or study withdrawal. Biopsies were performed on days -7 and 0. Safety was assessed every 3 weeks and response every 6 weeks by RECIST.

Results: Sixty-seven patients were included in the current analysis: 25% female, 75% male; 51% Caucasian, 45% Asian; median age 60 y (range: 22-89 y); 75% GC, 25% GEJ. All 67 patients were evaluable for response. The overall response rate was 22.4% (16.4% confirmed). 45% of patients had stable disease, and 24% had PD. No complete responses were observed. PD or death at < 5 mo was 63%. At the time of data cut off, PFS at 5 mo was 28.4% (17.3%–40.5%); median follow up was 26.4 weeks (CI: 22.1; 55.9); 39% of patients remain in follow up. Most frequent grade 3/4 events were anemia (13%), hand-foot syndrome (12%), decreased appetite (10%), and nausea (9%).

Conclusions: The combination of lapatinib + capecitabine shows promising efficacy and is well tolerated as 1st line treatment for advanced GC. An analysis of biomarker data may help identify who may benefit most from this regimen.

[Table: see text]
An integrated analysis of two phase II trials (JCOG0001 and JCOG0405) of preoperative chemotherapy followed by D3 gastrectomy for gastric cancer (GC) with extensive lymph node metastasis (ELM).
Authors: Tsuburaya A. , Katayama H. , Mizusawa J. , Nakamura K. , Katai H. , Imamura H. , Nashimoto A. , Fukushima N. , Sano T. , Sasako M. ,   The Gastric Cancer Surgical Study Group of JCOG
Published: February 2017

90

Background: GC with ELM (bulky N2 metastasis and / or para-aortic lymph node metastases [PAN]) is commonly regarded unresectable, while in JCOG combined modality treatment has been tested since 2000 (JCOG0001 and JCOG0405). Both trials met their primary endpoints (i.e., 3 year-survival of 27.3% in JCOG0001 and R0 resection of 82.4% in JCOG0405). The survival and the toxicity profile were quite different between the trials despite the similar eligibility with an outstanding 3-year survival of 58.8% in JCOG0405. This study is conducted to explore if survival is still better in JCOG0405 after adjusting baseline factors and if there is a subset of patients (pts) who benefit more from either treatment.

Methods: Eligibility criteria for both included histologically proven gastric adenocarcinoma; bulky nodal involvement around major branched arteries to the stomach and/or PAN; cM0 (except PAN); negative lavage cytology; not linitis plastica type; PS of 0 or 1. Pts received two or three cycles of induction chemotherapy of IP: irinotecan (70 mg/m2 on day 1 and day 15) and cisplatin (80 mg/m2 on day 1) in JCOG0001, or SP: S1 (80 mg/m2 from day 1 to 21) and cisplatin (60 mg/m2 on day 8) in JCOG0405, followed by D3 gastrectomy. Multivariate analysis for overall survival adjusting baseline factors and treatment (IP/SP) was performed with a Cox regression model. Interaction tests were also carried out between baseline factors and treatment.

Results: After adjusting baseline factors, SP was superior than IP for overall survival (HR=0.335: 0.184 – 0.612). There was only interaction effect between treatment and the status of lymph node metastases (bulkyN+/PAN- vs bulkyN-/PAN+ vs bulkyN+/PAN+; p=0.1306).

Conclusions: SP was shown to be the favorable treatment for GC with ELM by multivariate analysis, while poor prognosis in pts having both bulky N+ and PAN+ may necessitate further treatment improvement.

No significant financial relationships to disclose.
Quality of life in patients with advanced gastroesophageal (GE) adenocarcinoma treated with modified docetaxel, cisplatin, and fluorouracil (mDCF).
Authors: Smyth E. C. , Janjigian Y. Y. , Robinson E. , Sheehy E. C. , Karpenko I. , Capanu M. , Kelsen D. P. , Shah M. A.
Published: February 2017

92

Background: Although DCF is a standard first line chemotherapy option for advanced GE adenocarcinoma, the regimen is associated with significant toxicity. Even so, time to detriment in quality of life (QoL) was significantly better with parent DCF than CF (Ajani, JCO 2007). Modified DCF (mDCF) has demonstrated less toxicity than parent DCF without compromising efficacy in two phase II studies (Shah, GI ASCO 2010; Kelsen, ASCO 2009). We report the quality of life (QoL) over time of patients receiving mDCF on these two clinical trials.

Methods: Patients (pts) treated on two protocols utilizing the mDCF regimen, either alone or in combination with bevacizumab, were administered standard EORTC QoL questionnaires (QLC –C30 version 3), at baseline, 6 weeks, 3, 6, 9 and 12 months (m). Chemotherapy and QoL assessment continued until disease progression. Mean score change from baseline was assessed using Wilcoxon test.

Results: 94 eligible pts have been enrolled on both studies; QoL questionnaires are available on 87 pts. 74% are male, median age 58 years (range 28-78), with baseline Karnofsky performance status of 80% (range 70-100). Patient compliance with QoL assessment was high at baseline but diminished with time; 89% of pts completed the questionnaire at baseline and 41% at 12m. There was no significant detriment in EORTC QOL scores (including global health, physical and social functioning and fatigue) during treatment with mDCF (Table).

Conclusions: In patients with advanced GE cancer, we observed no detriment in QoL scores in patients receiving mDCF therapy. Specifically, physical and social functioning, fatigue, appetite, and global heath QoL scores were maintained at baseline levels during the first 6 months of therapy, and appear to improve in patients who remained on protocol therapy during the next 6 months of treatment.

[Table: see text]

No significant financial relationships to disclose.
A single-arm, phase II feasibility study of neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) chemotherapy in potentially resectable gastric or gastroesophageal junction adenocarcinoma.
Authors: Ryu M. , Choi Y. , Kim B. , Park Y. , Kim H. , Jung H. , Lee G. , Kim K. , Yook J. , Kang Y.
Published: February 2017

96

Background: The aim of this study was to evaluate feasibility and safety of neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) chemotherapy in patients with potentially resectable adenocarcinoma of stomach or gastroesophageal junction.

Methods: Forty-one patients with clinical stage T3-4N0M0 or T2-4N+M0 determined by CT, endoscopic ultrasonography, and laparoscopy were enrolled between DEC 2008 and MAR 2010. Gastrectomy with D2 lymph node dissection was conducted after 3 cycles of DOS chemotherapy. DOS chemotherapy consists of docetaxel 50 mg/m2 iv (day1), oxaliplatin 100 mg/m2 iv (day1), and S-1 40 mg/m2 po bid (days1-14) at 3 weeks interval. After curative gastrectomy, the patients were given 1 year of adjuvant chemotherapy with S-1 (40 mg/m2 D1-28, every 6 weeks).

Results: All patients finished the planned neoadjuvant chemotherapy. Twenty-three (56%) patients achieved a partial response, and the remaining 18 patients had stable disease by CT scan after 3 cycles of DOS chemotherapy. No disease progression was observed during the neoadjuvant chemotherapy. A median 4.7 weeks (range, 4.0-7.6) after the start of the 3rd cycle of DOS chemotherapy, 39 (95%) patients underwent R0 resection with no pathologic residual disease in 4 (10%) patients. Hematologic toxicities were common including grade 4 neutropenia (32%), grade 3 thrombocytopenia (17%), and febrile neutropenia (10%). However, hematologic toxicities were generally transient and manageable. There were no grade 3 or 4 non-hematologic toxicities with frequency > 5% of patients. With all toxicities taken together, 21 (51%) patients experienced grade 3 or 4 toxicities (except grade 3 neutropenia). There was no treatment-related death, and surgical complications included only mild wound problem in 4 (10%) patients.

Conclusions: In this study, neoadjuvant DOS chemotherapy could induce a sufficient down-staging and R0 resection of locally advanced gastric cancer with mild and manageable toxicities. A phase III randomized trial is planned for evaluating the benefit of neoadjuvant DOS chemotherapy in patients with locally advanced gastric cancer.

[Table: see text]
Initial report of RTOG 9601, a phase III trial in prostate cancer: Effect of anti-androgen therapy (AAT) with bicalutamide during and after radiation therapy (RT) on freedom from progression and incidence of metastatic disease in patients following radical prostatectomy (RP) with pT2-3,N0 disease and elevated PSA levels.
Authors: Shipley W. U. , Hunt D. , Lukka H. R. , Major P. , Heney N. M. , Grignon D. , Patel M. , Bahary J. , Lawton C. A. , Sandler H. M.
Published: February 2017

1

Background: To test if long term AAT when combined with RT in these patients (pts) with prostate cancer (PC) will improve cancer control outcomes as well as overall survival (OS).

Methods: Post-RP pts with pT3,N0 or with pT2,N0 (and positive margins) who have an elevated PSA were entered on a phase III, double-blinded, placebo-controlled trial of RT alone (64.8 Gy in 1.8 Gy fractions) vs RT + AAT (24 months of bicalutamide, 150mg daily) during and after RT. The primary end point is OS.

Results: From 3/98 to 3/03, 771 eligible pts (median age 65) were randomized to RT + AAT (387) or RT alone (383). Pretreatment characteristics were balanced. 672 (87%) had a PSA nadir after RP of < 0.5 ng/mL. 655 (85%) had an entry PSA value of <1.6, 115 (15%) had an entry PSA of 1.6-3.9. Median follow-up was 7.1 years. Actuarial OS at 7 years was 91% for RT + AAT and 86% for RT alone. Too few primary end-point events have occurred to allow a statistical comparison between groups. Freedom from PSA progression (FFP) at 7 years was 57% for RT + AAT and 40% for RT alone (P < 0.0001); for 226 pts with GS < 7 were 63% and 50% (P<0.02), for 411 GS 7 these were 55% and 39% (P<0.0006), and for 134 GS 8-10 were 56% and 26% (P < 0.0008). The 7-yr cumulative incidence of metastatic PC was less in the RT and AAT arm, 7% vs 13% in the RT arm (p<0.041). Late grade 3-4 toxicities were similar in both arms. By category the combined grade 3-4 toxicities for RT + AAT and RT alone were: bladder 6% vs 5% bowel 2% vs 1%, cardiac 3% vs 2%. Gynecomastia (mostly grades 1-2) differed significantly, 89% vs15%. In the RT + AAT arm grade 3 was the highest liver toxicity, which occurred in 3 pts.

Conclusions: The addition of 24 months of bicalutamide 150 mg daily during and after RT significantly improved FFP and reduced the incidence of metastatic PC without adding significantly to RT toxicity. The significance of benefit in OS, as well analysis of risk-stratified subsets, wait longer follow-up.

No significant financial relationships to disclose.
Can MRI accurately define tumor boundaries to guide focal salvage after radiotherapy?
Authors: Iupati D. , Haider M. A. , Chung P. W. , Bayley A. , Catton C. , Milosevic M. , Bristow R. G. , Morton G. , Warde P. R. , Menard C.
Published: February 2017

124

Background: We evaluated the role of MRI (plus/minus biopsy) in delineating tumour boundaries for focal salvage therapy of prostate cancer recurrence after external beam radiotherapy.

Methods: Patients with biochemical failure after radiotherapy were enrolled in a prospective clinical trial mapping sites of local recurrence. An integrated diagnostic MRI and interventional mapping biopsy procedure was performed under sedation in a 1.5T scanner. Patients were imaged with a pelvic coil and an endorectal coil attached to a stereotactic transperineal template assembly. Multiparametric MRI images were acquired, followed by targeted radial biopsy of suspicious regions and random sextant sampling of the normal-appearing peripheral zone. Histology maps were generated by delineation and registration of biopsy cores onto diagnostic images using point-based rigid image registration. Two independent blinded observers reviewed images offline and delineated tumours boundaries which were compared against overlaid histology maps. Coverage was considered accurate if all pathologically proven tumour sites were encompassed within delineated boundaries.

Results: Of the 18 patients analysed to date, the majority (83%) were found to have local recurrence. Patients with <6 informative cores were excluded, leaving 15 patients for analysis. Observers performed comparably, whereby mean MRI sensitivity, specificity, PPV and NPV for detecting tumor was 0.76, 0.7, 0.7, and 0.75. The MRI tumour boundary was accurate in 5/15 patients, and improved to 8/15 patients with addition of a 5-mm expansion margin. Targeted radial biopsies improved accuracy to 14/15 patients, by excluding false positive regions (n=2), increasing tumor volumes (n=2) or both (n=2). Random sampling biopsy was only relevant in 1 patient by detecting tumor not identified by MRI and targeted biopsy.

Conclusions: MRI alone is not sufficiently accurate to define boundaries for tumor-targeted salvage even with addition of an uncertainty margin. Targeted biopsy improved both detection and delineation accuracy for recurrent tumor regions, and changed salvage therapy planning in 40% of patients.

No significant financial relationships to disclose.
Phase II study of tasquinimod in chemotherapy-naive patients with metastatic castrate-resistant prostate cancer (CRPC): Safety and efficacy analysis including subgroups.
Authors: Armstrong A. J. , Haggman M. , Stadler W. M. , Gingrich J. R. , Assikis V. J. , Nordle O. , Forsberg G. , Carducci M. A. , Pili R.
Published: February 2017

126

Background: Tasquinimod (TASQ) is an oral quinoline-3-carboxamide derivative that binds to S100A9 and displays anti-angiogenic and anti-tumor activity in prostate cancer (PC) models. In a randomized blinded phase II study, 206 (136 TASQ, 70 placebo [P]) men with metastatic castrate resistant (CRPC) were assigned to TASQ/P once-daily at an initial dose level of 0.25 mg/day escalating to 1.0 mg/day over 4 weeks. The primary endpoint to demonstrate an improvement in PCWG2 criteria-defined progression at 6 months was met and presented at ASCO 2010. This abstract provides an update on safety and efficacy including CRPC subgroups.

Methods: Subgroups of patients based on baseline criteria were investigated for safety using NCI CTC v 3.0 criteria, PK and efficacy.

Results: 201 (134 TASQ, 67 P) pts with a median age of 72.6 years received treatment and were evaluable for efficacy and safety. The updated analysis based on 5 additional PFS events confirmed an improved PFS of 7.6 vs. 3.3 months for pts on TASQ vs. P. Most progression events in both arms were radiological, but more pts progressed on bone scan in the P group. Radiographic PFS was 8.8 vs 4.4 months. Significant PFS improvements were observed in the PCWG2 risk groups with bone metastatic and visceral disease. TASQ treatment led to a transient increase in inflammatory lab markers such as CRP and fibrinogen, as well as asymptomatic increases in amylase/lipase. CRP increase was associated with adverse events (AEs) such as muscle and joint pain, while increased amylase was associated with a lower risk for gastrointestinal AEs. TASQ treatment was associated with anaemia, but did not affect CV risk factors such as hypertension or QTc prolongation, and the rate of composite cardiac events was acceptably low. Clearance of TASQ is decreased with age (1.4 % per year) and patients over 80 often required dose reduction due to increased exposure and toxicities.

Conclusions: TASQ improved PFS in men with metastatic CRPC. Side effects are manageable and seem to correlate with laboratory markers. Individualized dosing based on tolerability is recommended and a phase III placebo-controlled study is being initiated.

[Table: see text]
Role of detection of metastatic disease as a leading cause of screening failure in an ongoing phase III trial of zibotentan versus placebo in patients with nonmetastatic castration-resistant prostate cancer (CRPC).
Authors: Yu E. Y. , Nathan F. E. , Higano C. S.
Published: February 2017

135

Background: Many patients with biochemical relapse after definitive therapy for prostate cancer receive androgen deprivation therapy. Although most patients experience a decline in PSA, PSA eventually rises despite a castrate level of testosterone. Many of these patients have non-metastatic disease and do not develop metastases for a median of 30 mos (Smith MR. JCO, 2005). However, there is no standard therapy for asymptomatic patients with non-metastatic CRPC. ENTHUSE M0 (Study 15) is an ongoing global phase III study comparing zibotentan 10 mg (an oral specific endothelin A receptor antagonist) vs placebo in non-metastatic CRPC patients. Co-primary endpoints are overall survival and progression-free survival; secondary endpoints are safety, PSA, quality of life, and time to symptomatic progression. Eligible patients are screened for metastases by bone and CT/MRI scan and other parameters. An unexpectedly high number of patients failed screening, prompting this analysis.

Methods: All patients who were screened were included in the analysis. Reasons for exclusion were recorded.

Results: As of June 3, 2010, 1,756 patients completed screening. Of these patients, 960 (55%) were randomized and 796 (45%) failed screening. The leading causes of screen failures are listed in the table. Exclusion rates by investigator specialty and country will be reported.

Conclusions: As 30% of patients had metastatic disease on screening and were excluded, these data suggest that the frequency of asymptomatic metastases is high in men thought to have non-metastatic CRPC. These findings stress the value of periodic staging studies in men progressing from hormone sensitive to non-metastatic CRPC as metastatic CRPC patients may benefit from standard treatments or research treatments on other protocols.

[Table: see text]

[Table: see text]
Phase II study of AT-101 to abrogate Bcl-2-mediated resistance to androgen-deprivation therapy (ADT) in patients (pts) with newly diagnosed androgen-dependent metastatic prostate cancer (ADMPC).
Authors: Stein M. N. , Khan I. , Hussain M. , Liu G. , Wilding G. , Posadas E. M. , Stadler W. M. , Jeyamohan C. , Eddy S. , DiPaola R. S. ,   Prostate Cancer Clinical Trials Consortium
Published: February 2017

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Background: Preclinical studies demonstrate that Bcl-2 is over-expressed in most pts with prostate cancer, causes drug resistance to ADT, and that modulation of Bcl-2 improves sensitivity of tumor cells. We are conducting a phase II study for men with ADMPC to test the hypothesis that AT-101, a small molecule Bcl-2 inhibitor, improves clinical results of pts initiating ADT for metastatic prostate cancer. Building on results from SWOG 9346 (Hussain JCO 2006) demonstrating that PSA nadir after 7 mo of ADT predicts survival, we are using a novel phase II trial design, in which the primary endpoint is the percentage of patients with PSA ≤ 0.2 ng/ml at 7 mo of ADT plus AT-101.

Methods: Pts had ADMPC, PSA > 5.0 ng/ml within 12 wks prior to registration and no prior ADT for metastatic disease. ADT with LHRH agonist and bicalutamide started 6 wks prior to initiation of oral AT-101, 20 mg/day for 21 days of 28 day cycle. Pts received up to 8 cycles of ADT and AT-101. A total of 55 pts were enrolled (to obtain 48 evaluable pts) to in a two stage design with null hypothesis 48% versus alternative 68% with PSA ≤ 0.2 at 7 mo. With α = 0.1 and β = 0.9, > 27 pts meeting this endpoint are required to recommend further study.

Results: 55 pts were enrolled, median age 61.5 y; Gleason score (GS) 6 (5%),GS 7 (30%), GS 8 (24%), and GS 9 (41%). 3 pts had visceral mets and the remaining pts had bone or nodal metastasis. 42 pts have discontinued (9 toxicity, 9 progression, 1 withdrew) or completed (n = 23) 7 mo of treatment. In intention to treat analysis, 11 of 42 pts (26%) met the primary endpoint 10, of 42 (23%) pts had PSA > 0.2 and < 4.0 ng/ml after 7 mo. Grade 1/2 toxicities (%) included fatigue (36/9), nausea (20/9), vomiting (13/7), anorexia (15/2), AST/ALT (25/5), hypercalcemia (9/0), constipation (13/3), dry skin (9/0), anemia (18/0), sensory neuropathy (7/7), vomiting (12/7), hyperglycemia (7/4). Grade 3 toxicities were sensory neuropathy 2 pts, GI obstruction 1 pt, syncope 1 pt.

Conclusions: Although final study results are pending the analysis of pts currently on therapy, 26% of pts achieved an undetectable PSA at 7 mo in a population with aggressive disease (66% GS ≥ 8).

No significant financial relationships to disclose.
Safety and efficacy of ketoconazole (K) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Contemporary experience and prognostic indicators.
Authors: Keizman D. , Huang P. , Carducci M. A. , Denmeade S. R. , Eisenberger M. A.
Published: February 2017

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Background: Intracrine conversion of adrenal androgens to testosterone play an important role in CRPC progression. Treatments (tx) that block adrenal steroid synthesis have shown significant clinical benefits in mCRPC. Aims: To evaluate contemporary data on safety and efficacy associated with K in mCRPC.

Methods: All/unselected mCRPC pts progressing on GnRH-a and antiandrogens (AA) treated with K were retrospectively analyzed. Pts were maintained on gonadal suppression, discontinued AA, and received and K 200-400 mg t.i.d. until disease progression or dose-limiting toxicity (DLT). Initial 600mg/d dose was escalated to 1,200mg/d if a PSA decrease was not seen at 3 months (mos) or if a response/subsequent progression to 600/mg/d was observed (optional). Follow up included hematological/chemical profile q 3 mos, scans upon clinical (physical exam/symptoms) or at biochemical progression (PSA increase ≥ 25% and ≥2ng/mL from nadir). A multivariate cox regression model was used to identify variables significantly associated with disease progression.

Results: From 1999-2010 (mean follow up 40 mos, range 5-129), 114 m-CRPR pts were treated with K 200mg (n=82, 72%) or 400mg (n=32, 28%) tid. Most common grade 3/4 tox events (n=23) were fatigue, abdominal discomfort, nausea, and dizziness. 9 pts (8%) had DLT (fatigue n=7, hepatotoxicity/thrombocytopenia n=1). 55/114 (48%) had ≥ 50% PSA decline. Overall median time to progression (TTP) was 8 mos (range 1-129). 14 pts remain progression free > 7 mos (range 7-129). Significant prognostic factors (table) were response to prior AA (≥6 vs <6 mos), pre-tx PSADT (≥3 vs <3 mos) and extent of disease (limited-axial skeleton and/or nodal vs extensive- appendicular skeleton and/or visceral).

Conclusions: K is effective and safe in m-CRPC. Prior response to AA, PSADT ≥ 3mos and limited metastatic disease is associated with TTP and further supports a therapeutic role for suppressing adrenal androgens in m-CRPC.

[Table: see text]

No significant financial relationships to disclose.
How does neoadjuvant bicalutamide 150 mg monotherapy compare to lutenising hormone-releasing hormone agonist (LHRHa) therapy in localized prostate cancer treated with radical radiotherapy? A case-matched comparison of PSA kinetics and biochemical outcome.
Authors: McGivern U. , Mitchell D. M. , O'Hare J. , Corey G. , O'Sullivan J. M.
Published: February 2017

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Background: In patients treated with neoadjuvant lutenising hormone-releasing hormone agonist (LHRHa) therapy prior to radical prostate radiotherapy the PSA nadir in the first week of radiotherapy has been correlated with subsequent biochemical failure free survival (BFFS). Bicalutamide monotherapy (BC) is increasingly being used as a neoadjuvant therapy in place of LHRHa. We wished to compare the initial PSA response to neoadjuvant BC or LHRHa in this setting as well as examining subsequent biochemical failure rates.

Methods: We retrospectively reviewed the case notes of consecutive men with prostate cancer treated with BC monotherapy prior to radical prostate radiotherapy from April 2004 to December 2008 and case-matched them to men treated with neoadjuvant LHRHa. PSA levels and kinetics prior to radiotherapy and subsequent BFFS were analysed.

Results: Eighty nine men treated with BC with a median follow-up of 42 months were case matched to 89 men treated with LHRHa. There were no significant differences in age, initial PSA, Gleason, or T stage. The median nadir PSA on day 1 of radiotherapy was 2.2ng/mL (0.1-11.2) for BC patients and 0.9ng/mL (0.1-11.2) for LHRHa patients (p=0.0007). There were no significant differences in PSA velocity or doubling time during the neoadjuvant period. A PSA of <1.0ng/mL on day 1 of radiotherapy was seen in 29 (32%) and 47 (52%) of BC and LHRHa patients respectively. Biochemical failure was seen in 10 (11.2%) and 2 (2.2%) of BC and LHRHa patients respectively. PSA kinetics did not predict for subsequent BFFS at this duration of FU for men receiving neoadjuvant BC.

Conclusions: In this case-matched study, neoadjuvant BC therapy does not provide the same level of pre-radiotherapy PSA suppression when compared to neoadjuvant LHRHa. Higher biochemical failure rates are seen in patients treated with BC than LHRHa however this may be a result of prolonged castration.

No significant financial relationships to disclose.
Tolerability and efficacy of anti-androgen manipulation versus taxotere and anti-androgen manipulation in patients with hormone-naive, high-risk/metastatic prostate cancer: A phase II, open-labeled, randomized study.
Authors: Pedley I. D. , Frew J. A. , Wilson J. M. , Abdul Razak A. R. , Azzabi A. , McMenemin R. , Stockley J. , Soomro N. , Durkan G. , Leung H.
Published: February 2017

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Background: Anti-androgen manipulation (AA) is considered the standard initial therapy for high-risk/metastatic prostate cancer. The role of chemotherapy and anti-androgen manipulation (TAA) is still undefined in this group. GenTax is a phase II trial investigating clinical outcome and gene profiling in prostate cancer before and after AA or TAA. Here we present the clinical outcome data.

Methods: Patients with T3/4 disease, PSA ≥ 50 ng/ml or Gleason score ≥ 8, or metastatic disease were enrolled. Patients were randomised at histological diagnosis to AA or TAA (goserelin 3.6 mgs q28 ± taxotere 75 mg/m2 q21 for 6 cycles). TRUS biopsies were taken at randomisation and 22 weeks after treatment initiation. Clinical assessment including KPS, QOL using QLQ-C30, bloods/PSA were measured 3 weekly until 22 weeks then 3 monthly. Data was analysed for PFS, OS, toxicities and QOL.

Results: 30 patients were recruited with 15 patients in each arm from 10/13/2005 to 12/02/2009. The median age was 62.2 yrs (range 48.9-75.1). All patients had a KPS of ≥ 90%. 12 (40%) and 18 (60%) of patients had stage 3 and 4 disease respectively. At randomization 10 patients had bone and 4 had visceral metastases. 29 had a Gleason score of ≥ 7. There were no statistical differences for age, KPS, disease stage or Gleason score between the two arms. Treatment was well tolerated in both groups with no G3-4 toxicity in the AA arm. In the TAA arm, 4 patients had dose delays or reductions; with one G3 incidence of neutropenia. G3-4 non-hematological toxicities were infrequent; fatigue and one episode of anaphylaxis occurring in separate patients. Median PFS and OS between the two treatments have not been reached at median follow up of 25 months. The 2-year PFS rate was not significantly different, (50% vs 60% p = 0.788) between the AA and TAA groups. There were no significant differences in QOL measures.

Conclusions: Combination therapy of taxotere and anti-androgen manipulation is safe and well tolerated. The gene profiling results may provide important information in selecting patients who will benefit from more aggressive initial therapy.

[Table: see text]
Using Gleason pattern 5 to refine risk stratification for prostate cancer patients treated with dose-escalated radiotherapy and androgen-deprivation therapy.
Authors: Sabolch A. , Feng F. Y. , Daignault-Newton S. , Halverson S. , Blas K. , Phelps L. , Olson K. B. , Sandler H. M. , Hamstra D. A.
Published: February 2017

15

Background: The division of Gleason score (GS) into three categories (2-6, 7, 8-10), may not fully utilize its prognostic power as shown by recent reports demonstrating that the presence of Gleason Pattern 5 (GP5) is a strong adverse prognostic factor. Therefore, we analyzed clinical outcomes for patients treated with dose-escalated radiation therapy (RT) based upon the presence or absence of GP5 within the biopsy specimens.

Methods: Clinical outcomes were analyzed for 718 men treated for localized prostate cancer with definitive external beam RT to at least 75 Gy. We assessed the impact of GP5 as well as pre-treatment and treatment related factors on freedom from biochemical failure (FFBF), freedom from metastasis (FFM), cause-specific survival (CSS), and overall survival (OS).

Results: Median follow-up was 64 months. At biopsy, 89% of patients had no GP5 while 11% had GP5. There was no difference in age, co-morbid illness, clinical T-stage, PSA, or the use or duration of androgen deprivation therapy (ADT) between GS8 without GP5 and GS8-10 with GP5. The presence of GP5 predicted lower FFM (p<0.002 [HR: 3.4{1.7-7.1}]), CSS (p<0.0001 [HR: 12.9 {5.4-31}]), and OS (p<0.0001 [HR: 3.6 {2.0-6.5}]) when compared to GS8 (without GP5). Ten-year FFM, CSS, and OS were 89%, 98%, and 57% for those with Gleason 8 prostate cancer without GP5 as compared to 61%, 55%, and 31% for those with GP5. In addition, both FFM and CSS were strongly influenced by ADT use concurrent with RT. On multivariate analysis GP5 was the strongest prognostic factor for all clinical end-points.

Conclusions: The presence of GP5 predicts for worse clinical behavior, which therefore needs to be accounted for by risk stratification schemes. Further intensification of local and/or systemic therapy may be appropriate for such patients.

No significant financial relationships to disclose.