bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II study of preoperative radiation with concurrent capecitabine, oxaliplatin, and bevacizumab followed by surgery and postoperative 5-FU, leucovorin, oxaliplatin (FOLFOX), and bevacizumab in patients with locally advanced rectal cancer: A trial of the Eastern Cooperative Oncology Group (E3204).
Authors: Cohen Steven J. , Feng Yang , Landry Jerome Carl , Staley Charles A. , Whittington Richard , Sigurdson Elin R. , Nimeiri Halla Sayed , Verma Udit N. , Benson Al Bowen 
Published: March 2020

3605 Background: Oxaliplatin and bevacizumab potentiate the antitumor activity of fluoroyprimidines and radiotherapy in preclinical and clinical studies of colorectal cancer. This phase II trial evaluated the efficacy of the preoperative combination of capecitabine, oxaliplatin, and bevacizumab with radiotherapy in rectal cancer. Methods: Eligibility: resectable T3/T4 adenocarcinoma of the rectum ≤ 12 cm. from anal verge. Preoperative treatment was capecitabine (825 mg/m² bid M-F), oxaliplatin (50 mg/m² weekly), bevacizumab (5 mg/kg D1,15,29), and pelvic external beam radiotherapy (50.4 Gy/28 fractions). Surgery was performed within 6-8 weeks. Within 12 weeks of surgery, patients received 12 cycles of FOLFOX + bevacizumab (5 mg/kg) Q2 weeks. Pathologic complete response (path CR) was the primary endpoint. Secondary endpoints included resection rate and toxicity. Results: Fifty-seven patients (pts) enrolled from 7/06 to 5/10 and 54 were eligible. Clinical staging: T3/4 (50/4), NX0/1/2 (2/16/31/5). Most common grade 3/4 non-hematologic toxicities during treatment were rectal pain (9), fatigue (8), and diarrhea (7). Two patients died of aspiration. Nine pts had early postsurgical complications (9 wound infections, 6 dehiscence, 1 abscess) and 23 had late surgical complications (23 non-healing wounds, 12 dehiscence, 5 bowel obstruction/ileus, 2 abscess). Pathologic staging: T0/1/2/3 (11/3/15/19), N0/1/2 (32/10/7). Nine pts had path CRs (17%, 90% CI:[9%-27%]. Surgery was LAR (38) and APR (11). Twenty-two pts did not receive postoperative chemotherapy (39%), 16 due to adverse events. Five local recurrences have been reported. RFS and OS data are immature. Conclusions: The addition of oxaliplatin and bevacizumab to capecitabine and radiotherapy for locally advanced rectal cancer resulted in downstaging for the majority of pts but did not improve the pathologic complete response rate compared to historical controls. The combination resulted in significant early and late postsurgical complications.
Six months versus twelve months of capecitabine as adjuvant chemotherapy for stage III (Dukes' C) colon cancer: Initial safety report for the open-label randomized phase III study (JFMC37-0801).
Authors: Kunieda Katsuyuki , Sadahiro Sotaro , Mishima Hideyuki , Hamada Chikuma , Saji Shigetoyo , Sakamoto Junichi , Sato Toshihiko , Hirai Takashi , Maeda Atsuyuki , Yoshida Kazuhiro , Akamatsu Hiroki , Ohue Masayuki , Ohta Naohiro , Kinugasa Yusuke , Fujii Shoichi , Hasegawa Junichi , Tamagawa Koji , Yamaguchi Shigeki , Tomita Naohiro 
Published: March 2020

3607 Background: The standard treatment duration of adjuvant chemotherapy (CT) in patients (pts) with stage III colon cancer is 6 months. On the other hand, no clinical trial showed the optimal treatment duration of oral chemotherapeutic agents in adjuvant setting for colon cancer. Sargent et al have reported that 83% of recurrences in stage II and III pts have occurred within the first 3 years after surgery and peak was observed around one year after surgery. Therefore, to clarify the benefit of 12 months administration of Capecitabine, we designed randomized phase III trial for a comparison of 6 months treatment and 12 months treatment of capecitabine as adjuvant CT for stage III colon cancer. Methods: JFMC37 is a multicenter, randomized Phase III trial. Patients with fully resected Stage III colon or recto sigmoid cancer were eligible. Capecitabine was administered orally as tablets, 2,500 mg/m²/day for 14 days followed by a 7-days rest. Treatment is continued to 8 cycles (6 months) in arm A (A) or 16 cycles (12 months) in arm B (B). Patients were randomized 1:1 to A or B. Data size was estimated by disease free survival as primary endpoint. The statistical design is based on superiority hypothesis; 5-yrs DFS is 60% in arm A, 67% in arm B ;unilateral α=0.05, 1-β=0.8;and planed accrual is 1200 pts. Results: Between September 2008 to December 2009, 1304 patients were enrolled and then randomized. Both arms were well balanced for mean age: (A) 64.1, (B) 63.8; ECOG PS (%0/1): (A) 95.0/5.0, (B) 97.1/2.9; involvement of lymph nodes (%N0/N1/N2): (A) 77.1/19.9/3.1, (B) 76.6/19.7/3.7. Treatment completion rate for A and B were 68.2% and 43.4%. Incidences of serious adverse events (SAEs) over 1% were neutropenia: (A) 2.6%, (B) 3.8%, diarrhea: (A) 2.9%, (B) 2.1%, loss of appetite: (A) 1.3%, (B) 1.0%, fatigue: (A) 1.8%, (B) 1.2%, hand-hoot syndrome: (A) 16.4%, (B) 22.1%. Conclusions: There were no obvious differences in SAEs between arm A and arm B. Although twelve months of capecitabine showed a tendency to increase G3/4 hand-foot syndrome, we concluded that incidence of SAEs were acceptable and comparable to previously report.
A population-based study of the effect of FDG PET/CT in the management of liver-limited colorectal adenocarcinoma (CRC) metastases.
Authors: Ho Maria Yi , Parhar Tarnjit , Wilson Don , Cheung Winson Y. , Lim Howard John 
Published: March 2020

3610 Background: PET/CT scans are publically funded in British Columbia for staging in liver limited metastatic CRC. However, past studies have been equivocal about the utility of PET/CT as some report as high as a 20-30% change in management while others report <10% change in management. Our primary objective was to assess the effect of the addition of PET/CT to CT scanning for the management of liver limited colorectal cancer. Methods: Patients who underwent PET/CT scan for de novo liver limited metastatic disease from 2005-2011 in the province of British Columbia were identified using the PET/CT database. Patients recently completed or currently on chemotherapy were excluded. We determined the concordance rates between CT and PET/CT scans with respect to the extra-hepatic disease, the number of lesions in the liver and the location of liver lesions. Results: 349 patients were identified. The most common indications for PET/CT scans after an initial CT scan were: detection of extrahepatic disease (77%), confirmation of the malignant nature of the liver lesions (8%) and the extent of extrahepatic disease (15%). PET/CT and CT were discordant in 39% of cases for the extent of metastatic disease. PET/CT revealed extrahepatic disease in 27% of the cases for which CT only detected liver limited disease. In contrast, 13% of patients were downstaged when CT liver lesions were demonstrated not to be FDG avid. Concordance of PET/CT and CT scans on the number and location of liver lesions was 52% and 85%, respectively. PET/CT revealed additional number of liver lesions and multilobar disease in 26% and 12% of cases, respectively. Furthermore, the median time between PET/CT and CT were 64.3 days and 64.1 days for concordant and discordant cases (p=0.88). Conclusions: PET/CT scans provided additional information compared to CT scans which could have implications for surgical management. Our study supports the utility and public funding of PET/CT in addition to CT in patients with potentially surgically curable metastatic CRC involving the liver.
Neoadjuvant treatment of colorectal liver metastases (CRLM) with drug eluting beads trans-arterial chemoembolization (DEBIRI-TACE): A multi-institute phase II study in resectable metastases.
Authors: Jones Robert Peter , Malik Hassan Zakria , Fenwick Stephen W , Byrne Clare , Terlizzo Monica , O'Grady Elizabeth , Stremitzer Stefan , Gruenberger Thomas , Poston Graeme John 
Published: March 2020

3613 Background: Perioperative chemotherapy confers 3-year progression free survival advantage following resection of CRLM and good pathologic response is associated with improved overall survival. However, systemic neoadjuvant chemotherapy can increase postoperative morbidity and mortality. TACE using preloaded Irinotecan eluting beads gives sustained delivery of drug directly to tumor, thereby maximising response and reducing systemic exposure. This study examined the feasibility and safety of neoadjuvant DEBIRI-TACE before CRLM resection. Methods: Patients with resectable CRLM received single DEBIRI-TACE (up to 200mg) 1 month pre-hepatectomy. Primary end-point: tumor resectability, secondary end-points: safety, radiologic response (RECIST) and pathologic tumor response. Results: TACE attempted in 49 patients, successful in 40. Reasons for failed TACE included consent withdrawal (n=2), bilobar disease (n=2), tumour involving gallbladder wall (n=1), suspected hepatoma (n=1), arterial access difficulty (n=2), contrast medium allergy (n=1). Post-TACE complications: 1 acute pancreatitis (3%); 4 post-embolization syndromes (10%). Imaging at 4 weeks post-TACE (30 patients): complete response 0/40 (0%); partial response 1/40 (3%); stable disease 19/40 (48%); ‘progressive’ disease 10/40 (25%). 40 patients proceeded to surgery, 38 underwent hepatectomy (2 peritoneal disease, resectability rate 95%). 30-day post-operative mortality 5% (n=2), neither death TACE related (1 intraoperative pneumomediastinum, 1 aspiration pneumonia). 63 lesions (median 2 per patient) targeted with TACE. Histology: no residual disease 17%; 1-49% residual disease 59%; >50% residual disease 22%; no response 2%. Conclusions: Resection after neoadjuvant DEBIRI-TACE for CRLM is feasible and safe. Single treatment with DEBIRI-TACE resulted in tumor pathologic response similar to that seen after protracted systemic chemotherapy.
Efficacy and safety of bevacizumab in metastatic colorectal cancer (mCRC): Pooled analysis from randomized controlled trials (RCTs).
Authors: Tebbutt Niall Christopher , Hurwitz Herbert , Kabbinavar Fairooz , Giantonio Bruce J. , Guan Zhongzhen , Mitchell Lada , Waterkamp Daniel , Tabernero Josep 
Published: March 2020

3614 Background: Bevacizumab (BV) with chemotherapy (CT) is a standard treatment for mCRC. This analysis pooled individual patient data from the clinical databases of seven RCTs (phase II or III) of BV in 1st- or 2nd-line treatment to further define clinical outcomes, including within subgroups. Methods: Patient data were pooled from 1st-line (AVF2107, NO16966, ARTIST, AVF2192, AVF0780, AGITG MAX) and 2nd-line (ECOG E3200) trials. All analyses were based on the intent-to-treat population. Overall and progression-free survival estimates (OS, PFS) were calculated by Kaplan-Meier methods. To assess differences in time to response variables by treatment arm (CT vs BV + CT), stratified random (overall) and fixed (subgroup comparisons) models were used to estimate pooled hazard ratios (HRs) and 95% confidence intervals (CIs), with each study included as a stratum. Results: Of the 3,763 pooled patients (CT [n=1773]; BV + CT [n=1990]), 58.8% were male, 39.6% were ≥65 years, and 45.7% had an ECOG performance status ≥1. OS and PFS were statistically significantly increased in BV-treated patients vs control patients. Safety data in this pooled analysis were consistent with the profile of BV from the individual studies. Conclusions: The addition of bevacizumab to CT resulted in statistically significant improvements in survival outcomes for mCRC patients in the overall analysis, with PFS benefit extending across subgroups defined by CT intensity, CT regimen, and KRAS status. [Table: see text]
Clinicopathologic and molecular associations of PIK3CA and PTEN mutation in colorectal cancer.
Authors: Day Fiona Lee , Desai Jayesh , Jorissen Robert N , Gibbs Peter , Mouradov Dmitri , Li Shan , Sieber Oliver 
Published: March 2020

3623 Background: The phosphatidylinositol 3-kinase (PI3K) signaling pathway has been implicated in the development of colorectal cancer (CRC), however a systematic analysis of pathway members and their association with clinical, pathological and other molecular features has been lacking. Methods: We determined the prevalence of PIK3CA (exons 9, 20) mutations in a large cohort (n=1092) of community-based patients (pts) with stage I-IV CRCs. A subset (n=744, 68%) were also tested for mutation in PTEN (exons 3,4,5,6,7,8), PTEN LOH and CIMP. All tumors were characterised for MSI, KRAS and BRAF mutations, and annotated for clinico-pathologic features and patient outcomes in a prospectively-recorded database. Detected novel PIK3CA exon-specific correlates were further explored in a combined analysis integrating the data of other published cohorts (total n=3677). Results: PIK3CA mutations occurred in 11.6% of primary tumors and were associated with older pt age (p=0.009), proximal site (p<0.001), lower lymphovascular invasion (p=0.018) and KRAS mutation (p<0.001), but not with gender, tumor stage or differentiation. Direct comparison of PIK3CA exon 9 and 20 mutations in the combined analysis (mixed effect logistic regression) finds both at increased frequency in KRAS-mutant tumors (p=0.098 for difference); however PIK3CA exon 20 mutations uniquely correlated with BRAF mutation (p=0.002 for difference), MSI (p<0.001) and CIMP-high status (p=0.031). PTEN mutations were present in 5.8% of tumors and associated with proximal site (p=0.013), mucinous histology (p=0.013), MSI (p<0.001), CIMP-high (p<0.001), and BRAF mutation (p<0.001). There was a trend toward mutation of both PIK3CA and PTEN and strong selection for two hits to PTEN (mut/mut or mut/LOH, p<0.001). In our cohort neither PIK3CA or PTEN mutation were associated with pt survival outcomes. Conclusions: In CRC, common mutations in the PI3K signaling pathway are universally associated with proximal site, however display unique gene- and exon-specific associations with tumor histology, MSI, CIMP, KRAS and BRAF mutation. These need to be considered when exploring targeted therapeutic options for pts with CRC.
Activity of cabozantinib (XL184) in hepatocellular carcinoma: Results from a phase II randomized discontinuation trial (RDT).
Authors: Verslype Chris , Cohn Allen Lee , Kelley Robin Katie , Yang Tsai-Shen , Su Wu-Chou , Ramies David A. , Lee Yihua , Shen Xiaodong , Van Cutsem Eric 
Published: March 2020

4007 Background: Cabozantinib (cabo) is an oral, potent inhibitor of MET and VEGFR2. MET over-expression has been observed in advanced hepatocellular carcinoma (HCC). Anti-VEGF pathway agents have shown clinical benefit in pts w/ HCC. Simultaneous targeting of the MET and VEGF signaling pathways with cabo may therefore be a promising treatment strategy. Methods: Eligible HCC patients (pts) were required to have measurable disease per RECIST, ≤ 1 prior systemic regimen and Child-Pugh score of A. Pts received cabo at 100 mg qd over a 12 wk Lead-in stage. Tumor response (mRECIST) was assessed q6 wks. Treatment ≥ wk 12 was based on response: pts with PR continued open-label cabo, pts with SD were randomized to cabo vs placebo, and pts with PD discontinued. Primary endpoint in the randomized phase was progression free survival (PFS). The primary endpoint was overall response rate (RR) per mRECIST in the Lead-in stage. Results: Enrollment has been completed (n = 41); all pts are unblinded. Median age: 61 years (33 to 83). Males: 76%; Asian: 37%. HCC etiology: Hep B 24%; Hep C 22%; alcohol abuse 20%; other 38%. Extra-hepatic spread observed in 70%. Median number of prior systemic treatments was 1; prior sorafenib was 51%. Median baseline AFP was 368 ng/mL (3 – 259,298); 86% had elevated AFP at baseline. Median follow-up was 5.5 mos (0.8 -18.5). 29 pts (71%) completed the Lead-in stage. Median PFS from Study Day 1 was 4.2 mos. 2/36 pts evaluable for tumor assessment at 12 weeks achieved a confirmed PR (cPR) by original RECIST (RR 5%). One more pt randomized at Week 12 achieved a cPR at 18 weeks. 28/36 pts (78%) with ≥1 post-baseline scan had tumor regression (with no apparent relationship to prior sorafenib therapy). The overall disease control rate (DCR = PR+SD) at Week 12: was 68% (Asian subgroup: 73%). AFP responses (defined as reduction from baseline of >50% in pts with elevated AFP at baseline) in 26 pts with ≥1 post-baseline result: 10/26 (38%). Most common Gr 3/4 AEs: diarrhea (17%), palmar-plantar erythrodyesthesia (15%), and thrombocytopenia (10%). Conclusions: Cabo treatment exhibits activity in HCC pts regardless of prior sorafenib treatment. The safety profile was comparable to that of other VEGFR TKIs.
Assessment of HER2 gene amplification in adenocarcinomas of the stomach or gastroesophageal junction in the INT-0116/SWOG9008 clinical trial.
Authors: Gordon Michael Alexander , Gundacker Holly , Benedetti Jacqueline , Macdonald John S. , Baranda Joaquina Celebre , Levin Wendy J. , Blanke C. D. , Elatre Wafaa , Weng Peggy , Lenz Heinz-Josef , Press Michael F. 
Published: March 2020

4010 Background: Trastuzumab has been approved for treatment of patients with HER2-positive metastatic gastric carcinoma; however, relatively little is known about the role of HER2 in the natural history of this disease. Methods: Patients enrolled in the INT-0116/SWOG9008 phase III gastric cancer clinical trial (n=559) were retrospectively evaluated for HER2 gene amplification by fluorescence in situ hybridization (FISH)(n=258), overexpression by immunohistochemistry (IHC)(n=148) and HER2 amplification by silver-enhanced in situ hybridization (n=77) based on availability of tissue specimens. The purpose of the original clinical trial was to evaluate the benefit of post-operative 5-fluorouracil/leucovorin plus radiation therapy compared to surgery alone. Results: HER2 gene amplification rate by FISH was 10.9% in tumor tissue from 258 patients evaluated. HER2 status determined by FISH was 92% concordant with SISH. HER2 overexpression rate by IHC was 12.2% among 148 patients evaluated, with 90% agreement between FISH and IHC. There was a significant interaction between HER2 status by FISH and treatment with respect to both OS (p=0.034) and DFS (p=0.020). Among patients with HER2 non-amplified cancers, treated patients had a median OS of 44 months compared to 24 months for patients in the surgery only arm (34 and 17 months respectively for DFS, p=0.003). Among 28 patients with HER2 amplified cancers, the medians for OS were 16 months in the treated arm, and 22 months in the surgery arm (p=0.55) (13 and 11 months respectively for DFS, p=0.87). We were unable to detect a statistically significant treatment benefit in this small subset of patients with HER2 amplification. HER2 amplification status was not an independent prognostic marker of OS among patients who received no postoperative chemotherapy or radiation therapy (p=0.76). Conclusions: Patients lacking HER2 amplification responded significantly to treatment as indicated by both OS and DFS.
Long-term survival in patients with pancreatic cancer: Relevant factors in CONKO-001.
Authors: Sinn Marianne , Sinn Bruno Valentin , Striefler Jana Kaethe , Stieler Jens , Niedergethmann Marco , Gellert Klaus , Neuhaus Peter , Dörken Bernd , Denkert Carsten , Riess Hanno , Oettle Helmut 
Published: March 2020

4020 Background: Long-term survival (LTS) in patients with pancreatic cancer is still rare, even in resectable and potentially curative stages. Few prospective data are available to identify predictive factors. The CONKO-001 study establishing adjuvant gemcitabine (GEM) may provide data to answer this question. Methods: CONKO-001 patients (pts) with an overall survival > 5 years were included in this analysis and compared to those with < 5 years. Central re-evaluation of the primary histology was done to confirm the diagnosis of pancreatic adenocarcinoma. Univariate analysis with the x²-test identified qualifying factors (p<0.10). Logistic regression with a stepwise selection process was used to investigate the influence of these covariates on LTS. Results: Of the 354 pts included in the intention-to-treat analysis of CONKO-001, 53 (15%) pts with an overall survival of more than 5 years could be identified, for 39 (74%) tumor specimens could be obtained. In 38 (97% of pts with LTS) the diagnosis of adenocarcinoma was confirmed, 1 showed a high-grade neuroendocrine tumor. Relevant factors for all 53 pts with LTS compared to remaining 301 non-LTS pts in univariate analysis were active treatment (GEM) (68% in LTS pts vs 48% in non-LTS pts; p=0.006), tumor grading (G1 17% vs 3%, G2 64% vs 55%, G3 17% vs 40%; p=0.000), tumor-size (T2 15% vs 9%, T3 74% vs 84%; p=0.004) and lymph nodes (N0 47% vs 25% N1 53% vs 74%; p=0.003. Significance could not be demonstrated for resection margin (R0 vs R1), sex, age, Karnofsky performance status (<80% vs 80% vs >80%) and CA 19-9 (40-100 U/ml vs <40 U/ml) at study entry. In the multivariate analysis tumor grading (gr) (odds ratio gr 3 vs gr 1=0.07; gr 3 vs gr 2= 0.38; p=0.017) and active treatment (odds ratio GEM vs observation=0.38; p=0.004) were the only independent prognostic factors. Conclusions: Long-term survival can be achieved in adenocarcinoma of the pancreas. In pts with completely resected pancreatic cancer, tumor grading and active treatment with GEM were the only predictive factor for LTS.
A phase IB/randomized phase II study of gemcitabine (G) plus placebo (P) or vismodegib (V), a hedgehog (Hh) pathway inhibitor, in patients (pts) with metastatic pancreatic cancer (PC): Interim analysis of a University of Chicago phase II consortium study.
Authors: Catenacci Daniel Virgil Thomas , Bahary Nathan , Edelman Martin J. , Nattam Sreenivasa R. , Marsh Robert de Wilton , Kaubisch Andreas , Wallace James Alfred , Cohen Deirdre Jill , Stiff Patrick J. , Sleckman Bethany G. , Thomas Sachdev P. , Lenz Heinz-Josef , Henderson Les , Zagaya Ciara , Vannier Michael , Karrison Theodore , Stadler Walter Michael , Kindler Hedy Lee 
Published: March 2020

4022 Background: Sonic Hh (SHh), the ligand for the Hh pathway, is over-expressed in >80% of PC. V, a small molecule antagonist of the Hh signaling pathway, has activity in preclinical PC models. Methods: We conducted a multi-center, placebo-controlled, phase IB/randomized phase II trial of GV or GP. Eligible pts, KPS 80-100, had previously untreated metastatic PC, or had completed adjuvant therapy > 6 months (mo) prior. Primary endpoint: progression-free survival (PFS). Correlatives: serial SHh serum levels; serial contrast perfusion CT imaging. To allow for early stopping due to lack of efficacy, a planned interim analysis was performed after approximately 50% of the expected number of PFS events occurred. The protocol stipulated that the trial would be terminated if the probability of rejecting the null hypothesis were the trial to continue (conditional power) was <10%. All pts received G 1000mg/m2 over 30 minutes, days (D) 1, 8, 15, Q28D. Pts, stratified by KPS (80 v 90/100), and disease status (newly-diagnosed/recurrent), were randomized to V (150 mg PO daily) or P. For pts on P, cross-over was allowed at progression. Results: 70 evaluable pts (V/P 35/35) enrolled at 12 sites 2/10-6/11. Pt characteristics: median age 63/63 (range 49-79/48-82); KPS 80: 8/8; 90: 12/14; 100: 15/13. Grade 3/4 toxicity (%pts): neutropenia 20/26; hyponatremia 3/11; fatigue 9/6; hyperglycemia 14/6; elevated alkaline phosphatase 9/11. Response (%): complete 0/3, partial 0/11, stable disease 49/31. Median PFS: 3.7/2.4 mo (95% CI: 2.4-4.6/1.9-3.7; adjusted HR 0.92 [0.52-1.64]). Upon progression/unblinding, 23 GP pts crossed over to GV. Median overall survival (OS): 6.3/5.4 mo (95% CI:4.9-7.8/4.2-8.0, adjusted HR 0.97, [0.47-2.01]). 1-year survival (%): 24/24. Laboratory and radiological correlatives will be presented. Conclusions: GV has an acceptable toxicity profile. This trial did not meet criteria for futility at this interim analysis. The study is expected to complete accrual of 112 pts in February 2012. The final analysis will be reported after 90 events. Funded by NCI N01-CM-62201.