bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aflibercept versus placebo in combination with FOLFIRI in previously treated metastatic colorectal cancer (mCRC): Mean overall survival (OS) estimation from a phase III trial (VELOUR).
Authors: Joulain Florence , Van Cutsem Eric , Iqbal Sheikh Usman , Hoyle Martin , Allegra Carmen Joseph 
Published: March 2020

3602 Background: VELOUR evaluated the efficacy and safety of the novel fusion protein aflibercept (VEGF Trap) in combination with FOLFIRI in mCRC patients previously treated with oxaliplatin. Median OS showed significant improvement with 12.06 months in placebo arm vs 13.50 months in aflibercept arm (p=0.0032; HR=0.82 [95.34% CI: 0.71 to 0.94]) [Van Cutsem, 2011]. Since survival data in oncology are usually right skewed, median survival is preferred for regulatory purposes. However, mean survival estimation can render a more meaningful estimate for long term benefit of interventions, and be effectively applied to clinical and economic decision support. Estimating mean OS also allows payers to derive an estimation of total costs and outcomes in the population. The purpose of this study was to estimate the mean OS for VELOUR trial. Methods: During the trial follow-up period, mean OS is not observable and can be estimated by extrapolating the trial Kaplan-Meier curve using a survival function. Several standard parametric distributions were tested: exponential, weibull, lognormal, loglogistic and gompertz. Akaike’s Information Criteria (AIC), Bayesian Information Criteria (BIC) and graphical method were used to evaluate the goodness of fit of the distributions. Models were run by treatment arm separately or combining the two arms and using treatment as covariate to control for variation. Results: Using AIC/BIC and graphical method, loglogistic function best fit the VELOUR data both with and without treatment as covariate. Weibull distribution is used for sensitivity analysis. Conclusions: Using loglogistic function, mean OS benefit for aflibercept in combination with FOLFIRI is at least 2.9 months (versus 1.4 months difference in median survival). The results have important implications for clinical and economic decision support. Study NCT00561470 was funded by sanofi, in partnership with Regeneron. [Table: see text]
Does multiple mutational analysis of the EGFR pathway have a prognostic role in advanced colorectal cancer (CRC)?
Authors: Foltran Luisa , Aprile Giuseppe , De Maglio Giovanna , Pisa Federica Edith , Casagrande Mariaelena , Ferrari Laura , Lutrino Stefania Eufemia , Mazzer Micol , Masiero Elena , Pella Nicoletta , Giovannoni Mariella , Iaiza Emiliana , Cardellino Giovanni , Ermacora Paola , Durastante Vittorio , Cristin Antonio , Petri Roberto , Pizzolitto Stefano , Fasola Gianpiero 
Published: March 2020

3612 Background: BRAF mutation is widely recognised as a strong negative prognostic factor in advanced CRC, while the prognostic value of KRAS mutations in codons 12-13 remains controversial. Exploring mutations in other downstream components of the EGFR pathway may have an impact on survival. Methods: A consecutive cohort of 201 metastatic CRC patients treated with systemic chemotherapy were analysed for KRAS (12-13-61-146), BRAF, PIK3CA and NRAS genotypes by pyrosequencing on PyroMarkTMQ96 ID instrument (Qiagen, Germany) with commercially available kits Anti-EGFR MoAb response (Diatech Pharmacogenetics, Italy). Accurate microdissection guaranteed more than 70% of cancer cells for each sample. For the purpose of the survival analysis 4 categories were created: (1) KRAS mutated (codons 12-13 only); (2) BRAF mutated; (3) any of KRAS codons 61-146, PIK3CA or NRAS mutations; (4) all-wild type. Log-rank and Cox proportional tests were applied for statistical analysis. Results: KRAS mutations were present in 96 (47.8%) patients: 86 (42.8%) were in codons 12-13. BRAF mutations were found in 11 (5.5%) samples while PIK3CA and NRAS in 33 (16.4%) and 7 (3.5%), respectively. All mutations were mutually exclusive except for 24 (11.9%) patients with concomitant KRAS/PIK3CA mutations. Median survivals for different categories are shown. Patients harbouring BRAF mutation had the worst outcome (p=0.0006). Mutations of any codon of KRAS (12-13-61-146) also negatively impacted on survival (p=0.026), while the all wild-type (KRAS/BRAF/PIK3CA/NRAS) patients had the longest survival (p=0.002). Conclusions: This study suggests the usefulness for early molecular profiling for advanced CRC patients. Mutational analysis of all EGFR pathway components may identify different prognostic subgroups. This information may drive treatment selection in clinical practice and stratification in clinical trials. [Table: see text]
Novel colon cancer tumor suppressor gene, β-defensin 1, to predict recurrence in patients with stage II and III colon cancer.
Authors: Labonte Melissa Janae , Bohanes Pierre Oliver , Yang Dongyun , Loupakis Fotios , Wilson Peter M.D. , Gerger Armin , Ning Yan , Wakatsuki Takeru , Zhang Wu , Benhaim Leonor , Ladner Robert D. , El-Khoueiry Anthony B. , El-Khoueiry Rita , Iqbal Syma , Lenz Heinz-Josef 
Published: March 2020

3622 Background: Human β-defensin 1 (hBD-1) encoded by the DEFB1 gene is an antimicrobial peptide involved in the innate immune response and is expressed in epithelial cells, including the colon. hBD-1 has been shown to have tumor suppressor functions in urothelial cancer models. We tested whether 4 germline single nucleotide polymorphisms (SNPs) in DEFB1 could predict time to tumor recurrence (TTR) in stage II and III colon cancer (CC) patients. We then sought to demonstrate if hBD-1 has tumor suppressor functions in CC models. Methods: A total of 234 patients, 105 stage II and 129 stage III, treated with 5-FU-based chemotherapy at the University of Southern California were included. The median follow-up time was 4.4 yrs. SNPs were analyzed from whole blood samples using direct DNA-sequencing. To gain insight into hBD-1’s function, hBD-1 expression in CC cell lines was determined by qRT-PCR and Western blotting. hBD-1 expression was induced ectopically and CC cells and viability, membrane permeability, cell-cycle and apoptosis analyzed. Results: Stage III patients with rs1800972 DEFB1 -44G containing genotypes had longer TTR than patients with C/C genotype (11.3 mo vs 2.7 mo; p=.008). In contrast in stage II, patients with rs1799946 DEFB1 -52A containing genotypes, had significantly longer TTR than patients with G/G genotype (16.8 mo vs 5.9 mo; p=.017). In the multivariate analysis, both DEFB1 -44C/G and DEFB1 -52G/A SNPs remained significant, respectively in stage III (HR=.419; 95%CI .201-.87; p=.020) and in stage II (HR=.360; 95%CI .152-.853; p=.020). Haplotype of all four SNPs was significantly associated with stage-specific TTR (to be presented at the meeting). In CC cell line models, there was a loss of hBD-1 expression, and induction of hBD-1 expression resulted in a loss of cell viability, membrane permeability and the induction of apoptosis. Conclusions: The results demonstrate for the first time evidence of hBD-1’s potential influence on the microenvironment and its role as a tumor suppressor in CC. Further studies need to be conducted to better understand the role of hBD-1 in CC development and progression and evaluate the potential utility of hBD-1 as a therapeutic strategy.
Impact of “poorly differentiated clusters” in primary lesion as a novel prognostic indicator in colorectal liver metastasis.
Authors: Konishi Tsuyoshi , Ueno Hideki , Ishikawa Yuichi , Ueno Masashi , Saiura Akio , Yamamoto Junji , Fukunaga Yosuke , Nagayama Satoshi , Yamamoto Chiriko , Hase Kazuo , Hashiguchi Yojiro , Hatsuse Kazuo , Muto Tetsuichiro , Yamaguchi Toshiharu 
Published: March 2020

3625 Background: Preoperative predictors for survival are needed in colorectal liver metastasis in order to select poor-risk group that truly requires perioperative chemotherapy. This study aimed to elucidate survival predictors in patients undergoing curative hepatectomy for colorectal liver metastasis, particularly focusing on the impact of poorly differentiated clusters (PDC); a novel histologic grading system in primary lesion. Methods: A total of 424 consecutive patients undergoing curative resection of both primary colorectal cancers and metastatic liver lesions at two referral centers were enrolled in the study. Determinants of overall survival (OS) and recurrence free survival (RFS) after hepatectomy were investigated by univariate and multivariate analysis, using detailed clinicopathological parameters in primary and metastatic lesions. Cancer clusters of ≥5 cancer cells and lacking a gland-like structure were counted under a x20 objective lens in a field containing the highest number of clusters at invasive front of primary lesions, and tumors with <5, 5 to 9, and ≥10 clusters were classified as PDC grade (G)1, G2 and G3, respectively (n=65, 132, and 227 tumors, respectively). Results: OS and RFS at 3 years were 59% and 27%, respectively, with average follow up period of 43 months. PDC grade in primary lesion was strongly associated with both 3-year-OS (83%, 62%, and 51%, respectively, p<0.0001) and 3-year-RFS (55%, 30%, and 17%, respectively, p<0.0001). Multivariate analysis revealed that PDC grade in primary lesion was the most potent prognostic factor after hepatectomy independent of T and N of primary lesion and size of liver metastasis. Conclusions: PDC grade in primary lesion is a novel potent prognostic indicator in colorectal liver metastasis, which is independent of T and N. It is noteworthy that PDC grade can bias the survival in clinical studies targeting perioperative chemotherapy in colorectal liver metastasis.
Effect of BSA dosing on 5-FU exposure among colorectal cancer patients depending on their gender and age.
Authors: Haregewoin Abebe , Hamilton Stephanie A. , Grier Charles E. , Kaldate Rajesh R. 
Published: March 2020

3627 Background: 5-fluorouracil (5-FU) remains the cornerstone of colorectal cancer (CRC) therapy and its dosing is based on body surface area (BSA). Although convenient, BSA dosing disregards factors that impact 5-FU PK such as genotype, age, gender, etc. Thus, patients receiving the same BSA based dose show a wide range of 5-FU plasma levels (measured as AUC in mg · h/L), resulting in ineffective or toxic doses affecting therapy outcome. An optimal therapeutic AUC target range of 20-30 mg · h/L has been proposed. Methods: Plasma samples from the initial treatment cycle of 927 CRC patients who received 2,400 mg/m2 continuous infusion of 5-FU over 44-48 hours, with or without bevacizumab, were tested for 5-FU exposure using an immune-based assay (OnDose). AUC results were analyzed to evaluate gender and age effects. Results: There are 391 (42.2%) female and 536 (57.8%) male patients with age ranging from 17-93 years (mean/SD: 58.5/11.8). See table. These analyses indicate that in comparison to the proposed optimal AUC target range of 20-30 mg · h/L, females receive supra-optimal doses compared to males (p=0.0083). Age also affects the 5-FU AUC (p=0.0002), with younger patients more likely to receive suboptimal doses than older patients. Conclusions: BSA dosing is an unreliable indicator of exposure and may lead to under dosing in males and younger patients, and overdosing in females and older patients, potentially resulting in corresponding diminished efficacy or increased toxicity. Data suggest that therapy could be optimizedby 5-FU dose adjustment in subsequent cycles based on PK monitoring so that AUC values will converge towards the target range irrespective of gender or age. A large clinical trial is in progress to validate these findings. [Table: see text]
Surgical resection and peri-operative chemotherapy for colorectal cancer (CRC) liver metastases in routine clinical practice: A population-based outcomes study.
Authors: Booth Christopher M. , Li Gavin , Biagi James Joseph , Krzyzanowska Monika K. , Mackillop William J. , Nanji Sulaiman 
Published: March 2020

3632 Background: Resection of liver metastases combined with peri-operative chemotherapy is an important treatment option for patients with advanced CRC. Most of the literature describes outcomes achieved in highly selected patients treated at a few high volume institutions. Here we report the results of a population-based study of the management and outcome of all patients who underwent resection of CRC liver metastases in Ontario, Canada. Methods: All cases of CRC in Ontario who underwent surgical resection of liver metastases in 1994-2009 were identified using the population-based Ontario Cancer Registry (OCR). The OCR captures diagnostic and demographic information on ~98% of all incident cancer cases in Ontario. We linked electronic records of treatment to the OCR to identify surgery, neoadjuvant (NACT) and adjuvant chemotherapy (ACT). We describe time trends in treatment and survival using 3 study periods: 1994-1999, 2000-2004, 2005-2009. Results: During 1994-2009, 2717 patients underwent resection of CRC liver metastases in Ontario; mean age was 65 years and 61% were male. From 1994-2009 there was a 103% increase in the number of patients undergoing resection of liver metastases (117/year to 237/year) while incident cases of CRC during this time increased by 31% (5285/year to 6956/year). Use of NACT increased over the study period: 94-99, 11% (78/700); 00-04, 15% (124/830); 05-09, 36%; (424/1187), (p<0.001). Use of ACT also increased: 94-99, 38% (263/700); 00-04, 40% (335/830); 05-09, 45% (532/1187), (p=0.006). In 2005-2009 there was substantial variation across geographic regions in use of NACT (range 19% to 46%, p=0.029) and ACT (range 31% to 56%, p=0.015). Five year overall survival during the 3 study periods was 36% (95%CI 32-39%), 40% (95%CI 36-43%), and 47% (95%CI 43-51%) (p<0.001). Conclusions: Resection of CRC liver metastases in routine practice in the general population of Ontario is associated with survival outcomes that are comparable to those reported in case series from leading comprehensive cancer centres. Survival improved over the study period despite a greater proportion of patients with CRC undergoing liver resection.
Optimum time to assess complete clinical response (CR) following chemoradiation (CRT) using mitomycin (MMC) or cisplatin (CisP), with or without maintenance CisP/5FU in squamous cell carcinoma of the anus: Results of ACT II.
Authors: Glynne-Jones Robert , James Roger , Meadows Helen , Begum Rubina , Cunningham David , Northover John , Ledermann Jonathan A. , Beare Sandra , Kadalayil Latha , Sebag-Montefiore David ,   ACT II Study Group
Published: March 2020

4004 Background: In the ACT I trial, relapse-free survival was improved with CRT compared to RT alone, but the CR rate at 6 weeks was similar (39% CRT, 30% RT alone; p=0.08). Most studies assessed CR between 6 and 12 weeks following completion of CRT. We investigated the association between observation of CR at 3 different time-points and progression-free and overall survival (PFS, OS), to determine the optimal time to assess this early endpoint. Methods: ACT II recruited 940 pts between 2001 and 2008. It compared, in a factorial design, CisP versus MMC when combined with 5-FU CRT, and two cycles of maintenance chemotherapy versus no maintenance. CR (complete absence of tumour and node negative) was assessed by rectal exam or imaging at 11, 18 and mandated CT at 26 weeks after the start of CRT. Median follow-up was 5 years. Pts were excluded from analysis if assessment was not done/ missing at one or more time points (n=245). Data from 695 pts were analysed. Results: Pt characteristics (all 940) median age 58 years; tumour site – canal (84%), margin (14%); stage T1-T2 (52%), T3-T4 (46%); N+ (32%), N0 (62%). CisP did not improve OS (HR: 0.96, p=0.89) or PFS (HR: 0.85, p=0.43) compared to MMC. This is consistent with the lack of an absolute difference at 18 and 26 weeks, but not at 11 weeks (where a difference was found). CR patients (compared to not-CR) had a significantly lower risk of progression/death. The association between these outcomes and response was strongest at 26 weeks. 202/695 (29%) pts not in CR at 11 weeks were CR at 26 weeks. Conclusions: 29% of pts not in CR at 11 weeks achieved CR at 26 weeks. Early surgical salvage would not have been appropriate for these pts. We recommend assessment at 26 weeks in future trials. [Table: see text]
A pooled analysis of phase II trials of gemcitabine (GEM)-containing doublets plus bevacizumab (BEV): Should combination chemotherapy serve as the backbone in clinical trials of advanced pancreatic cancer (APC)?
Authors: Van Loon Katherine , Kim George P. , Espinoza Anne Marie , Fogelman David R. , Iyer Renuka V. , Picozzi Vincent J. , Wolff Robert A. , Javle Milind M. , Ko Andrew H. 
Published: March 2020

4038 Background: GEM has served as the chemotherapy platform for most phase III clinical trials in APC, inc. CALGB 80303 (GEM +/- BEV). However, GEM-based combination regimens may confer superior outcomes in select pts and represent a preferred backbone in clinical trial design testing targeted agents. Methods: Data was pooled from 5 phase II trials evaluating GEM-based cytotoxic doublets plus BEV in APC. 1o endpoint was OS. 2o endpoints included ORR, CA19-9 response, and adverse events (AEs). Kaplan-Meier methods estimated time-to-event endpoints. The Cox proportional hazard model estimated univariate hazard ratios (HR) of death. Results: Of 261 pts, 90.7% were Caucasian, 95.4% had an ECOG PS 0-1, and 91.6% had metastatic disease. Median age = 60y. Pooled OS data (in mos), stratified for PS and stage, is shown in the table. ORR across all trials: CR 1.6%, PR 22.9%, SD 50.8%, PD 20.2%, NA 4.7%. HR for pts who achieved disease control (CR/PR/SD) was 0.35 vs. those with PD (95% CI 0.23-0.54, p<0.001). 76.5% of pts had elevated baseline CA19-9; of these, 62% achieved ≥50% reduction (HR 0.50; 95% CI 0.34-0.73, p<0.001). BEV-related AEs ≥grade 3: HTN (10.6%), hemorrhage (9.5%), VTE (10.1%), cardiac events (3.4%), and bowel perforation (2.2%). Median OS in pts with grade 3-4 HTN was 13.4 mos vs. 9.8 mos in those without (HR 0.77; 95% CI 0.48-1.24, p=0.29). Conclusions: Recognizing the limitations of single-arm phase II trial design and cross-study comparisons, these results compare favorably to those from CALGB 80303. The standard paradigm of GEM +/- drug X in clinical trial development for APC needs to be reconsidered. Based on our data as well as the recent phase III FOLFIRINOX study, building on more intensive combination chemo regimens in future trials may represent a better strategy, especially for pts with good PS. [Table: see text]
Evaluation of predictive factors for thromboembolic events in patients with advanced pancreatic cancer: Evaluation of the CONKO-004 (PROSPECT) study cohort.
Authors: Pelzer Uwe , Bischoff Sven , Stieler Jens , Sinn Marianne , Oettle Helmut , Dörken Bernd , Riess Hanno 
Published: March 2020

4044 Background: Patients (pts) with advanced pancreatic cancer (APC) often suffer from symptomatic thromboembolic events (sVTE). The CONKO-004 trial showed that the low molecular weight heparin (LMWH) enoxaparin reduces sVTE (p<0.05, number needed to treat: 12) without increasing the rate of major bleeding when prophylactically applied. Our goal was to identify predictive factors for sVTE in pts with APC undergoing first-line chemotherapy. Methods: We analyzed the 152 (out of 312) pts randomized in the observation group.SVTE incidence was 9.9%. To identify foremost risk factors we used clinical parameters like performance status, stage, grading, primary or recurrent, gender, age, body mass index, erythropoietin stimulating agents (darbepoetin), as well as baseline laboraty parameters such as creatinine, hemoglobin, WBC, platelets, INR, ptt, CEA, carboanhydrat 19-9, AST, ALT, AP and GGT. The multivariate logistic regression model with forward stepwise selection process was used for this estimation. With reference to a previously proposed scoring system (Khorana et al; Blood 2008) we evaluated the score as well. Results: No single parameter could be isolated demonstrating significant influence on the incidence of sVTE in pts with APC. We verified the Kohrana scoring model with our 152/312 pts. Applying the score to our pts we didn’t discriminate pts between the two high risks groups (Table). Conclusions: Predictive models may help to identify cancer pts at high risk for sVTE to consider preventive anticoagulation. Within a cancer entity at high risk for sVTE such as pts with APC we did not succeed in the identification of single predictive parameters.For pts with APC undergoing first line chemotherapy primary prevention with LMWH should therefore be considered for the whole group of pts for at least three months. [Table: see text]
Phase II trial of bevacizumab, irinotecan, cisplatin, and radiation as preoperative therapy in esophageal adenocarcinoma.
Authors: Ilson David , Goodman Karyn A. , Janjigian Yelena Yuriy , Shah Manish A. , Kelsen David Paul , Rizk Nabil P. , Rusch Valerie W. , Wu Abraham Jing-Ching , Campbell Jenny , Capanu Marinela , Bains Manjit S. 
Published: March 2020

4061 Background: Preop chemo and radiotherapy (RT) with weekly irinotecan (I), cisplatin (C) and 5040 cGy is tolerable and active [Cancer, in press]. Bevacizumab (B) + weekly I/C in advanced esophagogastric cancer increased response rate and PFS without an increase in toxicity [JCO 24: 5201; 2006]. In a phase II trial in esophageal adenocarcinoma (EA) we combed B + I/C with RT as preop therapy. A toxicity analysis after 10 patients (pts) undergoing surgery indicated no unexpected toxicity with B [JCO 27: Abstract 4573; 2009], and we completed a planned accrual of 33 pts. Methods: Pts had resectable distal esophageal or Siewert’s I or II EA, T2-3 or N1 staged by EUS, PET, and CT scan. Induction chemo: I: 50-65 mg/m2 + C: 30 mg/m2 weeks 1,2,4,5, B: 7.5 mg/kg weeks 1 and 4; Chemort: 180 cGy daily fractions to 5040 cGy, I/C weeks 7,8,10,11+ B weeks 7,10. Esophagectomy was planned 6-8 weeks after RT. Postop: B: 7.5 mg/kg every 3 weeks for 8 cycles. Results: 33 pts were enrolled. 26 male: 7 female; distal esophagus 11 (33%), GEJ 22 (67%); 21 T3N1 (64%); 10 T3N0 (30%); 2 T2N0-1 (6%). 25/33 pts went to surgery (76%), 24 had R0 resection (73%). Pathologic CR 5 pts (15%). 8 pts did not going to surgery: 2 for adverse events (9%, 1 CVA due to patent foramen ovale, 1 esophageal perforation due to endoscopic biopsy), 6 for progressive disease (18%). 21/24 pts (88%) received adjuvant B, 20 (95%) completed all cycles. Grade 3/4 toxicity in 30 evaluable pts during chemort: 24% neutropenia, 3% neutropenic fever, 23% esophagitis, 13% dehydration, 13% thrombocytopenia, 7% pulmonary embolism, 3% nausea/vomiting. Surgical complications: 3 anastomotic leaks (12%), 4 respiratory failure (16%), 1 pulmonary embolism (4%), 2 post op deaths (8%). At a median follow up of 20 months, PFS was 14 months and OS was 30 months. Conclusions: The addition of B to preop chemoRT in EA was tolerable without increase in treatment toxicity or surgical complications. There was no suggestion of improved pathologic CR, PFS, or OS with the addition of B to I/C/RT. Evaluation of B in phase III trials of chemort does not appear warranted. Supported by a grant from Genentech.