bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cetuximab combined with infusional 5-fluorouracil/folinic acid (5-FU/FA) and oxaliplatin in metastatic colorectal cancer (mCRC): A pooled analysis of COIN and OPUS study data.
Authors: Taïeb Julien , Maughan Tim , Bokemeyer Carsten , Van Cutsem Eric , Brodowicz Thomas , Folprecht Gunnar , Esser Regina , Schlichting Michael , Tabernero Josep 
Published: March 2020

3574 Background: Infusional 5-FU/FA + oxaliplatin is a widely used schedule in the first-line treatment of mCRC. In the randomized phase II OPUS study, the addition of cetuximab to one such regimen (FOLFOX4) significantly improved response and progression-free survival (PFS) in patients (pts) with KRAS wild-type (wt) mCRC. However, in the randomized phase III COIN study, a benefit for the addition of cetuximab to first-line fluoropyrimidine (administered as either infusional 5-FU or capecitabine) + oxaliplatin was not confirmed in pts with KRAS wt tumors. Methods: A pooled study-based analysis of treatment outcome in pts with KRAS wt tumors from the OPUS study and COIN subgroup who received infusional 5-FU/FA + oxaliplatin (as the OxMdG regimen) was carried out using a random effects model. Outcome in the pooled analysis was considered in the context of other randomized studies investigating first-line chemotherapy regimens +/- cetuximab in pts with mCRC. Results: The pooled KRAS wt population included 179 pts from the OPUS study and 244 from the OxMdG subgroup of the COIN study. A benefit for the addition of cetuximab to infusional 5-FU/FA was suggested for response (odds ratio 1.87, 95% CI 1.07–3.28) and PFS (hazard ratio, HR 0.69, 95% CI 0.52–0.92) but overall survival (OS) did not show a statistically significant improvement (HR 0.90, 95% CI 0.73–1.11). These response and PFS data are similar to those of the KRAS wt population of the CRYSTAL study investigating infusional 5-FU/FA and irinotecan +/- cetuximab (response: odds ratio 2.07, 95% CI 1.52–2.83; PFS: HR 0.70, 95% CI 0.56–0.87) whereas the improvement in OS was statistically significant in that study (HR 0.80, 95% CI 0.67–0.95). Similar efficacy of FOLFOX + cetuximab and FOLFIRI + cetuximab in the first-line treatment of mCRC was also suggested by data from the randomized phase II CORE 1.2.001 and CELIM studies. Overall, the safety profile of infusional 5-FU/FA and oxaliplatin + cetuximab was found to be acceptable and manageable. Conclusions: The pooled analysis supports the use of cetuximab combined with infusional 5-FU/FA and oxaliplatin in the first-line treatment of KRAS wt mCRC.
Is conversion to resection possible with hepatic arterial infusion (HAI) and systemic (SYS) even in previously treated patients (pts) with unresectable colorectal liver metastases (UnCLM)?
Authors: Kemeny Nancy E. , Fong Yuman , Paty Philip , Chou Joanne F. , Capanu Marinela , Gewirtz Alexandra N. , Jarnagin William R. , DeMatteo Ronald P. , Allen Peter J , Kingham T. Peter , Ang Celina , Cercek Andrea , D'Angelica Michael Ian 
Published: March 2020

3577 Background: Previously, we showed thatHAI with FUDR + dexamethasone (Dex) plus SYS produced a 47 % resectability rate in a retrospective study of 49 pts with UnCLM. Methods: Prospectively evaluated UnCLM pts in a new protocol were combined with the above protocol (n=105 pts) and all were treated with HAI FUDR/Dex + Sys. Unresectability was defined as diffuse bilateral metastases, involvement of all hepatic/portal veins, and/or inability to preserve remaining liver with adequate perfusion. Factors associated with conversion were identified using a multivariate logistic regression model. Overall survival (OS) and progression free survival (PFS) were calculated from pump placement by the Kaplan-Meier method. Resectability was a time-dependent covariate in a Cox regression model. Results: 61 of the 105 pts had prior SYS (56 %with prior Oxali) and 45 (74%) were progressing at the time of pump placement. In previously treated pts, 44% underwent resection, with a median OS of 45 mos. Of 44 chemo-naïve pts, 57% underwent hepatectomy, with a median OS of 68 mos. The following were significantly associated with resection conversion: lesion number [p=0.02], baseline CEA [p=0.04], females [p=0.03] and clinical risk score (CRS) [p=0.05]. In multivariate analysis, gender and CRS remained predictive of resectability. Surgery greatly reduced the hazard of death by 67% [HR: 0.33, 95%CI: 0.17-0.61, p=0.0004], after adjusting for several risk factors (Table). Median PFS was 12 mos for all pts. Conclusions: Even in previously treated pts,HAI + SYS is an approach to convert UnCLM to resection. Gender and CRS are associated with conversion to resectability. [Table: see text]
Activity of the anti-IGF-1R antibody dalotuzumab (MK-0646) in KRAS-mutant colorectal cancer: Preclinical and clinical data.
Authors: Sathyanarayanan Sriram , Ayers Mark , Cunningham David , Tejpar Sabine , Tabernero Josep , Hawkes Eliza Anne , Kim Tae Won , Kim Tae-You , Kim Sun Young , Loboda Andrey , Nebozhyn Michael , Mogg Robin , Naumov George , Bloecher Andrew , Valentine Erin , Brown Holly M. , Watkins David J. , Mauro David J. 
Published: March 2020

3587 Background: KRAS mutated metastatic colorectal cancer (mCRC) is inherently resistant to EGFR targeted therapy and carries an inferior prognosis to wild-type disease with a median survival of approximately 16 months. Methods: The activity of dalotuzumab (Dz) has been investigated in KRAS mutant pre-clinical colon cancer models. In addition efficacy data relating to a sub-set of KRAS mutant mCRC patients enrolled in a randomized phase II/III study (initiated prior to the introduction of KRAS genotyping) of Dz in combination with cetuximab (Cx) and irinotecan (Ir) are reported. All patients had received Cx and Ir with either placebo (n=20), weekly Dz (n=18), or 2 weekly Dz (n=31). Results: In pre-clinical models, Dz was found to be effective in inhibiting IGF-1 mediated cellular growth. Furthermore, in colorectal cancer xenograft models high IGF-1 was found to identify a sub-set of Dz responsive tumours. Combination studies demonstrated that Irinotecan exposure resulted in the activation of IGF-1R and PI3K signaling pathways, representing a possible cellular survival mechanism. In xenograft models the combination of Dz with irinotecan produced lasting tumor growth inhibition that persisted even after treatment withdrawal. Outcome data are reported for 69 patients with KRAS mutant mCRC enrolled in the randomized study. Efficacy data demonstrated differential activity between colon versus rectal tumours with evidence of activity in the rectal subgroup. Molecular analysis suggests that this observation may be mediated by differential IGF-1 expression. Conclusions: These data suggest that Dz in combination with irinotecan may have utility in the treatment of KRAS mutated colorectal cancer patients. Based on these data Dz is being further evaluated in a molecularly selected population of mCRC. [Table: see text]
Early tumor shrinkage in patients with metastatic colorectal cancer receiving first-line treatment with cetuximab combined with either CAPIRI or CAPOX: An analysis of the AIO KRK 0104 trial.
Authors: Modest Dominik Paul , Laubender Ruediger Paul , Fischer von Weikersthal Ludwig , Vehling-Kaiser Ursula , Stauch Martina , Hass Holger , Dietzfelbinger Hermann F. , Oruzio Daniel V. , Klein Stefan , Zellmann Klaus , Decker Thomas , Schulze Mathias , Abenhardt Wolfgang , Puchtler Gerhard , Kappauf Herbert W. , Mittermueller Johann , Haberl Christopher , Stintzing Sebastian , Mansmann Ulrich Robert , Heinemann Volker 
Published: March 2020

3588 Background: This study investigated the impact of early tumor-shrinkage (ETS) on progression-free (PFS) and overall survival (OS) in patients with metastatic colorectal cancer (mCRC) treated within the AIO KRK-0104-trial. ETS was previously shown to be a predictor of treatment response to cetuximab. The present analysis, for the first time, evaluates the correlation of ETS with outcome parameters in patients undergoing capecitabine-based therapy. It also aims to correlate the predictive value of ETS and cetuximab-induced skin toxicity. Methods: The AIO KRK0104 trial was performed as a randomised study comparing capecitabine/oxaliplatin (CAPOX) plus cetuximab to capecitabine/irinotecan (CAPIRI) plus cetuximab in the first-line treatment of mCRC. 121 patients were available for evaluation of ETS at 6 weeks. ETS was defined as a relative change of ≥20% in the sum of the longest diameters of target lesions compared to baseline. Results: Tumors of 63 patients (71% KRAS wild-type (wt), 100% skin reactions) developed ETS, 58 tumors did not develop ETS (53% KRAS wt, 86% skin reactions). ETS was associated with prolonged PFS (8.9 vs. 4.7 months, p<0.001, hazard ratio: 0.37) and OS (31.6 vs. 15.8 months, p=0.005, hazard ratio: 0.48) in patients with KRAS wt tumors but not in patients with KRAS mutant mCRC. ETS occurred more frequently with CAPOX- vs CAPIRI-based therapy (p=0.05). There was a highly significant correlation between the occurrence of ETS and cetuximab-related skin toxicity of any grade (I-III) (p=0.002). ETS was documented more frequently in patients with liver metastasis (p=0.09), metastatic involvement of <2 organs (p=0.09), KRAS wild-type tumors (p=0.06) and no previous adjuvant chemotherapy (p=0.06). Conclusions: In patients with KRAS wild-type mCRC receiving capecitabine- and cetuximab-based first-line therapy ETS correlates with prolonged PFS and OS. ETS also correlates with cetuximab-induced skin toxicity. Both parameters may therefore serve as post-randomisation surrogate markers of favourable outcome for cetuximab-based treatment.
Phase II trial of combined chemotherapy with irinotecan, S-1, and bevacizumab (IRIS/Bev) in patients with metastatic colorectal cancer: Update analysis—Hokkaido Gastrointestinal Cancer Study Group (HGCSG) trial.
Authors: Yuki Satoshi , Komatsu Yoshito , Miyagishima Takuto , Kato Takashi , Hatanaka Kazuteru , Nakamura Michio , Kudo Mineo , Akakura Nobuaki , Tateyama Miki , Sakata Yuh 
Published: March 2020

3593 Background: The FIRIS study (Muro K et al. Lancet Oncol 2010;11:853–860) previously demonstrated the non-inferiority of Irinotecan plus S-1(IRIS) to FOLFIRI for metastatic colorectal cancer(mCRC), with progression-free survival (PFS) as the primary endpoint. We previously reported that IRIS plus bevacizumab(IRIS/bev) is very effective as first-line treatment (Komatsu Y et al. ESMO 2010). We now report the updated results of this study. Methods: Eligible patients had to have mCRC with a confirmed diagnosis of adenocarcinoma, an age of >20 years, ECOG performance status (PS) of 0-1, and no history of prior chemotherapy. S-1 40-60 mg twice daily p.o. was given on days 1-14 and irinotecan 100 mg/m2 and bevacizumab 5 mg/kg i.v. were given on days 1 and 15 of a 28-day cycle. The primary endpoint was safety. The secondary endpoints included overall response (OR), progression-free survival (PFS), and overall survival (OS). Results: The target number of 53 patients was enrolled as of March 2009. The results are reported for 52 patients with evaluable lesions. The clinical characteristics of the patients were as follows. The median age was 63.5 years (range, 48 to 82). The male:female ratio was 3:2. The performance status on the Eastern Cooperative Oncology Group scale was 0. In January 2012, on safety analysis, the incidence of grade 3 or 4 neutropenia was 27%. The incidences of other grade 3 or 4 adverse reactions were as follows: diarrhea, 17%; anorexia, 4%; stomatitis, 2%; hypertension, 21%; and gastrointestinal perforation, 0%. The overall response rate was 63.5%. Three patients had complete response. Thirty patients had partial response, 16 had stable disease, none had progressive disease, and 3 were not evaluable. Median progression-free survival was 17.0 months and median survival time was 39.6 months. Conclusions: IRIS/Bev is a remarkably active and generally well-tolerated first-line treatment for patients with mCRC. Randomized control trial comparing this regimen with oxaliplatin containing regimen(XELOX or mFOLFOX6 plus bevacizumab) is being planned.
The effect of deprivation on uptake and outcomes in a population-based FOBt colorectal cancer screening program.
Authors: Mansouri David , Mcmillan Donald C. , Crighton Emilia M , Horgan Paul G 
Published: March 2020

3599 Background: Population-based FOBt colorectal cancer screening has been shown to reduce cancer specific mortality and is used across the UK. Despite evidence that socioeconomic deprivation is associated with increased incidence of colorectal cancer, uptake of screening may be lower in those who are more deprived. The aim of this study was to assess the impact of deprivation on the screening process. Methods: A prospectively maintained database, encompassing the first screening round in a single geographical area, was analysed with deprivation categories calculated from the Scottish Index of Multiple Deprivation 2009. Results: Overall, 395,698 individuals were invited to screening, 204,812(52%) participated and 6,094(3%) tested positive. 32% of screened individuals were in the most deprived quintile. Of the positive tests, 5,457(95%) agreed to be pre-assessed for colonoscopy. 839(16%) did not proceed to colonoscopy following pre-assessment. Of the 4,618 that attended for colonoscopy, cancer was detected in 7%. Colonoscopy results were not recorded in 1,035(22%) cases. Lower uptake of screening was seen in males, those that were younger and those who were more deprived (p<0.001). Higher levels of deprivation were also associated with not proceeding to colonoscopy following pre-assessment (p<0.001). Higher positivity rates were seen in males, those that were older and more deprived (p<0.001). Despite higher positivity rates in the more deprived individuals (4% most deprived vs 2% least deprived, p<0.001), the positive predictive value of detecting cancer in those attending for colonoscopy was lower in those who were more deprived (6% most deprived vs 8% least deprived, p=0.040). Conclusions: Socioeconomic deprivation has a significant effect throughout the FOBt screening process. Individuals who are more deprived are less likely to participate in screening, less likely to complete the screening process and less likely to have cancer identified as a result of a positive test. This study adds further weight to existing evidence that individuals who are more deprived are less likely to engage in population-based FOBt colorectal cancer screening. Novel strategies to improve this are required.
HER2 status in locally advanced rectal cancer and metachronous metastases: Opportunity for a new therapeutic approach?
Authors: Conradi Lena-Christin , Styczen Hanna , Sprenger Thilo , Homayounfar Kia , Wolff Hendrik A. , Bleckmann Annalen , Rüschoff Josef , Middel Peter , Becker Heinz , Ghadimi B. Michael , Beissbarth Tim , Liersch Torsten 
Published: March 2020

3600 Background: Even though the implementation of multimodal treatment strategies including neoadjuvant radiochemotherapy (RCT) has led to improved survival distant metastases are still limiting the prognosis of rectal cancer patients. In this context, we investigated the HER-2 status in rectal cancer patients, UICC stages II and III. Our aim was to assess the HER-2 positivity rate in primary tumors and metachronous metastases. Methods: In this study 264 rectal cancer patients (192 male, 72 female; median age 64 years) from phase-II/-III-trials of the German Rectal Cancer Study Group (CAO/ARO/AIO-94 and 04) were included. HER-2 status was determined pretherapeutically in tumor biopsies as well as resection specimens and metachronous metastases (n=27) using immunohistochemistry (IHC0 to IHC3+) scoring and S-ISH-amplification detection. Tumors with IHC3+ or S-ISH ratio ?2.0 were classified as HER-2 positive; results were correlated with clinicopathological parameters and long-term survival. Results: A positive HER-2 status was found in 12.4% of pre-treatment biopsies, in 29.3% of the resection specimens and 22.2% (n=6) of metastases. With a median follow-up of 46.5 months patients with HER-2-positivity showed better disease free survival (p=0.06) and cancer-specific survival (CSS, p=0.05). The 5-years survival rate was 96.4% (HER-2-positive) versus 79.5% (HER-2-negative). In multivariate analyses HER-2 status was as an independent (p=0.0053) predictor for CSS along with (y)pN-status (p<0.0001) and R-status (p=0.023). Conclusions: HER-2 amplification is detectable in a significant proportion (about 30%) of primary tumors of patients with advanced rectal cancer. Furthermore HER-2 amplification was detectable in 22% of resected metachronous metastases during follow-up. Therefore HER-2 represents a promising target and should be further assessed within prospective clinical trials.
Clinical utility of the preoperative Glasgow prognostic score in patients undergoing potentially curative resection for colorectal cancer.
Authors: Mcmillan Donald C. , Roxburgh Campbell SD , Horgan Paul G 
Published: March 2020

3611 Background: There is now good evidence that, in addition to TNM stage, the pre-operative combination of the standardised measurements of C-reactive protein and albumin, the Glasgow Prognostic Score (mGPS) provides valuable prognostic information. The aim of the present study was to examine the clinical application of the pre-operative mGPS in a large mature cohort of patients undergoing potentially curative resection for colorectal cancer. Methods: From a prospectively maintained database, consecutive patients (n= 797) with histologically proven colorectal cancer who were considered to have undergone potentially curative resection between January 1997 and December 2010 in a single surgical unit at the Royal Infirmary, Glasgow were included in the study. Results: Patients with an elevated mGPS were more likely to be older (p<0.001), female (p<0.05), have colonic tumours (<0.001), present as an emergency (p<0.001), had higher TNM stage (p<0.05) and more likely to die of their disease (p<0.01). The median follow-up was 66 months and using 3 year cancer-specific mortality as an endpoint, the area under the receiver operator curve was 0.652 (95% CI, 0.591–0.714; p<0.001) for the mGPS and 0.668 (95% CI, 0.610–0.727; p<0.001) for TNM stage. The cancer-specific survival, at 3 years, varied between 86% and 64% according to the mGPS and between 88% and 72% according to TNM stage. The cancer-specific survival, at 3 years, in patients with a mGPS 0 was 91% and 81% for TNM stage II and III respectively. The cancer-specific survival, at 3 years, in patients with a mGPS 1 was 89% and 66% for TNM stage II and III respectively. The cancer-specific survival, at 3 years, in patients with a mGPS 2 was 77% and 43% for TNM stage II and III respectively. Conclusions: The results of the present study show the clinical utility of the pre-operative mGPS in predicting cancer specific survival of potentially curative surgery for colorectal cancer.
A phase I dose-escalation study of TAS-102 in patients (pts) with refractory metastatic colorectal cancer (mCRC).
Authors: Patel Manish R. , Bendell Johanna C. , Mayer Robert J. , Benedetti Fabio M. , Rosen Lee S. 
Published: March 2020

3631 Background: TAS-102 is an oral combination of a novel antimetabolite 5-trifluorothymidine (FTD) and a thymidine phosphorylase inhibitor (TPI) that prevents degradation of FTD. In preclinical studies, TAS-102 is effective against human colorectal tumors with innate and acquired resistance to 5FU. A Japanese randomized phase 2 study demonstrated a significant survival improvement of TAS-102 over placebo in refractory mCRC (HR=0.56 p=0.0011, EMCC2011). The present study was conducted to determine the MTD of TAS-102 in Western pts with refractory mCRC. Methods: Pts with mCRC who had received at least 2 lines of chemotherapy including a fluoropyrimidine, irinotecan and oxaliplatin were enrolled at an initial dose level of 30 mg/m2 BID days 1- 5 and days 8-12 every 4wks using a standard 3+3 design. A second dose level of 35 mg/m2, which was the MTD for Japanese pts, was the maximal targeted dose in this study. Results: 12 pts received TAS-102 (30/35 mg/m2=3/9, M/F=7/5, Age 44-75, PS0/1=8/4). Pts received a median of 3 prior regimens for metastatic disease. No DLT was observed in the initial dose level (0/3) and one DLT (grade 3 febrile neutropenia) was observed at 35mg/m2 (1/9). Other drug-related ≥ grade 3 toxicities observed in cycle 1 included neutropenia at 58% (7/12). To date, a median number of treatment cycles at the MTD has not been reached as 5 pts are still receiving therapy (range 1-3+ cycles). Conclusions: Western patients with refractory mCRC showed the same MTD as Japanese pts (35 mg/m2 BID, days 1- 5 and days 8-12 every 4wks) and the safety profile was consistent between the populations. The trial has entered an expansion phase to assess further safety and preliminary efficacy. A phase 3 trial is being planned.
Randomized phase III study of irinotecan (CPT-11) versus weekly paclitaxel (wPTX) for advanced gastric cancer (AGC) refractory to combination chemotherapy (CT) of fluoropyrimidine plus platinum (FP): WJOG4007 trial.
Authors: Ueda Shinya , Hironaka Shuichi , Yasui Hirofumi , Nishina Tomohiro , Tsuda Masahiro , Tsumura Takehiko , Sugimoto Naotoshi , Shimodaira Hideki , Tokunaga Shinya , Moriwaki Toshikazu , Esaki Taito , Nagase Michitaka , Fujitani Kazumasa , Yamaguchi Kensei , Ura Takashi , Hamamoto Yasuo , Morita Satoshi , Okamoto Isamu , Boku Narikazu , Hyodo Ichinosuke ,   West Japan Oncology Group
Published: March 2020

4002 Background: A combination CT of FP has been regarded as the standard first-line treatment for AGC. Although two randomized trials showed a survival benefit of second-line CT (CPT-11 or docetaxel) compared with best supportive care, no standard regimen has been established. In Japan, wPTX has been used more frequently than docetaxel as the second‑line CT. The objective of this study was to compare CPT-11 with wPTX in patients (pts) with AGC refractory to FP. Methods: Patients with AGC refractory to the first‑line FP regimen were randomized 1:1 to either CPT-11 (150 mg/m2, q2w) or wPTX (80 mg/m2, days 1, 8, 15, q4w). The primary endpoint was overall survival (OS) and secondary endpoints were progression‑free survival (PFS), overall response rate (ORR), adverse events and receiving rates of third-line CT. To demonstrate an increase in median OS from 5 months (wPTX) to 7.5 months (CPT-11) with 2-sided alpha 5% and 80% power, 220 pts were required. Results: Between Aug 2007 and Aug 2010, 223 pts were enrolled; 112 pts were randomized to CPT-11 and 111 pts to wPTX. Baseline characteristics were well balanced between arms. Median OS was 8.4 months for CPT-11 and 9.5 months for wPTX (HR 1.132; 95% CI, 0.86-1.49; p=0.38). Median PFS was 2.3 months for CPT-11 and 3.6 months for wPTX (HR 1.14; 95% CI, 0.88-1.49; p=0.33). The ORR was 13.6% (12/88) for CPT-11 and 20.9% (19/91) for wPTX (p=0.20). The most common grade 3/4 adverse events were neutropenia (39.1% for CPT-11 vs. 28.7% for wPTX), anemia (30.0% vs. 21.3%), anorexia (17.3% vs. 7.4%) and fatigue (12.7% vs. 6.5%). Four (4%) CPT-11 and three (3%) wPTX recipients died within 30 days after the last administration. Subsequent CT was performed in 80 pts (71%) for CPT-11 and 97 pts (89%) for wPTX. Seventy-five pts (67%) in the CPT-11 group and 87 pts (80%) in the wPTX group received the crossover CT. Conclusions: The WJOG4007 trial, the first phase III study comparing second-line CT regimens for AGC, did not demonstrate the superiority of CPT-11 over wPTX. Thus, wPTX can be adopted as a control arm of future phase III trials of second-line CT for AGC.