bluuebunny/crossref_metadata_2025 huggingface dataset:
Adjuvant chemotherapy (AC) use and outcomes in stage II colon cancer (CC) with and without poor prognostic features.
Authors: Kumar Aalok , Kennecke Hagen F. , Lim Howard John , Renouf Daniel John , Woods Ryan , Speers Caroline , Cheung Winson Y.
Published: March 2020

3527

Background: AC is frequently considered inpatients (pts) with "high risk" stage II CC, defined by the presence of >/=1 poor prognostic features, such as obstruction or perforation, T4 stage, <12 lymph nodes retrieved, positive margins, and lymphovascular or perineural invasion. However, survival benefits associated with AC use in high risk pts remain largely unproven. Our aims were to 1) examine patterns of AC use in stage II CC and 2) explore the relationship between AC use and survival in high vs low risk pts. Methods: All pts diagnosed with stage II CC in British Columbia from 1999 to 2008 and evaluated at any 1 of 5 regional centers were reviewed. Kaplan-Meier and Cox regression methods were used to correlate a) high vs low risk status and b) receipt of AC with relapse-free (RFS), disease specific (DSS) and overall survival (OS). Results: We identified 1,697 stage II CC pts: 1,236 (73%) high risk and 461 (27%) low risk among whom 363 (29%) and 61 (13%) received AC, respectively. Individuals with high risk features who received AC were younger (median 62 vs 72 years, p<0.001) and had better performance status (ECOG 0/1 47% vs 34%%, p=0.02). In the high risk group, AC was associated with improved 5-year OS, but not with RFS or DSS (Table). After adjusting for confounders, an OS advantage from AC persisted for high risk pts (HR 0.67, 95CI 0.52-0.86, p=0.002), but no significant RFS or DSS benefits were seen (HR 0.76, 95CI 0.58-0.99, p=0.05 and HR 0.75, 95CI 0.55-1.02, p=0.11, respectively). Subgroup analyses showed that individuals with T4 lesions had improved RFS (HR 0.63, 95CI 0.42-0.95, p=0.03), DSS (HR 0.59, 95CI 0.37-0.93, p=0.02), and OS (HR 0.50, 95CI 0.33-0.77, p=0.002). Conclusions: In this population-based cohort of stage II CC, AC was associated with an OS advantage in high risk pts, likely due to pt selection. RFS and DSS benefits were mainly seen in T4 lesions, suggesting a limited role for AC in pts deemed high risk based on clinical and pathological factors. Risk stratification based on molecular testing should be further explored. [Table: see text]
Impact of body mass index (BMI) and weight changes on recurrence and survival in stage III colon cancer (CC).
Authors: Vergidis Joanna , Alipour Sina , Cheung Winson Y.
Published: March 2020

3560

Background: Research suggests that physical activity can lower the risk of relapse and mortality from CC. It is unclear if such potential benefits are mediated through an effect on weight. Our aims were to 1) evaluate the impact of pre-treatment BMI on recurrence and survival in early stage CC, 2) examine how weight gains and losses from baseline may affect outcomes, and 3) explore if the effects of different body compositions are modified by adjuvant therapy (AT). Methods: Patients (pts) diagnosed with stage III CC from 2006 to 2008, evaluated at any 1 of 5 cancer centers in British Columbia, and who had their weights measured serially throughout their AT period were reviewed. Using Cox proportional hazards models, we compared outcomes among a) BMI<25 [normal] vs. 25-30 [overweight] vs. >30 [obese] and b) weight increase or decrease of < vs. >/=5% and < vs. >/=10%, while controlling for confounders. Results: A total of 821 pts were included: median age was 65 years, 50% were men, and 83% were ECOG 0/1. At baseline, 43, 37, and 20% were normal, overweight, and obese, respectively. Compared to pts with normal BMI, those who were overweight or obese did not show an increased risk of recurrence (HR 0.81, 95%CI 0.42-1.58 and HR 1.09, 95%CI 0.48-2.51, respectively, p trend=0.74) or death (HR 0.54, 95%CI 0.26-1.13 and HR 0.62, 95%CI 0.22-1.74, respectively, p trend=0.24). A number of pts experienced weight gain or loss during their AT period, but none of these weight changes affected outcomes (Table). Receipt of AT did not modify the effects of BMI or weight change. In Cox models, advanced age and poor performance status were the main factors that consistently correlated with an increased risk of recurrence and death (p<0.05). Conclusions: Neither baseline BMI nor short-term weight changes during AT appear to affect outcomes in stage III CC. Physical activity likely exert its benefit on relapse and survival by influencing long-term weight changes or acting via other alternative mechanisms. [Table: see text]
Chemotherapy plus cetuximab in patients with liver-limited or non-liver-limited KRAS wild-type colorectal metastases: A pooled analysis of the CRYSTAL and OPUS studies.
Authors: Kohne Claus-Henning , Bokemeyer Carsten , Folprecht Gunnar , Sartorius Ute , Schlichting Michael , Rougier Philippe R , Van Cutsem Eric
Published: March 2020

3562

Background: In the CRYSTAL and OPUS studies, adding cetuximab (cet) to first-line chemotherapy (CT) improved clinical benefit in patients (pts) with KRAS wild-type (wt) metastatic colorectal cancer. In a pooled analysis of these trials the benefit of treatment according to whether pts had liver-limited disease (LLD) or non-LLD was analyzed. Methods: Cox‘s proportional hazards model for overall survival (OS) and progression-free survival (PFS) or logistic regression model for best overall response and R0 resection were used on individual pt data, stratified by study. Likelihood ratio tests were used to explore interactions. Results: Adding cet to CT significantly improved PFS and overall response rate (ORR) in LLD pts, and OS, PFS and ORR in non-LLD pts and increased R0 resection rates (table). No treatment-by-study interactions were found. Treatment effects did not vary significantly by LLD status (PFS p=0.60, OS p=0.68, ORR p=0.0737, R0 resection p=0.71). However LLD vs non-LLD pts had improved outcome in each treatment arm: PFS, CT hazard ratio, HR=0.74, p=0.0910; CT + cet HR=0.66, p=0.0309; OS, CT HR=0.70, p=0.0091; CT + cet HR=0.74, p=0.0388; ORR, CT odds ratio=1.20, p=0.47, CT + cet odds ratio=2.32, p=0.0015; R0 resection, CT odds ratio=3.15, p=0.0496, CT + cet odds ratio=3.82, p=0.0018. Kaplan Meier survival plots will be shown. Conclusions: The OS benefit from adding cet to CT is more pronounced in non-LLD pts, thus strengthening the value of cet in palliative treatment.LLD status is associated with improved prognosis and may be predictive for response in pts receiving CT + cet, facilitating potentially curative resection. More pts (with R0 resection and longer follow-up) may be needed to confirm an OS benefit from CT + cet in LLD pts. [Table: see text]
Evaluation of FDG-PET in pretreatment staging in locally advanced rectal cancer: A prospective study.
Authors: Guillem Jose G. , Ruby Jeannine Alberts , Leibold Tobias , Akhurst Timothy J. , Larson Steven M. , Gollub Marc , Ginsberg Michelle S. , Saltz Leonard
Published: March 2020

3563

Background: The utility of adding 18F-Fluorodeoxyglucose-Positron Emission Tomography (PET) to the pre-treatment staging of patients with locally advanced rectal cancer has not been well evaluated. Methods: Following completion of standard work-up, including physical examination, endorectal ultrasound, CT of the abdomen and pelvis, and chest CT or chest x-ray, 150 patients with primary, resectable, biopsy-proven rectal adenocarcinoma requiring neoadjuvant chemoradiation were enrolled in a prospective, single-stage, phase II study evaluating the role of PET. All patients underwent a dedicated whole-body PET prior to initiation of neoadjuvant chemoradiation. The primary endpoint of this analysis was to determine the accuracy of PET in detecting extrapelvic metastatic disease in primary rectal cancer patients considered operable on the basis of currently-standard work-up. Results: Among the 117 eligible patients found to be stage II or III by standard staging techniques, none (0%) were found by PET to have extrapelvic metastatic disease. PET yielded a false positive result in 3 patients (2.6%). PET yielded a false-negative result in 3 patients who were subsequently diagnosed with metastatic disease: 2 pre-operatively (liver, lung) and 1 intra-operatively (obturator lymph node). In 1 patient, PET did identify a previously unappreciated obturator lymph node metastasis; left pelvic sidewall dissection at the time of rectal resection confirmed metastatic adenocarcinoma in one obturator lymph node. Conclusions: Of the 117 rectal cancer patients evaluated and found to have locoregional disease by standard examination and imaging techniques, none had extrapelvic metastatic disease accurately identified by PET. PET did not improve the accuracy of pre-treatment staging. As such, consistent with current NCCN guidelines, PET does not have a role in pre-treatment staging of locally advanced rectal cancer.
The relationship between microRNA-126 and maintenance therapy with bevacizumab after bevacizumab plus chemotherapy as first-line treatment for patients with metastatic colorectal cancer: Results of the phase III Nordic ACT trial NCT00598156 translational study.
Authors: Hansen Torben , Christensen Rene dePont , Andersen Rikke Fredslund , Spindler Karen-Lise Garm , Soerensen Flemming Brandt , Johnsson Anders , Jakobsen Anders Kristian Moeller
Published: March 2020

3573

Background: Maintenance therapy during chemotherapy free intervals is a debatable topic in metastatic colorectal cancer (mCRC). In the Nordic ACT trial patients benefitting from induction chemotherapy plus bevacizumab were randomized to bevacizumab with or without erlotinib. MicroRNA-126 (miRNA-126) is believed to influence angiogenesis in several ways, and we investigated the relationship between miRNA-126 and progression free survival (PFS) under maintenance therapy. Methods: The miRNA-126 was analysed by polymerase chain reaction on both genomic DNA (by the pri-miRNA-126 (A24G) single nucleotide polymorphism (SNP)) and paraffin embedded primary tumors, (which were classified as low or high miRNA-126 expressing tumours using the median value as cut-off). Diagnostic biopsies were not processed due to limited tumour tissue. Of the 159 randomized patients blood samples were available from 151 and primary tumours from 91. The PFS (from time of randomization) was compared using the Kaplan-Meier method and the log rank test. The Cox Regression analyses were used to test for independent contributions. Results: The A24G SNP was not related to PFS, but a significant association was seen between genotypes and miRNA-126 expression levels.Furthermore, the PFS was increased in patients with high tumor miRNA-126 expression compared to patients with low expression, hazard ratio (HR) 0.58 (95% confidence interval (CI) 0.38-0.90), p = 0.015. The median PFS was 6.2 months (95% CI 4.3-6.6 months) and 4.0 months (95% CI 2.6-4.5 months), respectively. Results did not differ between treatment arms, but the Cox Regression analysis confirmed an independent prognostic value of the tumor miRNA-126 expression, HR 0.61 (95% CI 0.39-0.95), p = 0.030. Conclusions: The miRNA-126 may be a potential marker for bevacizumab containing maintenance therapy. A similar relationship with PFS has recently been demonstrated in patients with mCRC treated with chemotherapy only. The results call for validation.
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.
A randomized controlled phase II study of the prophylactic effect of urea-based cream on the hand-foot skin reaction associated with sorafenib in advanced hepatocellular carcinoma.
Authors: Ren Zhenggang , Zhu Kangshun , Kang Haiyan , Lu Minqiang , Qu Zengqiang , Lu Ligong , Song Tianqiang , Zhou Weiping , Wang Hui , Yang Weizhu , Wang Xuan , Yang Yongping , Shi Lehua , Bai Yuxian , Ye Sheng-Long
Published: March 2020

4008

Background: Sorafenib (SOR) has become the standard treatment for advanced hepatocellular carcinoma (HCC). Hand-foot skin reaction (HFSR) is one of the most common adverse events associated with SOR and its occurrence can impact patient quality of life and lead to dose modification or interruption, both of which may negatively impact clinical outcomes. This randomized controlled trial is the first large prospective study to investigate the prophylactic effect of urea-based creams on HFSR associated with SOR. Methods: Patients with advanced HCC treated with SOR were randomly assigned 1:1 to receive prophylactic urea-based cream (Arm A) or best supportive care (BSC) following development of HFSR (Arm B). SOR was administered 800 mg daily. Urea-based cream was given twice daily for up to 12 weeks starting on Day 1. BSC was at the physician’s discretion and excluded urea-based creams. The primary endpoint was the incidence of all-grade HFSR in the first12 weeks. Results: Eight hundred sixty eight patients were enrolled; 439 patients in Arm A and 432 patients in Arm B. There was no difference of baseline characteristics between two arms. Over the 12 week period of study, the incidence of all-grade HFSR was significantly lower in Arm A compared to Arm B; n=246 (56.0%) patients in Arm A versus n=318 (73.6%) patients in Arm B, p<0.0001. The incidence of grade ≥2 HFSR tended to be lower in Arm A compared to Arm B, but did not reach statistical significance; n=96 (21.9%) patients Arm A versus n=126 (29.2%) patients in Arm B, p=0.1638. The median time to the first HFSR event was 2.5 fold longer in Arm A compared to Arm B; 84 days (95% CI 45-93 days) in Arm A and 34 days (95% CI 29-43 days) in Arm B (p<0.001). Conclusions: This is the first large prospective, randomized control trial examining the prophylactic use of urea-based creams for treatment of HFSR associated with a multikinase inhibitor. Compared to BSC, prophylactic topical use of a urea-based cream appears to be effective in preventing and/or delaying the incidence of HFSR associated with SOR treatment in patients with advanced HCC.
Profiling of activated receptor tyrosine kinases in advanced gastric cancers identifies patients with poor prognosis.
Authors: Kim Phillip Sangwook , Lee Jeeyun , Kim Sung , Liu Xinjun , Park Joon Oh , Lee Tani Ann T. , Kim Kyoung-Mee , Kuller Anne , Singh Sharat , Kang Won Ki
Published: March 2020

4011

Background: Metastatic gastric cancer (GCA) remains a therapeutic challenge due to its poor prognosis. Trastuzumab is the only known targeted therapy that has demonstrated a survival benefit in a small subset of metastatic GCAs. Addition of molecular diagnostics for predicting prognosis and therapeutic outcomes can significantly enhance the clinical management of GCAs. Herein, we identify activated receptor tyrosine kinases (RTKs) in distinct GCA subsets that correlate with disease-free survival post-curative GCA surgery. Methods: Fresh frozen GCA tissues from 434 stage I to IV GCA patients were profiled for HER1, HER2, HER3, p95HER2, c-MET and IGF1R RTKs using the multiplexed Collaborative Enzyme Enhanced Reactive (CEER) immunoassay. CEER is a highly sensitive and specific proximity assay that relies on the formation of a triple antibody complex surrounding the target protein. Results: p95HER2, a known trastuzumab resistance mechanism, was identified for the first time in 79% of IHC/FISH-based HER2(+) GCAs. Full-length HER2 expression was heterogeneous with ~20% of HER2(-) GCAs still expressing the HER2 protein. 232/434 GCAs expressed at least one activated RTK analyzed in our study. Of these 232 patients, 121 patients that presented with stage II or III disease at the time of surgery; demonstrated a worse progression-free survival as compared to those where none of the analyzed RTKs were activated (32.6 months vs 76.5 months, p=0.0318). HER axis members were the most commonly activated RTKs with 64% of such GCAs. Approximately 71% of activated cMET tumors demonstrated a co-activation with a HER axis member with a preference for HER1 in ~61% of cMET-activated GCAs. Patients with p-MET(+):p-HER1(+) GCAs had a worse prognosis as compared to those with p-MET(+):p-HER1(-) GCAs (46.2 months vs 82.8 months, p=0.0184). Conclusions: CEER-based RTK characterization revealed concomitantly activated signaling pathways in GCAs which could predict disease recurrence. Comprehensive molecular profiles of GCA tumors can allow for the implementation of these companion biomarkers in GCA therapeutic clinical trials.
Actionable targets in pancreatic cancer detected by immunohistochemistry (IHC), microarray (MA) fluorescent in situ hybridization (FISH), and mutational analysis.
Authors: Von Hoff Daniel D. , Ramanathan Ramesh K. , Evans Douglas B. , Demeure Michael J. , Maney Todd , Wright Brian , Gatalica Zoran , McGinniss Matthew Jerome
Published: March 2020

4013

Background: A great need exists for new therapeutic approaches for patients with pancreatic cancer. Methods: The study cohort included 1029 patients analyzedfor a.) up to 29 different immunohistochemical biomarkers – (e.g., COX-2, MGMT, PGP, RRM1, TOPOI, TOPOII, SPARC etc.)b.); in up to 450 patients’ specimens a whole genome expression analysis was performed using HumanHT-12 v4 beadChips ( Illumina Inc.,San Diego, CA) c.) in up to 695 patients FISH for c-Myc, EGFR, HER2 and TOPO2A gene copy amplifications; and d.) in up to 783 patients sequencing for KRAS, EGFR, PI3CA and BRAF, was performed. Results: IHC identified actionable targets included; 74% high COX-2; 57% negative ERCC1; 8% negative MGMT; 22% negative MRP1; 47% negative PGP; 77% low RRM1, 44% high SPARC; 30% high TOPO2A; 61% high TOPOI and 73% negative TS. Other biologically important findings by IHC for possible new therapeutics included 27% negative PTEN; and 20% high PDGFR. Microarray results presented multiple overexpressed targets for consideration including 36% of specimens with overexpressed adenosine deaminase; 28% asparagine synthase; 17% BCL2; 20% survivin; 23% carboxylesterase; 67% DNMT1; 40% thymidine phosphatase; 49% EPHA2 (and others in the src family of kinases); 57% FOLR2; 41% HDAC1; 62% HiF1α; 23% IL2RA (CD25); 46% NFkB1; 48% OGFR; 32% RARA; 26% VEGFR; and 43% vitamin D receptor. FISH yielded 2% amplified EGFR and 10% amplified Her2neu. Sequencing noted 73% mutated KRAS and 3% mutated PIK3CA. Conclusions: Examining actionable targets in patients’ pancreatic cancers (a)reiterates the commonality and importance of KRAS mutations in this disease (needs renewed targeting effort) (b)suggests that TOPO2 inhibitors (particularly if transport into tumor can be improved) should be examined in this disease (c)suggests other pathways to target including DNA repair, epigenetic, Src and inflammation (d) suggests protein turnover, amino acid targets and folate receptor2 as fresh areas to explore against the disease. Supported in part by a Stand Up To Cancer Dream Team Award.
Dual blockade of epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor-1 (IGF-1R) signaling in metastatic pancreatic cancer: Phase I/randomized phase II trial of gemcitabine, erlotinib, and cixutumumab versus gemcitabine plus erlotinib (SWOG-0727).
Authors: Philip Philip Agop , Goldman Bryan H. , Ramanathan Ramesh K. , Lenz Heinz-Josef , Lowy Andrew M. , Whitehead Robert P. , Iqbal Syma , Gaur Rakesh , Benedetti Jacqueline K. , Blanke C. D.
Published: March 2020

4019

Background: Targeting a single pathway in pancreatic adenocarcinoma (PAC) is unlikely to impact its natural history. EGFR targeting with erlotinib added to gemcitabine (G) marginally improved the outcome of patients with advanced disease. We tested the hypothesis that if the EGFR and IGF-1R pathways are simultaneously blocked then progression free survival (PFS) would be significantly improved by abrogating reciprocal signaling that leads to resistance to either drug. Methods: This was a phase I/randomized phase II (RP2) study testing the anti-IGF-1R monoclonal antibody cixutumumab combined with erlotinib and G in patients with metastatic PAC. The control arm was erlotinib plus G. The primary endpoint of the RP2 portion of the study was PFS. Eligibility included patients with untreated metastatic disease, performance status 0/1, fasting blood glucose less than institutional upper limit of normal, and willingness to provide tissue and blood specimens for correlative studies. Results: In phase I portion (n=10) safety of cixutumumab 6 mg/kg IV/wk, erlotinib 100 mg/day orally and G 1000 mg/m2 IV D 1, 8, and 15 of a 28-day cycle was established. In the RP2 portion (n=124) 114 eligible patients (median age 63) were included. On the cixutumumab arm, 59% of patients were female vs. 40% on control arm. Median PFS and overall survival were 3.7 and 6.7 months, respectively, in both arms of the study. Major grade 3 and 4 toxicities were (cixutumumab/control) elevation of transaminases (12%/6%), fatigue (16%/12%), gastrointestinal (35%/28%), neutropenia (21%/10%), and thrombocytopenia (16%/7%). Grade 3/4 hyperglycemia was seen in 16% of patients on cixutumumab. Grade 3 or 4 kin toxicity was similar in both arms of the study (< 5%). Five treatment-related deaths were reported: 2 cardiac on each arm, 1 pulmonary on cixutumumab. Conclusions: IGF-1R inhibitor cixutumumab did not improve the progression free or overall survival of patients with metastatic PAC treated with erlotinib and G in a molecularly unselected population.
Observations of hepatocellular carcinoma (HCC) management patterns from the global HCC bridge study: First characterization of the full study population.
Authors: Park Joong-Won , Sherman Morris , Colombo Massimo , Roberts Lewis R. , Schwartz Myron E. , Degos Francoise , Chen Pei-Jer , Chen Minshan , Kudo Masatoshi , Johnson Philip James , Huang Baisong , Orsini Lucinda S.
Published: March 2020

4033

Background: HCC is a major health problem across the world. The global HCC BRIDGE study is the first global, large-scale, observational study to document the real-world experience of HCC patients from diagnosis to death. Methods: This longitudinal cohort study (started March 2009) includes HCC patients newly diagnosed between January 2005 and June 2011 and treated at major medical centers, with data collected retrospectively and prospectively as recorded in patient charts. Full patient enrollment is expected at the end of January 2012. Results: At the time of the first interim analysis (July 2011), 12,442 treated HCC patients were enrolled at 42 sites in Asia (n=8909, 72% [China: n=6295, 71%; Japan: n=295, 3%]), Europe (n=2040, 16%) and North America 1493 (n=1493, 12%). Mean age was 57 years; 82% were male. The predominant risk factor was HBV in Asia (76%) and HCV in Europe (48%), North America (45%) and Japan (69%). Most patients were diagnosed without surveillance (Asia, 82%; Europe, 73%; North America, 69%; Japan, 64%). In Asia, Europe and North America, the predominant BCLC stage at diagnosis was C (48%, 46%, 46%) followed by A (34%, 28%, 26%). First recorded treatments in Asia, Europe and North America were resection (31%, 15%, 21%), transplantation (1%, 3%, 1%), TACE (49%, 30%, 36%), other locoregional therapy (12%, 35%, 23%) and systemic therapy (3%, 10%, 8%). Treatments ever used (2005–2011) in Asia, Europe and North America were resection (33%, 17%, 24%), transplantation (2%, 6%, 12%), TACE (57%, 35%, 48%), other locoregional therapy (20%, 42%, 37%) and systemic therapy (9%, 20%, 21%). These results will be updated with data from the full study population (approx. 19,000 patients), and preliminary survival data will be presented. Conclusions: As the largest study of its type, in 19,000 patients worldwide, the HCC BRIDGE study provides valuable insights into global HCC disease characteristics and patient management. Based on prior analyses, differences in risk factors among regions confirm well-known trends, while other observed differences (e.g., treatment variations) may be related to country- and site-specific practices and patient characteristics.