bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heterogeneity in early lesion changes on treatment as a marker of poor prognosis in patients (pts) with metastatic colorectal cancer (mCRC) treated with first line systemic chemotherapy ± biologic: Findings from 9,092 pts in the ARCAD database.
Authors: Ou Fang-Shu , Hubbard Joleen Marie , Kasi Pashtoon Murtaza , Dixon Jesse , Van Cutsem Eric , Saltz Leonard , Schmoll Hans-Joachim , Punt Cornelis J. A. , Goldberg Richard M. , Hoff Paulo , Douillard Jean-Yves , Hecht J. Randolph , Hurwitz Herbert , Bokemeyer Carsten , Fuchs Charles , Diaz-Rubio Eduardo , Sargent Daniel J. , De Gramont Aimery , Shi Qian , Grothey Axel ,   ARCAD
Published: September 2018

3535 Background: CRC is known to be a heterogeneous disease. This study quantifies within pt heterogeneity in early lesion change rate (LCR) in the era of targeted agents compared to chemo alone and its potential impact on survival. Methods: Pts with 2-10 lesions measured at baseline were included. For each lesion, the early LCR was defined as the change in size (shrinking or growing) from baseline to 12 weeks on treatment. Within pt heterogeneity in early LCR among lesions was estimated by standard deviation (STD). A larger value of STD indicates larger variation of LCR per pt. Stratified multivariate Cox models were used to assess the associations between LCR STD with overall survival (OS). Adjusted hazard ratios (HRadj) and 95% confidence intervals (CIs) are reported. Results: Data were available on 9,092 mCRC pts (median age 61; 60% male, 55% ECOG PS 0; 61% 2+ metastatic sites) enrolled in 16 1st-line randomized trials, with 44%, 42%, and 10% of pts received chemo alone, + a VEGF inhibitor (VEGFi) or an EGFR inhibitor (EGFRi), respectively. LCR heterogeneity is the highest among pts received EGFRi but lowest among pts received VEGFi (Table). Overall, higher heterogeneity is associated with worst OS (HRadj1.22, 95% CI (1.16, 1.27)). The effect is most pronounced in pts received VEGFi (interaction p=0.0012). Conclusions: There was heterogeneity observed in lesion size changes within pts. Its magnitude varies across treatment approaches, and was associated with poor survival. This preliminary result reveals the great potentials to define novel response endpoint and refine treatment decision-making by incorporating heterogeneities in lesion changes. [Table: see text]
Treatments (tx) after progression to first-line FOLFOXIRI plus bevacizumab (bev) in metastatic colorectal cancer (mCRC) patients (pts): A pooled analysis of TRIBE and MOMA studies by GONO group.
Authors: Rossini Daniele , Moretto Roberto , Cremolini Chiara , Zagonel Vittorina , Tonini Giuseppe , Ricci Vincenzo , Aprile Giuseppe , Lonardi Sara , Tomasello Gianluca , Dell'Aquila Emanuela , Allegrini Giacomo , Bergamo Francesca , Mancini Marialaura , Antoniotti Carlotta , Ronzoni Monica , Zaniboni Alberto , Marmorino Federica , Bustreo Sara , Mori Elena , Falcone Alfredo 
Published: September 2018

3542 Background: FOLFOXIRI plus bev is regarded by international guidelines as a valuable option in the first-line tx of mCRC pts. One of the major concerns for the adoption of this regimen is the potential limitation of subsequent therapeutic options. The aim of the present analysis was to focus on treatments received after progression in TRIBE (NCT00719797) and MOMA (NCTNCT02271464) studies. Methods: We collected data of tx received after progression and their outcome in terms of 2ndPFS (time from 2nd line tx start to disease progression or death) and OS II (time from 2nd line tx start to death). For pts in which the same drugs used in first-line were totally or partially reintroduced, the chemotherapy-free interval (CFI, time from the last administration of irinotecan or oxaliplatin during first-line to disease progression) was calculated. Results: Out of 482 pts treated with upfront FOLFOXIRI plus bev, 429 progressed. 303 (70.6%) pts received a 2nd line tx: 93 FOLFOXIRI +/- bev (Group A), 119 FOLFOX/XELOX or FOLFIRI +/- bev (Group B) and 91 other tx (Group C), including an anti-EGFR moAb in 60 cases. No difference was observed among the three groups in terms of 2ndPFS (median 2nd PFS Group A: 5.6 vs Group B: 4.4 vs Group C: 3.9 mos; p = 0.60) or OS II (median OS II Group A: 14.9 vs Group B: 13.8 vs Group C: 11.7 mos; p = 0.49). In the subgroup of pts with a CFI < 6 mos, Group A (n = 52) reported longer 2ndPFS compared to both Group B (n = 58) (median 2ndPFS 5.3 vs 3.0 mos; HR: 0.61,95%CI 0.41-0.89; p = 0.009) and Group C (n = 58) (5.3 vs 3.2 mos; HR: 0.71, 95%CI 0.48-1.05; p = 0.07). Consistent results were achieved in OS II (Group A vs Group B; median OS 13.6 vs 10.8 mos; HR: 0.65, 95%CI 0.42-1.00; p = 0.053; Group A vs Group C 13.6 vs 8.9 mos; HR: 0.60, 95%CI 0.39-0.93; p = 0.002). In the subgroup of pts with a CFI ≥ 6 mos, no significant difference was shown between Group A (n = 41) and Group B (n = 61) or C (n = 33). Conclusions: Tx after progression to first-line FOLFOXIRI plus bev are feasible and show expected efficacy results. The reintroduction of the triplet plus bev seems more effective than doublets plus bev or other tx when a more aggressive disease biology is suggested (CFI < 6 mos).
Localization of the primary tumor (LPT) and maintenance strategies after first line oxaliplatin (Ox), fluoropyrimidine (FP), and bevacizumab (Bev) in metastatic colorectal cancer (mCRC): Results from the AIO 0207 trial.
Authors: Reinacher-Schick Anke C. , Noepel-Duennebacke Stefanie , Hertel Jan , Tannapfel Andrea , Arnold Dirk , Hinke Axel , Hegewisch-Becker Susanna 
Published: September 2018

3543 Background: Numerous trials have examined the prognostic and predictive value of the LPT in mCRC, but little is known about the predictive value of LPT on different maintenance strategies. We analyzed progression-free survival (PFS) and overall survival (OS) from start of maintenance according to LPT in patients (pts) from the AIO KRK 0207 trial. Methods: Following a 24-week standard induction 471 pts were randomized to FP/Bev, Bev mono or no treatment with 454 pts being evaluable for PFS. Right sided primary tumors were defined as located in the caecum, ascending colon, transverse colon up to the splenic flexure; left colon was defined as splenic flexure, descending and sigmoid colon and rectum. Results: Data on LPT was available in 414 pts. for PFS (91%). LPT was left sided (LPTl) in 291 (70%) and right-sided (LPTr) in 123 (30%) of pts, respectively (remaining pts: status was either unknown, n = 37 or LPT was located in both regions, n = 3). Median PFS1 was 3.9 months (mos.) for LPTr and 5.3 mos. for LPTl (p = 0.11; HR 1.19, 95%CI 0.96 - 1.48). Analyses on PFS did not demonstrate a major predictive impact of LPT on the efficacy of the three maintenance strategies. The pairwise comparison of treatment arms showed a better PFS for FP/Bev vs no treatment independent from LPT (left: p < 0.0001; HR = 2.39, 95%CI 1.73-3.31; right: p = 0.011; HR 1.78, 95%CI 1.14-2.80). In addition, Bev mono vs no treatment was superior in LPTl (p = 0.0032; HR 1.54, 95%CI 1.15-2.06) with less difference in LPTr (p = 0.17; HR 1.36, 95%CI 0.87-2.14). Analysis for OS (429 evaluable pts) confirmed the strong prognostic impact of LPT (left vs right: 24.0 vs 16.7 months; p < 0.0001; HR = 1.65, 95%CI 1.32 - 2.06), but without major interaction between LPT and maintenance arms. The impact related to RAS mutational status will be reported. Conclusions: The strong prognostic factor of the LPT is confirmed in pts with mCRC undergoing Ox/FP/Bev induction therapy while there seems to be no major predictive impact of LPT on different maintenance strategies. Clinical trial information: EudraCT-Nr: 2008-007974-39.
Efficacy of bevacizumab in second-line versus first-line treatment of metastatic colorectal cancer: Results from a new methodological approach based on the ITACa strategy trial.
Authors: Petracci Elisabetta , Scarpi Emanuela , Passardi Alessandro , Frassineti Giovanni Luca , Biggeri Annibale , Amadori Dino , Nanni Oriana 
Published: September 2018

3546 Background: Cancer trials collecting information on subsequent treatment lines offer an invaluable opportunity to gain a deeper understanding of therapeutic strategies. Still in the oncological literature, evidence comes from studies ignoring whole patient history. The few studies that consider more than one line of treatment often analyze data for each line separately. Methods: Data from the ITACa strategy trial investigating the role of bevacizumab (B) in first- and second-line of treatment in metastatic colorectal cancer patients (mCRC) were analyzed. The trial consisted of two arms with treatment crossover: chemotherapy (CT) plus B followed by CT alone vs CT alone followed by CT+B. The primary end-point was Progression-Free Survival (PFS). Our aim was to evaluate if the efficacy of B was greater or smaller in first- or second-line treatment. Survival analysis for repeated events taking into account of potential selection bias was performed. Indeed, patients starting a second-line treatment are a selected subgroup of patients initially enrolled. Results: Of the 370 patients in the intention-to-treat population, 175 (47.3%) received second-line treatment. Considering all available information from randomization to first and eventual second progression and accounting for the potential selection bias, the average effect of B in terms of PFS resulted in an HR = 0.80 [95% CI 0.68-0.95]. When evaluating the differential effect of B in first- and second-line, we found that the addiction of B to CT in first-line provided 10% (95% CI -28%; +12%) risk reduction (HR = 0.90, 95% CI 0.72–1.12) respect to CT alone and the addiction of B to CT in second-line provided 36% (95% CI -51%; -16%) risk reduction (HR = 0.64, 95% CI 0.49-0.84) respect to chemotherapy alone. Conclusions: The ITACa trial enabled us to analyze data in a unified framework considering first- and second-line treatment together. Results highlight an advantage of B when administered in combination with second-line chemotherapy, suggesting the best strategy for its administration. Clinical trial information: NCT01878422.
Classic or simplified LV5FU2 regimen: Multivariate analysis from a phase III study in metastatic colorectal cancer in elderly patients.
Authors: Legoux Jean-Louis , Aparicio Thomas , Maillard Emilie , Phelip Jean Marc , Jouve Jean-Louis , Locher Christophe , Michel Pierre , Lecomte Thierry , Bouche Olivier , Bedenne Laurent ,   FFCD
Published: September 2018

3550 Background: In the early 2000s, classic LV5FU2 (C) (folinic acid, 5FU bolus, then 5FU infusion on D1 and D2) was replaced with simplified LV5FU2 (S) (folinic acid and 5FU bolus on D1 only), considered as effective and less toxic. No trial proved this assertion. The LV5FU2 companion in the FOLFIRI or FOLFOX regimen was C or S. The FFCD 2001-02 study compared in a 2 x 2 factorial design, in not-pretreated elderly patients (75+) with metastatic colorectal cancer, C or S, with or without irinotecan. No significant differences in PFS and OS were observed in the comparison with or without irinotecan. The median OS was 15.2 months in C versus 11.4 months in S, HR = 0.71 (0.55–0.92) and objective response rate was 37.1% in C vs S 25.6% in S, p = 0.004. The aim of this study was to present the factors associated with these differences. Methods: Prognostic factors associated with OS were studied using a Cox model. The multivariate analysis used the significantly different items from the univariate analysis and the differences observed at the inclusion. For each of these items, a subgroup analysis was performed. The second- and third-line treatments were analysed. Results: The 282 patients from the intent-to-treat study were included in the model. In OS, the prognostic factors were C versus S, number of metastatic sites, alkaline phosphatases (AP) and CEA. The interaction test in each subgroup for OS was not significant but C was significantly better in the following subgroup: age > 80 years, male, Karnofsky 100%, 1-2 Charlson index, AP ≤ 2N, leucocyte count > 11,000, CEA > 2N, CA 19-9 ≤2N. No differences were observed in the NCI toxicities but 130 serious adverse events in S versus 102 in C. A second-line was used for 55% patients in C, 46% in S, 81% of them with oxaliplatin or irinotecan in C, 76% after S. The third-line administration (20%) and targeted therapy (15%) were similar in C and S. Conclusions: C-LV5FU2 was superior both in subgroups with better and lower prognostics and this difference cannot be explained by an imbalance between the populations. The toxicity was not higher and a second-line was more often possible after C. The switch from C to S without scientific proof was perhaps a mistake in our practices. Clinical trial information: NCT00303771.
Assessing outcome differences in the second line treatment of metastatic colorectal cancer (mCRC): An ARCAD analysis comparing sequence after first line trials (SAFL) and dedicated second line trials (DSLT).
Authors: Leal Alexis Diane , Ou Fang-Shu , Pederson Levi , Sobrero Alberto F. , Rothenberg Mace L. , Van Cutsem Eric , Peeters Marc , Pitot Henry C. , Punt Cornelis J. A. , Arnold Dirk , Giantonio Bruce J. , Tournigand Christophe , Dawood Shaheenah , De Gramont Aimery , Sargent Daniel J. , Grothey Axel 
Published: September 2018

3554 Background: There is considerable variability in the outcomes between second line (SL) trials in mCRC. The aim of this analysis is to compare the outcomes of patients (pts) with mCRC treated either on SAFL, with protocol defined SL treatment, or DSLT. Methods: Individual pt data was available on pts with mCRC enrolled in 1 of 10 trials (7 DSLT, 3 SAFL) in the ARCAD database. Regimens included FOLFIRI, FOLFOX, and irinotecan (IRI), since pts did not receive biologic agents in SL on SAFL. For pts on a SAFL, PFS and OS were defined as time from initiation of SL treatment to second progression (SP)/death and death, respectively. Descriptive statistics and multivariable Cox models were used to assess differences in PFS and OS. Results: 5,076 pts were included; 63% were male; median age was 62. See Table for treatment details. Pts treated on SAFL had shorter OS (0.7-1.5 months (mos>) shorter) and PFS (0.6-2.6 mos shorter), compared to those treated on DSLT. These findings were statistically significant and differences in OS did not attenuate after adjustment for age, gender, and prior treatment. PFS differences in FOLFOX became insignificant after multivariable adjustment. Conclusions: There are modest differences in both PFS and OS between pts with mCRC treated on SAFL and those on DSLT, suggesting differences in these pt populations. Caution is needed when applying these data to pts, as we were unable to control for potential confounders (ECOG PS, number and sites of metastases) at initiation of SL in SAFL, which may impact outcomes. [Table: see text]
Results of the Quad wild type arm of the AGITG ICECREAM study: A randomised phase II study of cetuximab alone or in combination with irinotecan in patients with refractory metastatic colorectal cancer with no mutations in KRAS, NRAS, BRAF or PIK3CA.
Authors: Shapiro Jeremy David , Thavaneswaran Subotheni , Underhill Craig , Robledo Kristy Pamela , Karapetis Christos Stelios , Day Fiona Lee , Nott Louise M. , Jefford Michael , Chantrill Lorraine A. , Pavlakis Nick , Tebbutt Niall C. , Price Timothy Jay , Khasraw Mustafa , Van Hazel Guy A. , Waring Paul Michael , Tejpar Sabine , Simes John , Gebski Val , Desai Jayesh , Segelov Eva 
Published: September 2018

3572 Background: Cetuximab (cet) increases survival in RAS wild-type (WT) metastatic colorectal cancer (mCRC) in first-line and chemorefractory patients (pts). Adding irinotecan (iri) to cet in refractory pts who had progressed on iri increased response and delayed progression in the BOND trial, which was conducted prior to recognition that RAS mutations are predictive of EGFR-inhibitor (EGFR-I) resistance. Subsequent trials in chemorefractory pts used single agent EGFR-I as standard. In the era of biomarker selection, the benefit of continuing iri versus single agent EGFR-I had not been resolved. Methods: ICECREAM is a randomised phase II trial evaluating cet v cet + iri in chemotherapy-refractory mCRC, stratified for KRAS G13D mutation (previously reported) or no mutations in KRAS, NRAS, BRAF and PI3KCA (Quad WT ). EGFR-I naïve, ECOG PS 0-1 pts, progressing within 6 months of iri and refractory (or intolerant) to fluoropyrimidine and oxaliplatin were randomised to cet 400mg/m2 IV loading then 250mg/m2 weekly +/- iri 180mg/m2q2 wks. The primary endpoint was progression-free survival at 6 months (6m PFS); secondary endpoints were response rate (RR), overall survival (OS), toxicity and quality of life (QOL). Results: From Nov 2012 to June 2016, 48 Quad WT pts were recruited: 2 ineligible (not iri-refractory, BRAF mutation) wre not included for analyses and a further 2 not evaluable for response. Characteristics were balanced between cet (n = 21) v cet-iri (n = 25), except for sex (male 62 v 72%) and primary site (left 95 v 68%). 6m PFS rate was 14% v 41%; HR 0.39 (95% CI: 0.20–0.78, p = 0.008). RR was 10% (2 PR) v 36% (1 CR, 8 PR); p = 0.04. Toxicities were higher with cet-iri; at least one grade 3/4 adverse event in 50 v 23%. No differences in global or specific QOL were seen. Conclusions: The AGITG ICECREAM trial confirms a significant synergy for the addition of iri to cet and improved PFS in Quad WT chemorefractory mCRC, echoing data in molecularly unselected pts. Clinical trial information: ACTRN12612000901808.
Prognostic implications of TAMs in colorectal cancer hepatic metastases.
Authors: Reilley Matthew , Basu Sreyashi , Katkhuda Riham , Patterson Nicolle , Chen Tenghui , Blando Jorge M , Menter David , Maru Dipen M. , Allison James Patrick , Kopetz Scott , Sharma Padmanee , Overman Michael J. 
Published: September 2018

3574 Background: A limited understanding of the immune microenvironment of mismatch repair-proficient metastatic colorectal cancer (mCRC) impedes efforts to develop effective immunotherapy treatments for the majority of CRC patients. Liver metastatic disease is common and associated with poor outcomes. While T-cell infiltration of liver metastases positively correlates with survival, most mCRC patients do not benefit from checkpoint-blockade therapy. Tissue associated macrophages (TAMs) have been associated with an immune suppressive environment, but their prognostic role in mCRC is largely unknown. Methods: Comprehensive analysis of gene expression and immunohistochemistry (IHC) in 25 microsatellite stable (MSS) untreated liver metastatectomy (LM) specimens was performed. Clinical outcomes including recurrence, immunologic data, and tumor microsatellite status were evaluated and correlated. Results: Principal component analysis of immune and cancer pathway related genes were performed and compared with recurrence status. All samples were confirmed MSS. There were distinct differences in gene expression between patients who remained disease free and those who recurred. Among immune related genes CXCL5, IRF4, IL6R, TNF, CTLA4, ICOS, and ARG1 were relatively over-expressed in non-recurrent tumors, while PPARG, AIRE, and EPCAM were over-expressed in recurrent tumors (FDR 0.2, p < 0.05). Cibersort analysis predicts a significantly higher number of M2 versus M1 macrophages regardless of recurrence status (p < 0.05), with an approximate M1:M2 ratio of 1:2 and a higher total number of M1/M2 macrophages in tumors that recur. On IHC, an average of 29% of cells per sample expressed macrophage marker CD68. Relatively fewer CD3, CD4, and CD8 T cells were observed with average infiltration rates of 7.4%, 3.6%, and 2.6% respectively. Conclusions: CRC liver metastases demonstrate evidence of a large TAM population with significant M2 component and a smaller T cell population. A greater number of TAMs appear to correlate with recurrence, while a more immunogenic phenotype correlates with lower recurrence risk.
Clinical outcomes and emergent circulating tumor (ct)DNA RAS mutations and allele fraction for patients with metastatic colorectal cancer (mCRC) treated with panitumumab from the ASPECCT study.
Authors: Price Timothy Jay , Peeters Marc , Boedigheimer Michael , Kim Tae Won , Gibbs Peter , Thomas Anne L. , Hool Kristina , Ang Agnes , Bach Bruce A. 
Published: September 2018

3584 Background: ASPECCT was a phase III clinical trial performed in the chemotherapy-refractory third-line mCRC setting (N = 1010). This analysis explores the relationship between circulating levels of mutations and clinical outcomes for panitumumab-treated subjects using univariate and multivariate models that treat total mutational load as a continuous measure. Methods: 238 subjects treated with panitumumab had paired plasma samples at baseline and post-treatment (PT). Samples were analyzed for mutations using the Plasma Select-R™ 63-gene panel (0.1% limit of detection). The fraction of mutant RAS reads was evaluated for association with tumor response (by RECIST) and overall survival using univariate and multivariate Cox proportional hazards models. Results: 52% of the subjects who were RAS wild-type by plasma at baseline never developed a RAS mutation. For those with mutant RAS ctDNA ( KRAS+ NRAS) detected at baseline or PT, there was an overall increase in RAS mutant DNA fraction at PT compared to baseline. By non-parametric analysis, there was no difference in the distribution of baseline mutant RAS fraction between those who achieved stable disease (SD) or those with progression ( P = 0.09). There was also no difference in the increase in mutant RAS fraction on therapy between subjects with SD or progressive disease (PD). In addition, RAS mutation was not required for progression: 48% of subjects with PD had no RAS mutant DNA detected. Conclusions: In this exploratory analysis, baseline plasma mutant RAS fraction is an unreliable predictor of subsequent tumor response. Subjects with objective response or SD may have stable or rising levels of mutant RAS DNA. Subjects without any detectable RAS mutation still experience PD. These findings suggest that detectable plasma ctDNA RAS mutations do not necessarily predict response to panitumumab and should be interpreted with caution. Further work is needed to establish clinically relevant and validated thresholds. Clinical trial information: NCT01001377.