bluuebunny/crossref_metadata_2025 huggingface dataset:
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.
Association of genetic variations in genes implicated in the axis with outcome in patients (pts) with metastatic colorectal cancer (mCRC) treated with cetuximab plus chemotherapy.
Authors: Miyamoto Yuji , Stintzing Sebastian , Heinemann Volker , Zhang Wu , Cao Shu , Okazaki Satoshi , Berger Martin D. , Suenaga Mitsukuni , Schirripa Marta , Soni Shivani , Matsusaka Satoshi , Ning Yan , Yang Dongyun , Gopez Roel , Melendez Elizabeth , Hanna Diana L. , Barzi Afsaneh , Baba Hideo , Lenz Heinz-Josef
Published: September 2018

3585

Background: Accumulating evidence suggests that right- and left-sided CRCs have different prognoses and different sensitivities to EGFR inhibitors in several phase3 trials. These differences might be related to different embryological origins, which are reflected in different molecular profiles of tumors. LEFTY, Nodal and ACVR2B, which are TGF-betasuperfamily, are key regulators of left-right axis during embryogenesis; these expressions control sidedness. Our aim was to evaluate whether SNPs in these genes are associated with clinical outcomes in mCRC pts enrolled in the FIRE3 trial. Methods: Genomic DNA was obtained from mCRC pts receiving cetuximab plus FOLFIRI as first-line treatment and analyzed by using PCR-based direct sequencing. Four functional SNPs in 4 genes ( LEFTY1, LEFTY2, Nodal, and ACVR2B) were tested in 305 pts in FIRE3 trial cetuximab cohort (NCT00433927). Main characteristics were the following: male/female = 207/98; median age = 64; RAS-wildtype/mutant = 195/95; median PFS = 9.6 months; median OS = 26.5 months, median follow-up time = 41.8 months. Results: In patients with left sided tumor ( N= 237), LEFTY2 rs3007716 G/G variants ( N= 14) showed shorter PFS than any A variants ( N= 222) in univariate (8.0 months (M) vs. 10.3 M, HR = 2.24, 95%CI = 1.27-3.94, P < 0.01) and multivariate analyses (HR = 2.12, 95%CI = 1.20-3.75, P < 0.01). Nodal rs1904589 T/T ( N= 36) showed longer OS than any C variants ( N= 196) in univariate analysis (50.1 m vs. 29.8 M, HR = 0.61, 95% = 0.37-1.01, P = 0.048) and multivariate analyses (HR = 0.59, 95%CI = 0.35-0.99, P = 0.046). In patients with right sided tumors ( N= 58), ACVR2B rs2268753 C/C ( N= 12) showed shorter PFS than any T variants ( N= 43) in univariate analysis (3.7 m vs. 7.7 M, HR = 1.93, 95% = 0.99-3.77, P = 0.038) and multivariate analysis (HR = 2.24, 95%CI = 1.12-4.51, P = 0.023). Conclusions: Our study showed for the first time that genetic variations in sidedness related genes are associated with PFS and OS in patients receiving cetuximab based chemotherapy, which may dependent on location.
Association of T-cell infiltration assessed in pretherapeutic biopsies (PTB) of patients with locally advanced rectal adenocarcinoma (LARC) with tumor response and relapse after chemoradiotherapy (CRT) and rectal surgery.
Authors: Van Den Eynde Marc , El Sissy Carine , Kirilovsky Amos , Marliot Florence , Haicheur Nacilla , Dragean Cristina Anca , Danse Etienne , Denis Marie-Armelle , Kartheuser Alex , Remue Christophe , Leonard Daniel , Bachman Radu , Baldin Pamela , Decuyper Astrid , Humblet Yves , Scalliet Pierre , Jouret-Mourin Anne , Galon Jerome , Pages Franck
Published: September 2018

3599

Background: Pre-operative CRT followed by total mesorectal excision (TME) is nowadays the standard of care for patient with LARC (cT3-T4N0 or cTxN+). Currently, pathologic complete response occurs in +/- 15% after CRT. Colorectal cancer T-cell infiltration is a strong prognostic factor for survival after primary tumor resection. Our aim was to determine whether T-cell infiltration in PTB could be predictive of tumor response and relapse after CRT + TME. Methods: Between 1999 and 2012, patients with LARC who underwent CRT + TME and with available clinical follow-up and PTB (with sufficient tumor cells density) were identified at the Cliniques universitaires St-Luc. The density of CD3 (T cells) and CD8 (cytotoxic) was quantified on immunostained PTB slides and analyzed with a dedicated image analysis software on whole-slide imaging. Comparisons were made using the Wilcoxon-Mann-Whitney test. Cumulative disease-free survival (DFS) was performed using the Kaplan-Meier estimator and compared by log-rank tests. Cox regression we used for uni- and multi-variate analysis. P value of less than 0.05 was considered statistically significant. Results: 154 patients (sex ratio M/F 1.8; mean age 65 years-old; upper (20%), mid (29%) and low rectum (51%), synchronous metastases (11%)) were analyzed. High CD3 and CD8 PTB densities were significantly associated with a higher pathological response (Dworak 3-4) and lower ypTNM stage after CRT +TME (p < 0,05). Higher CD3 and CD8 PTB densities were associated with higher patient DFS (CD3: HR = 2,30 (CI95%:1,15-4,59) p = 0,02; CD8: HR = 1,95 (CI95%: 1,01-3,75) p = 0,04). These results were confirmed in uni and multivariate analysis. CD3 and CD8 PTB densities added to pathological response (ypTNM/Dworak) but also clinical response (ycTNM) after CRT + TME increases significantly the accuracy prediction of tumor relapse. Conclusions: Pretherapeutic T-cell infiltration of LARC is predictive of tumor response and relapse after CRT +TME. This biomarker could be helpful for patient treatment decision. It must be validated in larger patient cohorts.
A randomized phase II trial of consolidation chemotherapy after preoperative chemoradiation (preop CRT) versus CRT alone for locally advanced rectal cancer (LARC).
Authors: Kim Sun Young , Kim Tae Won , Hong Yong Sang , Kim Jeong Eun , Lee Keun Wook , Kim Ji-Won , Hwang In Gyu , Kim Beom Gyu , Ahn Joong Bae , Oh Ho-Suk , Zang Dae Young , Joo Jungnam , Kim Dae Yong , Oh Jae Hwan , Baek Ji Yeon
Published: September 2018

3606

Background: In LARC, preop CRT followed by total mesorectal excision (TME) is a standard of care. Recently consolidation chemotherapy after CRT was shown to be safe and to improve pathologic complete response (pCR) rate in LARC. We aimed to evaluate downstaging (DS) rate (the proportion of ypT0-2N0M0) of CRT followed by consolidation chemotherapy (capecitabine and oxaliplatin: CapOx) compared to that of CRT alone. Methods: Patients (pts) with adenocarcinoma of rectum(≤ 12cm from anal verge), ECOG PS 0 or 1, and cT3-4NxM0 were enrolled. CRT (50-50.4Gy/25-28fx) with Cap (825mg/m2/day for 5 days per week throughout CRT) followed by TME was planned in Arm A (control arm). In Arm B, 2 cycles of CapOx was given a week after completion of CRT before TME (Cap 850mg/m2/day from day 1 to day 14; Ox 100mg/m2on day 1; q 3w). 110 pts (55 per arm) were needed to show improvement of DS rate in per-protocol population (PP set) from 30% to 50% in arm B with one-sided α = 0.15, 1- β = 0.85, and follow-up loss in 5%. Results: From 9/2014 Sep to 2/2016, 110 (56 in arm A; 54 in arm B) were enrolled; 108 (55 in arm A; 53 in arm B) were randomized and started study treatment. Median age was 56 years; male/ECOG PS 1/cT4 was 76%/70%/18%. 100 pts (54 in arm A; 46 in arm B) completed CRT ± CapOx and surgery (R0 or R1 resection), while 8 (1 in arm A, 7 in arm B) dropped out mainly due to consent withdrawal. 2 of each arm underwent non-TME; that leaves 96 (52 in arm A and 44 in arm B) in PP set. Relative dose intensity of CapOx was 96% (Cap) and 95% (Ox). The main treatment outcome is described in table. The mean interval days between completion of CRT and surgery was significantly longer in arm B (52.9 vs 61.3, p < 0.0001). Conclusions: 2 cycles of CapOx after completion of CRT was feasible and safe, and it showed improvement in DS rate, even with high dropout rates (13%). Clinical trial information: NCT01952951. [Table: see text]
Pathologic complete response rate after neoadjuvant chemoradiation in patients with locally advanced rectal cancer affects survival in patients with prolonged radiation-surgery interval.
Authors: Motz Benjamin Mitchell , Lorimer Patrick Daniel , Boselli Danielle , Perry I'sis N , Hill Joshua S. , Salo Jonathan C.
Published: September 2018

3608

Background: The current standard of care in locally advanced rectal cancer is neoadjuvant chemoradiation and R0 resection. An optimal radiation-surgery interval (RSI) has not been established. A small institutional dataset showed RSI > 49 days improved pathologic complete response (pCR) rates and disease free survival. However, in a national dataset, RSI greater than 60 days was associated with increased rates of positive margins and impaired overall survival. Because pCR is associated with improved survival, we used a national database to evaluate the relationship between RSI, pCR and survival after neoadjuvant therapy for rectal cancer. Methods: The NCDB was queried for cases 2004-2013 of AJCC stage II or III rectal adenocarcinoma that underwent neoadjuvant radiation followed by radical resection. We excluded patients with missing and outlier RSI. pCR was defined as ypT0N0M0. Chi-square, univariate, multivariable Cox model, and Cochran-Armitage time trend analyses were performed. Results: 23475 patients were identified. 7901 (33.7%) had RSI ≥60 days. pCR occurred in 1766 (11.3%) of the < 60 group and 1174 (14.9%) of the ≥60 group (p < 0.001). RSI ≥60 days has increased over time, from 22.1% in 2004 to 45.4% in 2013 (p < 0.001), as have pCR rates, from 8.4% in 2004 to 14.2% in 2013 (p < 0.001). Multivariable Cox model of the total cohort showed that RSI ≥60 days (HR = 1.11, 95% CI = 1.04-1.19) and residual disease (HR = 2.04, 95% CI = 1.78-2.34) were associated with increased mortality. Subgroup analysis of patients with pCR showed RSI ≥60 days was not associated with worse survival (HR = 1.07, 95% CI = 0.82-1.41). However, analysis of patients with residual disease showed RSI ≥60 days was associated with worse survival (HR = 1.13, 95% CI = 1.06-1.21). Conclusions: In a large national database, RSI ≥60 days worsens survival in patients who have residual disease after neoadjuvant therapy for locally advanced rectal cancer, while there is no difference in those with pCR. Emphasis should be placed on identifying patients who are unlikely to have pCR and to prioritize resection in these patients within 60 days of completion of chemoradiation.
Impact of adjuvant treatment in elderly patients with locally advanced rectal cancer: A population-based retrospective study.
Authors: Liu Shiru Lucy , O'Brien Pierre , Zhao Yizhou , Hopman Wilma M , Lamond Nathan William Dana , Ramjeesingh Ravi
Published: September 2018

3613

Background: Little is known about the benefit and use of adjuvant chemotherapy (ADJ) in the elderly population (age ≥ 65) with locally advanced rectal cancer (LARC). We undertook a provincial review of LARC patients to evaluate the potential benefits, including survival and time to relapse (TTR), of ADJ in elderly patients. Methods: We performed a retrospective analysis of 286 LARC patients (stage 2 and 3) diagnosed between January 2010 and December 2013 from Nova Scotia, Canada, who underwent curative-intent surgery. Baseline patient, tumor and treatment characteristics were collected. Survival and TTR analysis were performed using Kaplan-Meier and Cox-regression statistics. Results: 152 patients were age ≥65, and 92 age ≥70. Median follow-up was 46 months. 178 patients (62%) received neoadjuvant chemo-radiation (NEOADJ). While 109 patients (81%) age < 65 received ADJ, only 68 patients (45%) age ≥ 65 received ADJ. Kaplan-Meier analysis revealed a significant survival and TTR advantage for ADJ irrespective of age (table). In cox-regression multivariate analysis, ECOG status, T stage, and ADJ were significant predictors of survival (p < 0.04), while age was not. Similarly, N stage, NEOADJ, and ADJ were significant predictors of TTR (p < 0.007). Poor ECOG status was the most common cause of ADJ omission. There was a significantly higher amount of grade≥ 1 chemotherapy-related toxicity experienced by patients age ≥ 65 treated with ADJ compared to no ADJ (77% vs 32%, p < 0.0001), which consisted mostly of diarrhea and mucositis. Toxicity was the main reason for non-completion of ADJ in the elderly. Conclusions: Elderly patients with LARC have significantly improved overall survival with ADJ, but the use of ADJ is lower than in patients age < 65. However, elderly patients experience more chemotherapy-related toxicities, leading to higher rates of early treatment discontinuation. [Table: see text]
Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): A multicenter, randomized phase 3 trial.
Authors: Al-Batran Salah-Eddin , Homann Nils , Schmalenberg Harald , Kopp Hans-Georg , Haag Georg Martin , Luley Kim Barbara , Schmiegel Wolff H. , Folprecht Gunnar , Probst Stephan , Prasnikar Nicole , Thuss-Patience Peter C. , Fischbach Wolfgang , Trojan Jorg , Koenigsmann Michael , Pauligk Claudia , Goetze Thorsten Oliver , Jaeger Elke , Meiler Johannes , Schuler Martin H. , Hofheinz Ralf
Published: September 2018

4004

Background: The MAGIC trial established perioperative (periop) epirubicin, cisplatin, and 5-FU (ECF) as a standard treatment for patients (pts) with operable esophagogastric cancer, but survival continues to remain poor. FLOT4 (NCT01216644) is a multicenter, randomized, investigator-initiated, phase 3 trial. It compares the docetaxel-based triplet FLOT with the anthracycline-based triplet ECF/ECX as a periop treatment for pts with resectable gastric or GEJ adenocarcinoma. Methods: Eligible pts of stage ≥cT2 and/or cN+ were randomized to either 3 preoperative and 3 post-operative 3-week cycles of ECF/ECX (epirubicin 50 mg/m2, cisplatin 60 mg/m², both d1, and 5-FU 200 mg/m² as continuous infusion or capecitabine 1250 mg/m2 orally d1-21) or 4 pre-operative and 4 post-operative 2-week cycles of FLOT (docetaxel 50 mg/m2, oxaliplatin 85 mg/m², leucovorin 200 mg/m², and 5-FU 2600 mg/m² as 24-hour infusion, all d1). The primary endpoint was overall survival (OS; 80% power; HR of 0.76; 2-sided log-rank test at 5% type I error). Results: Between Aug 2010 and Feb 2015, 716 pts (360 ECF/ECX; 356 FLOT) were randomly allocated. Baseline characteristics were similar between arms (overall, male 74%; median age 62; cT3/T4 81%; cN+ 80%; GEJ 56%). 91% and 37% of pts with ECF/ECX and 90% and 50% with FLOT completed planned pre-operative and post-operative cycles, respectively. Median follow-up was 43 mon. 369 pts died (203 ECF/ECX; 166 FLOT). FLOT improved OS (mOS, 35 mon with ECX/ECF vs. 50 mon with FLOT; HR 0.77 [0.63 - 0.94]; p = 0.012). 3y OS rate was 48% with ECF/ECX and 57% with FLOT. FLOT also improved PFS (mPFS, 18 mon with ECX/ECF vs. 30 mon with FLOT; HR 0.75 [0.62 - 0.91]; p = 0.004). Periop complications were 50% with ECF/ECX and 51% with FLOT. 30- and 90-day mortality was 3% and 8% with ECF/ECX and 2% and 5% with FLOT. There was more G3/4 nausea and vomiting with ECF/ECX and more G3/4 neutropenia with FLOT. Conclusion: Periop FLOT improved outcome in patients with resectable gastric and GEJ cancer compared to periop ECF/ECX. Clinical trial information: NCT01216644.
KEYNOTE-059 cohort 2: Safety and efficacy of pembrolizumab (pembro) plus 5-fluorouracil (5-FU) and cisplatin for first-line (1L) treatment of advanced gastric cancer.
Authors: Bang Yung-Jue , Muro Kei , Fuchs Charles S. , Golan Talia , Geva Ravit , Hara Hiroki , Jalal Shadia Ibrahim , Borg Christophe , Doi Toshihiko , Wainberg Zev A. , Wang Jiangdian , Koshiji Minori , Dalal Rita P. , Chung Hyun Cheol
Published: September 2018

4012

Background: Preliminary analyses from the global, multicohort, phase 2 KEYNOTE-059 (NCT02335411) study suggested that safety of pembro + 5-FU + cisplatin is manageable as 1L therapy in pts with advanced gastric or gastroesophageal junction (G/GEJ) cancer (cohort 2). We present efficacy and updated safety data from KEYNOTE-059 cohort 2. Methods: Cohort 2 enrolled pts ≥18 y with HER2 – recurrent or metastatic G/GEJ adenocarcinoma, measurable disease, no prior therapy for metastatic/advanced disease, and ECOG PS 0-1. Pts received pembro 200 mg on day 1 of each 21-day cycle + cisplatin 80 mg/m2 for 6 cycles + 5-FU 800 mg/m2 (or capecitabine 1000 mg/m2 in Japan) Q3W for up to 2 y or until disease progression, investigator/pt decision to withdrawal, or unacceptable toxicity. PD-L1+pts had expression in ≥1% tumor or stromal cells using IHC (22C3 antibody). End points were safety and tolerability (primary), ORR (RECIST v1.1, by central review), DOR, PFS, and OS (secondary). Results: Of 25 enrolled pts, 64% were men, 68% were Asian, and 64% had PD-L1+ tumors. Median age was 64 y. At data cutoff (Oct 19, 2016), median duration of follow-up was 12.2 mo (range, 1.8 to 19.6) and 84% of pts had discontinued treatment, mainly owing to clinical or radiologic disease progression (64%). ORR (CR + PR) was 60% (95% CI, 38.7-78.9) in all pts. Overall, 32% of pts had SD (95% CI, 14.9-53.5), 4% had PD (95% CI, 0.1-20.4), and 4% were not evaluable (95% CI, 0.1-20.4). ORR was 68.8% (95% CI, 41.3-89.0) in PD-L1+ pts and 37.5% (95% CI, 8.5-75.5) in PD-L1– pts. Median DOR (range) was 4.6 mo (2.6 to 14.4+) in all pts, 4.6 mo (3.2 to 14.4+) in PD-L1+ pts, and 5.4 mo (2.8 to 8.3+) in PD-L1–pts. Median PFS was 6.6 mo (95% CI, 5.9-10.6); median OS was 13.8 mo (95% CI, 7.3-not estimable). Grade 3-4 treatment-related adverse events (TRAEs) occurred in 76% of pts. TRAEs led to discontinuation in 3 pts (grade 3 stomatitis, grade 2 hypoacusis, and grade 1 creatinine increase). No TRAEs were fatal. Conclusions: Pembro + 5-FU + cisplatin showed manageable safety and encouraging antitumor activity as 1L therapy for pts with advanced G/GEJ cancer. Further exploration of pembro + 5-FU + cisplatin in this setting is warranted. Clinical trial information: NCT02335411.
Assessment of conditional survival probability in resected esophageal adenocarcinoma.
Authors: Graham Donna M. , Bannon Finian , Lloyd Megan , Noble Fergus , Walker Rob , Griffiths Ewen , Bedford Matthew , Whiting John , Nutzinger Barbara , Grehan Nicola , O'Neill Robert , Skipworth Richard , Mercer Stuart , Saunders John , Parsons Simon L. , Kennedy Richard D. , Fitzgerald Rebecca C. , Underwood Timothy J , Turkington Richard C. ,   On Behalf of the Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium
Published: September 2018

4030

Background: Prognostication for cancer patients is based upon factors determined at baseline and becomes less relevant over time. Conditional survival (CS) estimates future prognosis based upon survival to a specific time point after treatment. We analyzed CS for patients in the United Kingdom (UK) undergoing surgery and neoadjuvant chemotherapy (NAC) for gastro-esophageal junction (GEJ) or esophageal adenocarcinoma (EAC). Methods: 1409 patients with GEJ/EAC treated with NAC and surgical resection at 7 centers across the UK from 2002-2014 were identified. Clinicopathological and survival data was collected as part of the Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) consortium. A multivariable Cox survival model was used to analyze the association of factors such as node positivity (N+), lymphovascular invasion (LVI+), tumor differentiation, circumferential resection margin involvement (CRM+) and pathological response by tumor regression grade (TRG ≤2) with risk of relapse (RR) or death from time of surgery. Results: Of 1409 patients, 726 (51.5%) were aged <65 years, and 1195 (84.8%) were male. Hazard ratios (HR) for RR conditional on recurrence-free (RF) years to date are detailed below. N+ was the most robust predictor of relapse and mortality over time. LVI+ and moderate to poor differentiation influenced relapse in the first 2 years whereas CRM+ and TRG≤2 had their greatest effect in the year following surgery. Age, sex, and year of surgery had no association with RR or mortality. Similar patterns were observed for risk of death. Conclusions: CS provides a more dynamic estimate of future RR and survival among patients who have accrued survival time, especially in patients with high-risk features. CRM+ and LVI+ govern early survival events but as time from surgery increases these factors become less relevant. [Table: see text]
Patterns of care and treatment outcomes of patients with stage I esophageal cancer: A National Cancer Database analysis.
Authors: Moreno Amy Catherine , Zhang Ning , Lin Steven H. , Giordano Sharon Hermes
Published: September 2018

4035

Background: The aim of this study was to examine current patterns of care and associated outcomes for patients with stage I esophageal cancer (EC) treated in the United States. Methods: The National Cancer Data Base (NCDB) was queried for patients diagnosed with clinical stage T1-2N0 EC from 2004-2012. Patients were categorized into four treatment groups: observation without definitive therapy (Obs), chemoradiotherapy (CRT), local excision (LE), and esophagectomy (Eso). Patient, tumor, and treatment parameters were compared between groups. Kaplan-Meier 5-year overall survival (OS) estimates, postoperative 30- and 90-day mortality comparisons, and multivariate Cox proportional hazards modeling are reported. Results: A total of 5,460 patients met the criteria. Of these, 21% were observed, 14% underwent CRT, 23% LE, and 42% Eso. Median age and follow up were 67 years and 28 months, respectively. Eso was the primary treatment for patients of age ≤ 80 while 48% of patients age > 80 were observed. Age, race, comorbidity score, tumor location within the esophagus, type of medical insurance, median income, type of facility (academic vs. non-academic), and distance from treating facility were significant factors for predicting receipt of local therapy over observation. Postoperative 30-day mortality between the LE and Eso groups was 0.5% and 2.9%, respectively ( P< .001), which increased to 1.4% and 5.5% at 90 days ( P< .001). Five-year OS was 21% for Obs, 26% CRT, 64% LE, and 63% Eso ( P < .001). Multivariate analyses demonstrated improved OS with any form of local definitive therapy: CRT ( HR: 0.54, 95% CI [0.48 - 0.61], P< .001), LE ( HR: 0.24, [0.20 - 0.27], P< .001), Eso (HR: 0.31, [0.28 - 0.35], P< .001). Age, comorbidity score, facility type, distance, median income quartile, and insurance status were also independently associated with OS. Conclusions: Management of stage I EC is influenced by several demographic and socioeconomic factors. Clinical observation yields suboptimal outcomes compared to any local therapy, and a surgical approach should be considered over CRT whenever feasible.
Ramucirumab (R) plus pembrolizumab (P) in treatment naive and previously treated advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: A multi-disease phase I study.
Authors: Chau Ian , Bendell Johanna C. , Calvo Emiliano , Santana-Davila Rafael , Arkenau Hendrik-Tobias , Mi Gu , Jin Jin , Rege Jessicca , Ferry David , Herbst Roy S. , Fuchs Charles S.
Published: September 2018

4046

Background: Angiogenesis and immunosuppression are hallmarks of tumor growth. This is the first study to combine R (anti-VEGFR2) with P (anti-PD-1) to simultaneously target both processes in the tumor microenvironment. Methods: Ongoing, multi-cohort, phase 1a/b trial enrolled pts with G/GEJ adenocarcinoma, measurable disease, ECOG PS 0-1, previously treated (Cohorts A and B) or untreated (Cohort A2) for advanced disease. PD-L1 was positive (tumor proportion score [TPS] ≥1%) or negative (TPS < 1%) using the DAKO PD-L1 22C3 IHC pharmDx assay. R was administered at 8 mg/kg on Days 1&8 (Cohorts A and A2) or 10 mg/kg on Day 1 (Cohort B) with P 200 mg on Day 1 q3W. Primary objective- assess safety and tolerability of R+P; preliminary efficacy will be examined. Results: As of 21-Nov-2016, 41 previously treated G/GEJ pts were enrolled. Median age was 58 y, 76% male, 66% had ECOG PS of 1, 46% were PD-L1+, and 59% received study treatment as third or subsequent line. Median duration on therapy was 2.8 mo and 4.1 mo for A and B, respectively. Overall, 33 (80%) pts experienced a treatment-related AE (TRAE) and similar between cohorts A and B. Ten (24%) pts experienced grade 3-4 TRAEs, most commonly colitis (7%) and hypertension (7%). One treatment-related death occurred (pneumonitis and pulmonary sepsis). Responses occurred in 3 (7%) pts with 46% disease control rate (DCR). Progression-free and overall survival rates at 6 mo were 22.4 % (95% CI, 9.8-38.0) and 51.2% (95% CI, 33.9-66.1) respectively. Nine (22%) pts remain on treatment. Eighteen of 25 planned treatment naïve G/GEJ pts were enrolled. Median age was 70 yr, 83% male, 56% had ECOG PS of 0, and PD-L1 status is pending. Median duration on therapy was 2.1 mo. Twelve (67%) pts experienced a TRAE. Grade 3 TRAEs occurred in 5 (28%) pts (hypertension [n = 3], diarrhea, and acute kidney injury). No grade 4-5 events occurred. Preliminary efficacy data showed 3 (17%) pts responded with 50% DCR. Median PFS is immature and 89% of pts remain on treatment. Conclusions: R+P generated no new safety signals and demonstrated encouraging antitumor activity in treatment naïve and previously treatedadvanced G/GEJ adenocarcinoma. Clinical trial information: NCT02443324.
Meaningful changes in quality of life (QoL) in patients with gastric cancer: Exploratory analyses from RAINBOW and REGARD.
Authors: Chau Ian , Fuchs Charles S. , Ohtsu Atsushi , Liepa Astra M. , Cui Zhanglin Lin , Hsu Yanzhi , Al-Batran Salah-Eddin
Published: September 2018

4047

Background: EORTC QLQ-C30 is a well-established QoL instrument for cancer patients (pts), but there is limited information for gastric cancer. To identify priority domains and describe meaningful changes, we explored data from 2 randomized ramucirumab phase 3 trials in pts with previously treated gastric or gastroesophageal junction cancer. Methods: Pts completed QLQ-C30 v3.0 at baseline and Q6W while on study. Data from all treatment arms were pooled (N=1020). Changes from baseline in QoL domains were compared by best overall response (BOR) and ECOG performance status (PS) using analysis of covariance. Odds ratios (ORs) for BOR and PS outcome groups per QoL unit (point) change were estimated by cumulative logit regression modeling, with OR≤0.85 considered meaningful. Results: Changes from baseline in QoL domains were significantly associated with BOR and PS outcomes (Table). ORs for BOR and PS outcomes for these domains were statistically significant (p<0.05) and suggested changes of 10-15 points predict clinical outcomes. Conclusions: QLQ-C30 is sensitive to clinical outcomes in advanced gastric cancer patients, particularly in global QoL, functional status and disease symptoms of fatigue, pain, and appetite loss. These analyses can inform trial designs and interpretation of results. [Table: see text]
Circulating tumor DNA analysis for outcome prediction in localized esophageal cancer.
Authors: Azad Tej D. , Chaudhuri Aadel , Newman Aaron M. , Stehr Henning , Schroers-Martin Joseph , Chabon Jacob J. , Fang Penny , Qiao Yawei , Liao Zhongxing X. , Komaki Ritsuko , Alizadeh Ash A. , Lin Steven H. , Diehn Maximilian
Published: September 2018

4055

Background: Blood-based biomarkers are not used in routine clinical practice in patients with esophageal carcinomas (ECs). Circulating tumor DNA (ctDNA) is an attractive biomarker that could be applied to ECs. We performed a study to explore pre- and post-treatment ctDNA analysis using the next generation sequencing-based CAPP-Seq method as a prognostic biomarker for localized EC. Methods: We prospectively enrolled 29 patients with localized EC treated with chemoradiotherapy (CRT) between June 2011 and October 2015. 12 (43%) patients were treated with CRT alone and 17 (57%) were treated with CRT followed by esophagectomy. Our cohort included patients with stage IB (1; 3.4%), II (7; 24.1%), and III (21; 72.4%) disease. Eight (27.6%) harbored squamous cell carcinoma (SCC) and 21 (72.4%) adenocarcinoma (AC). All patients received pre-treatment evaluation by thoracic CT, PET/CT, and esophagoduodenoscopy. ctDNA levels were quantitated in pre-treatment and post-treatment plasma samples using CAPP-Seq. Results: Median follow-up time was 21 months. We detected ctDNA pre-treatment in 72.4% of cases (N = 21) with a median concentration of 2.69 haploid genome equivalents per mL (hGE/mL; range 0.34-107.3). Pre-treatment ctDNA concentrations were strongly correlated with metabolic tumor volumes (MTV; R2= 0.74; p = 1.7e-07) and were significantly higher in SCC than AC patients (28.2 vs. 2.1 mean hGE/mL; p = 0.002). Overall survival (OS) at 2 years for pretreatment ctDNA+ vs. ctDNA- patients was 47% vs. 86% (HR = 6.0; 95% CI = 0.74-49.2; p < 0.05) and trended toward significance when accounting for stage, histology, and age (p = 0.09). A single post-treatment plasma sample was collected within 3 months of treatment and was available for 19 patients. Post-treatment ctDNA was detected in 3 (15.7%) patients with a median concentration of 11.5 hGE/mL (range 2.2–11.9). Post-treatment ctDNA detection was strongly predictive of poor event-free survival (p < 0.0001) and time to distant metastasis (p < 0.0001). Conclusions: Our data suggest that pre- and post-treatment ctDNA levels may be prognostic for patients with localized EC and could potentially guide risk-adapted adjuvant therapy approaches.
Phase II study of BKM120 in patients with advanced esophageal squamous cell carcinoma (EPOC1303).
Authors: Kato Ken , Doi Toshihiko , Kojima Takashi , Hara Hiroki , Takahashi Shunji , Muro Kei , Nishina Tomohiro , Wakabayashi Masashi , Nomura Shogo , Sato Akihiro , Ohtsu Atsushi
Published: September 2018

4069

Background: BKM120 is an oral pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, which showed promising activity in breast cancer and squamous cell carcinoma of head and neck. We prospectively investigated clinical activity, safety and biomarkers of BKM120 in advanced esophagus squamous cell carcinoma (ESCC). Methods: We conducted a multicenter phase II study of BKM120 monotherapy in patients with pretreated advanced ESCC. All the patients had a treatment history of fluoropyrimidine and platinum. BKM120 of 100 mg/day was orally administered in a 28-day cycle. A primary end-point was a disease control rate (DCR). Using Simon’s minimax two-stage design, total of 41 patients were required for primary analysis (promising DCR of 60%, non-promising one of 40%, one-sided alpha level of 10% and power of 90%). The response rate (RR), progression-free survival (PFS), overall survival (OS), and safety were also evaluated as secondary endpoints. Tumor samples for all the patients were required for gene alternation analysis in comprehensive genomic profiling assay (FoundationOne). Results: A total of 42 patients (median age, 62.5 years; performance status 0/1 = 28/14) were enrolled. One ineligible patient was excluded from primary analysis. Nineteen and two patients had SD and unconfirmed PR. DCR was 51.2% (95% CI, 35.1% to 67.1%), which met the primary endpoint of the study. Median PFS and OS was 2.0 months (95% CI, 1.8 to 3.2 months) and 9.0 months (95% CI, 6.4 to 11.7 months), respectively. Common grade 3 or 4 adverse events were anorexia, rash, hyponatremia, lipase increased, and abnormal hepatic function (including increased transaminase levels), which were profiles similar to previous studies of BKM120 monotherapy. No treatment-related deaths occurred. Further analyses of the gene alternation are ongoing. Conclusions: BKM120 monotherapy showed promising efficacy and mild toxicity profile in patients with pretreated advanced ESCC. BKM120 is worth evaluating in a further confirmatory study. Result of subgroup analyses with respect to gene alternation status will be presented. Clinical trial information: UMIN000011217.