bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact on survival of primary tumor resection in patients with colorectal cancer and unresectable metastasis: Pooled analysis of individual patients’ data from four randomized trials.
Authors: Faron Matthieu , Bourredjem Abderrahmane , Pignon Jean-Pierre , Bouche Olivier , Douillard Jean-Yves , Adenis Antoine , Elias Dominique , Ducreux Michel
Published: March 2020

3507

Background: In patients with colorectal cancer (CRC) and unresectable metastasis, the prognostic impact of primary tumor resection still remains a matter of debates. The goal of this study was to estimate, after adjustment for prognostic factors, the effect of primary tumor resection on survival. Methods: Individual patients’ data of the 1155 patients with metastatic CRC included in 4 first-line chemotherapy trials (FFCD 9601, FFCD 2000-05, ACCORD 13 and ML 16987) where retrieved. Patients were eligible for this study if they had synchronous metastasis judged unresectable. Primary endpoint was overall survival (OS), secondary endpoint was progression free survival (PFS). A Cox proportional hazard model stratified on the trial was used to estimate the impact on survival. Results: 810 patients beginning first-line chemotherapy with either fluoropyrimidine alone, oxaliplatin, irinotecan and/or bevacizumab were eligible. Patients with a history of resection (n = 478 (59%)), as compared to those without (n = 332 (41%)), were more likely to have colonic primary (p < 0.0001), lower carcino embryonic antigen (CEA) (p < 0.0001) or alkaline phosphatase (ALP) level (p=0.04) and normal white blood cell count (WBC) (p < 0.0001). In the univariate analysis, stratified on the trial, primary tumor resection was associated with a better OS (Hazard Ratio HR: 0.73 [0.63-0.84]; p < 0.0001) and PFS (HR : 0.73 [0.63-0.84]; p < 0.0001). Multivariate analysis, adjusted for primary tumor location, CEA, ALP and WBC levels, OMS performance status and number of metastatic sites confirmed that primary tumor resection was an independent predictor of better OS (HR : 0.63 [0.53-0.75] ; p < 0.0001), and PFS (HR : 0.82 [0.70-0.95] ; p = 0.0007). Significant interactions were found between resection and CEA level (p=0.02) and resection and primary tumor location (p=0.01) for OS (not for PFS) with a lower impact of resection with higher CEA levels or a colonic primary. Conclusions: This study confirmed the independent prognostic value on survival of primary tumor resection in patients with unresectable metastases of CRC.
BRAF, PIK3CA, and PTEN status and benefit from cetuximab (CET) in the treatment of advanced colorectal cancer (CRC): Results from NCIC CTG/AGITG CO.17.
Authors: Jonker Derek J. , Karapetis Christos Stelios , O'Callaghan Christopher J. , Marginean Celia , Zalcberg John Raymond , Simes John , Moore Malcolm J. , Tebbutt Niall Christopher , Price Timothy Jay , Daneshmand Manijeh , Hanson Jennifer , Shapiro Jeremy David , Pavlakis Nick , Gibbs Peter , Van Hazel Guy A. , Yu Min Lee Ursula Joan , Haq Rashida , Virk Shakeel , Tu Dongsheng , Lorimer Ian ,   NCIC Clinical Trials Group and the Australasian Gastro-Intestinal Trials Group
Published: March 2020

3515

Background: CET, a monoclonal antibody targeting the epidermal growth factor receptor, improves overall survival (OS) and progression free survival (PFS) in patients (pts) with KRAS wild-type (WT) chemotherapy refractory CRC. BRAF and PIK3CA mutation status, and PTEN expression levels may further predict benefit from CET therapy. Methods: Available colorectal tumour samples were analyzed from a phase III trial of CET plus best supportive care (BSC) vs BSC alone (NEJM 2007; 357(20)). BRAF and PIK3CA mutations (MUT) identified in tumour-derived DNA using a high resolution melting analysis to identify amplicons with mutations were confirmed by sequencing. PTEN expression by immunohistochemistry (IHC) was performed on tissue microarrays constructed from available tumour blocks. For each biomarker, prognostic (treatment independent) effects were assessed in patients on the BSC alone arm. Predictive effects (benefit from CET) on OS and PFS among all patients and those in the KRAS wild-type subset were examined using a Cox model with tests for treatment-biomarker interaction, adjusting for covariates. Results: Of 401 pts assessed for BRAF status (70% of CO17 population), 13(3%) had mutations. Of 407 pts assessed for PIK3CA status (71% of CO17 population), 61(15%) had mutations. Of 205 pts assessed for PTEN (36% of CO17 population), 148(72%) were negative for IHC expression. No biomarker was prognostic for OS or PFS, and none were predictive of benefit from CET, either in the whole study population or the KRAS WT subset. Conclusions: In chemotherapy-refractory CRC, neither PIK3CA mutation status nor PTEN expression were predictive of benefit from CET therapy. BRAF mutations are uncommon in this setting. Larger sample sizes would be required to determine if BRAF status is predictive for CET benefit. [Table: see text]
Comparative evaluation of capecitabine or infusional leucovorin/5-fluorouracil (LV/5-FU) with or without oxaliplatin (Ox) for stage III colon cancer (CC): A pooled analysis of individual patient data from four randomized controlled trials.
Authors: Sun Weijing , Schmoll Hans-Joachim , O'Connell Michael , Cartwright Thomas H. , Twelves Christopher , McKenna Edward , Saif Wasif M. , Lee Luen F. , Yothers Greg , Haller Daniel G.
Published: March 2020

3525

Background: A fluoropyrimidine + Ox is the standard of care for stage III CC but a fluoropyrimidine alone is recommended for selected patients in several practice guidelines. We assessed efficacy and safety of adjuvant capecitabine ± Ox vs. LV/5-FU ± Ox across a population of stage III CC patients enrolled in four trials. Methods: N = 5,819 patients from NSABP C-08, XELOXA, X-ACT, and AVANT were pooled and analyzed; bevacizumab-treated patients were excluded. Endpoints were disease-free survival (DFS, primary), relapse-free survival (RFS), overall survival (OS), and safety. Multivariate Cox regression analyses (MVA) controlled for age, gender, T, and N stage. Results: Patient demographics and disease characteristics (except lymph nodes examined) were well balanced across groups. The number of patients receiving capecitabine and LV/5-FU were 1,942 and 3,877, respectively. Median follow-up was shorter in NSABP C-08 and AVANT (36 and 50 months) vs. XELOXA and X-ACT (83 and 74 months). Five-year DFS was 62.8% for capecitabine ± Ox and LV/5-FU ± Ox. The capecitabine by Ox interaction was significant for OS with a trend for DFS and RFS; likely due to improved outcomes with capecitabine alone and similar outcomes for capecitabine or LV/5-FU + Ox. Serious adverse event (AE) rates were similar for LV/5-FU- and capecitabine-based therapy (16% vs. 20%, respectively). Overall, treatment-related grade 3/4 AEs were more common with LV/5-FU (59% vs. 47%). Treatment-related grade 3/4 AEs of interest included peripheral sensory neuropathy (5% vs. < 1%), diarrhea (12% vs. 15%), febrile neutropenia (2% vs. < 1%), and hand–foot syndrome (< 1% vs. 12%). Conclusions: Adjuvant capecitabine ± Ox and LV/5-FU ± Ox show comparableefficacy benefits for the treatment of stage III CC; further supporting capecitabine or LV/5-FU-based regimens as standard options for the adjuvant therapy of stage III CC. [Table: see text]
Analysis of PTEN in patients with advanced colorectal cancer (CRC) receiving capecitabine alone or in combination with bevacizumab with or without mitomycin C in the phase III AGITG MAX trial.
Authors: Price Timothy Jay , Hardingham Jenny , Lee Chee , Wrin Joe , Townsend Amanda Rose , Wilson Kate , Weickhardt Andrew James , Simes John , Murone Carmel , Tebbutt Niall Christopher
Published: March 2020

3534

Background: There is an urgent need for potential biomarkers for anti-VEGF therapies. The tumour suppressor gene PTEN is thought to have a potential role as a biomarker for anti-EGFR therapy in CRC, but there is also evidence that decreased levels of PTEN leads to increased expression of VEGF suggesting a potential relationship to outcome with anti-VEGF therapy*. The prognostic value of PTEN also remains controversial. Methods: Patients enrolled in the Phase III MAX trial of capecitabine (C) +/- bevacizumab (B) (+/- mitomycin C (M)) with available tissue were analysed for PTEN expression (loss v no loss) as assessed using a Taqman copy number assay to measure copy number variation at the PTEN locus. PTEN status was correlated with progression-free survival (PFS) and overall survival (OS) outcomes. The predictive value of PTEN status for bevacizumab efficacy was also examined. Results: Of the original 471 patients enrolled in the trial, tissue from 302 (64.1%) patients were analysed. Baseline characteristics of those with and without tissue were comparable. PTEN loss was observed in 38.7% of patients. There was no relationship between PTEN loss and KRAS or BRAF mutation. Patients with PTEN loss were more likely to have rectal primary (p=0.01) and less likely to have lung metastasis (p=0.03). By using the comparison of C v CB+CBM, PTEN status was not significantly predictive of the effectiveness of B for PFS or OS (Table). PTEN status is also not prognostic for PFS or OS in multivariate analyses adjusting for other baseline factors (Table). Conclusions: PTEN status did not significantly predict different benefit with anti-VEGF therapy. PTEN status was also not prognostic for survival in advanced colorectal cancer. [Table: see text]
Maintenance therapy with biweekly cetuximab (C) in the first-line treatment of metastatic colorectal cancer (mCRC): The NORDIC 7.5 study (NCT00660582), by the Nordic Colorectal Cancer Biomodulation Group.
Authors: Pfeiffer Per , Sorbye Halfdan , Qvortrup Camilla , Karlberg Mia , Naucler Gisela , Kersten Christian , Vistisen Kirsten , Lindh Birgitta , Glimelius Bengt
Published: March 2020

3538

Background: NORDIC 7.5 is a multi-center phase II trial of Nordic FLOX plus biweekly C followed by maintenance C in first-line treatment of mCRC, KRASwild-type (KRASwt). The aim was to complement the data of the NORDIC VII trial, arm C (Tveit et al, ASCO GI 2011). Specifically, the goal was to substantiate efficacy and safety of biweekly C as maintenance therapy and to assess time to failure of strategy (TFS) as an end-point in maintenance therapy studies. Methods: Patients had KRASwt, measurable, non-resectable mCRC; no prior chemotherapy for metastases; WHO PS 0-2 and good organ function. Patients received 8 courses of FLOX (bolus 5FU/folinic acid days 1 + 2 with oxaliplatin day 1 every 2 weeks) plus biweekly C (500 mg/m2 every 2 weeks) for 16 weeks followed by biweekly C as maintenance therapy until progression (PD). After at least 2 months of maintenance therapy, patients restarted FLOX plus biweekly C at the time of RECIST PD, and continued until a second RECIST PD. The primary endpoint was response rate (RR). Eighty-six patients were planned to confirm a response rate of 60%. While awaiting the results of Nordic VII, we amended the protocol to include 150 patients. Secondary endpoints included PFS, OS, resection rate, and safety. TFS was an explorative endpoint. Results: From July 2008 to September 2010, 152 KRASwt patients were included in 11 Nordic centers. Results were updated December 2011. Median age 64 years; 94% PS 0-1. RR 62%, median PFS 8.0 months, median OS 23.2 months, median TFS 11.9 months. Ten patients (15%) had R0-resection of metastasis. FLOX + C was re-introduced in 47 of 85 patients (55%) who were candidates for re-treatment and was started median 18 days after PD. Median duration of re-introduction was 5 months (1-29), 9 patients (20%) had response. Elevated baseline platelets and neutrofiles were associated with poor OS. The most common grade 3/4 non-hematologic AEs in were diarrea (9%), skin rash (9%), infection without neutropenia (7%), and fatigue (7%) Conclusions: Maintenance therapy with biweekly cetuximab is an encouraging strategy with efficacy and toxicity comparable to weekly cetuximab.
Prospective study of EGFR intron 1 CA tandem repeats to predict factor benefit from cetuximab and irinotecan.
Authors: Antoniotti Carlotta , Loupakis Fotios , Cremolini Chiara , Zhang Wu , Yang Dongyun , Wakatsuki Takeru , Schirripa Marta , Salvatore Lisa , Ricci Vincenzo , Graziano Francesco , Masi Gianluca , Ruzzo Annamaria , Labonte Melissa Janae , Ning Yan , El-Khoueiry Rita , Falcone Alfredo , Lenz Heinz-Josef
Published: March 2020

3540

Background: Retrospective experiences have investigated the potential influence of EGFR intron 1 CA repeats on the efficacy of cetuximab-containing treatments. Different series, adopting different criteria to define short (S) and long (L) variants, have provided contrasting results. Methods: We designed a prospective confirmatory study, to detect a HR for PFS of 1.75 for L- compared to SS genotypes in a population of KRAS and BRAF wild-type irinotecan-resistant mCRC pts treated with cetuximab and irinotecan. Estimating a prevalence of 60% of the SS variant and setting a two-sided alfa=0.05 with a power of 80%, 104 events were required. We defined S and L allelic variants those presenting < and ≥20 CA repeats, respectively. EGFR (CA)n repeat polymorphism was assessed following a 5’-end [γ-33P] ATP-labeled PCR protocol. Results: One-hundred-fifteen pts were included. At a median follow up of 21.9 months, PFS and OS were 5.2 and 13.4 months, respectively. Thirty-three (29%) out of 114 evaluable pts achieved response. EGFR (CA)n repeat genotype was L- and SS in 45 (40%) and 68 (60%) out of 113 evaluable cases. No differences in PFS or OS were observed between L- and SS genotypes (median PFS: 4.4 vs. 5.3 months, HR: 1.00 [95%CI: 0.67-1.51], p=0.991; median OS: 11.3 vs. 14.2 months, HR: 1.30 [95%CI: 0.80-2.22], p=0.261). Ten (22%) out of 45 L- pts achieved response compared to 22 (33%) out of 67 SS pts (Fisher’s Exact test: p=0.617). Other exploratory analyses adopting different cut-off values reported in literature led to similar results. Conclusions: This prospective study, including a clinically homogenous and molecularly selected population, does not confirm any predictive or prognostic effect for EGFR (CA)n repeat allelic variants with respect to the efficacy of cetuximab and irinotecan in advanced lines of treatment. The present experience strengthens the need of prospectively challenging retrospective findings, as an essential step on biomarkers’ way toward clinical practice.
Comparative effectiveness of sphincter-sparing surgery (SSS) versus abdomino-perineal resection (APR) in rectal cancer: Patient-reported outcomes (PROs) from NSABP R-04.
Authors: Ganz Patricia A. , Lopa Samia H. , Yothers Greg , Ko Clifford Y. , Arora Amit , Atkins James Norman , Bahary Nathan , Soori Gamini S. , Robertson John M. , Eakle Janice F. , Marchello Benjamin T. , Wozniak Timothy F. , Wolmark Norman ,   NSABP
Published: March 2020

3545

Background: R-04 is a trial of pre-surgical RT and either capecitabine or 5-FU with or without oxaliplatin in patients (Pts) with resectable rectal cancer. PROs were measured before treatment, post-RT, and 1 yr post-op. We compare PROs at 1 yr by type of surgery with hypothesis that APR Pts would have worse quality of life (QOL). Methods: Pts completed the FACT-C and EORTC-CR38 at all times. Baseline and 1 yr were compared within groups (SSS and APR) with paired t-test, and between groups at 1 yr, with adjustment for covariates of age, gender, clinical stage, baseline score, and surgery intent in a general linear model. These secondary/exploratory hypotheses were significant if p < 0.05. Results: 1,608Pts were randomized and 1405 completed baseline QOL form after consent, prior to treatment. 1,003 completed QOL form 1 yr post-op: 6 were ineligible, 10 did not have surgery, leaving 987 Pts. 615 had SSS and 372 had APR. 66.6% were male, 61.5% stage II, and almost all had post-surgical adjuvant chemotherapy. SSS Pts were significantly younger (60.3% vs. 53.5% < 59 yr, p=0.04). FACT-C total and subscale scores were not significantly different by surgery type at 1 yr, with only minimal decline from baseline in both groups. For SSS Pts, EORTC-CR38 scores significantly worsened for body image, sexual function, sexual enjoyment (all p <0.0001), while future perspective improved (p<0.0001) at 1 yr from baseline. All symptom subscales except weight loss and micturition showed worsened symptoms (GI tract, chemo side effects, defecation problems, sexual problems) all p < 0.0001 at 1 yr from baseline. Compared to APR Pts, SSS had less severe functional problems and symptoms, especially in sexual enjoyment, weight loss, GI symptoms, and body image, all significant. Conclusions: Contrary to prediction, there were no significant differences in FACT-C scores for SSS vs. APR. Symptoms and functional problems were detected by the EORTC-CR38, reflecting expected differences. The largest differences between the surgical treatments were for GI symptoms and body image. Information from these PROs may be useful in counseling Pts anticipating surgery for rectal cancer.
Phase Ib study of dulanermin combined with first-line FOLFOX plus bevacizumab (BV) in patients (Pts) with metastatic colorectal cancer (mCRC).
Authors: Kozloff Mark , Messersmith Wells A. , Kapp Amy V. , Ashkenazi Avi , Royer-Joo Stephanie , Portera Chia C. , Wainberg Zev A.
Published: March 2020

3552

Background: Dulanermin is a recombinant soluble human Apo2 ligand/TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) that activates apoptotic pathways by binding to the pro-apoptotic death receptors DR4 and 5. This study assessed the safety of dulanermin combined with FOLFOX+BV as first-line therapy in mCRC pts. Methods: This was a multicenter, open-label dose-escalation and cohort expansion study with treatment until disease progression or treatment intolerance. Dulanermin was administered intravenously in 14-day cycles on Days 1, 2 and 3 at 4.5 mg/kg or 9 mg/kg, with FOLFOX, and BV 5 mg/kg on Day 1. Dose-limiting toxicity (DLT) was assessed through 2 cycles (Days 1-28). Adverse events (AE) were recorded through all cycles. Response was assessed with RECIST (v1.0). Results: A total of 23 pts received 2-33 cycles (median 15) of dulanermin with FOLFOX+BV. No DLTs were reported. The most frequent AEs reported as dulanermin-related were fatigue (26%), neutropenia and nausea (22% each), and alanine aminotransferase increased and diarrhea (17% each). The most frequent Grade ≥3 AEs reported as dulanermin-related were neutropenia (13%) and infusion-related reaction (9%). Some of these events were reported as related to dulanermin and other study drugs. Three pts (13%) discontinued study treatment due to serious AEs: infusion-related reaction (2 pts, 9%; both reported as dulanermin-related) and pulmonary embolism (1 pt, 4%). Other reasons for discontinuation included disease progression (13 pts, 57%), physician’s decision and pt’s decision (2 pts each, 9%), and non-compliance (1 pt, 4%). Two pts are still receiving treatment. Among the 23 patients, best responses included 13 (57%) partial responses (9 confirmed and 4 unconfirmed), 7 (30%) stable disease and 3 (13%) progressive disease. Conclusions: Addition of dulanermin to first-line FOLFOX+BV was well tolerated overall in these mCRC pts. AEs were similar to those previously reported for FOLFOX+BV alone. Tumor responses suggest no adverse interactions between dulanermin and the standard first-line treatment evaluated in this study.
Prognostic impact of miR-146 polymorphism in patients with resected colorectal cancer.
Authors: Kim Jong Gwang , Chae Yee Soo , Lee Soo Jung , Kang Byung Woog , Moon Joon Ho , Sohn Sang Kyun , Choi Jun Young
Published: March 2020

3554

Background: MicroRNAs (miRNAs) are small noncoding RNAs with regulatory functions as tumor suppressors and oncogenes. The rs2910164 is a C to G polymorphism located within the sequence of miR-164a precursor, which leads to a change from a C:U pair to a G:U mismatch in its stem region. Recent evidence suggested that the rs2910164 SNP in miR-146a was associated with development of familial breast and ovarian cancers, and prostatic cancer. The aim of this study was to investigate the association between this genetic variant and prognosis of colorectal cancer (CRC) operated curatively. Methods: A total of 343 CRC patients underwent curative surgery were consecutively enrolled between 2004 and 2006. DNA was extracted from fresh frozen normal tissue and miR-146 polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: With a median follow up of 42.3 months, the combined GG+CG genotype demonstrated a better survival outcome compared with the CC genotype in a Kaplan-Meier survival analysis. Multivariate analysis showed that the G allele of miR-146 was associated with better progression-free and disease-specific survival as a dominant model adjusted to age, sex, histologic grade and stage [HR=0.54 and 0.49; p = 0.018 and 0.025, respectively]. Moreover, the tumors containing the G allele were histologically associated with more prominent lymphovascular invasion. Conclusions: Our results suggest that miR-146 polymorphism is possible prognostic marker in operated CRC patients in Korean.
Exploratory analysis of adjuvant chemotherapy benefits after preoperative chemoradiotherapy and radical resection for rectal cancer.
Authors: Chang George J. , Park In Ja , Eng Cathy , You Y. Nancy , Kopetz Scott , Overman Michael J. , Rodriguez-Bigas Miguel A. , Skibber John Michael
Published: March 2020

3556

Background: Evidence regarding adjuvant chemotherapy (CTx) for patients with rectal cancer after preoperative chemoradiotherapy (CXRT) is limited. The aim of study was to explore the relationship between CXRT response and adjuvant CTx for patients with rectal cancer treated by CXRT and radical resection. Methods: We performed a retrospective consecutive cohort study of patients with locally advanced (cStage II-III by EUS, CT, or MRI) rectal carcinoma treated with preoperative CXRT and radical resection, 1993 to 2008. To explore the late effects, we performed a landmark analysis of patients alive without recurrence at 24 months. The duration free from recurrence (FFR) was compared among patients with complete (CR, ypT0N0), intermediate (IR, ypT1-2N0), or poor (PR, ypT3-4 or N+) response according to adjuvant CTx use and type using multivariate Cox regression. Results: A total of 725 patients met criteria and were evaluated. Median follow-up was 69 months (IQR: 39-104 months). 611 patients received adjuvant CTx: 447 with fluoropyrimidine only (FP), and 139 also received oxaliplatin (Ox). Although receipt of adjuvant chemotherapy was not associated with 5-year FFR overall, (HR: 0.91, 95% CI: 0.58-1.43), adjuvant therapy did appear to suggest a benefit in the IR group (HR, 0.49; 95%CI, 0.21-1.19). 2-year landmark analysis showed that adjuvant CTx was associated with a significant improvement in FFR among the IR patients only (HR, 0.28; 95% CI, 0.08-1.00, p=0.04). Among PR patients FP alone did not improve FFR (HR, 1.22; 95% CI, 0.7-2.12) but the addition of Ox was associated with a non-significant reversal in the direction of the effect (HR, 0.53; 95% CI, 0.16-1.79). Conclusions: In this exploratory analysis, the addition of adjuvant FP CTx appeared to favorably affect the duration FFR only for patients with rectal cancer and intermediate response to CXRT followed by radical resection. These data support the investigation of the role for adjuvant fluoropyrimidine therapy among patients with CR or IR and the addition of oxaliplatin for PR patients.
Prognostic significance of lymph node retrieval in localized rectal cancer (RC): A registry analysis of 8,964 patients (pts).
Authors: Gill Amandeep , Brunson Ann , Lara Primo , Olson Kristin , Monjazeb Arta , Khatri Vijay P. , Semrad Thomas John
Published: March 2020

3566

Background: In contrast to colon cancer, the prognostic implications of reduced lymph node retrieval in RC are unclear. We investigated the association between the total number of lymph nodes examined in early stage RC and disease specific survival (DSS) in two cohorts: 1) pts who underwent surgery and adjuvant (ADJ) chemoradiation (chemoXRT), and 2) those who received neoadjuvant (NEO) chemoXRT. Methods: Using the California Cancer Registry, we identified 8,946 pts with stage I – III RC diagnosed from 2000 to 2007. Of these, 4,790 underwent tri-modality therapy: 2,946 patients (61.5%) had NEO chemoXRT and 1,844 patients (38.5%) had ADJ chemoXRT. Multivariate Cox proportional hazards models were constructed for DSS, adjusting for age, sex, race, socioeconomic status, T-stage and lymph node number. DSS was compared between NEO and ADJ cohorts within separate subgroups of pathologic node positive and node negative RC. Results: Although there was no difference in overall DSS between the NEO and ADJ cohorts, the median number of lymph nodes examined was reduced in patients who had undergone NEO chemoXRT (8 vs. 11, p<0.0001). For all pts treated with tri-modality therapy, advancing age and higher T-stage were associated with significantly reduced DSS. Positive lymph nodes were associated with worse DSS regardless of the timing of therapy, although the effect was stronger for residual lymph nodes in the NEO cohort (HR 2.8 vs. 1.8 in ADJ cohort, p<0.001). For node negative pts in the ADJ cohort, increased lymph node retrieval was associated with improved DSS (HR per node 0.952, p=0.017); however, no association between lymph nodes examined and DSS was seen in the NEO cohort (p=0.282). Conclusions: Residual positive lymph nodes in pts treated with NEO chemoXRT are more strongly associated with poorer DSS than in pts treated with surgery and ADJ chemoXRT. NEO chemoXRT dissociates the connection between lymph node retrieval and survival in RC. This finding highlights a key difference between colon and RC and underscores the need for a different interpretation of the pathologic findings after NEO therapy.
The role of TP, TS, and DPD as potential predictors of outcome following capecitabine plus oxaliplatin (XELOX) versus bolus 5-fluorouracil/leucovorin (5-FU/LV) as adjuvant therapy for stage III colon cancer: Biomarker findings from study NO16968 (XELOXA).
Authors: Schmoll Hans-Joachim , Tabernero Josep , Maroun Jean Alfred , De Braud Filippo G. , Price Timothy Jay , Van Cutsem Eric , Hill Mark , Hoersch Silke , Rittweger Karen , Chen David , Haller Daniel G.
Published: March 2020

3578

Background: In NO16968, XELOX was superior in terms of disease-free survival (DFS) and overall survival (OS) to bolus 5-FU/LV as adjuvant therapy for stage III colon cancer (Schmoll et al. ASCO GI 2012). Three key enzymes appear to have the potential to predict efficacy and/or safety of fluoropyrimidine-based treatment: thymidine phosphorylase (TP), thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD). We evaluated the association between baseline TP, TS and DPD and outcome (DFS and OS). Methods: Pts with stage III colon cancer received either XELOX (8 cycles, 24w) or bolus 5-FU/LV (Mayo Clinic, 6 cycles, 24w; Roswell Park, 4 cycles, 32w). The primary study endpoint was DFS; secondary endpoints included OS. TP, TS and DPD expression levels were determined in formalin-fixed, paraffin-embedded tissues by RT-PCR, and the median used as a cut-off point: high (above median) vs. low (below median). Results: The biomarker population included 498 (26%) of 1886 pts entered (XELOX, n=242; 5-FU/LV, n=256). Baseline demographics, tumor characteristics, cancer history and efficacy (DFS and OS) were similar to those in the main study population. Cox regression analysis for DFS (Table). In the XELOX group pts with low DPD and TP levels and a high TP/DPD ratio appeared to have significantly better DFS; this effect was not observed with 5-FU/LV. Subgroup analysis shows that the difference between XELOX and 5-FU/LV was also higher in pts with low DPD levels. Conclusions: These exploratory findings suggest that tumor DPD and TP RNA levels could be used to predict outcomes of adjuvant treatment with fluoropyrimidine/oxaliplatin combinations, and should be validated prospectively. Analysis of the current dataset is ongoing and further details on potential biomarkers will be available. [Table: see text]
Association of genetic variants in obesity-related genes with tumor recurrence in stage II/III colon cancer.
Authors: Ladner Robert D. , Gerger Armin , Zhang Wu , Labonte Melissa Janae , Yang Dongyun , Lenz Felicitas , Lenz Cosima , Bohanes Pierre Oliver , Ning Yan , Winder Thomas , Wilson Peter M.D. , Benhaim Leonor , El-Khoueiry Rita , El-Khoueiry Anthony B. , Iqbal Syma , Lenz Heinz-Josef
Published: March 2020

3584

Background: High body mass index (BMI) is an established risk factor for colorectal cancer incidence and death. Recent studies found obesity before the diagnosis of colon cancer was associated with worse survival compared with normal weight. Single nucleotide polymorphisms (SNPs) of obesity-related gene have been related with different cancer risk including colorectal cancer. Here we tested the hypothesis whether SNPs in obesity-related genes (PPAR, LEP, NFKB, CD36, DRG1, NGAL, REGIA and DSCR1) may predict tumor recurrence in adjuvant colon cancer. Methods: Either blood or FFPE tissue specimens were obtained from 234 patients (107 females and 127 males; median age 59 years (range 22–78 years)) with stage II (105 patients) or III (129 patients) colon cancer at the University of Southern California/Norris Comprehensive Cancer Center. The median follow-up was 4.4 years. SNPs in obesity-related genes were determined by PCR-RFLP or PCR-based direct sequence. The primary endpoint of the study was time to tumor recurrence (TTR). Results: in univariable analysis, PPAR rs1801282 and DSCR1 rs6517239 were independently associated with time to tumor recurrence (TTR). Patients with PPAR CC genotype had longer median TTR 9.4 months (95% C.I: 5.6, 12.4+) compared to those with CG genotype, had median TTR 3.4 months (95% C.I: 1.7, 16.8+)(p=0.04, log-rank test). Patients with DSCR1 AA genotype had shorter median TTR 6.6 months (95% C.I: 4.0, 16.8+) compared to those with AG and GG genotypes, which had longer median TTR 9.4 months (95% C.I: 5.7, 10.7+)(p=0.027, log-rank test). The multivariate analysis adjusting for stage and type of adjuvant therapy showed a trend in the association between PPAR rs1801282 and DSCR1 rs6517239 and time to recurrence (Wald test p=0.08 and 0.058, respectively). Conclusions: Our preliminary results demonstrated polymorphisms in obesity-related gene might be potential molecular markers to predict TTR in adjuvant colon cancer. Further large and biomarker embedded trial needed to confirm our findings.
Cost-effectiveness analysis per life-year gained based on predictors of response for first-line metastatic colorectal cancer therapy in Spain.
Authors: Belda-Iniesta Cristobal , Moreno Victor , Martinez-Amores Brezo , Barriuso Jorge , Mezquita Laura , Ibañez de Cáceres Inmaculada , Ayuso Sacido Angel , Peña Jose Maria , Perona Rosario
Published: March 2020

3601

Background: Economic crisis, increasing prevalence and cost of mCRC management endanger availability of biological therapies for public health systems due to budget limitations. We performed a cost-effectiveness analysis based on markers of response/resistance including biological therapies available in Spain for mCRC. Methods: We aimed to calculate incremental cost-effectiveness ratio (ICER) per life-year gained (LYG) and progression-free year gained based on predictive markers for mCRC. Efficacy data include randomized trials (RT) that guided on-label uses of bevacizumab and cetuximab. Control arms from these trials were used as reference to calculate ICERs. Markers of clinical benefit (biological and radiological) were included in this model. Toxicity as predictor of efficacy was excluded for any therapy. Prices for drugs in Spain were assumed to represent the best-value for each drug including all possibilities to reduce pharmacy costs. For 1st line, median duration of therapy reported by RT was used to calculate the final budget. 70kg and 1.7 m were used as reference for patients dose calculations. If accessible, HR for PFS and OS were used instead of medians. Results: K-Ras status and early response measured by CT at 8 weeks were used as predictors of resistance and increased efficacy for cetuximab-based combinations. We have not identified any predictor marker for other drugs from RT. In this regard, FOLFIRI+cetuximab combination obtained an ICER below the widely-proposed Spanish threshold of 30,000 € per LYG if patients harbored wt K-Ras tumors and evidenced an objective response at 8 weeks. Other ICERs for different schedules were too distant from this limit, they will be presented at the meeting. Multivariate analysis confirmed the robustness of results. Conclusions: 1st line FOLFIRI+cetuximab therapy for wt K-Ras patients that get an objective response measured by CT at 8 weeks is the only cost-effective therapy option for mCRC below usual health-economic thresholds for Spain. Our results are critical to design cost-effectiveness based clinical guidelines for mCRC that will contribute to financial sustainability of public health system in Spain.
Prognostic significance of intermediate mucinous carcinoma in patients with microsatellite stable stage II or III colon cancer.
Authors: Kim Gun Min , Ahn Joong Bae , Han Jung Woo , Kim Han Sang , Shin Sang Joon , Kwon Woo Sun , Park Chan Hee , Kim Tae Soo , An Sungwhan , Shin Im-Hee , Yang Woo Ick , Kim Nam Kyu , Chung Hyun Cheol
Published: March 2020

3606

Background: Mucinous adenocarcinoma (MC) is a histological subtype of colorectal cancer with ≥50% of mucinous component of tumor volume. According to WHO classification, tumor less than 50% of the lesion composed of mucin was considered as non-mucinous carcinoma (NMC).Mucinous histology has been shown to be an independent adverse prognostic factor in some studies, but not in others. However, prognostic implication of intermediate mucinous carcinoma (IMC) which had focal mucinous component <50% of tumor volume has not been studied yet. The aim of this study is to explore prognostic impact of IMC in patients with resected stage II or III colon cancer. Methods: This study involved 917 patients who underwent curative resection for stage II or III colon cancer in Severance Hospital, from 2003 to 2009. The proportion of mucinous component was reviewed and re-classified correctly by pathologists. MC was defined tumor having >50% mucinous component. Tumor with mucinous component but less than 50% regarded as IMC and less than 10% mucin as NMC. Results: Among 917 patients, 63 (6.9%) and 60 (6.5%) were MC and IMC, respectively. Median follow-up duration was 50.2 months (0.9~109.7) and Stage 3 was 48.1% (441/917). The similarities between MC and IMC were found as right colon dominant (MC: IMC: NMC = 60%: 67%: 34%, p<.001) and higher incidence of MSI-high compared to NMC (MC: IMC: NMC = 27%: 30%: 11%, p<.001). In stage III, the disease-free survival (DFS) rate at 5 years was 44% for MC, 56% for IMC, and 74% for NMC (p<.001). Subgroup analysis according to MSI status showed that DFS had significant inverse correlation with proportions of mucinous components in MSI-low or MSS group, but patients with MSI-high tumor showed higher five-year DFS rate (>85%) regardless of mucinous component. For stage II colon cancer patients, both mucinous histology and MSI had little clinical significance. Conclusions: In patients with curative resection for stage II or III colon cancer, IMC had similar characteristics to MC, which were right colon dominant and high incidence of MSI-high tumor. The prognostic impact of IMC was intermediate risk between MC and NMC in stage III patients with MSI-low or MSS tumor, but not in MSI-high group.
Colorectal cancer characteristics and outcomes in patients less than age 50: A comparison of an urban university hospital with the NCI SEER database.
Authors: Mitchell Edith P. , Topham Allan , Anne Pramila R. , Goldstein Scott , Isenberg Gerald , Guiles Fran , Palazzo Juan
Published: March 2020

3621

Background: Cancer of the colon and rectum is the third most commonly occurring cancer, as well as the third leading cause of cancer deaths in American men and women. Colorectal cancer in younger patients is believed to have worse pathological features and prognosis than in older patients. The objective of this study was to assess pathological features and outcomes of CRC in patients less than age 50 using an institutional sample and comparing to the Surveillance, Epidemiology and End Results (SEER) database. Methods: Included in the study were a total of 4595 cases from the Tumor Registry at Thomas Jefferson University Hospital (TJUH) over a twenty year period from 1988 through 2007 and 290,338 cases from the Surveillance, Epidemiology and End Results (SEER) database from 1988 through 2004. Patients less than age 50 were compared to those age 50 and older. Results: Patients under age 50 with CRC presented with more advanced stage tumors in both data sets (<0.0001) , and had more poorly differentiated tumors than older patients (PTJUH=0.02754; PSEER<0.0001). Patients under 50 also had more mucinous/signet ring cell tumors with 12 percent to 8.1 percent in the TJUH data (p=0.002916) and 13.2 percent to 10.3 percent in the SEER data (p<0.0001), with younger males having the highest prevalence in both data sets. Younger patients had fewer proximal tumors than patients 50 and over, and a higher proportion of rectal tumors (p<0.001). Patients under age 50 were more likely to have positive nodes at all stages (PSEER <0.0001) relative to 50 and over, as well as more likely to develop peritoneal metastases (PTJUH=0.3507),, but less likely to have lung metastases PTJUH=0.05249) than older pts. Despite their poor pathologic features, patients under age 50 had better than or equal survival to those 50 and older. Conclusions: Colorectal cancer patients under age 50 presented with worse histological characteristics and metastasized much sooner, yet the younger patients had better than or equal survival to those ages 50 and older. Ongoing studies will assess differences in treatment and molecular features between younger and older colorectal cancer patients.
Methylations of NEUROG1, p16, and MLH1 and recurrence following adjuvant FOLFOX in colorectal cancer.
Authors: Lee Hyun-Jung , Han Sae-Won , Bae Jeong Mo , Cho Nam-Yun , Lee Kyung-Hun , Oh Do-Youn , Im Seock-Ah , Bang Yung-Jue , Jeong Seung-Yong , Park Kyu Joo , Park Jae-Gahb , Kang Gyeong Hoon , Kim Tae-You
Published: March 2020

3624

Background: CpG island methylator phenotype (CIMP) is characterized by concurrent methylation of multiple CpG islands in tumor DNA, which can inactivate tumor suppressor genes or promote carcinogenesis. The prognostic impact of CIMP on treatment outcome of colon cancer patients receiving adjuvant 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) is unclear. We investigated CIMP markers in colorectal cancer patients treated with adjuvant FOLFOX. Methods: Sporadic colorectal cancer patients treated with curative resection followed by adjuvant FOLFOX were included. DNA was extracted from formalin-fixed paraffin-embedded surgical specimen. 8 CpG island loci (CACNA1G, CRABP1, IGF2, MLH1, NEUROG1, P16, RUNX3 and SOCS1) were examined using MethyLight analysis. Disease-free survival (DFS) was evaluated according to each methylation loci. Results: A total of 322 patients were included. Methylation at 1 or more loci was observed in 150 patients (46.6%) and 6 or more loci in 15 (4.7%). During a median follow-up duration of 39.7 months, 55 recurrences were observed. Three year DFS in the patient cohort was 84%. CRABP1 (23.9%) was the most frequently methylated loci, followed by p16 (22.7%) and NEUROG1 (20.8%). Patients having methylation at NEUROG1 (3 year DFS 78% in (+) vs. 86% in (-), p = 0.014) and p16 (3 year DFS 78% in (+) vs. 86% in (-), p = 0.12) had worse DFS, whereas methylation at MLH1 had better DFS (3 year DFS 100% in (+) vs. 86% in (-), p = 0.19). In a combined analysis, patients with MLH1(-)/NEUROG1(+)/p16(+) had worst treatment outcome compared to MLH1(-)/NEUROG1(+) or p16(+), MLH1(-)/ NEUROG1(-) /p16(-), and MLH1(+) (3 year DFS 62%, 82%, 87%, and 100%, respectively; p = 0.002). In multivariate analysis, NEUROG1(+)/p16(+) was associated with significantly higher recurrence compared with other patients (adjusted hazard ratio (HR) 2.15 (95% confidence interval (CI) 1.08 - 4.27, p = 0.029). Conclusions: Methylation status of NEUROG1, p16, and MLH1 is associated with recurrence following adjuvant FOLFOX in stage II/III colorectal cancer. Further validation and translational studies to improve treatment outcome in the subset of patients are warranted in the future.
Evaluation of MET pathway biomarkers in a phase II study of rilotumumab (R, AMG 102) or placebo (P) in combination with epirubicin, cisplatin, and capecitabine (ECX) in patients (pts) with locally advanced or metastatic gastric (G) or esophagogastric junction (EGJ) cancer.
Authors: Oliner Kelly S. , Tang Rui , Anderson Abraham , Lan Yun , Iveson Timothy , Donehower Ross C. , Jiang Yizhou , Dubey Sarita , Loh Elwyn
Published: March 2020

4005

Background: R is an investigational, fully human, monoclonal antibody to HGF/SF, the ligand of the MET receptor. A double-blind, P-controlled, phase 2 study randomized 121 G/EGJ cancer pts 1:1:1 to 15 mg/kg R + ECX (Arm A, n = 40), 7.5 mg/kg R + ECX (Arm B, n = 42), or P + ECX (Arm C, n = 39). OS and PFS improved with the addition of R to ECX (Iveson et al, European Multidisciplinary Cancer Congress 2011; abstr 6.504). High tumor MET levels have been associated with poor prognosis in G cancer (Nakajima et al, Cancer 1999;85:1894-1902). We explored MET pathway biomarkers to identify pts who may benefit from R. Methods: MET protein levels and gene copy numbers were measured in archival tumor samples by immunohistochemistry (IHC) and fluorescence in situ hybridization, respectively. High and low MET subgroups were defined by several predefined strategies. Total HGF and soluble MET (sMET) protein in plasma were measured by ELISA and MSD assays, respectively. Treatment and biomarker effects on OS and PFS were analyzed by Cox proportional hazard models and Kaplan-Meier estimates. Results: Tumor samples were evaluable for MET protein from 62 pts in Arms A + B and 28 pts in Arm C. Pts with METHigh tumors (> 50% tumor cells positive) in Arms A + B had improved median OS than those in Arm C (11.1 mo [80% CI: 9.2-13.3] vs 5.7 mo [80% CI: 4.5-10.4]; HR = 0.29, 95% CI: 0.11-0.76, p = 0.012). Conversely, pts with METLow tumors (≤ 50% positive) in Arms A + B had a trend toward unfavorable OS compared with those in Arm C (HR = 1.84, 95% CI: 0.78-4.34). In the chemotherapy only arm (Arm C), pts with METHigh tumors had poorer OS (HR = 3.22, 95% CI: 1.08-9.63) than pts with METLow tumors. Similar trends were seen with PFS. Predefined dichotomization schemes for tumor MET gene copy number and baseline plasma levels of total HGF or sMET did not correlate with OS or PFS. Conclusions: High MET expression by IHC may predict clinical benefit to R + ECX in G/EGJ cancer pts. High MET expression may also be associated with poor prognosis for ECX-treated pts. Further investigation is needed to confirm these findings.
Maintenance sunitinib (MS) or observation (O) in metastatic pancreatic adenocarcinoma (MPA): Clinical and translational results of a phase II randomized trial (NCT00967603).
Authors: Reni Michele , Cereda Stefano , Milella Michele , Novarino Anna , Passardi Alessandro , Mambrini Andrea , Di Lucca Giuseppe , Ferrari Laura , Belli Carmen , Danova Marco , Bergamo Francesca , Franceschi Enrico , Rovati Bianca , Fugazza Clara , Ceraulo Domenica , Villa Eugenio
Published: March 2020

4017

Background: Combination chemotherapy (CT) prolonged progression-free survival at 6 months (PFS6) of patients (pts) with MPA from <20% with gemcitabine (GEM) to >50%. To prolong CT over 6 months has unproven benefit and is hampered by cumulative toxicity. This open-label, randomised, multi-centre phase II trial explored the role of MS in pts with MPA without progressive disease (PD) after CT, using an O group as calibration arm. The role of circulating endothelial cells (CEC) as biomarker of MS activity was explored. Methods: Adult pts with pathologic diagnosis of MPA, performance status (PS) >50%, without radiological PD or CA19.9 raise >20% after 6 months of CT were stratified based on PS and previous CT and randomized to O (arm A) or MS at 37.5 mg daily until PD or a maximum of 6 months (arm B). Primary endpoint was PFS6. Sample size (H0 10%; H1 30%; a .10; b .10) was 26 pts per arm and MS had to be considered of interest with >5 pts PFS6. CEC were evaluated by flow cytofluorometry on a baseline peripheral blood sample. Results: 56 pts (29 arm A; 27 arm B) were enrolled. One arm B pt had kidney cancer and was excluded. Pts characteristics were (A/B): median age 64/61 years; median PS 90/100; median CA19.9 45/32; previous CT: GEM 3/3; combination CT 26/22. Main grade 3-4 toxicity in arm B was 15% neutropenia; 12% thrombocytopenia and hand-foot syndrome, 8% diarrhea. Second line CT was given to 76% of pts in both arms. One arm A (3%) and 6 arm B pts (23%; p=.01) were PFS6; 2y overall survival (OS) was 4% and 25% (p=.09). Blood sample for CEC analysis was available for 46 of 55 pts (84%). In arm A, median PFS was longer for pts with CEC number <30 (lower terzile group) when compared to >30 (2.9 versus 1.9 months; p.08). MS significantly increased PFS in CEC >30 group (3.4 months; p=.01). No PFS difference between arms was observed in <30 group (2.3 months). Conclusions: This is the first randomized trial on maintenance therapy in MPA. In arm B, the primary endpoint was fulfilled and 2y OS was remarkably high, suggesting that MS may have a role in pts with MPA. The number of CEC may be useful to predict benefit from MS.
FOLFIRI.3 (CPT-11 plus folinic acid plus 5-FU) alternating with gemcitabine or gemcitabine (G) alone in patients (pts) with previously untreated metastatic pancreatic adenocarcinoma (MPA): Results of the randomized multicenter AGEO phase II trial FIRGEM.
Authors: Trouilloud Isabelle , Dupont-Gossard Anne Claire , Artru Pascal , Lecomte Thierry , Gauthier Mélanie , Aparicio Thomas , Thirot-Bidault Anne , Malka David , Lobry Celine , Asnacios Amani , Lacombe Sophie , Fein Francine , Fanica Daniela , Dubreuil Olivier , Marthey Lysiane , Zaanan Aziz , Bonnetain Franck , Taïeb Julien
Published: March 2020

4018

Background: CPT-11 showed modest activity and tolerability in MPA. We developed a new strategy to improve efficacy and tolerability of CPT-11 based regimen in MPA pts. Methods: Chemotherapy-naive pts with histologically proven MPA, bilirubin levels < 1.5 ULN and performance status (PS) 0-1 were randomized in a phase II trial to receive either FOLFIRI.3 (CPT-11 90 mg/m2 as a 60-min infusion on day (D) 1, leucovorin 400 mg/m2 as a 2-hr infusion on day 1, followed by 5-FU 2000 mg/m2 as a 46-hr infusion and CPT-11 90 mg/m2, repeated on D3, at the end of the 5-FU infusion, every 2 weeks) for 2 months alternarting with G (1000 mg/m² at a fixed dose rate of 10 mg/m²/min on D1, D8, D15, D29, D36 and D43) for 2 months (arm A) or G alone (arm B). Using Fleming design the primary end point was rate of progression free survival (PFS) at 6 months from (H0) 25% over (H1) 45% needing to include 49 pts/arm. Results: Between 2007 and 2011, 98 pts were enrolled (males: 59, median age: 62 years, PS 0: 32%). Median follow-up was 23 months. Grade 3-4 toxicities per pts (%) in arm A/B were diarrhea 13/0, nausea-vomiting 11/4, neutropenia 51/25 and febrile neutropenia 4/0. No toxic death occurred. Response rate were 40 and 11% as disease control rate (CR+PR+SD) were 73 and 52% in arm A and B, respectively. The primary endpoint of the trial was met with rate of PFS at 6 months of 48% (95% CI: 33-63) in arm A while in arm B PFS was 30% (95% CI: 17 - 44). One year PFS was 23% (95%CI: 11.5-36) and 11% (95%CI: 4-21), respectively. Conclusions: FIRGEM strategy is feasible and efficient with a manageable toxicity profile in good condition pts with MPA. A phase III trial comparing this strategy with the FOLFIRINOX triplet therapy focusing on quality of life should now be performed.