bluuebunny/crossref_metadata_2025_split huggingface dataset:
CHFR methylation as an epigenetic marker for recurrence of colon cancer
Authors: Tanaka M. , Sethi S. , Li D. , Bland G. , Hamilton S. R. , Abbruzzese J. L. , Eng C. 
Published: August 2020

4043 Background: Currently, no definitive epigenetic markers exist to predict recurrence and overall survival (OS) of colorectal cancer patients after surgical resection. Promoter hypermethylation of the ID4 (inhibitor of DNA binding), RECK (reversion-inducing cysteine rich protein with Kazal motifs), and CHFR (checkpoint with forkhead-associated and RING finger domains) genes have been associated with reduced mRNA and protein expression in colorectal cancer. The purpose of this study was to determine the association of methylation of these genes and also MINT1 (methylated in tumor loci) with recurrence-free survival (RFS) and OS in colon cancer patients. Methods: DNA methylation was quantitatively evaluated using pyrosequencing in tissue samples from 64 patients with AJCC stage II and III colon cancer without HNPCC seen at M.D. Anderson during 1999–2007. Survival outcomes were determined by retrospective chart review and evaluated by Kaplan-Meier plot and log-rank test for univariate analysis and Cox's proportional hazard model for multivariate analysis. Mean methylation rate of multiple CpG sites in the promoter region was used. For this analysis, we defined <15%, 15%-30%, and >30% as methylation-negative, -low, and -high, respectively. Results: There were 19 stage II (30%) and 45 stage III (70%) patients. The median age was 62.1 years (range: 31–86). Adjuvant chemotherapy was completed in 49 patients (77%). After a median follow-up of 54.9 months, 12 (19%) patients developed recurrence and 7 (11%) have died. Methylation of MINT1, ID4, and RECK did not correlate with RFS and OS. The CHFR methylation-high (42%) group had low RFS (P=.04) and OS (P=.03) when compared with the CHFR methylation- negative (38%) and -low (20%) group. CHFR methylation-high was associated with N2 disease (P=.04) and right-sided tumors (P=.002). Multivariate analysis indicated T4 disease [P=.004, HR=8.42 (95% CI: 1.98–35.8)] and CHFR methylation-high [P=.04, HR = 3.79 (95% CI: 1.04–13.8)], were poor prognostic factors for recurrence. Conclusions: The presence of high CHFR promoter methylation correlates with advanced lymph node metastasis and shortened RFS and OS. Methylation of the CHFR promoter is a potential epigenetic marker for colon cancer recurrence and overall survival. No significant financial relationships to disclose.
Adjuvant therapy report card: Patients with stage II/III colon cancer grade their oncologists
Authors: Love N. , Ault Ziel K. , Bylund C. , Elder M. , Ellis L. M. , Grothey A. , Meropol N. J. , Paley D. , Ravdin P. M. , Saltz L. B. 
Published: August 2020

4045 Background: Our group previously reported on patient (Pt) recollections of adjuvant therapy (AT) for colon cancer and their grading of medical oncologists (MO) regarding various aspects of care. Overall, MO were highly rated, but grades for presenting information were lower, and patient expectations about side effects often did not match experiences. To further examine the Pt experience with AT, a prospective study was launched in Feb 2008. Methods: Pts with Stage II/III colon cancer about to begin or within 4 months of starting AT were recruited for a 4-part survey regarding sources and quality of treatment information and their experiences with AT. The survey also asked Pts to provide a grade (A-F) for their MO in 8 areas. Results: 85 Pts (71% female, 79% Stage III, median age 52 years) completed Part 1 of the survey. 93% stated that their MO explained the risks and benefits of AT. Of those, 92% stated they understood this information completely or almost completely (3 or 4 on a 0–4 scale) and 79% received numerical estimates of recurrence risk with and without treatment. When questioned about the potential absolute benefit of AT, 26% of Pts who received numerical estimates “had no idea” and other answers ranged from 3% to 100% for recurrence risk. Pt grade point averages for their MO ranged from 3.0 to 3.6 ( Table 1 ). As in the prior survey, expectations about side effects frequently did not accurately reflect experiences. For example, 54% of Pts expected alopecia but only 5% experienced it to a significant degree. 84% of Pts also sought information from websites, and 87% rated this as helpful and valuable (3 or 4 on a 0–4 scale). Conclusions: Pts are generally satisfied with their MO but less so with the presentation of treatment-related information and thus frequently consult additional resources, such as cancer information websites. This suggests an opportunity for improved information delivery within oncology offices and via the Internet. [Table: see text] [Table: see text]
Does delay of adjuvant chemotherapy affect the clinical outcome in patients with colon cancer?
Authors: Bayraktar U. D. , Bayraktar S. , Herna S. , Ku N. , Jones C. , Merchan J. , Sands L. R. , Marchetti F. , Montero A. , Rocha-Lima C. M. 
Published: August 2020

4046 Background: Adjuvant chemotherapy (AC) in patients with stage III colon adenocarcinoma prevents recurrences and improves survival. Although most trials mandate initiation of AC within 8 weeks of resection, the impact of timing of AC is still not clear with few studies reporting conflicting results. We hypothesized that AC commenced within 60 days of resection would increase survival in patients with stage II and III colon cancer. Methods: Patients with newly diagnosed stage II or III colon adenocarcinoma who received fluoropyrimidine based AC in two centers (a private cancer center and a large community hospital) between 2000 and 2007 were included into analysis. Time to adjuvant chemotherapy (TTC), overall survival (OS), and relapse-free survival (RFS) were calculated from the surgery date. Patients were dichotomized into early- (group 1) and late-treatment (group 2) groups using the TTC of 60 days. The demographic, clinical, and laboratory characteristics of patients in two groups were compared using chi-square and t-test. Kaplan-Meier survival curves were constructed employing univariate log-rank test to assess the effects of demographic and clinical characteristics on OS. Then the impact of TTC on OS and RFS was analyzed using a Cox proportional hazard model incorporating the significant factors found in the univariate analysis. Results: 190 patients were eligible for the study (median age: 57 yrs [range 14–84]). 116 patients (61%) were female and 35 patients (18%) had stage II disease. Median TTC was 49 days (range 24–196) and median follow-up was 143 weeks (range 9–451). 134 patients (70%) received AC within 60 days of surgery (group 1) and 56 (30%) received after (group 2). The only difference between the two groups was the higher N stage in group 1. The treating hospital and the N stage were found to be the factors affecting the OS in univariate analysis. Five-year OS for group I was 75.2% as compared to 61.3% for group II (HR 2.11, CI: 1.00–4.45, p=0.049). Five-year RFS for group I was 65.7% as compared to 59.0% for group II (HR: 1.19, CI: 0.65–2.20, p=0.570). Conclusions: Delay of AC more than 60 days after resection is associated with inferior survival in stage II/III colon cancer. No significant financial relationships to disclose.
Progression-free survival in intention to treat populations versus total KRAS populations in patients treated for metastatic colorectal cancer: A pooled review
Authors: Costello B. A. , Hecht J. R. , Grothey A. 
Published: August 2020

4054 Background: In treatment trials of patients with metastatic colorectal cancer (mCRC), KRAS mutation status of tumor samples has been retrospectively demonstrated to be predictive of treatment benefit. Historically, clinical trials have not required tissue samples to be tested for KRAS mutation status as a condition of enrollment. Therefore, KRAS analyses have been based on available tissue samples representing only a portion of patients retrospectively analyzed for KRAS status and correlated with treatment end- points. Methods: A weighted analysis of pooled data was performed using six recently presented or published clinical trials of targeted therapy in mCRC which tested for the association of KRAS status with Progression Free Survival (PFS). The goal of the analysis was to determine whether there is a significant difference in PFS between the intention to treat (ITT) population and KRAS population in both the treatment and control arms. Results: The total ITT population of the pooled studies is 3864, and for the total KRAS population, 2295; a 59.4% retrieval rate (range 28–92%) for tissue samples available for KRAS analysis. The weighted Δ PFS across all arms between the ITT population and the KRAS population was 0.2 months with a range of 0–0.7 months. Of the 12 subgroups (6 control and 6 treatment arms), five had no difference in PFS between ITT and KRAS evaluable populations at all, and two additional subgroups demonstrated a difference PFS of only 0.1 months. The two studies with the lowest tissue retrieval rates (28% and 45%) had the largest Δ PFS. Conclusions: There is no meaningful difference in the PFS between the ITT and KRAS populations based on our analysis of pooled data. The difference in PFS was greatest in the two studies with the lowest rate of retrieval of tissue samples for KRAS testing. As such, subgroup analysis is better able to estimate and reflect the ITT population if a higher percentage of samples is able to be obtained. Further, our results suggest that there is not an inherent systemic bias influencing any potentially observed differences in PFS. Tissue samples should be required for all patients entering a clinical trial to avoid this issue and to make retrospective analysis more valid. [Table: see text]
Correlation of KRAS status with clinical outcome in patients (pts) with metastatic colorectal cancer (mCRC) treated first-line with FOLFOX6 + cetuximab (FX+C) or FOLFIRI + cetuximab (FF+C): The CECOG/CORE1.2.001 trial
Authors: Koza I. , Wrba F. , Vrbanec D. , Ocvirk J. , Ciuleanu T. E. , Beslija S. , Papamichael D. , Messinger D. , Zielinski C. C. , Brodowicz T. 
Published: August 2020

4055 Background: Previous retrospective analyses of KRAS mutation status from the randomized CECOG/CORE 1.2.001 phase II trial has shown that treatment with cetuximab plus standard chemotherapy (CT) in pts with KRAS wild-type (wt) tumors leads to significantly better progression-free survival (PFS) and overall survival (OS) compared with KRAS mutant (mt) tumors. Methods: CECOG investigators performed a post-study survival update, re-assessing the impact of KRAS status and other possible predictive factors for OS using multivariable Cox proportional hazard methods. Results: KRAS-evaluable tissue was available from 117 (77%) of 151 pts in the ITT population. KRAS wt status was detected in 53% (n=62) of tumors (34/57 and 28/60 in the FX+C and FF+C arm, respectively). After a median follow up of 29 months (mo), OS in pts with KRAS wt tumors was significantly improved compared to pts with KRAS mt tumors (median 20.8 vs 15.9 mo; hazard ratio (HR)=1.62; p=0.0296). OS analysis by treatment arm revealed a statistically significant difference in favor of pts with KRAS wt tumors in the FX+C arm (median 22.5 vs 15.2; HR=2.06; p=0.0201) and no significant differences in the FF+C arm. Exploratory multivariable Cox proportional hazard analysis showed that as well as KRAS wt status (vs KRAS mt), an acne-like rash of grade 2/3 (vs grade 0/1) in the first 6 weeks and no prior treatment (vs prior neo-/adjuvant treatment) were the strongest independent predictors for prolonged survival (each p<0.005). Conclusions: This analysis confirmed the results of previous studies: treatment with cetuximab plus standard CT in pts with KRAS wt tumors leads to significantly better OS compared to pts with KRAS mt tumors. The early occurrence of a cetuximab-related grade 2/3 acne-like rash seems to be an independent predictor for prolonged survival in addition to KRAS status. The relevance of the lower predictive value of KRAS status noted for OS in the FF+C arm pts vs the significant effect in the FX+C arm is undetermined due to the low sample size of the subgroup analyses. [Table: see text]
Association of BRAF mutations and EGFR Intron-1 L/L genotype with resistance to cetuximab plus irinotecan treatment in KRAS wild-type metastatic colorectal cancer patients
Authors: Ruzzo A. , Cremolini C. , Loupakis F. , Fornaro L. , Santini D. , Vincenzi B. , Canestrari E. , Magnani M. , Falcone A. , Graziano F. 
Published: August 2020

4058 Background: KRAS and BRAF mutations are associated with resistance to anti-EGFR monoclonal antibodies. EGFR Intron-1 (CA)n genotype has been suggested to influence the activity of cetuximab. Methods: We retrospectively assessed KRAS and BRAF mutational status and EGFR Intron-1 (CA)n genotypes in 117 irinotecan-refractory EGFR-positive mCRC patients treated with cetuximab plus irinotecan. We defined short (S) and long (L) allelic variants those presenting < and ≥17 CA repeats respectively. Among KRAS wild-type patients, we investigated the association between BRAF mutational status and EGFR Intron-1 genotype and treatment outcome in terms of RR and PFS. Results: Among 66 (56%) KRAS wild-type patients, BRAF V600E mutation was detected in 9 (14%) patients. BRAF wild-type patients reported improved RR (0/9, 0% vs 19/57, 33%, p = 0.04) and PFS (3.3 vs 5.1 months, p = 0.076; HR = 0.54 [95%CI: 0.18–1.09]) in comparison with BRAF-mutated. EGFR Intron-1 L/L genotype was detected in 13 (20%) KRAS wild-type patients. Objective responses were reported in 1/13 (8%) EGFR Intron-1 L/L patients and in 18/53 (34%) S/L or S/S patients (p = 0.061). Significantly longer PFS was observed among EGFR Intron-1 S/L or S/S patients (5.3 vs 3.3 months, p = 0.0062; HR = 0.45 [95%CI: 0.14–0.72]). Among 57 KRAS and BRAF wild-type patients, 1/11 (9%) EGFR Intron-1 L/L patients and 18/46 (39%) S/L - S/S patients responded to treatment (p = 0.058), achieving median PFS of 3.7 and 5.4 months, respectively (p = 0.022; HR = 0.48 [95%CI: 0.15–0.87]). Conclusions: In KRAS wild-type patients, BRAF mutations are confirmed to predict resistance to cetuximab treatment. EGFR Intron-1 allelic variants are promising markers of benefit in patients with both KRAS and BRAF wild-type and may help to better select mCRC patients candidate to receive cetuximab-containing treatment. No significant financial relationships to disclose.
Duration of disease control (DDC) or time to failure of strategy (TFS) to evaluate a chemotherapy strategy in advanced colorectal cancer (ACC)
Authors: Chibaudel B. , Tournigand C. , Perez-Staub N. , Bourges O. , Maindrault-Goebel F. , André T. , Lledo G. , Louvet C. , Bonnetain F. , de Gramont A. 
Published: August 2020

4073 Background: Progression-free survival (PFS) is not an optimal endpoint in therapeutic strategies evaluating either stop and go or alternated therapies, or a fixed sequence of two therapies. DDC (Tournigand, JCO 2006) and TFS (Allegra, JCO 2007) composite endpoints have been proposed to evaluate efficacy of these strategies in ACC. This study compared these two alternative endpoints. Methods: DDC is defined as the sum of the PFS of each sequence, except when progressive disease is observed at either reintroduction or second-therapy (DDC=PFS1+PFS2 if treatment 2 achieved stabilization or response). TFS is defined as the total PFS from the initiation of the strategy to disease progression while on all the planned agents, or disease progression during a treatment-free interval and no further therapy received within 1 month, or death (TFS=PFS 1+2). Both DDC and TFS have been calculated in three trials: OPTIMOX1 (oxaliplatin stop and go vs continuous administration, updated database, Tournigand, JCO 2006), OPTIMOX2 (oxaliplatin stop and go vs complete stop and go, updated database, Maindrault-Goebel, ASCO 2007) and C97–3 (FOLFIRI1- FOLFOX6 or reverse sequence, Tournigand 2004). Results: The median potential follow-up time was 39.8 months. There was a moderately shorter DDC than TFS in the two stop and go studies, but a much shorter DDC than TFS in the sequential therapy study. There was a significant correlation between DDC and OS (r=0.96, p=.002) but not between TFS and OS (r=0.71, p=.11) Conclusions: Two bias impacted TFS 1) the results of resuming the planned therapeutic strategy for progression after a chemotherapy-free interval of more than one month was not considered, 2) patients who were not progressive at the end of planned strategy could not be censored at that time. The shorter duration of DDC over TFS may have an advantage in terms of sample size for evaluation of therapeutic strategies. In case of drug registration, DDC does not increase in case of inactive second sequence. [Table: see text] No significant financial relationships to disclose.
Efficacy of intraoperative radiofrequency ablation (IRFA) combined or not with resection to treat unresectable colorectal metastases, with or without preoperative chemotherapy: The ARF2003 Study (NTC 00210106): Preliminary results
Authors: Becouarn Y. , Mathoulin-Pélissier S. , Rivoire M. , Ayav A. , Arnaud J. , Sa Cunha A. , Brunet R. , Fonck M. , Bellera C. , Evrard S. 
Published: August 2020

4095 Background: Only few patients suffering from colorectal metastases (CRM) can have surgery and thus hope for a 40% 5-year survival rate. Adding IRFA to resection may improve the efficacy of surgery. Methods: The primary objective was to evaluate the efficacy of IRFA combined or not with resection in terms of 3-month complete hepatic response (CHR) in patients with unresectable CRM. Secondary endpoints were overall survival (OS), disease-free survival (DFS), morbidity and quality of life. A phase II study based on a Simon's two-stage design was conducted in 6 university French hospitals. Number of subjects estimated was 53, with 19 for the 1st stage. At the end of the 1st stage, 12 CHR were required to continue recruiting. At the end of 2nd stage, 37 CHR would be required to claim efficacy. Results: Fifteen of the first 19 patients exhibited CHR allowing the study to pursue accrual which ended in Nov 08; some patients are still followed up. As of Nov 08, data had been collected on 47 patients (mean age 61 years): 6 had RFA alone (13%), 37 had RFA and resections (82%), 2 could not be treated (4%). Median number of CRM was 5 (1–12). All had chemotherapy pre-op and 12 post-op (29%). Three-month data were available for 36 patients: 1 patient died on the 3rd week following intervention. Scans were available for 35 patients (independently reviewed). Of these, 29 had CHR (83%); 13 had 3-month morbidity (37%). The median follow-up was 15 months. One-year OS and DFS rates were 92.3% and 26% respectively. Analysis on all 53 patients will be communicated in June 09. Conclusions: These preliminary results suggest that IRFA combined or not to resection may be efficient in treating unresectable diseases despite their more aggressive pattern. This corroborates the EORTCC CLOCC Trial findings which demonstrated IRFA superiority upon chemotherapy alone. IRFA could thus be valuably associated to resection in treating patients with colorectal metastases that resection alone could not handle. No significant financial relationships to disclose.
Addition of bevacizumab to induction plus concomitant capecitabine-oxaliplatin (XELOX) chemoradiotherapy (CRT) in MRI poor prognosis locally advanced rectal cancer: Avacross study
Authors: Nogue M. , Salud A. , Vicente P. , Pericay C. , Arriví A. , Roca J. M. , Losa F. , Ponce J. , Safont M. J. , Guasch I. 
Published: August 2020

4100 Background: Concomitant CRT with 5-FU followed 6–8 weeks later by TME surgery is well accepted standard treatment for locally advancer rectal cancer. This approach focuses only into local control. Trimodal induction approaches with chemo, radiation and anti VEGFR therapy may induce additional tumor growth delay. Methods: Eligible patients (pts) had high-risk rectal adenocarcinoma defined by MRI: distal T3 at/below levators, T3 at any other level within 2 mm of mesorectal fascia, resectable T4 and any T3 with nodal metastases. We excluded pts with any antecedent of heart disease. Treatment consisted in four 21 day cycles of oxaliplatin 130 mg/m2 d 1, bevacizumab 7.5 mg/kg d 1 and capecitabine 1000 mg/m2/12 h d 1–14. After 3–4 weeks they received concomitant RT (50.4 Gy in 28 fractions) with capecitabine 825 mg/m2/12 h plus bevacizumab 5 mg/kg, three biweekly doses. TME was planned 6–8 weeks after CRT. Primary end point was pathologic complete response rate with standarized pathology examination. Results: From July 2007 to July 2008, 47 pts were enrolled. Median age was 58 (30–78). Median KPS was 90%. Clinical stage was T3N1: 51.1%, T3N2: 25.5%, T4N0–2: 10.6%, T3N0: 8.5% of pts. 40 pts completed the induction phase: G 3–4 toxicity were diarrhea 12.7%, neutropenia 8.5%, peripheral neuropathy 6.3% and thrombocytopenia 4.2%.. 39 pts completed the CRT phase. Grade 3–4 toxicity were rectitis, linfopenia and hipertrigliceridemia in 2.5% of pts. Until now we have data on 35 resections, 2 with only one induction cycle. R0 resections were achieved in 34 pts (R1 resection in a patient with only one induction cycle). There were 7 wound complications and 10 pts required surgical reintervention. pCR were obtained in 13 pts (37,1 %, 95% CI:21.1–53.2) with 18 (51.4%) additional pts with only residual microscopic foci. There were two treatment related-deaths: one sudden death and one grade 4 diarrhea and diabetic ketoacidosis. Conclusions: Preliminary results show that our preoperative schedule appears feasible, with impressive activity level (pCR + Tmic of 88.5%), achieving downstaging in nearly all pts. Toxicity was manageable, nevertheless we stress caution with cardiac and GI events and surgical complications. No significant financial relationships to disclose.