bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of FOLFOXIRI and bevacizumab (bev) compared to FOLFOX and bev on health related quality of life (HRQOL) in patients with metastatic colorectal cancer (MCRC): Analysis of the CHARTA-AIO 0209 trial.
Authors: Quidde Julia , Schmoll Hans-Joachim , Garlipp Benjamin , Junghanss Christian , Leithaeuser Malte , Vogel Arndt , Schaefers Michael , Kaiser Ulrich , Hoeffkes Heinz-Gert , Florschütz Axel , Rüssel Jörn , Kanzler Stephan , Edelmann Thomas , Forstbauer Helmut , Goehler Thomas , Hannig Carla , Hildebrandt Bert , Bokemeyer Carsten , Steighardt Jörg , Stein Alexander 
Published: September 2018

3544 Background: FOLFOXIRI/bev is a highly efficacious first line regimen in MCRC. Despite higher rates of neutropenia, diarrhea and stomatitis, FOLFOXIRI/bev is tolerable and feasible in MCRC patients. To date nothing is known about the impact of this regimen on HRQOL. Methods: 250 patients were randomized to FOLFOX/bev (arm A) or FOLFOXIRI/bev (arm B). HRQOL were assessed at baseline, every 8 weeks during induction treatment (6 months) and every 12 weeks during maintenance treatment, using the EORTC QLQ-C30, QLQ-CR29 and QLQ-CIPN20. The mean values of every score were calculated as the average of week 8, 16 and 24 assessment. Test concerning mean values were performed as t-test, with global type I error set at 0.05. HRQOL deterioration and improvement rates were analyzed and compared between treatment groups using chi² tests. Results: For HRQOL analysis, 237 patients were eligible (arm A: 118; arm B: 119). Compliance rate with the HRQOL questionnaires was 95.4% at baseline, 72.6% at week 8, 59.5 % at week 16 and 43.5% at week 24. Whereas mean global quality of life score (GHS/QOL) was similar between arm A and B (59.8 vs. 58.8; p = 0.726), mean scores for nausea/vomiting (9.4 vs. 16.0; p = 0.015) and diarrhea (23.7 vs. 32.1; p = 0.051) significantly or borderline significantly favored arm A during induction period. Furthermore, at week 8 scores of nausea/vomiting (9.2 versus 17.3, p = 0.006) appetite loss (19.5 vs. 29.4; p = 0.035) and financial problems (18.3 vs. 29.5; p = 0.021) and at the end of treatment physical functioning (75.0 vs. 65.8; p = 0.048) were significantly better for arm A compared to arm B. No significant differences were observed in the remaining EORTC scores. The rates of deterioration and improvement between baseline and week 8 of at least 10 points in the EORTC scores were similar (e.g. deterioration-rate GHS/QOL score 21.5% vs. 26.5% for arm A vs. B; p = 0.461). Conclusions: Although no remarkable detriment in HRQOL was noted, the better efficacy of FOLFOXIRI/bev compared to FOLFOX/bev is associated with a decrease in mainly gastrointestinal QOL scores. Further subgroup-analyses will be presented at the meeting. Clinical trial information: NCT01321957.
A randomized phase II study evaluating efficacy and safety of SOX versus mFOLFOX6 as neoadjuvant chemotherapy for patients with resectable rectal cancer (KSCC1301).
Authors: Katsumata Kenji , Oki Eiji , Kato Hiroyuki , Miwa Keisuke , Sugiyama Masahiko , Murakami Hidetsugu , Hasegawa Hiroshi , Mori Shinichiro , Nakayama Goro , Saeki Hiroshi , Shimokawa Mototsugu , Kakeji Yoshihiro , Baba Hideo , Akagi Yoshito , Maehara Yoshihiko 
Published: September 2018

3549 Background: Neoadjuvant radiotherapy is the current standard of care for rectal cancer. However, radiation therapy is sometimes associated with short-term severe toxicity and long-term morbidity. Perioperative introduction of new chemotherapy agents without radiotherapy for locally advanced rectal cancer (LARC) may be a promising option. Several studies of combination chemotherapy with oxaliplatin plus S-1 (SOX) have reported promising efficacy and safety in patients with metastatic colorectal cancer, suggesting a potential replacement for mFOLFOX6. Methods: A randomized phase II trial was undertaken to compare the efficacy and safety of SOX and mFOLFOX6 as neoadjuvant chemotherapy for patients with LARC. Patients were randomly assigned to receive mFOLFOX6 (every 2 weeks; day 1: 400 mg/m2 bolus 5-fluorouracil [5-FU]; days 1 and 2: 2,400 mg/m2 continuous 5-FU; day1: 200mg/m2 l-LV; and day 1: 85 mg/m2 oxaliplatin) or SOX (every 3 weeks; days 1–14: 80 mg/m2 oral S-1; and day 1: 130 mg/m2oxaliplatin). The protocol period for neoadjuvant chemotherapy was 3 months. The primary endpoint was the 3-year disease-free survival rate (3y DFS), and the secondary endpoints included pathological effect, R0 resection rate, survival and safety. Results: Between September 2013 and October 2015, 110 patients were enrolled and randomized (56 received SOX and 54 received mFOLFOX6). Baseline characteristics were balanced between the two arms. The major adverse events were neutropenia, peripheral neuropathy, loss of appetite, and fatigue. The incidence of grade 3 or higher neutropenia based on the CTCAE Vers.4.0was 13.2% in the SOX group and 32.0% in the mFOLFOX6 group. The surgical completion rate was 100% for the SOX group and 96% for the mFOLFOX6 group. The incidence of grade II or more surgical site infection based on Clavien-Dindo classification (CD) was 11.3% and 4.2% for the SOX and mFOLFOX6 groups, respectively. The CD grade III anastomosis-related complications developed in 7 cases in total. Conclusions: The KSCC1301 study suggests that neoadjuvant chemotherapy without radiation is active and safe. The results of pathological response will be provided. Clinical trial information: UMIN000011486.
Clinical and molecular characterization of patients with metastatic colorectal cancer harbouring DNA mismatch repair deficiency.
Authors: Cohen Romain , Hain Elisabeth , Cervera Pascale , Buhard Olivier , Dumont Sylvie , Bardier Armelle , Bachet Jean-Baptiste , Gornet Jean Marc , Dumont Sarah , Kaci Rachid , Bertheau Philippe , Renaud Florence , Bibeau Frederic , Parc Yann , Duval Alex , Svrcek Magali , Andre Thierry 
Published: September 2018

3563 Background: Prognosis of patients (pts) with metastatic colorectal cancer (mCRC) harboring microsatellite instability (MSI) is poorly characterized. We aimed to assess the clinical relevance of distinguishing sporadic (SP) from Lynch syndrome (LS)-related mismatch repair deficiency (dMMR). Methods: Pts with diagnostic of dMMR and/or MSI mCRC between 1998 and 2016 were retrospectively identified in 6 French hospitals. Tumor samples were systematically collected and screened for RAS/RAF mutations and MLH1 promotor methylation. dMMR and MSI statuses were confirmed using immunohistochemistry and Pentaplex© PCR assay. Sporadic cases were molecularly defined as those displaying MLH1 loss of expression with BRAFV600E mutation and/or MLH1 hypermethylation. Clinical data (demographic data, metastatic sites, therapeutic strategies) were recorded. Results: 129 pts, of which 48 SP and 81 LS, were included. Compared with LS, SP were associated with female (P < .001), older age at diagnostic (P < .001), proximal colon (P = 0.002), and less liver metastasis (25% vs 47%, P = .02). For initially localized CRC, median disease free survivals (DFS) were 9.1 months (m) for SP (n = 22) and 12.3 m for LS (n = 47) (hazard ratio (HR) = 0.5, 95%CI 0.28-0.90, P = .02). Median overall survivals (OS) from stage IV diagnosis were 43.9 m in the overall population, 23 m for SP and not reached for LS (HR = 0.23, 95%CI 0.10-0.52, P < .001). BRAF mutation was harbored by 29 SP tumors (60%) and did not impact OS among SP pts (P = .52). Metastatic disease was less frequently resectable for SP than LS (21% vs 56%, P < .001). Median DFS for pts with resected metastatic disease (n = 55) were respectively 6.7 and 10.5 m (HR = 0.28, 95%CI 0.10-0.73, P = .01). At the data cut-off date, 16 pts (15 LS and 1 SP) were still in complete remission. Median progression free survivals with first-line chemotherapy for pts with unresectable metastasis (n = 61) were 3.9 m for SP and 5.0 m for LS (P = .71). Conclusions: This retrospective study suggests a worse prognosis of pts with SP MSI mCRC compared to these with LS-related mCRC.
Bevacizumab and its impact on survival for patients receiving subsequent anti-EGFR therapy: Updated results from the SA metastatic CRC registry.
Authors: Price Timothy Jay , Karapetis Christos Stelios , Padbury Robert , Burge Matthew E. , Roy Amitesh Chandra , Maddern Guy , Roder David , Piantadosi Cynthia , Townsend Amanda Rose 
Published: September 2018

3569 Background: Debate exists as to whether first line bevacizumab effects subsequent sensitivity to anti-EGFR therapy. Authors hypothesize that initial anti-VEGF therapy may induce biological changes that then increase the risk of acquired resistance to subsequent EGFR inhibitors. Methods: A retrospective cohort study was performed to compare the characteristics and survival of patients who were treated with an anti-EGFR therapy 2nd line and beyond by two groups defined by the first line therapy; 1. chemotherapy (chemo) plus bevacizumab (bev) and 2. chemo alone. Survival for this analysis is from the time of commencing first line chemotherapy and secondly from anti-EGFR therapy. Pearson chi test analysis was performed to determine whether receiving first line bev was associated with worse overall survival (OS). Results: 348 mCRC patients who received chemo with or without bev and then an anti-EGFR therapy were studied. Patient characteristics are summarised in the table below. The significant differences between group 1. Vs. 2. were as follows; median age 63.8 years v 67.9 years (p = 0.005), lower use of single agent FU 6.4% v 19.2%, KRAS status not tested (reflecting the practice changes over time) 19.3% v 39.2%, KRAS MT 2% v 4%, and where BRAF MT status was known (11%); BRAF MT rate 23% v 0. Median OS for the 2 groups was 34.2 months, and 28.2 months respectively (p = 0.12) from first line therapy. Median OS for patients who underwent single agent anti-EGFR as subsequent therapy was also not significantly different, 31.1 months group 1 (n = 60) versus 27.7 months group 2 (n = 85), p = 0.52. Results based on commencement of anti-EGFR therapy are under way. Conclusions: Survival was not significantly different between the two groups, and the trend was towards higher OS with chemo plus bev suggesting that in our registry population, bev administration in first line therapy with chemo did not lead to a worse outcome overall for those patients subsequently receiving anti-EGFR therapy, either with chemotherapy or as a single agent. Updated results from commencement of anti-EGFR therapy will give further insights and will be presented at the meeting.
Upfront short course radiotherapy (SCRT) in metastatic rectal cancer (mRC): A way forward.
Authors: Jain Shanu , Engineer Reena , Ostwal Vikas S. , Ramaswamy Anant , Chopra Supriya , Desouza Ashwin , Lewis Shirley Christabel , Arya Suprita , Patil Prachi , Saklani Avanish 
Published: September 2018

3570 Background: To evaluate the feasibility and efficacy of SCRT followed by chemotherapy (CT) in locally advanced metastatic rectal cancer (LAmRC). Methods: Between May 2012 and August 2015, 70 patients having LAmRC with or without circumferential resection margin (CRM) positive disease treated with SCRT (25Gy/5#) followed by 3-6 cycles of capecitabine/5-FU, oxaliplatin or irinotecan based CT were assessed. Results: Fifty one had single site metastases (23 liver, 16 lung, 10 retroperitoneal lymph nodes and 2 peritoneum), 9 had combined lung and liver metastases and 10 had combined nodal and organ metastases. Sixty five (93%) patients could complete planned SCRT and 3-6 cycles of chemotherapy (starting 7-10 days after RT completion) with dose reduction in 21 (32%) patients owing to CT induced toxicities. Local tumor down-staging was achieved in 43 (61.4%) patients and the rest had a stable primary disease. Radiologically, CRM was free in 25 (46.3%) patients out of 54 initially involved. Surgery of the primary was planned in 38 (58%). R0 resection in 26 (40%), R1 in 7 (pCRM positive). Five refused surgery in spite of being resectable. Rest of the 27 (41%) received palliative CT due to progression of distant disease. Metastatectomy along with primary surgery was done in 16 (25%) patients. Median follow up was 29 months. Overall survival (OS) of entire cohort at 2 years was 40%. Median progression free survival (PFS) and OS of patients with resected primary was 17 (10-24) and 37 (28-45) months, respectively, which is significantly better than those who were not resected (p = < 0.001). Of these 33 resected patients, 13 (39.4%) are disease free and 20 have progressed (16 distant, 2 loco-regional and 2 local and systemic). Conclusions: Upfront SCRT followed by systemic CT in an unresectable group of metastatic rectal cancer patients is safe and feasible and is having encouraging results in terms of downstaging and resectability of the primary. [Table: see text]
Comparison of 5-FU vs capecitabine in combination with mitomycin or cisplatin in the treatment of anal cancer.
Authors: Yu Irene , Cheung Winson Y. 
Published: September 2018

3576 Background: The patterns of capecitabine use as an alternative form of fluoropyrimidine to infusional 5-FU in the non-operative management of anal cancer in the real world are poorly described. Our objectives were to determine the frequency of capecitabine use, compare the observed outcomes between oral and intravenous fluoropyrimidines, and examine for variations in treatment-related adverse events between the two agents. Methods: All anal cancer patients who received either capecitabine or infusional 5-FU as part of their chemoradiation treatment from 2004 to 2013 at any 1 of 6 cancer centers in British Columbia were included. Chi-square and Wilcoxon-Mann tests were used to assess for associations between treatment groups and clinical characteristics and outcomes. Results: A total of 486 patients were identified: median age was 59 (IQR 53-67) years, 175 (36%) were men, 418 (86%) had ECOG 0/1, and 30 (6%) were HIV positive. Median total radiation dose was 54 cGy (IQR 50-54) and 47 (10%) underwent a colostomy prior to chemoradiation. Baseline characteristics were balanced between the two groups with respect to age, gender, ECOG, and HIV status (all p > 0.05). Prior to 2010, only 5-FU was utilized. From 2010 to 2013, 155 and 82 patients (65% vs 35%) received capecitabine vs 5-FU, respectively. Overall (68% vs 67%, p = 0.831) and disease-free survival rates (59% vs 59%, p = 0.926) at 3 years were similar in the capecitabine vs 5-FU groups. Rates of subsequent abdomino-perineal resection were also similar (10% vs 14%, p = 0.164). Patients who received 5-FU were more likely to report adverse effects (76% vs 57%, p < 0.01). The capecitabine group had a lower incidence of stomatitis (7% vs 43%, p < 0.01) whereas the 5-FU cohort reported less frequent hand-foot syndrome (1% vs 7%, p < 0.01). The rates of myelosuppression, nausea/vomiting, diarrhea, and rash were similar between the two groups (all p > 0.05). Conclusions: This represents one of the largest population-based studies to demonstrate a preference for capecitabine in place of 5-FU in the management of anal cancer. Survival outcomes were similar between the two treatment groups, but capecitabine may be better tolerated in the real world.
Colorectal cancer: Impact of primary tumor location on genetic alterations.
Authors: Salem Mohamed E. , Lenz Heinz-Josef , Xiu Joanne , Hwang Jimmy J. , Philip Philip Agop , Shields Anthony Frank , Marshall John 
Published: September 2018

3578 Background: Recent data show that patients with left sided colon tumors (LT) have better survival and respond differently to biologics compared to patients with right-sided tumors (RT), likely due to molecular differences. We sought to examine these differences. Methods: Primary colorectal tumors (n = 1730) with origins clearly defined as RT (cecum to hepatic flexure; n = 273), LT (splenic flexure to sigmoid colon; n = 585), or rectal (RC; n = 872) were examined by NextGen sequencing, protein expression and gene amplification. Tumor mutational load (TML) was calculated in 1001 of these tumors using only somatic nonsynonymous missense mutations. Chi-square was used for comparison. Results: When compared to LT, RT carried a significantly higher rate of BRAF (25% vs 7%; p < 0.0001), PTEN (5.4% vs 1.3%; p = 0.008), and ATM (4% vs 1%; p = 0.04) mutations. RT were likely to have more MSI-high tumors (22% vs 5%; p < 0.0001) and PD-1 overexpression (58% vs 44%; p = 0.01). There were no differences in the rate of KRAS (50% vs 42%; p = 0.07) or NRAS mutations (2.2% vs 3.4%; p = 0.4). When compared to RC, RT had a higher rate of BRAF (25% vs 3%; p = 7E-07), PIK3CA (22% vs 11%; p = 0.001), CTNNB1 (3% vs 0.3%; p = 0.02); ATM (3% vs 1%; p = 0.04), PTEN (5% vs 1%; p = 0.004), and BRCA1 mutations (4% vs 0%; p = 0.02), and a lower rate of TP53 (56% vs 71%; p = 0.001) and APC (53% vs 66%; p = 0.003) mutations. When compared to RC, LT showed higher rates of BRAF (6.7% vs 3.2%; p = 0.04) and CTNNB1 (2.1% vs 0.3%; p = 0.04) mutations, and a higher rate of MSI-high tumors (4.6% vs 0.7%; p = 0.04), whereas RC had a higher rate of KRAS mutation (50% vs 42%; p = 0.04). There were no differences between RT, LT, and RC for the frequency of PD-L1 (2%, 2%, and 1%) or Her-2 (1%, 2%, and 3%) overexpression, although Her-2 amplification was significantly different (1%, 3%, and 5%, RT vs RC; p = 0.03). Mean TML was 12, 11, and 8 mutations/megabase for RT, LT, and RC, respectively (RT vs RC; p = 0.01). There was a correlation between TML and PD-L1 (p = 0.04) and PD-1 (p = 0.01). Conclusions: Tumors arising in the right colon carry genetic alterations that are different from LT as well as RC. However, it appears that CRCs carry a continuum of molecular alterations from the right to the left side, rather than displaying sharp, clear-cut differences.
Association of high microsatellite instability (MSI-H) with a high immunoscore (IS) compared to PD-L1 expression and increased survival in patients (pts) with metastatic colorectal cancer (mCRC) treated with oxaliplatin (Ox) and fluoropyrimidine (FP): A pooled analysis of the AIO KRK 0207 and RO91 trials.
Authors: Noepel-Duennebacke Stefanie , Juette Hendrik , Schulmann Karsten , Graeven Ullrich , Porschen Rainer , Stoehlmacher Jan , Hegewisch-Becker Susanna , Mosig Axel , Arnold Dirk , Reinacher-Schick Anke C. , Tannapfel Andrea 
Published: September 2018

3595 Background: MSI-H is an established prognostic marker in early colon cancer. Moreover, MSI-H, tumor immune cell infiltration and PD-L1 expression are also discussed as potential predictive biomarkers for immunotherapy. However, little is known about the prognostic value of these biomarkers and their association among each other in mCRC. Methods: We analyzed samples from pts. with mCRC uniformly treated with a FP and Ox within two randomized AIO trials (KRK 0207 and RO91). MS status was assessed by immunohistochemistry (IHC) of mismatch repair proteins and subsequent fragment length analysis in case of protein loss or incoherent results. PD-L1 expression was determined by IHC (1% expression threshold). Tumor lymphocytic infiltration (CD8 and CD45RO) was scored according to the immunoscore (IS) concept by Galon et al (J Transl Med 2016). Results: 41/550 cases (7.5%) displayed MSI-H. The mean IS of the total population was 0.57 (SD 0.97), the IS of MSI-H pts. was significantly higher (mean of 2.4; SD 1.4; p≤0.0001). 17 cases were PD-L1 positive (pos.) (3 %), only four of these were MSI-H. MSI-H status was significantly correlated with a higher IS, but not with PD-L1 expression (table 1). There was no difference in median overall survival (mOS) between MSI-H and MS stable (MSS) pts. (mOS MSI-H/MSS: 17.6/22.5 months (mos.), log rank: p=0.85), PD-L1 negative (neg.) and pos. pts. (mOS PD-L1 neg./pos.: 22.1/28.9 mos., log rank: p=0.49) and IS high or low pts. (mOS IS high/low: 21.1/22.1mo., log rank: p=0.25). Conclusions: In contrast to early stage colon cancer, none of these parameters was prognostic in mCRC patients. Panel-sequencing with a total of 35 genes including RAS, BRAF and POL-E on cases with PD-L1 expression, high IS or MSI-H status to further characterize these cases will be reported. Clinical trial information: AIO-R091, AIO-KRK-0207: EudraCT-Nr: 2008-007974-39. [Table: see text]
Circulating tumor DNA analysis before and after resection for colorectal cancer.
Authors: Symonds Erin L. , Pedersen Susanne Kartin , Murray David , Young Graeme P 
Published: September 2018

3597 Background: Detection of circulating tumor DNA (ctDNA) has broad clinical utility including disease monitoring, prognostication and response to chemotherapy. ctDNA is commonly detected by targeting tumor-specific features including mutations, insertions, deletions or hypermethylation. The two genes, BCAT1 and IKZF1, are methylated with high frequency in colorectal cancer (CRC). This study aimed to analyze the impact of tumor resection on ctDNA levels by assaying pre- and postoperative blood samples for methylated BCAT1 and IKZF1. Methods: 91 people (age 32-86 years, 53% male) with invasive CRC, but without neoadjuvant therapy, had blood collected prior to surgery and within 12 months (1-12 months) after resection. Cancers were clinicopathologically staged. DNA extracted from plasma was assayed for methylated BCAT1/ IKZF1 and detection of either marker was deemed positive for ctDNA. Results: 47 (52%) of the 91 CRC patients were ctDNA positive before resection, including 5/30 (17%) stage I, 17/28 (61%) stage II, 23/31 (74%) stage III and 2/2 (100%) stage IV. After resection 75% (35/47) became ctDNA negative (median 2 months after resection), and all had apparent tumour clearance. Of the 35 postoperative ctDNA negative cases 22 had further surveillance CT scans within study timeframe. 86% (20/22) showed no recurrent CRC but 2 of these developed a new cancer (metachronous CRC, prostate). The remaining 2 tested ctDNA positive 14 and 25 months later and recurrence was confirmed. Of the 12 postoperative ctDNA positive cases, two were found to not have complete tumour clearance at surgery (residual disease). Follow-up CT scans were available for a further 8 patients which revealed that 4 later presented with cancer (3 recurrence, 1 thyroid) at a median 15 months after resection. The remaining 4 postoperative positive cases were negative at subsequent blood testing (median 8 months later). Conclusions: Methylated BCAT1/IKZF1 DNA in preoperative blood is dependent on tumor stage, but informs the completeness of resection given the high rate (74.5%) of ctDNA disappearance post-surgery. If cases persistently test ctDNA positive after surgery or become ctDNA positive later, residual or recurrent disease should be suspected, respectively.