bluuebunny/crossref_metadata_2025_split huggingface dataset:
A large multicenter study evaluating prognosis and chemosensitivity of metastatic colorectal cancers with microsatellite instability.
Authors: Tougeron David , Sueur Benjamin , Sefrioui David , Gentilhomme Lucie , Lecomte Thierry , Aparicio Thomas , DES Guetz Gaetan , Artru Pascal , De La Fouchardiere Christelle , Moulin Valérie , Hautefeuille Vincent , Coriat Romain , Touchefeu Yann , Lecaille Cedric , Gael Goujon , Ferru Aurélie , Tourani Jean-Marc , Emambux Sheik , Taieb Julien , Zaanan Aziz 
Published: September 2018

3536 Background: Deficient Mismatch Repair (dMMR) in colorectal cancers (CRC) represent 12% of all tumors. In non-metastatic CRC setting, dMMR are associated with good prognosis but also with resistance to adjuvant 5-FU chemotherapy. In metastatic CRC (mCRC) setting, dMMR is found in less than 5% and its influence on prognosis and treatment response is little known. Methods: This multicenter retrospective study included all consecutive patients with dMMR mCRC treated between 2005 and 2015 in 17 centers. The Kaplan-Meier method was used to calculate overall survival (OS) and progression-free survival (PFS). Prognostic variables were evaluated in univariate analysis using the Log rank test and in multivariate analysis using the Cox regression model. Results: A total of 198 patients with dMMR mCRC were included (median age 64.6 years). dMMR mCRC were mostly diagnosed with synchronous metastases (59%) and frequent peritoneal carcinosis (43%). Lynch syndrome was found in 34% of cases and 36% of tumors had a BRAFV600E mutation. Median OS was 20.6 months. A low risk Kohne's prognostic index (HR = 0.40 [0.22-0.72], p = 0.02) and absence of peritoneal carcinosis (HR = 0.51 [0.29-0.90], p = 0.02) were associated with better OS in multivariate analysis. Main first-line regimens were 5FU-based (n = 20), oxaliplatin-based (n = 75) or irinotecan-based (n = 46) chemotherapy. Median PFS on first-line treatment was 5.9 months. The objective response rate (ORR) was 0%, 19% and 36% for 5FU-based, oxaliplatin-based and irinotecan-based chemotherapies, respectively (p = 0.02). A trend for a longer PFS (3.3, 5.5 and 10.2 months, respectively, p = 0.06) and OS (17.7, 21.1 and 34.2 months, respectively, p = 0.05) was also observed for irinotecan-based chemotherapy. The addition of bevacizumab to chemotherapy was associated with a significant increase of ORR (p = 0.01) and PFS (p = 0.04) as compared to the addition of an anti-EGFR therapy. Conclusions: This study suggests that dMMR mCRC are associated with poor prognosis and chemoresistance, especially to 5FU-based chemotherapy. Efficacy of irinotecan and bevacizumab should be evaluated in a prospective trial in combination with immune checkpoint inhibitors.
Concordance of DNA mismatch repair deficient (dMMR)/microsatellite instability (MSI) assessment by local and central testing in patients with metastatic CRC (mCRC) receiving nivolumab (nivo) in CheckMate 142 study.
Authors: Kopetz Scott , Lonardi Sara , McDermott Raymond S. , Aglietta Massimo , Hendlisz Alain , Morse Michael , Leach Joseph W. , Neyns Bart , Chan Emily , Chen Franklin , Wong Ka Yeung Mark , Lee James J. , Garcia-Alfonso Pilar , Hill Andrew G , Lenz Heinz-Josef , Desai Jayesh , Moss Rebecca Anne , Cao Z. Alexander , Overman Michael J. , Andre Thierry 
Published: September 2018

3548 Background: MMR or MSI testing is recommended for mCRC pts and is often done locally by IHC or PCR testing, respectively (NCCN V1.2017) Nivo, a fully human anti-PD-1 mAb, demonstrated durable responses and a 12-mo OS rate of 73.8% in pts with mCRC locally assessed for dMMR/MSI-H status in the CheckMate 142 study (NCT02060188; Overman M, et al. 2017). Here we describe the results of local and central testing with respect to MMR/MSI status and clinical outcomes in the CheckMate 142 study. Methods: MMR/MSI status was assessed locally on archival tumor using IHC/PCR at screening and confirmed centrally by PCR (modified Bethesda panel) testing of tumor biopsy at enrollment. dMMR was defined by IHC as a loss of expression in ≥1 mismatch repair proteins. Stable microsatellite (MSS), low MSI (MSI-L), and high MSI (MSI-H), were defined as instability in 0, 1, or ≥2 markers, respectively. Pts with dMMR/MSI-H mCRC who progressed on or were intolerant of ≥1 prior line of therapy received nivo 3 mg/kg Q2W. Results: 74 pts were dMMR/MSI-H by local testing. Of these pts, 53 (72%) were centrally confirmed as MSI-H, 7 pts had insufficient tissue sample for PCR testing, and 14 pts had a central test that did not match local test results. Of the 14 pts, 3 pts with a clinical history of LS were identified locally as dMMR but centrally as MSS (Table). INV-reported ORR was 31.1% in 74 pts locally determined as dMMR/MSI-H, 35.8% in 53 pts locally and centrally confirmed as MSI-H, and 21.4% in 14 pts not centrally confirmed as MSI-H. Conclusions: The similar clinical activity between pts locally confirmed as MSI-H and pts who were centrally confirmed as MSI-H suggest local testing is appropriate for identifying the dMMR/MSI-H pts who may benefit from nivo monotherapy. Clinical trial information: NCT02060188. [Table: see text]
Prolonged (PI) vs short-term irinotecan (STI) administration: The Martha trial—A SICOG (Southern Italy Cooperative Oncology Group) randomized phase III study in the first-line setting of metastatic colorectal cancer (mCRC) patients (pts).
Authors: Formica Vincenzo , Ionta Maria Teresa , Giacomo Vessia , Maiorino Luigi , Casaretti Rossana , Natale Donato , Barberis Giuseppe , Filippelli Gianfranco , Greco Ettore , Blasi Livio , Mancarella Sergio , Russo Anna , Barbato Enrico , Di Lullo Liberato , Roselli Mario 
Published: September 2018

3552 Background: FOLFIRI+bevacizuamab(B) is a standard first-line regimen for mCRC pts. It should be delivered until progression, though an early switch to a de-intensified maintenance regimen is often adopted because of toxicity. The MARTHA trial compared FOLOFIRI+B for 6 months(mo) followed by maintenance B monotherapy up to 12mo (PI arm) vs FOLOFIRI+B for 3mo followed by capecitabine+B for further 3mo followed by B monotherapy up to 12mo (STI arm). Methods: Chemotherapy-naïve pts with histologically confirmed mCRC and measurable disease were deemed eligible and randomized to PI or STI arm in a 1:1 ratio. Co-primary endopoints were progression free (PFS) and overall survival (OS). The Kaplan-Meier method was used for survival analysis. A novel analysis (the Death Pace Analysis, DPA) was performed to identify pts benefiting more from a specific treatment. A multivariable logistic regression analysis (MLRA) was used to identify clinicopathological predictors of DPA-defined patient subsets. Results: 199 pts (100 in PI arm, 99 in STI arm) were enrolled. A non-significant superior OS was observed for STI (HR 0.81, p 0.26), no PFS differences were seen. The DPA demonstrated a 6% of pts identifiable as STI-benefiting pts. According to MLRA including 15 common clinicopathological variables, baseline Hemoglobin (Hb) level was the only independent predictor of the DPA-defined STI-benefit status (OR 2.3, p 0.009, i.e. 2.3-fold increased risk of not being a STI-benefiting patient for 1-point increase in Hb). Indeed, among pts with low baseline Hb ( < 13 gr/dL, cutoff determined upon ROC analysis), n = 128, a statistically significant prolonged OS was observed for STI over PI arm (median OS: 21.8 vs 14.4 mo, respectively, HR 0.64, p 0.04).No survival difference was seen between arms in pts with high Hb. Conclusions: mCRC pts with low baseline Hb levels are better treated with a STI first-line strategy. Published preclinical data suggest that low Hb may increase the risk of developing early chemo-resistant and aggressive disease with the prolonged use of irinotecan. Clinical trial information: EudraCT 2008-004890-17.
A curative intent trimodality approach for advanced isolated abdominal nodal metastasis in metastatic colorectal cancer: Update of a single-institutional experience.
Authors: Johnson Benny , Jin Zhaohui , Haddock Michael G. , Hallemeier Christopher Leigh , Martenson James A. , Smoot Rory L. , Larson David W. , Dozois Eric J. , Nagorney David M. , Grothey Axel 
Published: September 2018

3556 Background: To define and update survival rates and relapse patterns in patients (pts) with isolated advanced abdominal nodal metastasis secondary to colorectal cancer (CRC), treated with curative intent using aggressive trimodality therapy. Methods: Fifty-seven pts with isolated advanced abdominal lymph node metastasis (retroperitoneal and mesenteric) secondary to colorectal cancer received trimodality therapy defined as chemotherapy delivered in conjunction with external beam radiotherapy (EBRT) followed by lymphadenectomy and intraoperative radiotherapy (IORT). Infusional 5-FU was the most common radiosensitizer used (66%, 38 pts). The median dose of EBRT was 50 Gy & the median dose of intraoperative radiotherapy was 12.5 Gy. End points included distant metastasis, toxicities, local failure within EBRT field, recurrence within the intraoperative radiotherapy field, and survival. Results: 49% of pts were male, median age 50.5 yrs. All patients had ECOG ≤ 1. 27 pts had primary right sided colon cancer, 16 left sided colon cancer and 14 rectal primaries. Median time from initial CRC diagnosis to development of abdominal lymph node metastatic disease was 24 months (95% CI, 23.5-45.1 months). 84% (48 pts) had paraaortic nodal metastases, 12% (7 pts) had mesenteric nodal metastases, and 3% (2 pts) had both. With a median follow up of 89.4 months, the median overall survival and 5-year estimated survival rate were 53.2 months (95% CI, 46.4-78.8 months) and 42%, respectively. Median progression free survival was 19.3 months (95% CI, 15.6-32.8 months). 21 (37%) pts never developed distant disease. Outcome was not affected by disease sidedness, rectal primary, or mutational profile. Treatment was well tolerated without any grade 3/4 toxicities. Conclusions: The use of trimodality therapy including EBRT with radiosensitizing chemotherapy, lymphadenectomy and IORT produces sustainable long-term survival in selected metastatic CRC pts presenting with isolated retroperitoneal/mesenteric nodal relapse.
The impact of cumulative toxicity on physical quality of life in patients with metastatic colorectal cancer receiving first line chemotherapy.
Authors: Schuurhuizen Claudia , Konings Inge , Braamse Annemarie , Buffart Laurien , Bloemendal Haiko , Dekker Joost , Verheul Henk M.W. 
Published: September 2018

3564 Background: We have previously suggested that treatment related toxicity has impact on physical quality of life (QOL) scores, as opposed to global QOL. Moreover, the cumulative effect of experienced toxicities, including low-grades AEs, may be of more importance. The purpose of this observational cohort study was to evaluate the association between cumulative toxicity and physical and global QOL in patients with metastatic colorectal cancer (mCRC) receiving chemotherapy. Methods: 105 patients with mCRC starting first line chemotherapy were evaluated. All patients completed the EORTC-QLQ-C30 questionnaire at baseline and after 10 weeks. Toxicity, clinical outcomes and demographics were retrieved from patient records. For each patient, we calculated cumulative toxicity in three different ways: i) total number of adverse events (AEs) (all grades), ii) total number of grade 3-4 AEs, and iii) total number of AEs multiplied by their grade. The relation between each cumulative toxicity score and QOL assessed at 10 weeks, was studied. Results: The mean age of patients was 64.8 ± 9.7 years, 70.5% were male, and 83.8% received first line oxaliplatin based combination chemotherapy. AEs occurred in 98.1% of patients, grade 3-4 AEs in 37.1%, and grade 1-2 AEs in 61.0%. The mean number of experienced AEs (all grades) was 5.3 ± 2.7. The most common toxicities included diarrhea, neuropathy and fatigue. None of the toxicity scores was related to global QOL outcome. A higher total number of all grades AEs (β = - 2.2, 95%CI = -3.7; -6.6) and total number of AEs multiplied by grade (β = -1.3, 95%CI = -2.2; -3.5) were significantly associated with worse physical QOL. Conclusions: Cumulative toxicity, defined as the total of all grades AEs, significantly affects physical QOL in patients with mCRC receiving first line chemotherapy. Improvement of treatment related toxicity management by reducing the total number of AEs, may result in relevant improvements in patients’ QOL. Our results emphasize that future RCTs should present physical QOL outcomes instead of global QOL, as well as all grades and total number of toxicities for individual patients.
Impact of tumor location on outcomes in patients with metastatic colorectal cancer (mCRC) treated with regorafenib (REG): An interim analysis from the prospective, observational CORRELATE study.
Authors: Ducreux Michel , Öhler Leopold , Scheithauer Werner , Metges Jean-Philippe , Dourthe Louis-Marie , De Groot Jan Willem , Thaler Josef , Yeh Kun-Huei , Lin Jen-Kou , Falcone Alfredo , Punt Cornelis J. A. , Kalinovsky Jan , Fiala-Buskies Sabine , Cervantes Andres , O'Connor Juan Manuel ,   On Behalf of the CORRELATE Investigators
Published: September 2018

3567 Background: The anatomical location of the primary tumor has been associated with outcomes in mCRC, with left-sided (L) tumors having a better prognosis than right-sided (R) tumors and location predicting response to treatment. REG significantly improved overall survival (OS) vs placebo in patients with mCRC who progressed on available treatments in 2 randomized, phase 3 trials (CORRECT, CONCUR). This exploratory analysis evaluated outcomes by primary tumor location in patients with mCRC treated with REG in the CORRELATE study. Methods: CORRELATE is an observational study designed to characterize the safety and effectiveness of REG in unselected patients for whom the decision to treat with REG has been made by the treating physician according to the local health authority label. Primary L tumors were located in the rectum, splenic flexure, recto-sigmoid, descending, or sigmoid colon; R tumors were in the appendix, hepatic flexure, cecum, or ascending colon. OS was analyzed by the Kaplan–Meier method and comparisons were by a 2-sided log-rank test. Results: Primary tumor location was available for 474 patients (L, n = 375 [79%]; R, n = 99 [21%]). Median time from initial diagnosis and from diagnosis of metastatic disease to treatment was slightly longer in L vs R tumors (32 vs 28 months and 25 vs 22 months, respectively). A higher proportion of patients with L vs R tumors, respectively, had prior radiotherapy (34% vs 13%) and a lower proportion had a partial colectomy (40% vs 70%). Best response to prior systemic therapy (partial response + stable disease) was 72% for L tumors and 68% for R tumors with a median duration of treatment of 26 and 22 months, respectively. REG treatment duration was similar in the 2 groups. Median OS (95% CI) was 6.7 months (6.1, 7.7) for L tumors vs 6.3 months (4.9, 8.1) for R tumors (P = 0.3); median progression-free survival (95% CI) was 2.8 months (2.6, 3.0) vs 2.6 months (2.4, 3.0) (P = 0.5), respectively. Conclusions: Interim results from this observational study suggest that OS is similar in patients with R and L tumors treated with REG. Clinical trial information: NCT02042144.
Association between timing and duration of adjuvant chemotherapy and survival for colorectal cancer in korea, 2011-2014: A nationwide study based on the database of quality assessment and the health insurance.
Authors: Hwang In Gyu , Lee Ji Sung , Lee Sang-Cheol , Baek Sun Kyung , Kim Jong Gwang , Kim Tae Won 
Published: September 2018

3605 Background: Few population-based analyses on treatment outcomes of colorectal cancer (CRC) have been conducted in Asian countries. We conducted a nationwide study to assess relationship between timing and duration of adjuvant chemotherapy (AC) and survival for patients with CRC in South Korea. Methods: Data from the Health Insurance Review and Assessment Service Database (HIRA) were analyzed for demographics, tumor characteristics, adjuvant chemotherapy, and survival of patients who underwent curative-intent surgical resection for CRC from 2011 to 2014. Results: From the HIRA data, a total of 61315 patients were identified: 15620 (25.5%) in stage I, 20525 (33.5%) in Stage II, and 25170 (41.0%) in stage III. Chemotherapy regimens were consisted: 11332 (18.5%) in 5-fluorouracil and leucovorin/capecitabine (FL/CAP), 13183 (21.5%) in FL/CAP plus oxaliplatin (FOLFOX/CAPOX), 357 (0.6%) in uracil and tegafur/doxifluridine (UFT/D) and 36443 (59.4%) in surgery alone. For patients with stage II and III CRC, the initiation of AC ≥ 8 weeks after surgery was associated with a significant decrease in overall survival (OS) (FL/CAP: HR, 1.82; 95% CI, 1.53 to 2.17, and FOLFOX/CAPOX: HR, 2.92; 2.47 to 3.45, respectively), however UFT/D regimens were not statistically significant. For patients with stage II and III colon cancer, receiving AC < 3 months had lower OS (FL/CAP: HR, 3.72; 95% CI, 2.80 to 4.94, FOLFOX/CAPOX: HR, 2.15; 1.87 to 2.47, and UFT/D: HR, 1.74; 0.56 to 5.41, respectively). For patients with stage II and III rectal cancer, receiving AC < 3 months regardless of chemotherapy regimens had a significant lower survival (FL/CAP: HR, 1.91; 1.66 to 2.20, FOLFOX/CAPOX: HR, 2.20; 1.75 to 2.77, and UFT/D: HR, 3.71; 1.45 to 9.44, respectively). Conclusions: Time to initiation and duration of AC after surgery were associated with survival. Based on our results, starting within 8 weeks and receiving more than 3 months of AC are needed to have an overall survival benefit.
Phase I study of trametinib with neoadjuvant chemoradiation (CRT) in patients with locally advanced rectal cancers (LARC).
Authors: Wu Christina Sing-Ying , Williams Terence Marques , Wei Lai , Umar Hamida , Mikhail Sameh , Ciombor Kristen Keon , Chan Emily , Noonan Anne M. , Roychowdhury Sameek , El-Dika Samer S , Krishna Somashekar , McCarthy Sean T , Arnold Mark , Harzman Alan , Abdel-Misih Sherif , Cirocco William , Traugott Amber , Bekaii-Saab Tanios S. , Wuthrick Evan John 
Published: September 2018

3612 Background: The RAS/RAF/MEK signal transduction pathway is critical to the development of colorectal cancer, and tumors harboring KRAS, NRAS, and BRAF mutations were shown to be resistant to radiation. Thus, we conducted a phase I study of trametinib, a potent MEK1/2 inhibitor, in combination with CRT in patients with LARC. Methods: Phase I trial for patients with Stage II/III rectal cancers with a 3+3 design, and an expansion cohort of 12 patients at the maximum tolerated dose (MTD). Trametinib is given orally at 3 dose levels: 0.5mg, 1mg, and 2mg (Mon-Fri). CRT regimen is infusional 5-flourouracil (5FU) 225mg/m2/day (Mon-Fri) and daily fractions of 1.8 Gy (total 50.4Gy). There is a 5-day trametinib lead-in followed by trametinib and CRT. Six to 10 weeks after completion of CRT, patients then proceed to their surgery and adjuvant therapy. The primary endpoint is to identify the MTD and recommended phase 2 dose of trametinib with CRT. Immunohistochemistry staining for phosphorylated –ERK (pERK) and genomic profiling is performed on the tumor samples. Results: Enrollment is complete at all dose levels with18 patients, and 15 patients evaluable for toxicity and response as of Feb 6. One dose-limiting toxicity of diarrhea was observed at the 2mg dose. Grade 3 and most common toxicities are shown in Table 1. No grade 4/5 toxicities have been observed. At 2mg dose level, 3/9 (33%) patients had pathological complete response (pCR) and 2/9 (22%) had a near pCR. Correlative studies confirm decrease in pERK levels with increasing doses of trametinib. Correlation of genomic mutational status with toxicity, response, and outcomes is being analyzed. Conclusions: The combination of trametinib with 5FU CRT is tolerable with promising preliminary activity. Final results will be presented at the meeting. Toxicities. Clinical trial information: NCT01740648. [Table: see text]
Comparison of two different neoadjuvant chemoradiatiotherapy regimens for locally advanced rectal cancer: Results of a phase II, multicenter, randomized trial.
Authors: Zhu Ji , Guan Yun , Yan Senxiang , Xu Ye , Li Xinxiang , Cai Sanjun , Zhang Zhen 
Published: September 2018

3614 Background: The aim of this study is to compare clinical outcomes between two groups of different chemoradiation Regimens. Methods: Eligible patients were randomly assigned to Patients received either IMRT to the pelvis of 50 Gy/25Fxs concurrent with oxaliplatin 50 mg/m2 weekly and capecitabine 625 mg/m2 bid d1–5 weekly (Arm A), or IMRT to the pelvis of 50 Gy/25Fxs and a concomitant boost of 5 Gy to the primary tumor in 25 fractions, followed by a cycle of XELOX two weeks after the completion of chemoradiotherapy (Arm B). Surgery was scheduled eight weeks after the completion of CRT. All patients were recommended to receive adjuvant CT regardless of pathological stages. A total of six cycles of XELOX chemotherapy was recommended including neoadjuvant and adjuvant period. The primary end point was pCR. Results: From February 2010 to December 2011, a total of 120 patients were randomly assigned to Arm A (n = 60) or Arm B (n = 60). One hundred and ten patients (Arm A = 53, Arm B = 57) underwent surgery, the other 10 patients didn’t receive surgery because of unresectable disease. Eight and 14 cases were evaluated as pCR in two groups respectively ( p= .157). Tumor response was further classified into good response and poor response, the former was defined as ypT0N0, ypT1-2N0 and ypT0N1a. The rate of good responses were 30.0% and 55% ( p= .006). No significant differences were found in grade 3 or 4 acute adverse events during the treatment between the two groups. However, number of patients who had delayed incision healing was 13 and 3 patients ( p= .007). There were no statistical differences in OS ( p= .553), DFS ( p= .349) and local-regional control ( p= .856) between the two groups. In the univariate analysis, N stage, MRF involvement and tumor response had significant impacts on OS, DFS and LC. In the multivariate analysis, MRF involvement had significant impacts on OS ( p= .02), DFS ( p= .01) and LC ( p= .01). Conclusions: A dose-intensified radiotherapy in neoadjuvant chemoradiotherapy demonstrated contribution to tumor regression with acceptable toxicity, but led delayed incision healing after surgery. The impact of MRF involvement on survival merits further investigation. Clinical trial information: NCT01064999.