bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multicenter phase II study of FOLFOX or biweekly XELOX and cetuximab as first-line treatment in patients with wild-type KRAS/BRAF metastatic colorectal cancer (mCRC) (FLEET study).
Authors: Kim Ho Min , Soda Hitoshi , Hazama Shoichi , Takahashi Takao , Nagata Naoki , Kotaka Masahito , Kono Emiko , Terada Itsurou , Fukunaga Mutsumi , Oba Koji , Hasegawa Junichi , Sakamoto Junichi , Mishima Hideyuki 
Published: February 2017

463 Background: Cetuximab and chemotherapy as first-line therapy for patients with KRAS wild type prolong survival. However, COIN trial has not demonstrated the survival benefit of FOLFOX or XELOX and cetuximab therapy. Few data are available on its benefit for patients with KRAS and BRAF wild-type. Methods: The aim of this study was to assess the efficacy of first-line FOLFOX or bi-weekly XELOX and bi-weekly cetuximab in KRAS/BRAF wt mCRC. Chemonaive patients received FOLFOX or biweekly XELOX (oxaliplatin 85 mg/ m2/day 1 plus capecitabine 2000/m2/days 1-7) and biweekly cetuximab 500mg m2/ day 1 every 2 weeks. Primary endpoint was response rate(RR), other secondary endpoints were PFS, OS, DCR, safety, DI and resection rate. KRAS test (codon12,13) and BRAF test (V600E) by direct sequence were performed in Yamaguchi University. Patients with KRAS/BRAF wt were enrolled in this study. The regimen of FOLFOX or XELOX were selected by investigator’s preference, not randomized. Results: From April 2010 to May 2011, 139 pts were preregistered. KRAS and BRAF were examined from paraffin-embedded sample. 70 (50.3%) pts were KRAS/BRAF wt, and 62 pts were enrolled: The main characteristics of the entered pts were: sex (M/F) 34/28, median age 66 yrs (range 34-83 yrs). Grade 3/4 adverse events were leucopenia 4.8%, neutropenia 25.8%, skin toxity (paronychia/fissure) 9.7%, and acne 9.7%. Two CR (3.2%) and 40 PR (64.5%), 15 SD (24.2%) and 3 PD (4.8%) 2NE were observed, with an overall response rate of 67.7% and a disease control rate (CR+PR+SD) of 91.9%. The RR of FOLFOX or XELOX were 64.9% (24/37) and 72.0% (18/25), DCR were 89.2% and 96% respectively. Conclusions: FLEET was the first multicenter phase II study with prospective KRAS/BRAF analysis as a predictive biomarker for cetuximab in first-line mCRC in Japan. Results of this study indicate that both biweekly combination regimens are feasible, tolerable, and clinically active. Biweekly XELOX+cetuximab study (FLEET2) is ongoing. Clinical trial information: UMIN000003253.
A novel molecular tool for lymph node upstaging in colon cancer patients: Results of a prospective European, multicenter study.
Authors: Zuber Markus , Geppert Carol-Immanuel , Bader Franz , Nitsche Ulrich , Rosenberg Robert , Zettl Andreas , Tarragona Jordi , Matias-Guiu Xavier , Croner Roland 
Published: February 2017

464^ Background: A new diagnostic semi-automated system, One Step Nucleic Acid Amplification (OSNA), was designed for the detection of cytokeratin 19 (CK 19) mRNA in lymph node (LN) metastases of colon cancer (CC) patients (Güller U et al. CANCER 2012: DOI 10.1002/cncr.27667). Recently it has been shown that occult metastases detected in pN0 patients have an adverse effect on survival based on stage migration. In this study we investigated whether pN0 patients diagnosed by standard histopathology can be upstaged by OSNA analysis to stage III. Methods: In this international, multicenter (4 institutions: CH, G [2], E) study 103 patients-originally diagnosed as pN0 by the standard use of 1 single section haematoxylin & eosin (H&E)-were subjected to OSNA analysis. LN were isolated from fresh tissue, homogenised, and directly subjected to OSNA without prior isolation of mRNA. OSNA results were provided in qualitative categories (- / + / ++), along with the exact CK19 mRNA copy number (+: 250-5000 copies, ++: >5000 copies). Results: In total, 1,594 LN from 103 CC patients (median 14 LN / patient, range 1-46) were analyzed with OSNA. From the 103 histology pN0 patients 26 were positive with OSNA, resulting in an upstaging rate of 25.2%. Sixteen patients had 1 OSNA positive LN, three had 2, three had 3, and one had 4 positive LNs, resulting in a total of 35 positive LN. Patients with pT1, pT2, and pT4 tumors only had 1 positive LN, while all patients with multiple positive LN were from the pT3 group which also contained 9/10 patients with a (++) OSNA result. Concerning stage categories, 6/37 (16.2%) CC patients with stage I were upstaged and 20/66 (30.3%) patients with stage II. Conclusions: OSNA is a novel molecular tool for LN upstaging in CC patients with similar performance as very intensive histological investigation (Güller U et al. CANCER: 2012 DOI 10.1002/cncr.27667). The present study confirms that OSNA improves staging in CC patients and provides a standardized, observer-independent technique for a more accurate staging than the standard histopathology.
A phase II trial of 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) chemotherapy plus bevacizumab (bev) for patients (pts) with unresectable stage IV colon cancer and a synchronous asymptomatic primary tumor: Updated results of NSABP C-10 with definitive survival analysis.
Authors: McCahill Laurence E. , Yothers Greg , Sharif Saima , Petrelli Nicholas J. , Lopa Samia H. , O'Connell Michael J. , Wolmark Norman 
Published: February 2017

468 Background: Surgical resection of asymptomatic primary colon tumor for pts presenting with synchronous yet unresectable metastatic disease is controversial. We published results for the primary endpoint in JCO in September 2012. Here we update the primary endpoint and present definitive survival results. Methods: Eligible pts had ECOG Performance 0 or 1, an asymptomatic colon tumor and unresectable distant metastases. Primary endpoint (PE) was major morbidity, defined as surgical resection or death related to the intact primary tumor. Major morbidity rate of 25% was considered acceptable and the trial had 85% power to rule out a rate of 40%. Secondary endpoints were overall survival and morbidity related to the intact primary requiring hospitalization, transfusion, or interventional procedure. Results: Between March 2006-June 2009, 90 pts were registered and 86 eligible pts with follow-up comprise this analysis. 52% were female and 47% were age 60+. Median follow-up was 61.5 mos. There were 15 (17.4%) major morbidity events, 12 (14.0%) required surgery: obstruction (9), perforation (2), and pain (1). Three (3.5%) resulted in pt death: perforation (2), obstruction (1). Cumulative incidence of major morbidity at 42 mos was 17.7% (95% CI 9.5-26.0%). Fourteen other primary tumor resections were performed: attempted cure (11), other reasons (3). There were 6 secondary endpoint events: 4 obstructions (2 required stents, 2 resolved with conservative management), 2 pts with suspected perforation required percutaneous drainage (1) and hospitalization and antibiotics (1). Median survival was 18.3 mos (95% CI 15.2-24.2). Two year OS rate was 38.7% and 3 year OS rate was 15.1%. Conclusions: The primary endpoint holds with the updated analysis justifying observation for asymptomatic primary colon cancers even in patients with a good clinical response of distant metastases. Clinical trial information: NCT 00321828.
On-treatment progression-free survival analysis of aflibercept-FOLFIRI treatment within 28 days of progression in metastatic colorectal cancer: Updated efficacy results from the VELOUR study.
Authors: Ferry David Raymond , Kim Tae Won , Guren Tormod Kyrre , Desai Jayesh , Villanueva Luis Marcelo , Andria Michael L. , Van Cutsem Eric , Tabernero Josep 
Published: February 2017

469 Background: The phase III VELOUR study demonstrated that adding the novel antiangiogenic agent aflibercept (known as ziv-aflibercept in the United States) to FOLFIRI in patients with metastatic colorectal cancer previously treated with oxaliplatin significantly improved overall survival, progression-free survival (PFS), and overall response rate versus placebo-FOLFIRI. We performed an additional analysis of PFS “on-treatment,” censoring events that occurred more than 28 days after last treatment dose. Methods: Patients were randomized to receive aflibercept 4 mg/kg or placebo every 2 weeks in combination with FOLFIRI. An independent review committee determined progression based on radiologic review. PFS was estimated using Kaplan-Meier analysis, with censoring of events after the last dose plus 28 days. Treatment groups were compared using a log-rank test stratified by ECOG performance status and prior bevacizumab therapy. Hazard ratio (HR) and confidence interval (CI) were estimated using a Cox proportional hazard model. Results: On-treatment PFS results are shown in the Table. Patients on aflibercept-FOLFIRI showed significantly increased on-treatment PFS compared with patients on placebo-FOLFIRI. More patients were censored in the aflibercept arm due to adverse events, thus decreasing the number of events. Conclusions: On-treatment PFS with aflibercept-FOLFIRI was significantly increased compared with placebo-FOLFIRI, which is consistent with the PFS benefit observed in the primary analysis. Clinical trial information: NCT00561470. [Table: see text]
Effect of short course radiation followed by four cycles of FOLFOX as preoperative therapy for rectal cancer on rate of PCR: A phase II trial.
Authors: Myerson Robert J. , Parikh Parag J. , Hunt Steven R. , Tan Benjamin 
Published: February 2017

471 Background: Preoperative radiotherapy (RT) with 5FU chemotherapy (CT) is a standard of care for cT3-4 rectal cancer. Studies incorporating additional cytotoxic agents have resulted in increased morbidity with little benefit. We evaluate a template that seeks to (1) include the benefits of preoperative RT on local response/control, (2) provide preoperative multi-drug CT, (3) avoid the morbidity of concurrent RT and multi-drug CT. Methods: Patients with cT3-4, any N, any M rectal cancer were eligible. Patients were confirmed to be candidates for surgery, provided the response was sufficient. Preoperative treatment was 5 fractions RT (25 Gy to involved mesorectum, 20 Gy to elective nodes), followed by 4 cycles of mFOLFOX6. Postoperative CT was at the discretion of the medical oncologist. The principal objectives were to achieve T stage down staging (ypT < cT) and acute grade 3+ gastrointestinal (GI) morbidity equal or better than historic controls. Results: 80 patients were enrolled from 11/2009 through 4/2012. All have had sufficient time for principal endpoint analysis. Four are inevaluable for response: 1 patient withdrew consent after completing RT and never received CT and 3 did not undergo surgery (new comorbidity in 2 cases, progression of distant metastatic disease in 1 case). Grade 3 preoperative GI morbidity occurred in 7 cases (9%) (no grade 4 or 5). The 76 evaluable cases included 7 cT4 and 69 cT3; 59 (78%) cN+, 8 cM1. Sphincter preserving surgery was performed on 49 (64%) cases. At surgery 53 (70%) had ypT0-2 residual disease including 21 (28%) ypT0; 24 (32%) were ypN+. For M0 evaluable cases 2 year NED survival is 91+/-6% with no local failures. Cases were sub-analyzed by whether disease met requirements for the recently activated ACOSOG preoperative FOLFOX vs. 5FU-RT trial. Thirty eight cases met ACOSOG eligibility and achieved 16 ypT0 (42%) and 33 ypT0-2 (87%). Conclusions: This regimen achieved high response and low morbidity rates that compare favorably with conventionally fractionated RT and concurrent CT. The ongoing RAPIDO trial compares a similar regimen to conventional chemoradiation in poor risk locally advanced rectal cancer patients.
Uptake of adjuvant chemotherapy for colon cancer in older and younger patients in the Irish population.
Authors: Coyle Seamus , Rehman Zia , Lee Chalen , Deady Sandra , Comber Harry , O'Connor Miriam , Calvert Paula , Horgan Anne M 
Published: February 2017

478 Background: Colon cancer is predominantly a disease of the elderly, with recent evidence supporting the use of adjuvant chemotherapy in the older population. However, it remains unclear to what degree such patients are receiving adjuvant therapy in clinical practice. We examined uptake of adjuvantchemotherapy and it’s impact on survival in older patients with stage II and stage III colon cancer in a national cohort. Methods: Using the National cancer Registry of Ireland, we identified 3,486 patients with stage II and III colon cancer who were treated with curative resection from 2004-2009. Clinopathological features and chemotherapy use were compared between those ≥70 years and those < 70 years. Results: A total of 2,026 patients with stage II disease were identified, 56% male and 60% ≥ 70 years. T3 tumors accounted for 81%, T4 19% and 89% were grade 2/3. Adjuvant chemotherapy was utilized in 10% and 40% of ≥ 70 and <70 years, respectively (p<0.0001). A benefit for chemotherapy over observation alone was seen in both the older [HR 0.36; 95% CI 0.36 – 0.68; p <0.0001] and younger patient groups [HR 0.43; 95% CI 0.2701 - 0.6881; p<0.0004]. Of 1,460 patients with stage III disease, 51% were ≥ 70 years, 54% male. 34% of older and 83% of younger patients received adjuvant therapy (p<0.0001). A similar magnitude of benefit from chemotherapy compared to observation was seen in patients ≥ 70 years [HR 0.30; 95% CI 0.29 - 0.45 ; p <0.0001] and <70 years [HR 0.22 95%CI 0.1 – 0.2; p<0.0001] with stage III disease. Conclusions: Adoption of adjuvant chemotherapy appears to be associated with significant survival benefit in older patients (age ≥ 70 years), however, is still underutilized in clinical practice. The impact of sociodemographic and clinicopathological features as potential drivers of treatment decisions in a cohort of this population will be reported.
Biomarker distribution and characteristics for the first 100 patients in MAVERICC, a randomized phase II study of mFOLFOX6-bevacizumab (BV) versus FOLFIRI-BV in previously untreated metastatic colorectal cancer (mCRC).
Authors: Starodub Alexander , Thomas Sachdev P. , Lee Fa-Chyi , Harish Vallathucherry , Koh Han A. , Mitchell Edith P. , Mandanas Romeo Ang , Huh Sang Y. , Badarinath Suprith , Mittan Angelique , Leon Larry , Vogt Tobias , Langer Christiane , Lenz Heinz-Josef 
Published: February 2017

483^ Background: Retrospective analyses have suggested that ERCC1 is a chemo-resistance marker to platinum compounds; a median tumoral ERCC1 level of 1.7 × 10–3ERCC1/β-actin mRNA has been reported in metastatic colon cancer (Grimminger et al, Pharmacogenomics J, 2011). MAVERICC is the first prospective study of tumoral ERCC1and plasma VEGF-A as potential biomarkers for oxaliplatin- and BV-containing regimens, respectively. We present data from a planned interim biomarker distribution assessment of the first 100 patients (pts) in MAVERICC. Methods: In this randomized, open-label, phase II study, pts (N=360) with histologically or cytologically confirmed CRC and ≥1 measurable metastatic lesion are stratified at screening by tumoral ERCC1 mRNA expression (low vs high, cutoff of ≤ vs >1.7). Stratified pts are randomized 1:1 to mFOLFOX6-BV or FOLFIRI-BV administered in 2-week cycles. The primary objectives are: 1) to assess ERCC1 and VEGF-A as biomarkers of progression-free survival (PFS) for oxaliplatin- and BV-containing 1st-line regimens, and 2) within ERCC1 high pts, to test whether FOLFIRI-BV is associated with a prolonged 1st-line PFS vs mFOLFOX6-BV. Results: With a data cutoff of June 19 2012, 100 pts have been enrolled. Of these, 75 pts were stratified to the ERCC1 high group and 25 pts to the ERCC1 low group. The median ERCC1 mRNA expression was 3.00 (range, 1.73–13.16) and 1.32 (range, 0.70–1.70) in the ERCC1 high and low stratification groups, respectively. Among all pts, the median ERCC1 mRNA expression was 2.37. Pt demographics by group are shown (Table). Plasma VEGF-A evaluation is ongoing. Conclusions: An analysis of the first 100 pts in MAVERICC showed that the median tumoral ERCC1 expression level was higher than the predefined cutoff, providing an adequate population of ERCC1 high pts to assess PFS by treatment regimen. Clinical trial information: NCT01374425. [Table: see text]
Metastatic colorectal cancer (mCRC) with primary in situ: An Australian registry.
Authors: Wong Shu Fen , Field Kathryn M , Kosmider Suzanne , Tie Jeanne , Wong Hui-Li , Tran Ben , Tacey Mark , Shapiro Jeremy David , McKendrick Joseph J , Gibbs Peter 
Published: February 2017

498 Background: The role of primary tumor resection in patients presenting with mCRC remains controversial. While recent data suggest resection of the primary tumor is unnecessary with modern systemic therapies, other series indicate that non-operative intervention may be associated with inferior survival outcomes. We aimed to evaluate the Australian approach to primary tumor resection in patients with mCRC and to explore its impact on survival outcomes. Methods: This study was conducted using a clinician-designed mCRC registry involving 15 participating Australian sites. Patients were excluded if planned for curative resection of metastatic disease or had incomplete data. Cox logistic regression analyses were used to identify and quantify associations between overall survival (OS) and patient/clinical variables. Results: We identified 533 mCRC patients with median follow up 12.5 mo. 41% (n=220) had their primary in-situ. Rates of primary tumor resection were higher in older patients (>70 yrs old) (64.5% vs 52.7%; p=0.006), colon versus rectal primaries (64.6% vs 42.7%; p<0.001) and those without liver metastases (70.7% vs 52.9%; p<0.001). Median OS was significantly better in patients undergoing primary tumor resection compared to the non-resected population (28.3 mo vs 15.9 mo; Hazard Ratio (HR): 0.52; log-rank p<0.001). Univariate analyses indicate that older age (HR: 1.69; p<0.001), poor performance status (HR: 4.44; p<0.001) and peritoneal involvement (HR: 1.94; p<0.001) were associated with poorer survival outcomes while chemotherapy administration (HR: 0.33; p<0.001) predicted improved survival. Multivariate analyses, when adjusted for known prognostic factors, confirms that primary tumor resection remains an independent predictor of better survival (HR: 0.50; p<0.001). Conclusions: The 41% of primary cancers in-situ is higher than previous mCRC studies and suggests a tendency for non-operative intervention in Australia. Given the survival outcomes demonstrated in this study, a review of Australian clinical practice is required. Future studies will examine the survival differences in patients with de novo versus relapsed metastatic disease, motivation for resection and other confounding variables.
A multicenter phase I study on preoperative chemoradiotherapy with S-1 and CPT-11 for locally advanced lower rectal cancer (SAMRAI-1).
Authors: Noda Masafumi , Sato Takeo , Hayakawa Kazushige , Tomita Naohiro , Kamikonya Norihiko , Ishihara Soichiro , Kato Daiki , Sakai Yoshiharu , Hiraoka Masahiro , Shimada Mitsuo , Ikushima Hitoshi , Baba Hideo , Oya Natsuo , Oya Masatoshi , Oguchi Masahiko , Takeuchi Masahiro , Watanabe Masahiko 
Published: February 2017

503 Background: Preoperative chemoradiotherapy with 5-FU is a standard therapy for locally advanced lower rectal cancer. This therapy is useful for increasing local control rates and maintaining anal functions, but there is no evidence indicating that this therapy can extend survival. We performed a phase I study with the objective of developing a new chemoradiotherapy with irinotecan (CPT-11) and S-1, containing gimeracil, a dihydropyrimidine dehydrogenase inhibitor with radiosensitizing effect. Methods: Patients with locally advanced lower rectal cancer (T3-4, N0-2) of which the inferior border was located closer to the anal verge than to the peritoneal reflection were used for analysis. The radiation dose was 45 Gy in 25 fractions. The radiation field included the internal iliac, pararectal, and obturator lymph nodes in addition to the primary tumor and enlarged lymph nodes. S-1 was administered for five consecutive days and withdrawn for two consecutive days (administration: Days 1-5, 8-12, 22-26, and 29-33). The dose of S-1 (80, 100, 120 mg/day) was controlled in accordance with the body surface area. CPT-11 was administered on days 1, 8, 22, and 29. The initial dose of CPT-11 was 60 mg/m2 (Level 1), and the dose was increased gradually. Total mesorectal excision was performed 6-10 weeks after completion of the chemoradiotherapy. Results: 20 patients were enrolled. Excluding 2 patients who discontinued the study, 18 patients were subject to analysis. Dose-limiting toxicity (DLT) was not seen in 3 patients treated with CPT-11 at 80 mg/m2 (Level 2), but was seen in 3 of the 6 patients treated with CPT-11 at 90 mg/m2 (Level 3). DLT was seen in 3 other patients administered a Level 2 dose. At Level 2 or Level 3, DLTs, namely neutropenia, thrombocytopenia and diarrhea were seen. Level 2 was regarded as a maximum tolerated dose, and Level 1 as a recommended dose (RD). The pathological complete response rate was 28%, and the downstaging rate 56%. Conclusions: The results of the study suggest that the RD of CPT-11 is 60 mg/m2. We plan to perform a phase II study to evaluate the efficacy and safety of chemoradiotherapy with S-1 and CPT-11. Clinical trial information: UMIN000001639.
Are the numbers of retrieved lymph nodes (LNs) within and outside the radiation field significant prognostic factors in patients who received chemoradiotherapy (CRT)?
Authors: Okada Kazutake , Sadahiro Sotaro , Suzuki Toshiyuki , Tanaka Akira , Kamijo Akemi 
Published: February 2017

510 Background: We had presented last year that the number of lymph nodes (LNs) significantly decreased within the radiation field, but not outside the radiation field in rectal cancer patients who received preoperative chemoradiotherapy (CRT) as compared with patients who underwent surgery alone. In the present study, we examined the relation between survival and the number of LNs within and outside the radiation field, separately. Methods: The study group comprised 210 patients who underwent radical surgery for clinical stage II or III rectal cancer from 1991 through 2010. A total of 108 patients underwent surgery alone (S group), and 102 patients received preoperative CRT, 40 or 45 Gy with concurrent oral UFT or S-1, (CRT group). LNs were divided into two groups according to their distribution; within the radiation field (within the mesorectum) or outside the radiation field. Results: Patient demographics did not differ between the groups. The number of LNs examined was 2617, of which 290 (11%) were metastatic. The mean total number of LNs was significantly higher in the S group (16 ± 11) than in the CRT group (9 ± 7; p<0.01). The number of LNs within the radiation field was significantly higher in the S group (6 ± 6) than in the CRT group (4 ± 4; p<0.01), but the number of LNs outside the radiation field did not differ. The total number and the number of metastatic LNs outside the radiation field did not differ between the groups, however, the number of metastatic LNs within the radiation field was significantly higher in the CRT group (S group, 2 ± 2; CRT group, 3 ± 4; p<0.01). In the S group, the total number of LNs and the number of LNs within the mesorectum were both prognostic factors in pStage II disease. A total number of ≥18 LNs and ≥5 LNs within the mesorectum were associated significantly with better outcomes. The number of metastatic LNs within the mesorectum was a prognostic factor in pStage III disease. In the CRT group, however, the total number of LNs and the number of LNs within the mesorectum were not related to survival. Conclusions: The number of LNs within the mesorectum might be a prognostic factor in patients who receive surgery alone, but not in patients who receive CRT.