bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictive factor for toxicities and treatment termination in adjuvant S-1 therapy for stage III colorectal cancer using data from JCOG0910.
Authors: Yamazaki Kentaro , Yoshida Yukio , Mizusawa Junki , Kanemitsu Yukihide , Kinugasa Yusuke , Komori Koji , Ohue Masayuki , Ota Mitsuyoshi , Takiguchi Nobuhiro , Nishizawa Yusuke , Ojima Hitoshi , Takii Yasumasa , Yamagami Hideki , Tanada Minoru , Sekimoto Mistugu , Yamaguchi Takashi , Bandou HIroyuki , Katayama Hiroshi , Hamaguchi Tetsuya , Shimada Yasuhiro
Published: February 2017

669

Background: S-1 has demonstrated antitumor effects in various cancers. Gastrointestinal (GI) toxicities associated with S-1 sometimes cause treatment interruption or termination, and previous reports suggested that low creatinine clearance (Ccr) was associated with the dose reduction and schedule modification during adjuvant S-1 therapy for gastric cancer. However, there are few reports evaluating these associations in colorectal cancer (CRC). Methods: We used the data of patients (pts) allocated to S-1 arm in JCOG0910 trial which evaluated the non-inferiority of S-1 to capecitabine as adjuvant therapy for stage III CRC. The association between pts’ background factors including age, gender, BSA, BMI, surgical procedures, Ccr, AST, ALT, and T-bil, versus treatment termination due to toxicity, and ≥ Grade 2 (G2) diarrhea, ≥ G2 anorexia, and ≥ G2 nausea were evaluated by using logistic regression. Results: Between Mar. 2010 and Aug. 2013, 1564 pts were enrolled, 782 pts were randomized to S-1 arm and 766 pts were analyzed. Pts’ background factors were as follows: ≥ 70 years, 34%; male, 49%; BSA higher, 28%; BMI ≥ 25 kg/m2, 17%; low anterior resection (LAR) or abdominoperineal resection (APR), 19%; Ccr < 50 ml/min, 7%; AST or ALT ≥ upper limit of normal, 16%; T-bil ≥ 1.0 mg/dL, 7%. Among them, 139 pts (18%) terminated treatment due to toxicity or death. The incidence of ≥ G2 diarrhea, anorexia, and nausea were observed in 18, 14 and 10%. The multivariate analysis revealed that some pts’ background factors were significantly associated with the incidence of treatment termination, or ≥ G2 GI toxicities (see table). Conclusions: Low Ccr, female, higher age or lower BMI might be risk factors of treatment termination due to toxicity or > G2 GI toxicities for pts treated with S-1. Clinical trial information: UMIN000003272. [Table: see text]
Effect of vorinostat (VOR) and hydroxychloroquine (HCQ) on immunity and autophagy in metastatic colorectal cancer (mCRC).
Authors: Patel Sukeshi R. , Hurez Vincent , Nawrocki Steffan T , Goros Martin , Michalek Joel , Sarantopoulos John , Curiel Tyler J. , Mahalingam Devalingam
Published: February 2017

670

Background:HCQ enhances the anti-cancer activity of the histone deacetylase inhibitor, VOR in pre-clinical CRC models. Our phase 1 dose escalation trial found that patients (pts) with mCRC obtained prolonged clinical benefit from VOR + HCQ. Thus, a single arm expansion cohort in refractory mCRC was done. Methods: Pts with refractory mCRC received VOR 600 mg by mouth (PO) + HCQ 400 mg PO daily, in a 3-week cycle. The primary endpoint was median progression-free survival (mPFS). Secondary endpoints: median overall survival (mOS), adverse events (AE) (NCI-CTCAEv3.0), flow cytometry (FACS) of peripheral blood mononuclear cells (PBMCs), tumor biopsies. Results: 20 pts were enrolled (19 evaluable for survival): mean age 61 (44-74). Female 7/male 23, 9 Caucasian/10 Hispanic/1 Black, 11 KRAS mutated. ECOG 0-1 (18 pts). 3+ prior lines (13), previous regorafenib (4). Dose level reduction on study (7). mPFS 2.8 months (95% CI: 1.63-8.16). mOS 6.7 months (95% CI: 4.63-NR). Treatment-related grade 3 AEs: nausea/vomiting (3), anemia (3). Grade 4 thrombocytopenia (3). Grade 4 INR elevation (1 pt on Coumadin). No grade 5 AEs. Five pts (26%) had stable disease ≥12 weeks. Treatment significantly reduced regulatory and PD-1+ (exhausted) CD4+ and CD8+ T cells and increased CD45RO+CD62L-CD4+ (effector) T cells, consistent with improved anti-tumor immunity. On-study biopsies (3) showed increased lysosomal protease CTSD and LC3-II consistent with autophagy inhibition. Conclusions: VOR/HCQ is active, safe and tolerated in refractory CRC patients, resulting in potentially improved anti-tumor immunity (decreased exhausted and regulatory T cells and increased effector phenotype T cells) and reduced tumor autophagy. A randomized phase II trial of VOR/HCQ versus regorafenib is now open. Clinical trial information: NCT01023737.
Induction treatment with FOLFOXIRI + bevacizumab (BV) followed by chemo-radiotherapy (CRT) + BV and surgery in locally advanced rectal carcinoma (LARC): The phase II TRUST trial.
Authors: Vivaldi Caterina , Sainato Aldo , Lonardi Sara , Buccianti Piero , Marcucci Lorenzo , Di Clemente Francesco , Musettini Gianna , Montrone Sabrina , Bergamo Francesca , Franceschi Matteo , Ginocchi Laura , Martignetti Angelo , Laliscia Concetta , Battaglin Francesca , Urbani Lucio , Manfredi Bruno , Rumano' Laura , Sidoti Francesco , Falcone Alfredo , Masi Gianluca
Published: February 2017

673

Background: Induction chemotherapy (CT) is a promising option in LARC. FOLFOXIRI + BV is an effective treatment in metastatic colorectal cancer. Methods: Patients (pts) with LARC at < 12 cm from the anal verge, N+ or cT4 or high risk cT3 (MRI criteria) underwent 6 cycles of FOLFOXIRI + BV followed by CRT (50.4 Gy + 5FU 225 mg/m2/day or capecitabine 800 mg/m2/bid 5 days/week + BV 5 mg/kg on days 1, 15, 28). Surgery was planned 8 weeks after CRT. Primary endpoint is 2-year disease-free survival (DFS). Results: From April 2012 to April 2015 48 pts were enrolled. At now, 46 pts completed induction CT, 43 completed CRT and 39 underwent surgery (5 pts ongoing). Pts characteristics were: median age, 53 years (range 30-74); cT2/cT3/cT4, 4%/60%/36%; cN0/N+, 4%/96%. Main grade (G) 3/4 toxicities during induction were neutropenia (42%), febrile neutropenia (4.2%), diarrhea (12.5. Two pts did not complete induction: one died due to bowel perforation and sepsis and one discontinued CT after acute kidney injury. Response rate (RR) after induction was 77%. Forty-five pts started CRT (1 pts underwent surgery after induction because of SAE). After the first 13 patients, protocol was amended and schedule of capecitabine modified due to an excessive rate of G3 toxicities during CRT: hand-foot syndrome (23%), proctalgia (23%), proctitis (23%) and diarrhea (15%). After amendment all pts completed CRT with acceptable toxicity: G3 proctitis 6.7% and proctalgia 3.3%. One pts died due to early progressive disease (PD) after CRT. RR after CRT was 88%. Surgery was low anterior resection 87%, abdomino-perineal resection 8%, other 5%. Radical resection was achieved in 95% of pts. Early post-surgical complication rate was 31%. Pathologic complete response was reached in 33% and pathological downstaging in 44% of pts. At a median follow up of 17 months, 8 pts had PD and estimated 2y-DFS is 72%. Conclusions: Induction CT with FOLFOXIRI + BV is feasible and highly active. A protocol amendment was needed due to toxicities during CRT. The rate of early post-surgical complications is not negligible. A longer follow up is needed for DFS. Clinical trial information: 2011-003340-45.
A phase II study of bevacizumab in combination with irinotecan plus S-1 as first-line treatment in patients with KRAS mutant-type metastatic colorectal cancer.
Authors: Eto Tetsuya , Masuishi Toshiki , Suzuki Kohei , Shibata Isamu , Fukami Yuichi , Matsui Toru , Ichida Takashi , Kusano Fumihiko , Tazawa Junichi , Sakai Yoshinori
Published: February 2017

676

Background: FOLFIRI+bevacizumab (BV) is considered as a first-line treatment in patients (pts) with metastatic colorectal cancer (mCRC). The FIRIS study showed the non-inferiority of irinotecan plus S-1 (IRIS) to FOLFIRI. Therefore, we conducted a phase II study to evaluate the efficacy and safety of BV in combination with IRIS as first-line chemotherapy for KRAS mutant-type (mt) mCRC (clinical trial information: UMIN000004630). Methods: Eligibility criteria included histologically confirmed mCRC, KRAS mt, no previous chemotherapy, ECOG performance status (PS) of 0/1, and adequate organ function. S-1 was administered at 80 mg/m2 on days 1–14 and irinotecan at 100 mg/m2 on days 1 and 15 every 28 days. BV was administered at 5 mg/kg on days 1 and 15 every 28 days. The primary endpoint was response rate (RR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. The sample size was calculated to reject a RR of 25% in favor of a target RR of 50% with a significance level of 0.05 and a statistical power of 80%. Results: Of 26 patients enrolled for the study between December 2010 and September 2015, 23 met the inclusion criteria. The patient characteristics were as follows: median age, 66 (range, 46–77) years; male/female, 15/8; PS 0/1, 9/14; number of metastatic tumors 1/ ≥ 2, 8/15; colon/rectum as the primary tumor site, 13/10; primary tumor +/−, 15/8; and unresectable/recurrent, 15/8. The RR was 60.9% (95% confidence interval (CI): 40.8%–77.8%) with complete response, 0; partial response, 14; stable disease, 8; progressive disease, 0; and not evaluable, 1. With a median follow-up period of 58.1 months, the median PFS and OS were 10.7 (95% CI: 4.7–16.8) and 28.5 (95% CI: 17.6–39.3) months, respectively. The most common grade 3 or 4 adverse events were neutropenia (35%), diarrhea (22%), leukopenia (17%), febrile neutropenia (13%), anemia (13%), and hypoalbuminemia (13%). Conclusions: BV in combination with IRIS as first-line chemotherapy showed promising anti-tumor effects and manageable toxicities for KRAS mt mCRC. Clinical trial information: UMIN000004630.
Prognostic significance of lymph node sampling in node-negative appendiceal carcinoids.
Authors: Raoof Mustafa , Dumitra Sinziana , Singh Gagandeep , Fong Yuman , Lee Byrne
Published: February 2017

678

Background: Surgical resection is the primary therapy for local and locally advanced carcinoid tumors of the appendix. The extent of surgery is largely dictated by the size of the tumor. Tumors >2 cm require a right hemicolectomy with associated mesenteric lymphadenectomy. What constitutes an adequate mesenteric lymphadenectomy is not known. Methods: This is a study of a contemporary cohort from NCI’s SEER database (Jan, 2004- Nov, 2012). Patients with non-metastatic appendiceal carcinoid tumors were included. Surgical extent was defined as limited (appendectomy or illeocecectomy) or extended (hemicolectomy). Primary outcome was overall survival (OS). Survival analysis was performed using the Kaplan-Meier and Cox-proportional hazards model. Results: Of the total 1,104 patients that met the inclusion criteria, 52% were female, 88% were white and majority were middle aged (40-60y) 45%. Majority of the tumors were <2 cm (49.3%) and lymph node(LN) negative 85%. Median LN retrieved were 10 (IQR 0-17). Median follow-up was 32 months (IQR 10-61). A multivariate Cox-proportional hazard model demonstrated that increasing age, tumor size > 3cm, tumor spread to contiguous organs, LN positivity and LN count <11 (HR 1.78: 95%CI 1.17-2.69; p=0.006) are associated with worse OS. Five-year overall survival increased with the number of LN retrieved (LN 1-10, 81.4%; LN >10, 85.9%, p=0.035). Stratified analysis by LN status demonstrated that LN count <11 was an independent predictor of worse OS in node negative patients (HR 2.10: 95%CI 1.25-3.53; p=0.005) but not node positive patients (p=0.65). Subset analysis by tumors size demonstrated that prognostic value of LN count <11 was only significant for tumors greater than 3 cm (HR 2.32: 95%CI 1.15-2.03; p=0.018). Conclusions: This is the largest study to date that looks at prognostic significance of LN count for appendiceal carcinoids. The number of LNs evaluated is an independent prognostic factor in pathologic node-negative, appendiceal carcinoid tumors measuring greater than 3 cm. This data supports performing a formal lymphadenectomy (>10 LN) even if no mesenteric disease is visible for adequate staging.
A phase I study of MEK162 and FOLFOX in chemotherapy-resistant metastatic colorectal cancer.
Authors: Cho May Thet , Lim Dean , Synold Timothy W. , Frankel Paul Henry , Leong Lucille A. , Chao Joseph , Chung Vincent M. , Chen Yuan , Sentovich Stephen , Luevanos Eloise , Fakih Marwan
Published: February 2017

679

Background: Pre-clinical studies have shown that the combination of MEK inhibitors and 5-FU improves antitumor activity and that MEK inhibition overcomes both 5FU and platinum resistance. This phase I study was conducted to determine the maximum tolerated dose (MTD) of the combination MEK162 and FOLFOX. Methods: Patients (pts) with metastatic colon or rectal cancer who progressed or failed prior 5FU, irinotecan, oxaliplatin and anti-EGFR therapy (in cases of RAS wild type tumors) received twice daily MEK162 in combination with every-2-week FOLFOX. Two dose levels of MEK162 (30mg and 45mg) were investigated in a standard 3 + 3 escalation design in combination with standard doses of FOLFOX without bolus 5-FU. Dose limiting toxicity (DLT) was defined as any treatment-related grade (G) 3 or 4 non-hematological toxicity (with the exception of G3 diarrhea or vomiting < 48 hrs) or G 4 neutropenia or thrombocytopenia within the first 2 cycles (4 weeks) of the treatment. Limited pharmacokinetic (PK) analysis of 5FU, oxaliplatin and MEK162 was performed at the MTD level. Results: 16 pts were enrolled (median age (range) 53 yrs (49-78); 11 men; ECOG 0/1 in 9/7 patients). No DLT was noted on the study. The MTD of MEK162 was 45 mg PO BID. An additional 6 pts (for a total of 12) were enrolled at the MTD for PK analysis and none of them developed DLT defining toxicities. A median of 8 cycles (range 1-19) was administered. Treatment-related ≥ grade 3 toxicities included anaphylaxis due to oxaliplatin (n = 1), CPK elevation (n = 2), neutropenia (n = 1), peripheral neuropathy (n = 3), thrombocytopenia (n = 1), retinal vascular disorder (n = 1), and acneiform rash (n = 1). 10 pts had SD at 2 months (m) by radiographic assessment, 5 of whom with stabilizations of > 5 months (5-10 months). There were no significant differences in the PKs of 5FU or oxaliplatin when administered with or without MEK162. Conclusions: The combination of MEK162 and FOLFOX has a manageable toxicity profile and promising antitumor activity in heavily pretreated metastatic colorectal cancer patients. Clinical trial information: NCT02041481.
The relationship between systemic inflammation and postoperative outcomes following neoadjuvant chemoradiotherapy for rectal cancer.
Authors: McSorley Stephen Thomas , Khor Bo , Horgan Paul G. , McMillan Donald C
Published: February 2017

682

Background: The magnitude of the systemic inflammatory response before and after surgery for rectal cancer is increasingly understood to have an impact on clinical outcomes. The aim of the present study was to examine the impact of neoadjuvant chemoradiotherapy (nCRT) on pre- and postoperative systemic inflammation and clinical outcomes in patients undergoing surgery for rectal cancer. Methods: Data was recorded prospectively for patients who underwent elective, potentially curative surgery for rectal cancer, from 2008 to 2015 at a single centre, n = 251. Patients had routine pre- and postoperative blood sampling. Results: Of the 251 patients, the majority were male (62%) and over 65 years old (57%) with node negative disease (66%). 85 patients (33%) were allocated to preoperative nCRT based on probable margin threatening disease at preoperative MRI. nCRT was significantly associated with a higher proportion of patients having neutrophil lymphocyte ratio (NLR) > 5 (39% vs. 12%, p < 0.001), and a modified Glasgow Prognostic Score (mGPS) of 2 (14% vs. 6%, p = 0.035) prior to surgery. There was no significant association between nCRT and the magnitude of the postoperative systemic inflammatory response or complications. Of the 85 patients who underwent nCRT, there was a small but significant reduction in CRP following treatment (3.25 mg/L vs. 4.1 mg/L, p = 0.007). Of the 16 patients who were systemically inflamed prior to nCRT, 9 patients achieved mGPS score 0 after treatment (p = 0.004). There was a significant association between having an mGPS score 1 or 2 both before and after nCRT and breaching established thresholds of CRP on postoperative days 2 (190mg/L, 86% vs. 33%, p = 0.002), 3 (170mg/L, 86% vs. 38%, p = 0.015) and 4 (145mg/L, 71% vs. 36%, p = 0.031). Conclusions: Allocation to nCRT was significantly associated with a systemic inflammatory response prior to surgery for rectal cancer. nCRT was significantly associated with attenuation of existing systemic inflammation. Such attenuation of the systemic inflammatory response may in part explain the efficacy of nCRT in patients with rectal cancer.
Activity of aflibercept (Afli) in combination with FOLFIRI (F) for patients with metastatic colorectal cancer (mCRC) in a real-life setting in Spain: Final results of the retrospective study Named Patient Program.
Authors: Sastre Javier , Feliu Jaime , Martinez Purificación , Buges Cristina , Mendez Jose Carlos , Alcaide Julia , Garcia Teresa , Valladares Manuel , Marrupe David , Delgado Ignacio , Salgado Fernandez Mercedes , Martin Valades Jose Ignacio , Juarez Asuncion , Martin Martinez Jose Miguel , Lopez Ana , Quintero Aldana Guillermo Alfonso , Donnay Olga , Vera Ruth , del Pozo Nieves , Diaz De Corcuera Frutos Isabela
Published: February 2017

689

Background: InVELOUR trial the addition of aflibercept to FOLFIRI regimen, demonstrated a statistically significant overall survival improvement in mCRC patients (pts) who progressed on or after a prior oxaliplatin based regimen with or without biologic agents. Our goal is to assess in the real-life setting the activity and safety profile of Afli+F in mCRC. Methods: Retrospective data collection (baseline characteristics, progression free survival [PFS], objective response rate [ORR], salvage surgeries, and safety profile) of pts who received Afli+F as a 2nd line treatment on a compassionate use program in Spain. GERCOR prognostic model has been applied to evaluate PFS. These are the final results of the analysis (Cut-off date June 2015). Results: The retrospective study population comprised 71 pts (34 hospitals); 60.6% men and 39.4% women, median age 64 years (19.7% > 70) and 98.6% had ECOG scores = 0-1. 63.4% (n = 45) had ≥ 2 metastatic sites (liver [81.7%], lung [38.0%]) and 67.7% (46/68) patients were K-RAS mutated. 60.6% (n = 43) had received prior bevacizumab (BVZ) treatment, 16.9% (n = 12) had received prior cetuximab and 5.6% (n = 4) panitumumab. Patients received a median of 6 cycles (range: 1-30) of Afli+F. Median PFS with Afli+F was 5.3 months (CI 95%: 3.7-8.6); which was not significantly modified by the presence of K-RAS mutation (HR: 1.1663; 95%CI: 0.6676-2.0373; p = 0.5867), by prior BVZ treatment (HR: 1.2424; 95%CI: 0.7238-2.1327; p = 0.4283) or by anti-EGFRs treatment (HR: 0.5681; 95%CI: 0.3117-1.0356; p = 0.0604). ORR was 19.7% (CI 95%: 11.2-30.9) and 8.5% (n = 6) of salvage surgeries. The most frequent adverse events grade ≥ 3 related with treatment were asthenia (n = 8), neutropenia (n = 7) and diarrhea (n = 6). The characteristic anti-angiogenic events were hypertension (n = 8), proteinuria (n = 1), vascular events (n = 1), and one intestinal perforation resulting in death. GERCOR prognostic model: Median PFS = 8.30 months [1.28-18.71] low risk, 5.29 [4.08-9.93] intermediate risk and 2.56 [1.94-4.57] high risk. Conclusions: In spite of the differences in sample size, in the real-life setting, Afli+F achieve a PFS comparable to VELOUR, regardless of K-RAS status or prior BVZ and anti-EGFR’s treatment, with an appropriate safety profile. Funding: Sanofi.
Clinical significance of MET amplification in metastatic or locally advanced gastric cancer treated with first-line fluoropyrimidine and platinum (FP) combination chemotherapy.
Authors: Seo Seyoung , Park Seong Joon , Park Sook Ryun , Ryu Min-Hee , Ryoo Baek-Yeol , Park Young Soo , Na Young-Soon , Lee Chae-Won , Lee Ju-Kyung , Kang Yoon-Koo
Published: February 2017

69

Background: Amplification of the MET proto-oncogene has been reported in a subset of gastric cancer (GC). However, clinical information of MET amplified GC is limited, especially in the metastatic setting. We investigated the clinical significance of MET amplification in GC patients treated with palliative chemotherapy. Methods: MET amplification was analyzed in formalin-fixed, paraffin-embedded GC tissues by a quantitative PCR-based copy number assay, using advanced GC cohorts between 2008 and 2014 in Asan Medical Center (AMC), Seoul, Korea. A total of 327 patients with tumor portion ≥ 70% were analyzed for clinical features and among them, 260 patients treated with first-line FP were analyzed for survival. MET amplification was defined as > 5 copy number. Results: Twenty one out of 327 patients (6.4%) were classified as harboring MET amplification. Clinical characteristics were compared between patients with or without MET amplification (AMP vs. no AMP group). The AMP group was related with ECOG performance status ≥ 2 (33.3% vs. 10.5% p = 0.007), peritoneal metastasis (76.2% vs. 46.2%, p = 0.008) and poor risk category (47.6% vs. 14.2%, p = 0.001) by AMC prognostic model (Koo et al. Cancer Chemother Pharmacol 2011, 68:913-921). A total of 174 patients had measurable lesions from 260 patients treated with FP and 80 patients (51.4%) obtained objective responses. There were no significant differences in response rate between two groups (61.5% vs. 52.2%, p = 0.518). With a median follow-up of 27.8 months (range, 8.2-68.5), median overall survival (OS) and progression-free survival (PFS) were 12.7 and 5.8 months, respectively. In univariate analysis, neither PFS nor OS was different between two groups (hazard ratio [HR] = 0.677, 95% confidence interval [CI] 0.347-1.322, p = 0.254 for PFS; HR = 0.676, 95% CI 0.347-1.318, p = 0.251 for OS). Conclusions: In advanced GC, MET amplification was associated with poor performance status, peritoneal metastasis, and poor risk category. However, MET amplification was not an independent prognostic predictor in patients with metastatic or locally advanced GC treated with palliative FP chemotherapy.
Utilization and effectiveness of adjuvant chemotherapy (ACT) for colon cancer (CC) in the general population.
Authors: Biagi James Joseph , Mackillop William J. , Nanji Sulaiman , Wei Xuejiao , Peng Yingwei , Hanna Timothy P , Krzyzanowska Monika K. , Booth Christopher M.
Published: February 2017

702

Background: International guidelines recommend ACT for patients (pts) with stage III CC based on level I evidence showing improved survival. For stage II CC ACT is not routinely recommended but may be considered for pts with high-risk features. Here we describe practice patterns and outcomes associated with ACT in a routine population-based setting. Methods: All CC cases treated with surgery in Ontario 2002-2008 were identified using the population-based Cancer Registry. Electronic treatment records were linked to the registry to identify surgical procedures and utilization of ACT. Pathology reports were obtained for a 25% random sample of all cases to obtain details of extent of disease; pts with stage II or III were included in the study population. High-risk stage II was defined as: T4, <12 lymph nodes, poorly differentiated histology and/or lymphovascular invasion. Logistic regression was used to evaluate factors associated with ACT utilization. Cox proportional hazards model was used to evaluate cancer-specific (CSS) and overall (OS) survival. Results: The study population included 2,801 stage III and 2,488 stage II pts (47% of which were high-risk). In the stage III subgroup 66% received ACT, but was 90% among ages 20-49 vs 68% for ages 70-79 (p<0.001). ACT was associated with increased CSS (HR 0.63, 95% CI 0.54-0.73) and OS (HR 0.63, 95% CI 0.55-0.71). Among all stage II pts 18% received ACT but 24% in the high-risk disease subset. ACT utilization was higher in younger patients (51% for ages 20-49 vs. 16% ages 70-79, p<0.001) and varied across geographic regions (range 10-39%, p<0.001). Among all stage II pts ACT was not associated with improved CSS (HR 1.41, 95%CI 1.09-1.82) or OS (HR 1.16, 95%CI 0.94-1.42). Stratified analysis for high-risk stage II disease also did not show benefit to ACT (CSS HR 1.14, 95%CI 0.84-1.55; OS HR 1.02, 95%CI 0.79-1.31). Conclusions: One third of pts with stage III CC in the general population do not receive ACT, with age the strongest predictor of treatment. For stage II pts, ACT utilization varies substantially across age groups and geographic regions. ACT is associated with improved CSS and OS in stage III pts but not stage II pts, including those with high-risk disease.
Randomized phase II trial of prophylactic use of celecoxib for the prevention of oxaliplatin-related peripheral vascular pain in CapeOX for stage II/III colon cancer patients (YCOG1205).
Authors: Watanabe Jun , Ota Mitsuyoshi , Watanabe Kazuteru , Saito Shuuji , Nagamine Koutaro , Suwa Yusuke , Suwa Hirokazu , Momiyama Masashi , Ishibe Atsushi , Ichikawa Yasushi , Oba Mari Saito , Endo Itaru
Published: February 2017

703

Background: CapeOX is widely used as a six month adjuvant chemotherapy regimen of colorectal cancer which does not need central vein catheter insertion. However, oxaliplatin-related vascular pain interferes with peripheral administration. We assessed the prophylactic effect of COX-2 inhibitors on oxaliplatin-related vascular pain. Methods: A multicenter of Yokohama Clinical Oncology Group in Japan, open label, randomized non-comparative phase II study with 400mg of celecoxib with CapeOX group (C+ group) and CapeOX group (C- group) was conducted. Stratification factors were performance status 0/I, usage of low dose aspirin and institution. Primary endpoint is the appearance frequency of grade 2 or more vascular pain assessed using the Verbal Rating Scale (VRS) by a medical therapist who has no information about celecoxib administration. C- group patients who developed grade 2 or more vascular pain received celecoxib and were estimated with VRS. Results: Between October 2012 and February 2014, 81 patients were recruited from nine institutions in this study and randomly divided into two groups: 42 patients in C+ group and 39 patients in C- group. Grade II or more vascular pain rate was 55.3% in C+ group and 56.8% in C- group (p = 1.000). Fourteen patients in C- group who developed grade II or more vascular pain were given celecoxib and 50% of patients showed downgrading of vascular pain. Rate of grade II or more peripheral neuropathy was 36.6% in C+ group and 39.5% in C- group (p = 0.7916). Conclusions: Celecoxib has no prophylactic impact on either vascular pain or peripheral neuropathy. However, celecoxib effectively diminished vascular pain in patients with onset of grade II or more vascular pain. Clinical trial information: 000008814.
Efficacy and safety of bevacizumab combined with fluoropyrimidine monotherapy in unfit or older metastatic colorectal cancer patients: A systematic review and pooled-analysis.
Authors: Antonuzzo Lorenzo , Aprile Giuseppe , Barni Sandro , Maiello Evaristo , Masi Gianluca , Petrelli Fausto , Porcu Luca , Scartozzi Mario , Torri Valter , Pinto Carmine
Published: February 2017

705

Background: Bevacizumab (BEV) improves progression-free survival (PFS) and overall survival (OS) of metastatic colorectal cancer (mCRC) patients (pts) when added to doublets in first-line setting. Yet, its use in unfit and older mCRC pts remains controversial. This systematic review and pooled-analysis evaluated the efficacy and safety data of BEV combined with first-line fluoropyrimidine monochemotherapy in unfit or elderly mCRC pts. Methods: A literature search to identify studies using first-line fluoropyrimidine monochemotherapy plus BEV in unfit pts was performed in PubMed and EMBASE databases up to May 2015. Unfit pts were selected based on age, comorbities and health status, along with monochemotherapy as the only therapeutic option. The random-effects model was used to combine the effect estimates and the I2 index to quantify the between-study heterogeneity unexplained by sampling error. Results: We screened 1,304 papers and, after a double check, 56 were considered for full text evaluation: 38 were excluded and 10 were deemed not evaluable for lack of data on unfit pts, whereas 8 (3 RCTs, 4 single arm phase II trials and 1 prospective cohort study), including 782 pts, were considered eligible for the meta-analysis. Administered monochemotherapy was capecitabine in 531 (67.9%) pts and 5-fluorouracil (5-FU) in 251 (32.1%); 500 (63.9%) pts also received BEV. Median age was 75 years, 441 (56.4%) pts were male, ECOG performance status was 0-1 in 684 (87.7%) pts. The combination with BEV produced advantages in terms of both OS (HR 0.79; 95% CI: 0.64-0.98, P = 0.03; I2= 0%) and PFS (HR 0.52; 95% CI: 0.43-0.64, P < 0.00001; I2= 0%; pooled effect estimates of RCTs have been previously reported). As expected, higher rates of all grade hypertension (27% vs 4.9%), bleeding (24% vs 6.4%), thromboembolic events (10% vs 5%) and proteinuria (25.6% vs 8.2%) were observed in the BEV combination. Conclusions: Adding BEV to first-line fluoropyrimidine monochemotherapy, either capecitabine or 5-FU, significantly improved PFS and OS in unfit and elderly pts with mCRC, with a manageable safety profile and no unexpected side effects.
Personalized dose monitoring of fluorouracil and metabolites of capecitabine (XELODA) in colorectal cancer patients (PersonaX).
Authors: Nakamura Masato , Makihara Katsuya , Onikubo Toshihide , Nakamura Kumi , Uchibori Kazuya , Azuma Sayaka , Murotani Kenta , Iwamoto Shigeyoshi , Mishima Hideyuki
Published: February 2017

706

Background: Capecitabin is a prodrug converted into 5-FU via two phases of metabolites, 5' -DFCR and 5' -DFUR. In order to elucidate intra-individual variation of capecitabine, we have investigated pharmacodynamics and kinetics of fluoroprymidine in patients with colon cancer (UMIN000008852). Methods: A dose of 2000mg/m2/day of capecitabin were administered from day 1 to day 14 twice a day every 3 weeks with or without oxaliplatin and bevacizumab. Blood samples were collected on day 8 at 1 hour and 2 hour after morning meal in the first cycle. Concentrations of plasma 5-FU were measured by using ‘My5FU’, and concentrations of 5'-DFCR, 5'-DFUR and unchanged capecitabine were mesured by LC-MS. Results: A total of 34 patients with colorectal cancer were enrolled and evaluated. Although systemic 5FU are low after capecitabine intake, the concentrations of plasma 5FU were successfully measured by ‘My5FU’. Wide variation are shown in plasma 5FU, 5'-DFCR,5'-DFUR and unchanged capecitabine. There was a correlation between unchanged capecitabin and the AUC of their metabolites, 5' -DFCR and 5' -DFUR. The strongest correlation exists in 5FU and 5’DFUR (Spearmann correlation index: 0.82). Median and IQR (Interquartile Range) of 5FU was 175.1 (98.6-304) ug/mL. Conclusions: The monitoring of 5FU concentrations by ‘My5FU’ elucidated intra-individual variation of capecitabine. It will contribute to individual cancer treatment for patients administered capecitabine. The correlation between concentrations of capecitabine metabolites (5-FU, 5'-DFCR, 5'-DFUR,capecitabin) and their efficacy and toxicity are under examination. Clinical trial information: 000008852.
The role of cytoreductive surgery and heated intraperitoneal chemotherapy (CRS/HIPEC) in patients with peritoneal carcinomatosis (PC) of appendiceal origin (AO).
Authors: Sardi Armando , Milovanov Vladimir , Sittig Michelle , Gushchin Vadim
Published: February 2017

707

Background: Peritoneal carcinomatosis of mucinous appendiceal tumor origin is a rare condition which has poor prognosis if treated with limited surgery or systemic chemotherapy. Several publications show that CRS/HIPEC gives a significant survival benefit for patients with PC of AO. However, many patients do not get appropriate treatment. We show data from our 17-year experience using CRS/HIPEC in PC of AO. Methods: Retrospective analysis of a prospective database of 251 patients with PC of AO was performed. Peritoneal cancer index (PCI), completeness of cytoreduction (CC), lymph node (LN) status, and histopathology data was collected. The impact of each variable evaluated by Hazard ratio analysis. Overall survival (OS) estimated by Kaplan-Meier curves. Results: Mean age 53 years (range 23-81). 251 patients underwent 290 CRS/HIPEC procedures. 31 patients had 2, and 4 patients had 3 CRS/HIPEC. A total of 149 patients (59%) had peritoneal mucinous carcinomatosis (PMCA) and 102 (41%) had disseminated peritoneal adenomucinosis (DPAM) (Ronnett classification). Mean follow-up 4.8 years with a median of 4.7 years. Complete cytoreduction was achieved in 84% (89% DPAM, 80% PMCA; p = 0.047). Mean length of surgery 11.3 hours, mean hospital stay 14 days. No in-hospital or 30-day mortality. 73% had PCI > 20 (78% DPAM; 68% PMCA). LN metastasis in 42% with PMCA. OS from date of HIPEC was 93%, 86%, 81% in DPAM and 90%, 60%, 44% in PMCA for 1, 3, and 5 years, respectively. With CC, the 5-year OS was 84% in DPAM and 49% in PMCA. All PMCA patients with incomplete cytoreduction (n = 30) had PCI ≥ 20 (p < 0.001). Hazard ratios were 2.5 (95% confidence interval [95% CI] 1.3-4.5), 3.1 (95% CI 2.0-4.9), 3.6 (95% CI 2.1-6.2), for PCI < 20, complete cytoreduction, and histopathology (DPAM vs. PMCA), respectively. Hazard ratio (for LN status in patients with PMCA was 3.0 (95% CI 1.8-5.1). Conclusions: Meaningful survival could be achieved in PC of AO even with extensive peritoneal disease (PCI > 20). We consider CRS/HIPEC a standard of care for these patients. CRS/HIPEC should be provided in specialized centers by trained surgeons where complete cytoreduction could be frequently accomplished.
Does the dose of leucovorin (LV) matter with 5-fluorouracil (5FU) in colorectal cancer (CRC)?
Authors: Biagi James Joseph , Coakley Nadia , Earle Craig , Erlichman Charles , Fields Anthony L.A.
Published: February 2017

708

Background: In June 2015 Cancer Care Ontario convened an expert panel to determine if there is an optimum LV dose in 5FU-LV combinations for the treatment of CRC. This request arose out of observed variation in LV dosages between some cancer centers. The research question was effect of LV dose on overall survival (OS), progression free survival (PFS), disease free survival (DFS), response rate (RR) and adverse events/toxicity, given a constant dose of 5FU. Methods: A systematic search was conducted for guidelines (GL) and comparative trials; eligibility included English language, with > 30 patients, that examined different doses of LV where dose of 5FU was not varied. Assessment of studies for inclusion was completed by 4 reviewers. Results: We identified 5 GL, 0 systematic reviews and 12 trials that defined a LV dose in combination with 5FU. None of the GL informed an optimal dose of LV. RR was assessed in 10 trials; 4 showed trends to higher RR with higher LV dose, but differences were not statistically significant (SS) between arms. PFS or DFS was reported in 6 trials and was similar between arms. Time to recurrence reported in one trial that included bevacizumab (BV) was longer in the high dose LV group that was SS. OS was addressed in 10 studies: no difference found in 7 studies; in one RCT OS was longer with the higher dose LV 55 vs. 45 months (p not reported); in one retrospective study OS was 23 vs. 20 months in favor of high dose LV (p not reported); one study of LV and BV had longer OS vs. lower dose LV at 26 vs. 21 months (SS). Toxicity: higher dose LV was associated with greater toxicity in 3 of 4 studies that reported stomatis, and increased rates of diarrhea in 9 of 11 trials. Meta-analysis was not appropriate as studies were too heterogeneous. Conclusions: There is no convincing evidence to identify an optimum dose of LV to be used in 5-FU/LV combinations. Amongst studies that did show a difference the trend was improved survival in favor of the higher dose. Similarly, differences in toxicities when identified were consistently greater with the higher dose LV. The expert panel concludes that the existing literature provides insufficient data to suggest that chemotherapy protocols should deviate from standard protocol doses.
Leptomeningeal carcinomatosis in colorectal cancer: The Mayo Clinic experience.
Authors: Taylor Gretchen E , Karlin Nina J. , Halfdanarson Thorvardur Ragnar , Coppola Kyle , Grothey Axel
Published: February 2017

710

Background: Leptomeningeal metastasis (LM) has been described as a rare form of metastatic disease progression in colorectal cancer (CRC). There remains a paucity of literature with regards to the course and management of LM in CRC. The aim of this study was to estimate the incidence of LM in CRC patients seen at our institution over a 15-year period, and to describe the clinical course and outcome of these cases. Methods: LM in CRC primary cases between 2000 and 2014 were identified in the Mayo Clinic databases. The charts were retrospectively reviewed. Results: Of 17,095 CRC primaries, we identified 10 patients with LM (0.058%) in this 15-year period. Nine cases were included in the analysis. Four had metastatic disease at the time of their initial CRC diagnosis. One patient also had a lung adenocarcinoma diagnosed during initial staging for the CRC primary. Median overall survival after CRC diagnosis was 25.7 months (range 4.7-74.8). Median time to diagnosis of LM after CRC diagnosis was 25.3 months (range 1-68.1). All patients had MRI findings consistent with LM: 3 patients with spinal LM, 5 patients with intracranial LM, 1 with both. One of three CSF analyses at the time of LM workup was positive for malignant cells; all had elevated protein. Neurologic symptoms correlated with site of the lesions, with headache, cranial nerve palsy, lower extremity weakness, and gait disturbance among the most frequently reported. However, not all patients had neurologic findings, with LM lesions found incidentally in two cases. Seven patients (78%) had palliative radiotherapy (RT) for LM. Three patients continued to receive systemic chemotherapy after diagnosis of LM. No patients underwent intrathecal chemotherapy. Median survival after LM diagnosis was 7 weeks (range 2-39). Conclusions: The diagnosis of LM is an exceedingly rare development in the natural course of CRC. It continues to confer an extremely poor prognosis with limited treatment options. At our institution, most patients had their disease addressed by palliative means, with many receiving RT to control their neurologic symptoms. Based on our series, supportive care remains a sensible approach to the management of LM in CRC.
Predictors of lymph node metastasis and prognosis in early colorectal cancer patients with signet-ring cell and mucinous adenocarcinomas.
Authors: Song Baorong , Yu Yongming , Song Xiao , Li Xinxiang , Dai Xiaoyu , Cai Sanjun , Xu Ye , Cai Guoxiang
Published: February 2017

717

Background: The local excision of early colorectal cancer is limited by the presence of lymph node metastasis. Signet-ring cell carcinomas and mucinous adenocarcinomas are two relatively infrequent histological subtypes. However, little is known about the predictors of lymph node metastases and prognosis to support the feasibility of local excision in early-stage signet-ring cell and mucinous colorectal adenocarcinomas. Methods: The Surveillance Epidemiology and End Results Database (1988 to 2006) from the National Cancer Institute was used to identify all patients with T1 adenocarcinomas, including conventional adenocarcinoma (AC), mucinous adenocarcinomas (MAC), and signet-ring cell carcinoma (SRC). The prevalence of lymph node metastasis was assessed, and the long-term survival rate in the above three types of colorectal cancer was calculated. Results: Final cohorts of 47,260 patients were eligible for analysis. SRC accounted for 0.3% and MAC accounted for 3.7% of the entire cohort of colorectal adenocarcinomas. Compared to AC, SRC and MAC more frequently presented at a younger age, were located in the proximal colon, and exhibited a higher grade. The incidence of lymph node metastasis in AC, MAC, and SRC was 5.8%, 10.8%, and 15.3%, respectively. Patients with SRC were associated with a worse prognosis, regardless of the tumor location. Patients with MAC of the rectum, but not the colon, were associated with a reduced implication of prognosis. After adjusting for other clinicopathological factors, SRC and MAC of the rectum were independently associated with a high risk of death (HR 2.70, CI 1.77-4.12 and HR 1.65, CI 1.38-1.98 for SRC and MAC, respectively). Histology was not found to be an independent prognostic factor in patients with colon cancer. Conclusions: MAC and SRC are two distinct subtypes of colorectal cancer that require special attention despite their relatively rare prevalence. T1 patients with SRC and patients with MAC of the rectum have higher incidences of lymph node metastasis (LNM), and with these adverse outcomes, local excision is not recommended. Although MAC of the colon has a high rate of LNM, the prognosis of this type is similar to that of AC.
Effects of adjuvant oxaliplatin on anal function in locally advanced rectal cancer treated with preoperative chemoradiotherapy and low anterior resection.
Authors: Arias Fernando , Eito Clara , Viudez Antonio , Asin Gemma , Ibañez Berta , Hernandez Irene , Cambra Koldo , Errasti Marta , Barrado Marta , Campo Maider , Visus Ignacio , Mata Elena , Ciga Miguel
Published: February 2017

718

Background: The main purpose of the present study was to determine if the addition of adjuvant oxaliplatin (OXA) could have some influence on sphincter function in patients with locally advanced rectal cancer (LARC) treated with preoperative capecitabine/radiotherapy followed by lower anterior resection (LAR). Methods: Those patients with LARC treated at our center with LAR and without two-years loco-regional relapse were retrospectively analyzed independent of the type of adjuvant treatment received. Anal sphincter function was assessed by Wexner´s incontinence score (0 to 20 points, being punctuation inversely proportional to sphincter function). All questionnaires were completed between January 2010 and December 2012. Comparisons of sphincter function measured with the Wexner test between patients with and without OX were conducted with the Mann-Whitney test. Statistical analyses were conducted using IBM SPSS Statistics, version 20. Results: From 2006, 92 consecutive patients were included in our study. Mean time from LAR to fecal function assessment was 58 months (25 to 96 months). Wexner test median values did not differ significantly (p=0.450) between patients with and without adjuvant OXA. The median (IQR) for the group without adjuvant OXA was 6.0 (1.0-11.25), being for group that received adjuvant OXA of 5.0 (1.0-10.0). Conclusions: Based on our findings, OXA could be used as adjuvant treatment in LARC, due to its absent of deleterious influence over the sphincter anal function. Because of the retrospective nature of our study, prospective studies should be warranted in similar scenarios. This study has been supported by a grant of “Mutua Madrileña Fundation.”
Preliminary safety and efficacy of perioperative COI-B (capecitabine, oxaliplatin, irinotecan, and bevacizumab) in patients with borderline resectable or high–recurrence risk colorectal cancer liver metastases (CLM).
Authors: Caporale Marta , Cotsoglou Christian , Berenato Rosa , Scotti Mauro , Di Bartolomeo Maria , Coppa Jorgelina Clara , Milione Massimo , Mennitto Alessia , Flores Reyes Maria , Bossi Ilaria , Consonni Paola Valentina , Brunero Federica , de Braud Filippo , Pietrantonio Filippo , Mazzaferro Vincenzo
Published: February 2017

719

Background: FOLFOXIRI and bevacizumab achieves high objective response rate (ORR)/R0 resections in pts with unresectable CLM. Bevacizumab increases pathological response, a surrogate endpoint of survival after CLM resection. COI-B regimen is feasible in pts with advanced colorectal cancer. In this phase II study, we aimed at assessing safety and efficacy of perioperative COI-B for pts with borderline resectable or high recurrence risk CLM. Methods: Inclusion criteria: borderline resectability with portal embolization/2-stage hepatectomy, involvement of > 1 hepatic vein or > 4 segments; and/or at least one poor prognostic factor: > 4 metastases; CEA > 200; synchronicity. Limited resectable extraepatic disease and in situ primary allowed. Primary endpoint: TRG1-3 (Rubbia-Brandt et al) according to Simon 2-stage design (first step 22; target 46 pts); secondary endpoints: ORR; R0 resection; safety; progression-free and overall survival. Pts received bi-weekly irinotecan (180 mg/m2) and bevacizumab (5 mg/Kg) day 1, oxaliplatin (85 mg/m2) day 2 and capecitabine (1000 mg/m2/day b.i.d.) days 2–6; 5 cycles pre-operatively (the last without bevacizumab) and 4 post-operatively. Results: We present preliminary data on the first 25 pts. M/F: 13/12, median age 61 years, synchronous disease 19 (76%), multiple nodules 15 (60%), N+ primary tumour 14 (56%), CEA > 200 4 (16%), extrahepatic disease 1, RAS mutation 15 (60%)/BRAF mutation 0. Involvement ≥ 4 hepatic segments 9 (36%) and involvement of > 1 hepatic veins 4 (16%). ORR was 91% (21 out of 23 evaluable, 2 too early), while 1 SD and 1 PD. Surgery performed in 21 pts (4 awaiting) and R0 resection in 18 (86%). TRG1-2 was observed in 6 (29%), TRG3 in 9 (43%), i.e. pathological response 72% (first step reached). Grade ≥ 3 toxicities: neutropenia 2, diarrhea 2, thrombosis 2. Median follow up 13 months, with only 4 relapses and 1 death. Conclusions: COI-B regimen is a feasible neoadjuvant strategy for borderline resectable or high recurrence risk CLM. This is the first trial to select pathological response as primary surrogate endpoint with encouraging results. Clinical trial information: NCT02086656.
Safety and feasibility of laparoscopic surgery for colorectal cancer in elderly patients (YSURG1401 study).
Authors: Atsumi Yosuke , Numata Masakatsu , Aoyama Toru , Hayashi Tsutomu , Yamamoto Naoto , Oshima Takashi , Yukawa Norio , Shiozawa Manabu , Yoshikawa Takaki , Rino Yasushi , Masuda Munetaka
Published: February 2017

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Background: The safety and feasibility of laparoscopic surgery (LAP) for colorectal cancer has not yet been fully evaluated in elderly patients. The aim of this study was to compare the short term surgical outcomes of LAP and evaluate the safety and feasibility of LAP in colorectal cancer patients aged > 75 years. Methods: This retrospective study enrolled consecutive patients who underwent laparoscopic surgery for colorectal cancer between April 2013 and March 2014 at Yokohama City University Hospital and its related general hospitals. The patients were categorized into two groups: elderly patients (≧75 years of age: group A) and non-elderly patients ( < 75 years of age: group B). Surgical outcomes and postoperative complications were compared between the two groups. The severity of complications was evaluated using the Clavien–Dindo classification. Results: A total of 237 patients were evaluated in the present study. Eighty-four patients were classified into group A, and 153 into group B. Preoperative clinicopathological outcomes demonstrated no significant differences except for the ASA score. When comparing the surgical outcomes between group A and group B, the rate of conversion to open procedure (3.6 % vs 5.2 %, P = 0.751), median operation time (232 min vs 232 min, P = 0.318), median blood loss (20 ml vs 12 ml, P = 0.353). There was no significant difference in the surgical outcomes. Although the incidence of Japanese D3 dissection was significantly lower in Group A (56 % vs 69.3 %, P = 0.047), the incidences of postoperative surgical complications of grade ≧ Ⅱ were similar between two groups (15.5 % vs 11.8 %, p = 0.427). The length of postoperative hospital stay was also similar (10days vs 10days, p = 0.347). Conclusions: The present study suggested that laparoscopic surgery for colorectal cancer is safe and feasible, regardless of the age of the patient, especially for elderly patients who may be candidates for colorectal cancer surgery.