bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and efficacy of accelerated hypofractionation and stereotactic body radiotherapy for hepatocellular carcinoma in the setting of advanced liver dysfunction.
Authors: Nabavizadeh Nima , Waller Joseph , Fain Robert , Chen Yiyi , Degnin Catherine , Elliott David , Mullins Brandon T , Patel Ishan , Dyer Brandon Alan , Naugler Willscott E , Farsad Khashayar , Tanyi James , Fuss Martin , Thomas Charles R. , Hung Arthur
Published: March 2017

403

Background: To report toxicities and outcomes for stereotactic body radiotherapy (SBRT) and accelerated hypofractionated radiotherapy (AHRT) in patients with Child-Pugh (CP) A/B/C and Albumin-Bilirubin (ALBI) score 1/2/3 hepatocellular carcinoma (HCC). Methods: We retrospectively reviewed 151 patients with HCC treated with SBRT (50 Gy in 5 fractions) or AHRT (45 Gy in 18 fractions) between 2007 and 2015. Primary endpoint was incidence of grade 3 or higher toxicities within 6 months of radiotherapy (RT). Patients were censored for toxicity upon local progression, further liver-directed therapy, or if they exhibited grade 3 or higher toxicities prior to RT, unless RT elevated the grading or a new toxicity class was observed. Secondary endpoints of overall survival and local control were calculated. Results: Median follow-up was 11 months (1 – 90 months). Most received SBRT (72%), while 28% received AHRT due to size criteria ( > 5 cm) or proximity to a critical organ-at-risk. Grade 3 or higher hyperbilirubinemia and hypoalbuminemia was greater in the CP-B8/B9/C patients (42% and 22%) or ALBI-3 patients (45% and 31%) compared to patients with CP-A/B7 (11% and 4%, p < 0.001) or ALBI-1/2 (14% and 4%, p < 0.001). For all other toxicity classes, no difference between liver functionality groups was seen. Eleven grade 4 and no grade 5 toxicities were observed. For all pts, 1- and 2-year treated-lesion local control (LC) rates were greater for SBRT as compared to AHRT (2-year LC 95% vs. 66%, p < 0.0001). When excluding patients with planning treatment volumes > 115 cc (equivalent to a 6 cm sphere), SBRT still yielded superior outcomes. Conclusions: Other than higher rates of grade 3+ hypoalbuminemia and hyperbilirubinemia, highly conformal RT appears to be a potentially safe and effective treatment option for HCC patients with advanced liver dysfunction. Compared to AHRT, SBRT is associated with superior local control.
A phase II trial of modified gemcitabine plus S-1 combination as the first-line treatment in patients with advanced biliary tract cancer.
Authors: Chiang Nai-Jung , Chen Jen-Shi , Chen Ming-Huang , Yang Shih-Hung , Hsu Chiun , Yen Chia-Jui , Tsou Hsiao-Hui , Yanshen Shan , Chen Li-Tzong
Published: March 2017

417

Background: Gemcitabine plus platinum, notably cisplatin, is conceived as the standard regimen for advanced biliary tract cancer (ABTC) nowadays. Recent randomized phase II study (JCOG0805) showed that gemcitabine plus S-1 was more promising than S-1 alone in ABTC, and a randomized phase III, UMIN 000001685, is currently ongoing to compare the efficacy of gemcitabine plus either S-1 (GS) or cisplatin (GC) in ABTC. Herein, we report the results of a single arm phase II of modified GS in Taiwanese ABTC patients, NCT02425137. Methods: Patients with chemonaïve ABTC were eligible to receive 800mg/m2 gemcitabine with 10 mg/m2/min infusion, on day 1 plus daily 80/100/120 mg of S-1 (based on BSA) days 1-10, in a 2-week cycle. With Optimal Simon’s two-stage design and (p0= 0.4, p1= 0.6) for 12-week disease control rate (proportion of patients with complete or partial response [CR/PR] or stable disease ≥ 12 weeks [SD≥ 12weeks]) and given error probabilities (alpha = 0.05, beta = 0.2), the null hypothesis (p0) would be rejected if 24 or more patients with CR/PR/SD≥ 12weeks were observed among 46 accruals. Tumor response was assessed by CT/MRI every 6 weeks according to RECIST v1.1. Results: Between May 2015 and April 2016, totally 46 evaluable patients were enrolled to receive a median of 9.5 cycles (range: 3-31) of modified GS. After a median of 8.7 months (95% CI, 6.7-9.1) follow-up, 10 (21.7%) patients achieved PR and additional 23 (50%) had SD>12weeks. The median progression-free survival and overall survival was 5.6 (95% CI, 4.4-7.2) and 10.8 (95% CI, 7.6-not reached) months, respectively. All grade 3 treatment-related AEs were < 5%. The dose intensity of S-1 and gemcitabine were both more than 95%. Conclusions: By the observation of 33 patients with PR/SD≥ 12weeks, the null hypothesis was rejected. Modified GS is an active regimen with excellent safety profiles and deserves further investigation for the management of Asian ABTC patients. Clinical trial information: NCT 02425137.
Clinical outcome of modified FOLFIRINOX versus gemcitabine plus nab-paclitaxel as first line chemotherapy in metastatic pancreatic cancer.
Authors: Watanabe Kazuo , Hashimoto Yusuke , Umemoto Kumiko , Takahashi Hideaki , Sasaki Mitsuhito , Imaoka Hiroshi , Ohno Izumi , Mitsunaga Shuichi , Ikeda Masafumi
Published: March 2017

438

Background: FOLFIRINOX and Gemcitabine plus nab-paclitaxel (GN) have been established as first line chemotherapy in metastatic pancreatic cancer (mPC). But few data support preferable first line choice of these two regimens in “real-world” clinical setting. Methods: We retrospectively enrolled 135 chemotherapy-naive mPC patients treated with modified FOLFIRINOX (mFFX) or GN at National Cancer Center Hospital East between December 2013 and September 2015. mFFX is a modified regimen of reduced dose of irinotecan 150mg/m2 and eliminated bolus 5-FU from original FFX. GN consists of gemcitabine 1000mg/m2 plus nab-paclitaxel 125mg/m2 day1,8,15 every 4 weeks. We compared characteristics, efficacy and adverse events between mFFX and GN. Results: Seventy patients were treated with mFFX and 65 patients with GN as first line therapy. Demographic and baseline characteristics (mFFX/GN) were similar as follows: ECOG performance status (0-1): 100% / 99%, Gender (male): 66% / 69%, liver metastasis: 56%/49%, peritoneal metastasis: 34% / 31%, prior biliary drainage: 21%/17%, median observation period: 330 / 265 days, respectively. The population of elderly patients ( > 75y) was smaller in mFFX than GN (4.3% vs. 12%, p = 0.05). Objective response rate (27% vs. 39%, p = 0.02) and disease control rate (79% vs. 92%, p = 0.02) were significantly lower in mFFX than in GN. Median OS was 11.5 months (95% CI: 9.7-16.8) in mFFX and 14.0 months (95% CI: 12.2 - not reached) in GN. Median PFS was 5.7 months (95% CI: 3.4-7.1) in mFFX and 6.5 months (95% CI: 6.1-7.9) in GN. One-year survival rate was significantly higher in GN than in mFFX (44% vs. 67%, p = 0.0006). Incidences of grade 3 or 4 neutropenia (47% vs. 45%), diarrhea (1.4% vs. 2.0%), and peripheral neuropathy (4.2% vs. 4.6%) were similar in each group. On the other hand, incidences of febrile neutropenia (8.5% vs. 2.0%, p = 0.06) and G-CSF use rate (21% vs. 0%, p < 0.0001), anorexia (13% vs. 3%, p = 0.03) were significantly higher in mFFX than those of GN. Conclusions: Patients treated with GN showed more favorable efficacy and survival. Incidences of most adverse events did not differ between mFFX and GN,whereas febrile neutropenia occurred more frequently in mFFX.
Surgical intervention in early-stage pancreatic adenocarcinoma.
Authors: Jabbari Javaneh , Ahmed Aabra , Walters Ryan W , Silberstein Peter T.
Published: March 2017

443

Background: Bilimoria et al (2007) reviewed 9,559 patients from the 1995-2004 National Cancer Database (NCDB) showing that 38.2% of patients with early-stage pancreatic cancer without any identifiable contraindications failed to undergo pancreactomy. We used the 2004-2013 NCDB to look at the role of surgery in initial care plans of patients with stage I pancreatic adenocarcinoma. We also assessed differences in practice in this regard at different types of cancer centers. Methods: We analyzed 12,927 patients diagnosed with stage I pancreatic adenocarcinoma between 2004-2013 from the NCDB. Survival differences between patients who received surgery at the primary site versus patients not offered surgery were estimated by the Kaplan-Meier method. Differences in surgery were compared using chi-squared analysis. Results: Of the stage I patients, 27.3% had surgery, 52.8% were not offered surgery, 9.3% were not offered surgery due to risk factors, 4.4% refused surgery. Patients who received surgery had an increased median survival time compared to patients who were not offered surgery (30.2 months versus 7.1 months, p < 0.05). Patients at academic/research programs were most likely to have surgery compared to those at community cancer programs who were least likely to have surgery (39.8% versus 22.9%, p < 0.05). Conclusions: Patients who had surgery of the primary site had a significantly longer median survival time than those that were not offered surgery. Patients were most likely to be offered surgery if they were at an academic/research facility. Future studies should examine other factors that could possibly influence whether a patient is offered surgery or not for early-stage pancreatic adenocarcinoma. [Table: see text]
Cell free circulating tumor DNA (ctDNA) landscape in patients with advanced gastroesophageal adenocarcinoma (GEC).
Authors: Catenacci Daniel V.T. , Nagy Rebecca J , Braiteh Fadi S. , Kim Seung , Kwak Eunice Lee , Maron Steven Brad , Banks Kimberly C. , Lanman Richard B. , Talasaz Amirali , Lee Jeeyun
Published: March 2017

47

Background: Esophageal (EC), gastroesophageal junction (GEJ) and gastric cancer (GC), together GEC, have a poor prognosis with few targeted therapeutic options. As genomic profiling is becoming increasingly useful, we queried whether comprehensive genomic profiling of ctDNA would reveal relevant genomic alterations leading to targeted therapies. Methods: Patients (pts) with advanced GEC undergoing next-generation sequencing (NGS) of ctDNA in a CLIA certified lab were identified. ctDNA was analyzed using Guardant360, a digital NGS assay to identify single nucleotide variants, indels, amplifications and fusions in 54-70 genes. Results: 546 pts with GEC had ctDNA testing and 54 pts (10%) had more than one ctDNA test (range 2-6). Pts were similar across the 3 groups, with the exception of an increased male:female ratio (5:1) in the GEJ and EC cohorts. Mean age was 61.5 yrs (range 24-91). ctDNA alterations were detectable in 455 pts (83.3%). Recurrent alterations and therapeutic options for each cohort are shown in Table 1. Serial monitoring of ctDNA correlated with tumor markers, imaging and clinical response. Multiple antitumor responses to targeted therapy will be presented. Conclusions: ctDNA was detected in 83.3% of pts with advanced GEC with a frequency similar to TCGA. The diverse genomic landscape of GEC, obtained noninvasively, along with matched therapies have potential to improve outcomes for this aggressive disease. [Table: see text]
Premorbid body mass and mortality in patients with hepatocellular cancer: A systematic review and meta-analysis.
Authors: Gupta Arjun , Das Avash , Arora Nivedita , Majumder Kaustav , Singh Preet Paul , Beg Muhammad S. , Singh Siddharth
Published: March 2017

477

Background: Excess body weight is associated with increased risk of developing hepatocellular cancer (HCC), but its effect on HCC mortality remains unclear. We performed a systematic review and meta-analysis to assess the association between premorbid body mass index (BMI) and HCC mortality. Methods: Through a systematic search of major databases and conference proceedings, up to March 2016, we identified observational studies reporting the association between premorbid BMI, and HCC-related mortality. We estimated summary adjusted hazard ratio (aHR) with 95% confidence intervals (CI), comparing obese (BMI > 30 kg/m2) and overweight (BMI 25-29.9 kg/m2) categories with reference category using random effects model; heterogeneity was measured using the inconsistency index (I2). Results: 9 studies were included in which 6,052 HCC deaths occurred in 1,599,453 cancer-free individuals at cohort inception. 5 studies reported data as obese vs. overweight vs. normal BMI, and 4 reported data as obese + overweight combined (BMI > 25 kg/m2). On meta-analysis, pre-morbid obesity was associated with higher HCC-related mortality, as compared to individuals with normal BMI (obese: aHR, 1.96; 95% CI, 1.46-2.46, I2= 37%; overweight: aHR, 1.08; 95% CI, 0.97-1.21, I2= 0%), in dose-dependent manner. This effect was stronger in males [3 studies, aHR, 2.50; 95% CI, 2.02-3.09] vs. females [2 studies, aHR, 1.45; 95% CI, 1.08-1.97]. This effect was seen primarily in Western populations [4 studies, aHR, 2.10; 95% CI, 1.77-2.48], but not in Asian population [1 study, aHR, 1.10; 95% CI, 0.63-1.92]. Conclusions: In this meta-analysis, there was a dose-dependent increase in HCC-related mortality with pre-morbid obesity, particularly in men, and in Western populations. Strategies targeting obesity-induced metabolic abnormalities may provide novel pathways for HCC therapy.
Nivolumab in patients with DNA mismatch repair deficient/microsatellite instability high metastatic colorectal cancer: Update from CheckMate 142.
Authors: Overman Michael J. , Lonardi Sara , Leone Francesco , McDermott Raymond S. , Morse Michael A. , Wong Ka Yeung Mark , Neyns Bart , Leach Joseph L. , Garcia Alfonso Pilar , Lee James J. , Hill Andrew , Lenz Heinz-Josef , Desai Jayesh , Moss Rebecca A. , Cao Z. Alexander , Ledeine Jean-Marie , Tang Hao , Kopetz Scott , Andre Thierry
Published: March 2017

519

Background: Approximately 4% of metastatic colorectal cancers (mCRCs) are associated with high microsatellite instability (MSI-H), indicating a deficient DNA mismatch repair (dMMR) system. dMMR/MSI-H CRC exhibits an increased tumor neoantigen load and immune cell infiltration and is hypothesized to be targetable by immune checkpoint inhibitors. CheckMate 142 (NCT02060188) evaluates the efficacy and safety of nivolumab (nivo) in patients (pts) with dMMR/MSI-H mCRC. Methods: Pts with dMMR/MSI-H mCRC who progressed on/were intolerant to ≥1 prior line of therapy received nivo 3 mg/kg (nivo 3) every 2 weeks (Q2W). The primary endpoint was objective response rate (ORR) per investigator (INV). The secondary endpoint was ORR per independent radiology review committee (IRRC); exploratory endpoints included safety, PFS, OS, and efficacy in biomarker-defined populations. Results: Among pts treated with nivo 3 Q2W (N = 74), 84% had received ≥2 prior lines of therapy. ORRs were 31% (INV) and 27% (IRRC); disease control rates were 69% (INV) and 62% (IRRC). The median time to response was ≈2.7 mo (INV/IRRC). PFS rates at 12 mo were 48.4% (INV) and 45.6% (IRRC). The duration of response and OS medians were not yet reached; OS rates were 83.4% (6 mo) and 73.8% (12 mo). Responses were observed in pts regardless of tumor programmed death-1 ligand 1 (PD-L1) expression level or BRAF or KRAS mutation status and were observed in pts with or without a history of Lynch syndrome (Table). Grade 3–4 treatment-related adverse events (TRAEs) occurred in 20% of pts. TRAEs leading to discontinuation included acute kidney injury, increased ALT, colitis, and stomatitis (1 each). No treatment-related deaths occurred in this arm. Conclusions: Nivo showed durable responses and disease control in heavily pretreated pts with dMMR/MSI-H mCRC. Treatment was well tolerated, with no new safety signals. Clinical trial information: NCT02060188. [Table: see text]
Sidedness matters: Surrogate biomarkers prognosticate colorectal cancer upon anatomic location.
Authors: Ben-Aharon Irit , Goshen-Lago Tal , Geva Ravit , Beny Alexander , Dror Ygael , Steiner Mariana , Hubert Ayala , Idelevich Efraim , Purim Ofer , Mishaeli Moshe , Shulman Katerina , Man Sofia , Soussan-Gutman Lior , Liebermann Nicky , Brenner Baruch
Published: March 2017

523

Background: Recent evidence indicate that the anatomic location of primary tumors across the colon correlate with survival in the metastatic setting, whereas left-sided tumors may exhibit superior survival compared with right-sided. The Oncotype DX, a 12-gene colon cancer assay, is a clinically validated predictor of recurrence risk in stage II colorectal cancer (CRC) patients. Previous studies had indicated that CDX2-negative colorectal tumors are often associated with several adverse prognostic variables. Recently, it has been shown that without adjuvant chemotherapy, CDX2-negative stage II CRC tumors were associated with a lower rate of disease-free survival than CDX2-positive stage II CRC tumors. We aimed to evaluate whether these validated two prognostic biomarkers may correlate with primary tumor location, and whether tumor location may reflect differential prognosis in stage II CRC. Methods: We retrospectively analyzed a cohort of patients with T3 mismatch repair proficient (MMR-P) stage II CRC for whom 12-gene assay was performed (between 1/2011-2/2016). Pathological report was reviewed for exact primary tumor location and CDX2 immunostaining. Recurrence score (RS) and CDX2 expression were correlated with primary tumor location. Results: The analysis included 1087 patients with MMR-P stage II CRC (median age 69 years (range 29-93)). Tumor distribution across the colon was as follows: 46% (n = 500) were right-sided (cecum, ascending colon, transverse colon) and 54% (n = 587) were left-sided (splenic flexure, descending colon, sigmoid colon and rectum). Recurrence score was higher in right-sided tumors compared with left-sided tumors (p = 0.01). The RS gradually decreased across the colon (cecum - highest score, sigmoid-lowest score, p = 0.04). Right-sided tumors exhibited more CDX2-negative tumors compared with left-sided tumors (p = 0.07). Conclusions: Our study indicate that right-sided colorectal tumors may display worse prognosis compared with left-sided tumors in MMR-P stage II CRC. Primary tumor location may serve as a prognostic factor that should be accounted for recurrence risk assessment and consideration of adjuvant treatment.
Impact of CEA alone or as part of a high intensity surveillance strategy in detecting curative colorectal cancer recurrence: A systematic review and meta-analysis.
Authors: Mercado Marck , Hart Rachel , Scheer Adena , Tricco Andrea , Hamid Jemila , Brezden-Masley Christine
Published: March 2017

566

Background: Consensus is lacking regarding an effective surveillance strategy for the detection of colorectal cancer (CRC) recurrence at a curative stage. This study aims to evaluate the effect of carcinoembryonic antigen (CEA) measurement alone vs. CEA as part of an intensive surveillance strategy for the detection of curative CRC recurrence. Methods: A systematic review was performed using MEDLINE and EMBASE from January 2000 to April 2016 to identify randomized controlled trials (RCTs), cohort studies, quasi-experimental design studies, and case control studies including stage II/III CRC patients with curative resection and surveillance with repeated CEA measurements. Data screening, abstraction, and risk of bias assessment was independently performed by two reviewers. Risks of recurrence amenable to surgical resection, local and distant recurrence, disease-specific mortality and overall mortality were pooled using random effects meta-analysis. Results: Two RCTs and 9 cohort studies were included. A meta-analysis of 861 patients in RCTs demonstrated a non-significant reduction in the detection of curative recurrence using CEA measurement alone vs. intensive surveillance strategies with CEA (RR 0.76; 95% CI 0.41-1.41). There were no significant differences observed in the risk of locoregional or distant recurrence. Patients with CEA alone had a non-significant higher risk of disease specific and overall mortality ([RR 1.19; 95% CI 0.89-1.60], [RR 1.21; 95% CI 0.84-1.76], respectively). The heterogeneity of the cohort studies inhibited a quantitative meta-analysis. Among 2783 patients in 9 cohort studies using intensive surveillance strategies with CEA measurement, the rate of curative recurrence ranged from 21.3% to 56.8%. Conclusions: Limited data exists to guide the optimal surveillance strategy post-curative CRC resection. This study highlights the potential benefit of intensive surveillance strategies with CEA measurement as compared to CEA measurement alone in detecting curative CRC recurrence. However, further research to determine optimal CRC surveillance strategies is warranted.
Micrometastasis volume in stage II colorectal cancer: A prospective study by Clinical Study Group of Osaka University (CSGO).
Authors: Murata Kohei , Yamamoto Hirofumi , Fukunaga Mutsumi , Ohnishi Tadashi , Noura Shingo , Miyake Yasuhiro , Ikenaga Masakazu , Kato Takeshi , Takahashi Hidekazu , Haraguchi Naotsugu , Nishimura Junichi , Hata Taishi , Mizushima Tsunekazu , Ikeda Masataka , Ohue Masayuki , Hasegawa Junichi , Sekimoto Mitsugu , Nezu Riichiro , Doki Yuichiro , Mori Masaki ,   Clinical Study Group of Osaka University (CSGO), Colorectal Group
Published: March 2017

597

Background: We reported in a retrospective study that the presence of micrometastasis in lymph nodes (LNs), when assessed by CEA-specific RT-PCR, is a significant prognostic factor in stage II colorectal cancer (CRC). The aim of this study was to clarify the clinical value of micrometastasis in a prospective multicenter trial. Methods: From November 2001 to December 2005, a total of 419 CRC cases were preoperatively registered at a central data center. Of them, 315 node-negative stage II CRC were enrolled. After RNA quality check, 304 CRC cases were analyzed for CEA mRNA in LNs by both conventional RT-PCR (a band method) and quantitative RT-PCR. Long-term prognosis of the patients was determined by each method. Results: A positive band for CEA mRNA was detected in 73 (24.0%) of 304 patients. Post-operative adjuvant chemotherapy was applied in 31 CEA band-positive cases with an oral 5-FU derivative HCFU (1-hexylcarbamoyl-5-fluorouracil) for one year, while chemotherapy was not administered to CEA band-negative group. Multivariate Cox regression analyses revealed that a high micrometastasis volume (High-MMV, n = 95) was an independent poor prognostic factor for 5-year DFS ( P= 0.001) and 5-year OS ( P= 0.016). Conclusions: This prospective clinical trial demonstrates that micrometastasis volume is a useful marker in identifying patients who are at high or low risk for recurrence of stage II CRC.
Genetic variants of genes in CCL5/CCR5 pathway to predict regorafenib-induced hand-foot skin reaction in patients with refractory metastatic colorectal cancer: A report of ethnic difference.
Authors: Suenaga Mitsukuni , Schirripa Marta , Cao Shu , Zhang Wu , Yang Dongyun , Salvatore Lisa , Lonardi Sara , Moretto Roberto , Borelli Beatrice , Ning Yan , Okazaki Satoshi , Berger Martin D. , Miyamoto Yuji , Gopez Roel , Hanna Diana L. , Barzi Afsaneh , Wakatsuki Takeru , Yamaguchi Toshiharu , Loupakis Fotios , Lenz Heinz-Josef
Published: March 2017

615

Background: CCL5/CCR5 pathway is involved in VEGF-A production and a recent study reported that serum CCL5 levels predict onset of hand-foot skin reaction (HFSR) due to regorafenib. We therefore tested whether genetic polymorphisms in the CCL5/CCR5 pathway predict onset of HFSR in patients with refractory metastatic colorectal cancer (mCRC) receiving regorafenib. Methods: Two independent cohorts treated with regorafenib were included in this study: a training cohort from Japan with 79 patients (median age 62 years, male 47%); and a testing cohort from Italy with 150 patients (median age 62 years, male 54%). Single nucleotide polymorphisms (SNPs) of genes in CCL5/CCR5 pathway ( CCL5, CCR5, PRCKD, CCL3, CCL4, KLF13, HIF1A) were selected for analyses using PCR-based direct sequencing. Adverse events were graded according to the CTCAE version 4.0. Comparisons of variants’ and adverse events’ distributions across two cohorts, and association between SNPs and adverse events were analyzed using contingency tables and Fisher’s exact test. Results: Grade 3 ≤ HFSR was more frequent in Japanese patients compared with Italian patients (32.9% vs. 16.0%, P= 0.004). The frequency of homozygous variant in CCL5 SNPs varied between Japanese and Italian patients (G/G variant in rs2280789, 21.5% vs. 1.3%, P< 0.001; T/T variant in rs3817655, 22.8% vs. 2.7%, P< 0.001). In the training cohort, patients with the G/G variant in rs2280789 had a higher incidence of grade 3 ≤ HFSR compared to those with any A allele (53% vs. 27%, P= 0.078); and the T/T variant in rs3817655 was significantly associated with onset of grade 3 ≤ HFSR compare to any A allele (56% vs. 26%, P= 0.026). These findings were not confirmed in the testing cohort, and no significant differences for toxicities were observed in the other candidate SNPs. Conclusions: Germline CCL5 polymorphisms in the CCL5/CCR5 pathway may serve as predictor of onset of severe HFSR in refractory mCRC patients receiving regorafenib. The different percentage of homozygote of CCL5 SNPs confers the ethnic difference in developing severe HFSR between Italian and Japanese patients.
Poorly differentiated clusters as a prognostic marker at the invasive front of colon cancer.
Authors: Konishi Tsuyoshi , Shimada Yoshifumi , Lee Lik Hang , Cavalcanti Marcela Santos , Morris Martin , Hsu Meier , Gonen Mithat , Smith Jesse Joshua , Nash Garrett Michael , Temple Larissa K. F. , Guillem Jose G. , Paty Philip , Garcia-Aguilar Julio , Vakiani Efsevia , Shia Jinru , Weiser Martin R.
Published: March 2017

621

Background: Histology at the invasive front of colon cancer can predict malignant potential. However, the optimal histological marker is yet to be established. This study compares the various invasive front histologic markers. Methods: A single-institution prospective database was queried for consecutive patients who underwent curative resection for Stage I-III colon adenocarcinoma from 2007-14. Histologic features were reviewed by a pathologist, including poorly differentiated clusters (PDC), tumor budding (BD), perineural invasion (PN), desmoplastic reaction (DR) and Crohn’s like reaction (CLR) at the invasive front, and WHO grade of the whole tumor. PDC was defined as cancer clusters of ≥ 5 cancer cells that lack a gland-like structure, and was graded into G1 ( < 5), G2 (5-9) and G3 ( ≥ 10) by the highest number of the clusters /HPF. Clinical outcome included recurrence free survival (RFS) and peak hazard function of recurrence and death identified using the kernel-smoothing method. Predictive accuracy was measured with concordance probability estimate (CPE) for proportional hazards regression. Inter-observer agreement was assessed by weighted kappa values on diagnoses rendered by 3 pathologists on 50 randomly selected cases. Results: The study cohort consisted of 851 patients with a median follow up of 36 months. PDC, BD, PN, DR and CLR at the invasive front were significantly associated with RFS. When analyzed by stage, PDC, BD and PN were associated with RFS both in Stage II and Stage III, while the others were prognostic only in Stage III. CPE was the highest in PDC (0.642), indicating the best predictive accuracy, while it was the lowest in WHO grade (0.526). Weighted kappa was also the highest for PDC, indicating the best inter-observer agreement (PDC: 0.824, WHO grade: 0.568). The smoothed graph of the hazard function showed that the risk of recurrence was not only the highest but peaked earlier for PDC G3 (between0 and 12 months) than PDC G2 (between12 and 24 months) and G1 (no evident peak). Conclusions: Of the commonly evaluated histologic markers at the invasive front, PDC grade is the most predictive and reproducible. Further confirmatory investigations are warranted to determine if PDC can replace WHO grade.
Screening of 129 FDA approved anti-cancer drugs in colorectal cancer cell lines resistant to oxaliplatin or irinotecan (SN38).
Authors: Stenvang Jan , Andreassen Christine Hjorth , Brünner Nils
Published: March 2017

642

Background: In metastatic colorectal cancer (mCRC) only 3 cytotoxic drugs (oxaliplatin, irinotecan and fluorouracil (5-FU)) are approved and the first and second line response rates are about 50% and 10-15%, respectively. Thus, new treatment options are needed. Novel anti-cancer drug candidates are primarily tested in an environment of drug resistance and the majority of novel drug candidates fail during clinical development. Therefore, “repurposing” of drugs has emerged as a promising strategy to apply established drugs in novel indications. The aim of this project was to screen established anti-cancer drugs to identify candidates for testing in mCRC patients relapsing on standard therapy. Methods: We applied 3 parental (drug sensitive) CRC cell lines (HCT116, HT29 and LoVo) and for each cell line also an oxaliplatin and irinotecan (SN38) resistant cell line. We obtained 129 FDA approved anti-cancer drugs from the Developmental Therapeutics Program (DTP) at the National Cancer Institute (NCI) ( https://dtp.cancer.gov/ ). The parental HT29 cell line and the drug resistant sublines HT29-SN38 and HT29-OXPT were exposed to 3 concentrations of each of the anti-cancer drugs. The effect on cell viability was analyzed by MTT assays. Nine of the drugs were analyzed for effect in the LoVo and HCT116 and the SN38- and oxaliplatin-resistant derived cell lines. Results: None of the drugs caused evident differential response between the resistant and sensitive cells or between the SN38 and oxaliplatin resistant cells. The screening confirmed the resistance as the cells displayed resistance to drugs in the same class as the one they were made resistant to. Of the drugs, 45 decreased cell viability in the HT29 parental and oxaliplatin- or SN-38 resistant cell lines. Nine drugs were tested in all nine CRC cell lines and eight decrease cell viability in the nine cell lines. These included drugs in different classes such as epigenetic drugs, antibiotics, mitotic inhibitors and targeted therapies. Conclusions: This study revealed several possible new “repurposing” drugs for CRC therapy, by showing that 45 FDA-approved anti-cancer drugs decrease cell viability in CRC cell lines with acquired drug resistance.
Randomized phase II study of panitumumab (Pmab) + irinotecan (CPT-11) versus cetuximab (Cmab) + CPT-11 in patients (pts) with KRAS wild-type (WT) metastatic colorectal cancer (mCRC) after fluoropyrimidine (FU), CPT-11, and oxaliplatin (L-OHP) failure: WJOG6510G.
Authors: Sugimoto Naotoshi , Sakai Daisuke , Tamura Takao , Hara Hiroki , Nishina Tomohiro , Esaki Taito , Okuda Hiroyuki , Denda Tadamichi , Tsuda Masahiro , Satoh Taroh , Makiyama Akitaka , Yamazaki Kentaro , Kuramochi Hidekazu , Hosokawa Ayumu , Tsuda Takashi , Taniguchi Hiroya , Kishimoto Junji , Boku Narikazu , Hyodo Ichinosuke , Muro Kei ,   West Japan Oncology Group (WJOG)
Published: March 2017

661

Background: Continuation of CPT-11 in combination with Cmab after CPT-11 failure has a survival benefit over Cmab alone. However, it is not clear whether CPT-11 with Pmab shows similar benefits. Methods: Pts with KRAS WT mCRC previously treated with FU-, L-OHP-, and CPT-11- based chemotherapies were randomized 1:1 to either Cmab + CPT-11(Cmab arm), or Pmab + CPT-11(Pmab arm). Primary objective was progression free survival (PFS), with an expected hazard ratio (HR) of 1.0 with non-inferiority margin of 1.3 (80% CI) using cox proportional hazards model. Median PFS with both arms were assumed to be 6.0 months. Secondary objectives were overall survival (OS), response rate (RR), disease control rate (DCR), and safety. Results: From December 2011 to September 2014, 121 pts were enrolled from 31 sites in Japan. Because 1 patient declined before treatment, totally, 120 (Cmab arm: 59, Pmab arm 61) pts were eligible for efficacy analysis. Baseline characteristics were well balanced between the two arms. 116 pts (96.7 %) were previously treated with bevacizumab. Efficacy results are shown in the table. The common grade 3 or 4 adverse events in Cmab/Pmab arm were leukopenia 19.0/3.3%, neutropenia 27.6/8.3%, hypomagnesaemia 6.9/16.7%, and rash 5.2/13.3 %, respectively. Conclusions: Non-inferiority of Pmab to Cmab in combination with CPT-11 was suggested for patients with KRAS WT mCRC previously treated with FU-, L-OHP-, and CPT-11- based chemotherapies, associated with favorable PFS and OS. Clinical trial information: UMIN000006643. [Table: see text]
Total neoadjuvant therapy for locally advanced rectal cancer.
Authors: Cercek Andrea , Roxburgh Campbell SD , Strombom Paul , Smith Jesse Joshua , Temple Larissa K. F. , Nash Garrett Michael , Guillem Jose G. , Paty Philip , Garcia-Aguilar Julio , Yaeger Rona D. , Stadler Zsofia Kinga , Segal Neil Howard , Reidy Diane Lauren , Shia Jinru , Vakiani Efsevia , Wu Abraham Jing-Ching , Crane Christopher H , Gollub Marc Jeffrey , Saltz Leonard , Weiser Martin R.
Published: March 2017

662

Background: Current therapy for locally advanced rectal cancer (LARC) consists of 6 months of perioperative therapy, either with pre-operative chemo-radiotherapy (CRT) and post operative adjuvant chemotherapy (PAC) or total neoadjuvant therapy (TNT) with induction chemotherapy (ICT) followed by CRT then surgery. The aim of our study was to report on the safety, efficacy and complete response rates comparing TNT to PAC in a larger series of LARC patients (pts) at Memorial Sloan Kettering Cancer Center (MSKCC). Methods: Pts treated at MSKCC (2009-15) were analyzed based on the intended treatment schedule (TNT or PAC). 730 LARC pts were treated with CRT, of these 320 received neoadjuvant CRT and 308 received TNT. Results: In the TNT group 205 pts (73%) underwent surgery within 26 weeks of completion of treatment, of which 38 (19%) had a pCR. Of the 78 pts who did not undergo surgery within 26 weeks, 68 (87%) had a complete clinical response (cCR). In the PAC group 293 pts (92%) underwent surgery within 26 weeks and 45 (15%) had a pCR. Of the 27 pts who did not undergo surgery within 26 weeks 22 (81%) had a cCR. The median follow up was 25 mo in the TNT group and 29 mo in the PAC group. There was no statistically significant difference in the distant metastasis free survival between the treatment regimens, despite a higher number of cT4 and cN + tumors in the TNT group. Fewer distant recurrences were seen in pts who had evidence of T downstaging (P < 0.001), N downstaging (P < 0.005), the presence of a cCR (P = 0.005) or a pCR (P < 0.005). Of the pts who received all treatment at MSKCC, comparison of dose of 5-FU and oxaliplatin between the preoperative (N = 249) and postoperative regimens (N = 101) was notable for a higher average dose received of both 5FU and oxaliplatin (p < 0.005 and p < 0.001) in the ICT group. Conclusions: These data add weight to the evidence already included in the NCCN guidelines that pre-operative chemotherapy as part of TNT is a viable treatment strategy with superior compliance and delivery of systemic therapy. Given the high complete response rate, TNT may be used as part of an organ preservation treatment strategy.
Efficacy and safety of atezolizumab (atezo) and bevacizumab (bev) in a phase Ib study of microsatellite instability (MSI)-high metastatic colorectal cancer (mCRC).
Authors: Hochster Howard S. , Bendell Johanna C. , Cleary James M. , Foster Paul , Zhang Wei , He Xian , Hernandez Genevive , Iizuka Koho , Eckhardt S. Gail
Published: March 2017

673

Background: Blockade of the PD-L1/PD-1 axis is a proven immunologic approach for treatment of many cancers; however, not all pts respond to monotherapy. Bev, an anti–VEGF-A antibody, has demonstrated clinical efficacy in mCRC and enhanced T-cell infiltration in tumors in preclinical studies. Thus, we postulated that combining atezo (anti-PD-L1) with bev would augment anti-tumor immune responses, resulting in improved and more durable clinical benefit. We report results from the first study of an anti-PD-L1 agent + VEGF-A blockade in MSI-high mCRC. Methods: A Ph Ib study (NCT01633970) investigated atezo + various chemotherapeutic/biologic regimens (eg, bev) in pts with advanced solid tumors, including mCRC. Pts received atezo 1200 mg q3w plus bev 15 mg/kg q3w (data cutoff, May 20, 2016). The primary objective was to evaluate the safety of atezo + bev. Secondary objectives included anti-tumor activity per RECIST v1.1. MSI status was tested locally. Results: Ten MSI-high mCRC pts were enrolled. Three pts had received 1 prior chemotherapy and 7 pts had received ≥ 2. Median age was 52.5 y. The minimum (range) of safety follow-up was 2.6 (2.6-20.3) mo. Median (range) treatment duration with atezo + bev was 10.1 (2-20) and 9.0 (2-19) mo, respectively. Efficacy results are shown below; the confirmed ORR per RECIST v1.1 was 30% (95% CI, 6.7%-65.3%). Median OS had not been reached with a median follow-up of 11.1 mo. Treatment-related all-grade AEs occurred in 80% of pts; 40% of pts had a related G3/4 AE. The most common related AE was proteinuria (40%; n = 3 G2 and n = 1 G3). No G5 events occurred. One AE led to discontinuation of atezo and 3 AEs led to discontinuation of bev. Biomarker data will be presented. Conclusions: Initial clinical activity was observed in heavily pretreated pts with MSI-high mCRC receiving atezo + bev; the disease control rate was 90%. This combination was well tolerated without unexpected toxicities. Further follow-up is ongoing. Clinical trial information: NCT01633970. [Table: see text]
Comparison of 5-FU versus capecitabine in combination with mitomycin or cisplatin in the treatment of anal cancer.
Authors: Yu Irene S. , Cheung Winson Y.
Published: March 2017

680

Background: Capecitabine is used as an alternative fluoropyrimidine to infusional 5-FU in the non-operative management of anal cancer due to its ease of administration. However, its patterns of use and long-term outcomes in the real world are poorly described. Our objectives were to determine the frequency of capecitabine use, compare the difference in outcomes, and examine the difference in treatment-related adverse events between oral and intravenous fluoropyrimidines. Methods: All anal cancer patients who received either capecitabine or infusional 5-FU as part of their curative intent chemoradiotherapy from 2010 to 2013 at any 1 of 6 comprehensive cancer centers in British Columbia were included. Chi-square and Wilcoxon-Mann tests were used to assess for associations between treatment groups and clinical characteristics and outcomes. Results: A total of 237 patients were identified; median age was 59 (IQR 53-67) years, 71 (30%) were men, 202 (85%) had ECOG 0/1, and 12 (5%) were HIV positive. Median total radiation dose was 54 cGy (IQR 50.4-54.0) and 21 (9%) underwent a colostomy prior to chemoradiation. Baseline characteristics were balanced between the two groups with respect to age, gender, ECOG, and HIV status (all p > 0.05). Overall, 155 patients (65%) received capecitabine. Comparing patients who received capecitabine vs 5-FU, overall (69% vs 74%, p = 0.388) and disease-free survival rates (68% vs 71%, p = 0.637) at 5 years from diagnosis were similar between treatment groups. There were no differences with respect to rates of subsequent colostomy (16% vs 23%, p = 0.185) and abdominoperineal resection (11% vs 12%, p = 0.777). However, patients who received capecitabine were less likely to report adverse effects (51% vs 26%, p < 0.001) than those who underwent 5-FU. The capecitabine group had a lower incidence of stomatitis (6% vs 40%, p < 0.001) whereas the 5-FU cohort reported less frequent hand-foot syndrome (1% vs 8%, p = 0.036). Conclusions: This population-based study demonstrates a preference for capecitabine use in place of 5-FU in the curative management of anal cancer. Survival outcomes are similar between the two treatment groups, but capecitabine may be better tolerated.
Safety and efficacy of regorafenib post-marketing surveillance (PMS) in Japanese patients with metastatic colorectal cancer (mCRC).
Authors: Komatsu Yoshito , Muro Kei , Yamaguchi Kensei , Satoh Taroh , Uetake Hiroyuki , Yoshino Takayuki , Nishida Toshirou , Takikawa Hajime , Kato Takeyuki , Chosa Masayuki , Sunaya Toshiyuki , Yamamoto Yuka , Hamada Yoko , Watanabe Toshiaki , Sugihara Kenichi
Published: March 2017

721

Background: The oral multikinase inhibitor regorafenib (REG) was approved for unresectable mCRC in Japan in 2013 based on the results of the global CORRECT phase 3 trial, which included 100 Japanese patients (pts). A PMS (NCT01843400) was conducted to assess the safety and efficacy of REG for the treatment of Japanese mCRC in clinical practice. Methods: Pre-registration was applied in the PMS. Adverse events (AEs), laboratory tests, drug exposure and anti-tumor effects were prospectively monitored for 6 months after initiating REG. One-year survival data was also collected. Target enrollment was 1,250 pts. Results: 1,303 pts were enrolled from March 2013 to May 2015. At the interim analysis as of August 2015, 787 pts were evaluable for safety and efficacy: male 57%; age ≥ 65 yrs 52%; ECOG Performance Status (PS) 0/1/2 40%/51%/10%; KRAS status wild-type/mutant 50%/47%; treatment line of REG 3rd /4th/ ≥ 5thline 40%/36%/24%; starting dose of REG 160 mg/120mg 66%/22%. Drug related adverse events (AE) were reported in 702 pts (89%). Most common AEs were hand foot skin reaction [(HFSR) 56%], liver dysfunction (32%, including 17% hepatic laboratory abnormalities), hypertension (27%), platelet count decreased (17%) and fatigue (14%). Rates of any grade of the major AEs typically peaked the first 2 months after starting REG and were relatively stable afterwards. Median time to treatment failure (TTF) was 2.1 months [range 1.9– 2.2]; median overall survival (OS) was 7.0 months [range 6.3– 7.8]. In exploratory analyses, rates of any grade and ≥ grade 3 HFSR and liver dysfunction were higher at the starting dose of 160mg (the dose of the first day of the first cycle) than in that of 120mg or less. Pts who had HFSR had a significantly longer OS than pts who did not (hazard ratio 0.573; 95% confidential interval0.470–0.698; p < 0.0001). TTF of pts with PS 0 tended to be longer than that of pts with PS ≥ 1. Conclusions: The safety and efficacy profiles of REG in Japanese pts in clinical practice are consistent with those of Japanese pts in the CORRECT trial. The results from > 1200 pts enrolled in the PMS will be presented at the meeting. Clinical trial information: NCT01843400.
Onset of neutropenia as an indicator of treatment response in the phase 3 RECOURSE trial of trifluridine/tipiracil (TAS-102) versus placebo in patients with metastatic colorectal cancer.
Authors: Ohtsu Atsushi , Yoshino Takayuki , Falcone Alfredo , Garcia-Carbonero Rocio , Argiles Guillem , Sobrero Alberto F. , Peeters Marc , Makris Lukas , Benedetti Fabio M. , Zaniboni Alberto , Shimada Yasuhiro , Yamazaki Kentaro , Komatsu Yoshito , Hochster Howard S. , Lenz Heinz-Josef , Tran Ben , Yoshida Kenichiro , Van Cutsem Eric , Mayer Robert J. ,   On Behalf of the RECOURSE Study Group
Published: March 2017

775

Background: TAS-102 is comprised of an antineoplastic thymidine-based nucleoside analog, trifluridine (FTD), and a thymidine phosphorylase inhibitor, tipiracil. Primary results of the RECOURSE trial demonstrated a significant improvement in overall survival (OS) and progression-free survival (PFS) with TAS-102 vs placebo (pbo) in patients (pts) with metastatic colorectal cancer refractory/intolerant to standard therapies. Neutropenia is a common TAS-102–associated adverse event and it has been hypothesized to be associated with a relatively high FTD concentration in pts. Methods: RECOURSE data were analyzed post hoc for correlations between onset of neutropenia (Grade 3/4) and survival benefit. Results: Of 533 pts given TAS-102, 75 (14%) developed Grade 3/4 neutropenia in treatment cycle 1, 86 (16%) for the first time in cycle 2, and 39 (7%) for the first time in cycle ≥3. Onset of neutropenia at any cycle was associated with longer median OS and PFS compared with no neutropenia. A consistent survival benefit was observed regardless of the cycle of initial onset of neutropenia, as demonstrated by the hazard ratio (against cycle-matched pbo control groups) and corresponding median OS differences (Table). Conclusions: An association between occurrence of earliest onset of Grade 3/4 neutropenia and survival benefit was observed. The data indicate that such survival benefit occurred regardless of whether the initial onset of neutropenia occurred after cycle 1, cycle 2, or later. Further analyses are required to fully determine whether FTD pharmacokinetics correlate with TAS-102 efficacy and onset of neutropenia, and whether cycle initiation delays affect response. Clinical trial information: NCT01607957. [Table: see text]
Time to grade ≥3 adverse events in pts receiving trifluridine/tipiracil (TAS-102).
Authors: Van Cutsem Eric , Ohtsu Atsushi , Lopez Busto Natividad , Kanehisa Akira , Fougeray Ronan , Winkler Robert , Mayer Robert J.
Published: March 2017

788

Background: The phase 3 RECOURSE showed that treatment with trifluridine/tipiracil in patients (pts) with refractory metastatic colorectal cancer was associated with significantly improved survival versus placebo (7.1 versus 5.3 months, respectively; HR for death 0.68, 95% CI 0.58–0.81, p < 0.001), with few serious adverse events. Trifluridine/tipiracil is administered in 4-week cycles comprising 2 weeks with 5 days at 35 mg/m2 bid followed by 2 rest days, and then a 2-week rest period. Exploration of timing for AEs, particularly within the first cycle of treatment, is important for pt monitoring in the outpatient setting. Methods: We performed a post hoc analysis of the RECOURSE safety population (533 trifluridine/tipiracil; 265 placebo) to explore timing of hematological and nonhematological AEs. Results: Grade ≥ 3 adverse events (AEs) were more frequent with trifluridine/tipiracil than placebo for both hematological AEs (38% vs 0% neutropenia; 4% vs 0% febrile neutropenia; 18% vs 3% anemia; and 5% vs < 1% thrombocytopenia) and nonhematological AEs (2% vs 1% nausea; 2% vs < 1% vomiting; and 3% vs < 1% diarrhea). The median time to nadir in cycle 1 for hematological events was 28 days (17–31) for grade ≥ 3 neutropenia, 22 days (9–39) for grade ≥ 3 anemia, and 18 days (9–33) for grade ≥ 3 thrombocytopenia; similar values were obtained in subsequent cycles. The median times to nadir and values at nadir over the whole treatment duration (all cycles) are presented in the table for hematological and nonhematological AEs. Conclusions: Hematological and nonhematological AEs with trifluridine/tipiracil appear to be most intense towards the end of treatment cycles, which is reassuring for its use in the outpatient setting. Clinical trial information: NCT01607957. [Table: see text]