bluuebunny/crossref_metadata_2025 huggingface dataset:
M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in Asian patients with advanced solid tumors.
Authors: Fujiwara Yutaka , Koyama Takafumi , Helwig Christoph , Watanabe Morihiro , Doi Toshihiko
Published: January 2019

762

Background: Inhibiting the transforming growth factor β (TGF-β) pathway, which plays a key role in tumor immunosuppression, may enhance the response to programmed death 1/programmed death ligand 1 (PD-1/PD-L1) monoclonal antibodies (mAbs). M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a mAb against PD-L1 fused with the extracellular domain of TGF-β receptor II, which serves as a TGF-β “trap.” We report results in Asian patients (pts) with advanced solid tumors. Methods: NCT02699515 is a phase 1, open-label, 3 + 3 dose-escalation study. Pts receive M7824 at 3, 10 or 20 mg/kg q2w until confirmed progressive disease, unacceptable toxicity or trial withdrawal. The primary objective is to determine the safety and maximum tolerated dose (MTD); secondary objectives include pharmacokinetics (PK), immunogenicity and best overall response per RECIST v1.1. Results: As of 28 February 2017, 14 heavily pretreated pts (85.7% received ≥3 prior therapies) received M7824 for a median duration of 5.9 weeks (range: 2-40 weeks). Grade (gr) ≥3 treatment-related adverse events occurred in 3 pts (21.4%): 1 pt (3 mg/kg) had gr 4 hyponatremia and gr 3 hypopituitarism; 1 pt (20 mg/kg) had gr 3 intracranial tumor hemorrhage (dose-limiting toxicity; treatment discontinued [TD]); 1 pt (20 mg/kg) had gr 3 increased blood creatine phosphokinase, hyponatremia and hypoacusis (TD). PK data showed a dose-linear increase in exposure. Signs of efficacy were seen across all dose levels: 2 pts (colorectal cancer [CRC] associated with Lynch syndrome [3 mg/kg] and ovarian cancer [20 mg/kg]) achieved a confirmed partial response (PR) and 3 pts (gastric/gastroesophageal junction cancer [3 mg/kg], gastric cancer [3 mg/kg] and adenoid cystic carcinoma of the tongue [10 mg/kg]) achieved stable disease. Durations of response were 1.1+ months (ovarian; PR occurred after TD, with no further anticancer therapy) and 7.0+ months (CRC; treatment ongoing); both PRs were ongoing beyond the data cutoff. Conclusions: M7824 had a manageable safety profile in Asian pts with heavily pretreated advanced solid tumors; the MTD was not reached. Early signs of clinical efficacy are encouraging. Clinical trial information: NCT02699515.
Interplay of grade and stage on survival outcomes in appendiceal adenocarcinoma: Corroboration of the AJCC (8th edition) Cancer Staging Classification.
Authors: Raghav Kanwal Pratap Singh , Fournier Keith F. , Johnson Benny , Taggart Melissa W. , Foo Wai Chin , Matamoros Aurelio , Mehdizadeh Amir , Ahmed Shahab U. , Guerra Jennifer L. , Mansfield Paul F. , Royal Richard Eldon , Eng Cathy , Overman Michael J.
Published: January 2019

773

Background: Histological grade is a key prognostic factor in appendiceal adenocarcinomas (AAs) and has been incorporated in classification of stage IV AAs (IVA – Grade 1: Well; IVB – Grade 2/3: Moderately/Poorly differentiated) in AJCC Cancer Staging (8th edition). The purpose of the study was to corroborate the prognostic impact of this staging classifier. Methods: We performed a retrospective review of 98 AA patients (pts) at UTMDACC (2013 - 2017). Kaplan-Meier method was used to estimate median overall survival (mOS), compared with log-rank tests with emphasis on stage and grade. Results: The cohort included 18, 8, 14, 47 and 11 cases of stage II, III, IVA, IVB and IVC AAs. Histologically, 75 were mucinous (21 non mucinous) and 19, 35 and 42 were grade 1, 2 and 3 respectively. Median age of cohort was 54 years. Median follow-up was 46 months (m). The mOS of stage II, III, IVA, IVB and IVC was 136, 106, 140, 48, 23 m, respectively (P < 0.0001). The mOS of grade 1, 2 and 3 was 160, 75 and 33 m, respectively (P < 0.0001). In univariate analysis (restricted to stage IV pts), grade, AJCC stage, and cytoreductive surgery (CRS) were found to be associated with OS. In multivariate analyses (restricted to stage IV pts), only AJCC stage (HR 3.9, 95% CI: 1.5 - 10.6, P = 0.005) and CRS (HR 3.4, 95% CI: 1.4 – 8.3, P = 0.009) were found to be independently associated with poor OS. In subgroup of mucinous AAs, mOS of grade 3 (32 m) was significantly shorter than grade 2 (54 m) (P = 0.02). In non-mucinous AAs, mOS of grade 3 and grade 2 pts was 38 and 29 m, respectively (P = 0.97). Conclusions: AJCC staging classification has a strong prognostic value in AAs. Beyond the well differentiated AAs which are regarded as a distinct entity in stage IV disease, moderate and poor differentiation also has strong and dissimilar prognostic impact which appears to be dependent on mucinous or non-mucinous subtype in stage IV AAs. Further efforts are needed to incorporate the complex interplay of all grades and mucinous characteristics within the staging system for better prognostication and management.
Association of adjuvant hepatic artery infusion chemotherapy after resection of colorectal liver metastases with improved survival in patients with both right- and left-sided primary tumors.
Authors: Gholami Sepideh , Kemeny Nancy E. , Gonen Mithat , Cercek Andrea , Kingham Peter , Balachandran Vinod P. , Allen Peter J. , DeMatteo Ronald P. , Jarnagin William R. , D'Angelica Michael Ian
Published: January 2019

776

Background: Patients with a right-sided (R) and/or KRAS-mutated (KRAS-MUT) primary tumors have inferior outcomes compared to patients with left sided (L) and/or KRAS-wildtype (KRAS-WT) cancers. Adjuvant hepatic artery pump infusion (HAI) chemotherapy improves overall survival (OS) in patients with colorectal liver metastases (CRLM). We investigated the impact of HAI in relation to the laterality and KRAS status of the primary tumors. Methods: Patients with resected CRLM and available KRAS-status, treated with and without adjuvant HAI were reviewed from a prospective institutional database. Rectal tumors were excluded. Correlations between adjuvant HAI, clinicopathological factors including laterality, KRAS status and OS were analyzed. Cox proportional hazard regression was used to assess survival outcomes comparing R (cecum to transverse colon, excluding appendix) versus L (splenic flexure to sigmoid) colon cancers. Results: 490 patients (R, n = 183; L, n = 307) were evaluated between 1993-2012 (median follow up of 6.5 years). Fifty-six percent (n = 277) received adjuvant HAI. Adjuvant HAI was associated with improved median OS in both R (7.0 vs. 4.4 years, p = 0.006) and L tumors (10.5 vs. 5.4 years, p < 0.01). On multivariate analysis, HAI remained associated with improved OS (HR 4.49, p = 0.001) independent of primary tumor site and other clinical predictors (Table). Conclusions: Adjuvant HAI after resection of CRLM is independently associated with improved OS regardless of laterality of primary tumor. Treatment with adjuvant HAI correlates with improved prognosis in patients with resectable L/KRAS-MUT and R/KRAS-WT tumors. The biological difference for these outcomes requires further investigation. [Table: see text]
Up-front short-course radiotherapy and systemic chemotherapy for locally advanced rectal cancers with distant metastasis: Does it provide meaningful benefit?
Authors: Kapoor Akhil , Ostwal Vikas S. , Pande Nikhil , Ramaswamy Anant , Kothari Rushab , Engineer Reena , Desouja Ashwin , Arya Suprita , Ramadwar Mukta , Saklani Avanish
Published: January 2019

778

Background: The optimal sequencing of treatment for locally advanced rectal cancer with distant metastasis (mLARC) is not well established. Methods: We retrospectively reviewed the records of mLARC patients receiving SCRT (25Gy/5#) and chemotherapy between July 2013 and December 2016. Patients were evaluated for surgery after SCRT and chemotherapy with the decision for further treatment being taken in a multidisciplinary team. Those patients who underwent surgery also received adjuvant chemotherapy as per the standard practice. Results: One hundred five consecutive mLARC patients were included in this study. Median age was 48 years (range 16-78) and 60 patients (57%) were male. Thirty-six patients (34%) had a single site of metastases. Sixty-one patients (58%) had obstruction at baseline and required stoma placement and another 19 patients (18%) had near obstructive lesions; these patients did not require stoma post SCRT and chemotherapy. With first line chemotherapy, objective response rate was 39% while 29% patients had stable disease. Twenty-four patients (23%) underwent definitive surgery. Median PFS and OS for entire cohort was 10.5 months (95% CI: 9.1-11.8) and 15.7 months (95% CI: 10.2-21.2), respectively. Median PFS was 23 months (95% CI: 18.7-27.7) for patients who could undergo surgery while it was 7.7 months (95% CI: 5.9-9.5, HR 5.0) (log rank <0.001) for patients in whom surgery was not possible. Median OS was not reached for patients who underwent surgery while it was 10.9 months (95% CI: 9.6-12.3, HR 9.8) (log rank p<0.001) for patients in whom surgery was not possible. OS at 3 years was 60% for patients who underwent surgery while it was only 7% in whom surgery was not possible. Conclusions: Upfront SCRT followed by systemic chemotherapy with delayed surgery in locally advanced rectal cancer with distant metastasis is an effective, feasible and attractive option. [Table: see text]
Gene expression profile of genes-related canceration, invasion, or conversion for metastasis in patients with poorly differentiated adenocarcinoma treated by gastric ESD.
Authors: Kawanishi Natsuko , Azuma Mizutomo , Takeuchi Atsuko , Yamane Sakiko , Watanabe Akinori , Wada Takuya , Ishido Kenji , Yano Takafumi , Katada Chikatoshi , Tanabe Satoshi , Yoshida Tsutomu , Koizumi Wasaburo
Published: January 2019

78

Background: We encounter some cases of early gastric cancer treated by endoscopic submucosal dissection (ESD) that are out of the indication criteria after pathologic diagnosis. These cases require additional treatments because of a risk of lymph node metastasis in Japanese Classification. So further prediction factors associated with lymph node metastasis is expected. We are focusing on poorly differentiated adenocarcinomas in early gastric cancer that we treated by ESD and used these tissues to characterize their gene expression profiles related to canceration, invasion or conversion for metastasis. Methods: We examined two cases of intramucosal carcinoma and three of submucosal infiltrating carcinoma histologically diagnosed as poorly differentiated adenocarcinoma after ESD. Those samples are separated five adjacent normal tissues (N), five tumor tissues in mucosal layer (M) and three tumor tissues in submucosal layer (SM) in total 13 lesions. Formalin-fixed, paraffin-embedded tissues were dissected by the laser-captured microdissection technique and were analyzed for targeted 158 gene expressions using a quantitative real-time polymerase chain reaction (PCR) using commercial PCR plate (profile PCR array of genes related to cancer stem cells and epithelial mesenchymal transition). Results: Among genes that elevated in the cancer tissues (M or SM) against the normal tissues, five gene expressions (DKK1, TIMP1, THY1, FN1, COL1A2) were tended to much higher in the submucosal layer compared to the mucosal layer (N < M < SM). When we compared tumor gene expressions in depth of M, three gene expressions (FZD7, ZEB 2, CD 44) are higher in the tumors with submucosal invasion compared to within mucosal layer. Conclusions: Poorly differentiated adenocarcinoma of stomach had high expression level in cancer-related genes even if it was intramucosal tumor. Some of these genes tended to increase as its depth of invasion and the presence of invasion of the SM. It suggested that the biopsy specimen could be a prediction factor of invasion from the surface of gastric cancer, but additional specimens and analysis are necessary to prove these findings.
Phase I clinical trials in refractory colorectal cancer (CRC): Do older adult patients benefit?
Authors: Arora Sukeshi Patel , Ketchum Norma S. , Gelfond Jonathan , Michalek Joel , Mahalingam Devalingam
Published: January 2019

784

Background: Current clinical trial data are largely driven by younger participants, yet half the population diagnosed with CRC are 70+. Upon progression, many CRC patients (pts) with refractory cancer are referred to phase 1 clinical trials; however, tolerability and clinical benefit is unclear in the elderly. Given our robust phase 1 program, we assessed the efficacy and safety of early therapeutics in the elderly CRC pts. Methods: A historical cohort analysis included mCRC pts enrolled amongst 44 phase I trials from 3/2004 - 9/2012. Median Progression free survival (mPFS) and overall survival (mOS) were estimated from Kaplan-Meier curves and groups were statistically compared with the log rank test. The magnitude of association between dichotomous factors and survival was estimated with the hazard ratio (HR). Results: 139 pts, median age 59 (33-81), 70+ 16.5% (n = 23); KRAS mut 39.4 %. ≥3 prior lines of therapy 73.9 %; Prior EGFR-I 75.5% (100% of KRAS wt). Location: Right 20.9 %, Left 61.9 %, Transverse 4.3 %, Unknown 12.9 %. Phase I agents: VEGF I 19.4%, EGFR/Growth Factor I 9.3%. mOS for < 70 (n = 108) vs 70+ (n = 22): 6.5 vs 4.2 months (HR 1.88, p 0.007). mPFS for < 70 (n = 116) vs 70+ (n = 23): 2.0 months vs x 1.5 months (HR 1.73, P 0.03). There was not a statistical difference between < 70 versus 70+ in regards to dose cohort, number of cycles completed, or adverse events. Survival analysis in terms of risk factors in pts 70+ are in the Table below. Conclusions: Elderly CRC pts are underrepresented (16.5%) in phase 1 clinical trials and have worse survivals than non-elderly pts. Elderly CRC pts with liver and hematologic toxicities had a trend toward worse PFS but no OS. Phase I studies should incorporate prospective assessments to identify risk factors of morbidity and mortality in elderly CRC pts. [Table: see text]
Relevance of KRAS status in relation to clinical outcome of anti-VEGF-based therapy of metastatic disease in patients with right-sided primary colorectal cancer.
Authors: Obermannova Radka , Zdrazilova-Dubska Lenka , Hejduk Karel , Chloupkova Renata , Vocka Michal , Ostrizkova Lenka , Benscikova Beatric , Kiss Igor , Petruzelka Lubos
Published: January 2019

785

Background: Right-sided location of primary colorectal carcinoma is associated with worse prognosis and predicts worse outcome of treatment of metastatic disease. Prognostic role of KRAS status in 1st-line treatment with anti-VEGF of mCRC remains controversial. We aim to study prognostic role of KRAS in the context of primary tumor location for anti-VEGF-based therapy of mCRC. Methods: Data from 3 national comprehensive cancer centers in the Czech Republic were collected prospectively from 01/2009 - 09/2015. A retrospective analysis of outcomes of 1059 pts with mCRC with known KRAS status was performed. Patients were treated with 1st-line bevacizumab (bev) plus FOLFOX or CapOx, irrespective of the KRAS status (all-RAS since 2015). The primary objective of our retrospective analysis was assessment of OS and PFS in right-sided primary tumors in connection with KRAS status. OS and PFS were calculated using the Kaplan-Meier method. Results: KRAS mutation was significantly more common in right- vs left-sided mCRC. Unlike in left-sided subgroup, both PFS and OS was poor in right-sided subgroup irrespective of KRAS status. Targeted therapy in subsequent lines of treatment was evenly spread among primary location subgroups. 769 (71.4%) patients were treated by CTx alone. Conclusions: Known KRAS status (Table) is not relevant for the treatment with 1st-line anti-VEGF plus CTx in righ-sided primary tumors. [Table: see text]
Plasma biomarker dynamics following ramucirumab treatment and survival analysis after ramucirumab treatment failure in patients with advanced gastric cancer.
Authors: Ota Yumiko , Wakatsuki Takeru , Mashima Tetsuo , Takahari Daisuke , Chin Keisho , Ichimura Takashi , Ogura Mariko , MATSUSHIMA TOMOHIRO , Osumi Hiroki , Nakayama Izuma , Shinozaki Eiji , Suenaga Mitsukuni , Kawata Naomi , Horiike Yuki , Seimiya Hiroyuki , Fujita Naoya , Yamaguchi Kensei
Published: January 2019

79

Background: Ramucirumab (RAM) showed significantly improved survivals of gastric cancer in the second line with paclitaxel or single use. It is known that RAM causes pharmacodynamic changes of plasma VEGF-A family levels during treatment. However, its clinical significance is still unclear. The aim of this study is to reveal the changes of plasma biomarker levels until disease progression, and to examine associations between plasma biomarker levels at disease progression and survival after RAM treatment failure. Methods: Plasma samples were collected at three points: base line, day 8, and disease progression. Nine kinds of plasma biomarker related to angiogenesis: VEGF-A, C, D, PlGF, sVEGFR-1, 2, Neuropilin-1 (NRP1), Angiopietin-1, and SDF-1α, were measured by means of ELISA. The dynamics of plasma biomarkers were compared using the ANOVA. Patients were dichotomized by optimal cut-off value in each biomarker. Survival after RAM treatment failure was estimated by Kaplan-Maier methods and compared by log-rank test. Results: Plasma samples were collected from 21 patients. Median age was 67 y.o and female was dominant (57%). Plasma VEGF-A and PlGF levels sharply increased at day 8 and these higher plasma levels were sustained until disease progression: the median VEGF-A and PlGF levels at baseline, day 8, and disease progression were 20.2, 350.2, and 596.7 pg/ml for VEGF-A (p<0.001) and 10.5, 223.4, and 261.1 pg/ml for PlGF (p<0.001), respectively. Conversely, plasma NRP1 levels consistently decreased during treatment course: the median NRP1 levels at baseline, day 8, and disease progression were 444.3, 309.2, and 230.9 mg/ml (p=0.001). The median survival after disease progression was 3.1 months (95%CI 2.5-3.7). Patients with higher VEGF-A and NRP1 levels showed shorter survival with 4.5 vs. 0.9 months (HR 3.15 95%CI 1.6-6.4 p<0.001) for VEGF-A and 8.8 vs. 2.6 months (HR 2.92 95% CI 1.4-6.3 p=0.002) for NRP1. Conclusions: Our data suggest that not only a clue of mechanism of acquired resistance of RAM but necessity of new treatment strategy after RAM treatment failure. Further understanding of molecular correlates and clinical validation are warranted.
Laparoscopic versus open surgery for locally advanced rectal cancer following neoadjuvant chemoradiotherapy with S-1: Short- and long-term outcomes of multicenter prospective phase II trials.
Authors: Hara Takao , Akagi Tomonori , Empuku Shinichiro , Nakajima Kentaro , Kentaro Iwaki , Kai Seiichiro , Etoh Tsuyoshi , Takeuchi Yu , Tahara Koichiro , Matsumoto Toshifumi , Ishikawa Koichi , Bando Toshio , Mimori Koshi , Shiraishi Norio , Inomata Masafumi
Published: January 2019

793

Background: We have reported the effectiveness of neoadjuvant radiotherapy (RT) combined with S-1 in terms of compliance and pathologic response for locally advanced rectal cancer. In the present study, we aimed to evaluate the safety and efficacy of laparoscopic surgery for locally advanced rectal cancer following neoadjuvant RT combined with S-1 in comparison with open surgery. Methods: Two multicenter prospective phase II trials were conducted (UMIN003396, UMIN003398). A total of 63 patients with locally advanced rectal cancer classified as T3-4, N0-3, and M0 were enrolled, and neoadjuvant RT combined with S-1 and total mesorectal excision with D3 lymphadenectomy was performed. Of these, 57 patients were analyzed and divided into a laparoscopic group (LAP, n = 43) and open group (OP, n = 14). We evaluated the short- and long-term outcomes of laparoscopic surgery compared with open surgery by univariate and multivariate analyses. Results: In the patient background, there were no significant differences between the two groups except that cases with T3 and N0 were significantly higher in the LAP compared with the OP. In the operative findings, operation time was longer (mean 447 min vs. 352 min, p = 0.007) and blood loss was lesser (median 220 ml vs. 485 ml, p = 0.033) in the LAP than those in the OP. Although there were no significant differences observed in the incidence of perioperative and late complications between the two groups, reoperation within 30 days was significantly less in the LAP compared with the OP (1 case vs. 5 cases, p = 0.0004). In the multivariate analysis, a distance of the tumor from anal verge within 3 cm was the independent risk factor for reoperation within 30 days. Furthermore, estimated 5-year disease-free survival (LAP 72 % vs. OP 73 %, p = 0.945) and 5-year overall survival (LAP 76 % vs. 75 %, p = 0.836) didn’t significantly differ between the two groups in the Kaplan–Meier curve. Conclusions: The findings of this study demonstrated that laparoscopic surgery for locally advanced rectal cancer following neoadjuvant RT combined with S-1 could be an optional procedure in terms of short- and long-term outcomes. Clinical trial information: UMIN000003396, UMIN000003398.
Efficacy of daikenchuto for the intestinal hypomotility after open abdominal surgery: A pooled analysis of three randomized controlled trials.
Authors: Kono Toru , Shimada Mitsuo , Nishi Masaaki , Morine Yuji , Yoshikawa Kozo , Katsuno Hidetoshi , Maeda Koutarou , Koeda Keisuke , Morita Satoshi , Watanabe Masahiko , Kusano Mitsuo , Sakamoto Junichi , Saji Shigetoyo , Sokuoka Hiroki , Ohtake Yuya , Sato Yasuto , Kanematsu Takashi , Kitajima Masaki
Published: January 2019

801

Background: Postoperative intestinal hypomotility (IH) is very common after open abdominal (OAS) surgery. Although several advances have been made in medical therapy, very few recognized treatment or prevention methods are currently available. Daikenchuto (DKT), a traditional Japanese prescribed medicine, peripherally stimulates the neurogenic pathway, attempted to reduce postoperative IH in three exploratory randomized controlled trials (RCT). For further analysis of whether DKT accelerates IH recovery after scheduled OAS we conducted a pooled analysis of three RCTs. Methods: A pooled retrospective subset analysis of OAS patients with colon, liver, or gastric cancer in DKT RCTs was performed; RCTs were supported by the Japanese Foundation for Multidisciplinary Treatment of Cancer (JFMC). Among all patients enrolled and randomized in the three RCTs (JFMC project numbers 39-0902, 40-1001, and 42-1002), 740 patients who were eligible were included for the efficacy analysis. The modified intent-to-treat population was 410 patients, who did not have their bowel movement before the first meal; these patients were randomized to receive either 5 g DKT (n = 214) or placebo (n = 196) orally, three times a day for up to 12 days. The primary end point of each trial was the time from the end of the surgery (extubation) to the first bowel movement; this was assessed using survival analysis. Results: Compared with the placebo group, the time from the end of the surgery to the first bowel movement was accelerated in the DKT group (p = 0.004, hazard ratio;1.337 (95% CI 1.096-1.631)), with a difference of median 14.8 h. The tolerability profiles were similar in both the groups. Conclusions: Compared with the placebo, DKT was well tolerated, and it significantly accelerated IH recovery in patients who underwent OAS. Clinical trial information: UMIN000026292.
A retrospective cohort study evaluating the safety and efficacy of TAS-102 in patients with metastatic colorectal cancer (HGCSG1503): Analysis of tumor location.
Authors: Ogawa Kohei , Yuki Satoshi , Kawamoto Yasuyuki , Yagisawa Masataka , Harada Kazuaki , Okuda Hiroyuki , Furukawa Kouichi , Honda Takuya , Dazai Masayoshi , Kato Takashi , Sasaki Takahide , Shindo Yoshiaki , Ota Sakae , Sato Atsushi , Ueda Akira , Kato Sosuke , Fukunaga Akira , Nagai Hikari , Sakata Yuh , Komatsu Yoshito
Published: January 2019

802

Background: Recent analysis from some clinical trials showed that primary tumor location in patients with metastatic colorectal cancer (mCRC) correlates with different outcome. The J003 trial and RECOURSE trial revealed the safety and efficacy of TAS-102 for patients with metastatic colorectal cancer (mCRC). In March 2014, TAS-102 was approved in Japan. However, the impact of primary tumor location in mCRC treated TAS-102 is unclear. Methods: We retrospectively analyzed the clinical data of 411 patients who received TAS-102 in the multi-institutional retrospective study (HGCSG1503). This study was analyzed by CTCAE v4.0 for adverse events (AEs), RECIST v1.1 for response rate (RR)/disease control rate (DCR). To compare with right-sided tumor (RT : Cecum to Transverse colon) and left-sided tumor (LT : Descending colon to Rectum), Fisher’s exact test was used in terms of patient characteristics, AE, RR/DCR, and Log-rank test was used in terms of TTF, PFS and OS. Results: Patients with RT and LT were 137 and 274, respectively. The patient’ characteristics between RT and LT were generally balanced except for Gender (Male ; 45.3% in RT, 56.9% in LT ; p = 0.028), Age (Median ; 68.0y in RT, 66.0y in LT ; p = 0.007), Liver metastasis (70.8% in RT, 57.7% in LT ; p = 0.010), Peritoneal metastasis (47.4% in RT, 24.5% in LT ; p < 0.001), and KRAS exon2 status (wild ; 40.5% in RT, 59.0% in LT ; p = 0.001). The AEs between RT and LT were also generally balanced except for Platelet count decreased (≥Grade 3 ; 8.8% in RT, 2.9% in LT ; p = 0.014). RR/DCR were 0/30.9% in the RT and 0.8/40.3% in the LT (p = 1.000/0.088). Median TTF was 2.2 months in the RT and 2.1 months in the LT (HR 0.962, p = 0.712). Median PFS was 2.2 months in the RT and 2.2 months in the LT (HR 1.024, p = 0.826). Median OS was 7.3 months in the RT and 7.3 months in the LT (HR 1.114, p = 0.327). Conclusions: As a result of this analysis, efficacy was no significant difference between RT and LT for patients who were administered TAS-102 in the real-world clinical practice. This analysis suggested TAS-102 benefits mCRC patients regardless of primary tumor location. Clinical trial information: 000020551.
Predictors of rectal cancer resection at high-volume hospitals among Medicare patients.
Authors: Charlton Mary E. , Chioreso Catherine , Gribovskaja-Rupp Irena , Lin Chi , Ward Marcia M , Lynch Charles F , Chrischilles Elizabeth A.
Published: January 2019

808

Background: Hospitals that perform high volumes of rectal cancer resections achieve superior rates of sphincter preservation and survival compared to those that do not, but many rectal cancer resections are still performed in low-volume centers. We aimed to determine the patient, provider and pathway characteristics associated with receipt of surgery from high-volume hospitals. Methods: Patient and provider characteristics were extracted from the SEER-Medicare database for Medicare beneficiaries (age 66+) with stage II/III rectal adenocarcinoma diagnosed 2007-2011 who received rectal cancer-directed surgery. Hospitals were divided into quartiles by volume of rectal cancer resections, and were also classified by NCI cancer center designation. Results: 2056 patients were included, and 57% received surgery in a high-volume hospital or NCI-designated center. Those residing in census tracts classified as rural and having higher median incomes, lower poverty, and higher levels of education more frequently received surgery in high-volume hospitals; there were no differences by age, gender, stage, or co-morbidity status. 55% of patients received surgery at the same facility where they received the colonoscopy that identified their cancer. In multivariate analyses, the strongest predictor of receiving one’s surgery in a high-volume hospital was receipt of colonoscopy at a high-volume facility (OR = 3.75, 95% CI: 2.93-4.79). Those treated in high-volume hospitals more often had guideline-recommended staging (TRUS/MRI) and treatment (neoadjuvant chemoradiation). Conclusions: Rectal cancer patients tended to stay at the facility where their cancer was diagnosed; and did not typically seek out high-volume providers if their colonoscopy was performed in a low-volume facility. This suggests that colonoscopists may have substantial influence over where patients receive surgery. Given that rurality, income and education appear to more strongly predict receipt of surgery at a high-volume hospital compared to clinical characteristics, further research is needed to understand considerations driving patient decisions and referring providers’ recommendations for care.
Outcomes after major cancer surgery: Can we predict them using parsimonious models?
Authors: Goel Neha , Ward William H. , DeMora Lyudmila , Manstein Samuel , Smaldone Marc C. , Farma Jeffrey M. , Chu Christina , Kutikov Alexander , Chen David , Lango Miriam , Viterbo Rosalia , Ridge John A. , Ross Eric A. , Uzzo Robert , Esnaola Nestor F.
Published: January 2019

811

Background: Major cancer surgery is associated with significant risks of morbidity/mortality. Retrospective studies have demonstrated an association between Surgical Apgar Score (SAS) and postoperative risk of serious complications (SC). This study prospectively evaluated the predictive value of SAS to predict SC, as well as other adverse postoperative outcomes and length of stay (LOS), both singly and in combination with parsimonious measures of “fitness for surgery” (American Society of Anesthesiology [ASA] classification) and surgical complexity (work relative value units [wRVU]). Methods: Demographic, comorbidity, procedure, intraoperative, and outcome data was collected prospectively for 442 cancer patients undergoing elective major surgery between 2014-17. ASA and wRVU were assigned preoperatively; SAS was calculated postoperatively. Logistic regression was used to analyze association of ASA versus (vs) wRVU vs SAS vs ASA/wRVU/SAS (combined) with perioperative outcomes, including SC, return to the operating room (ROR), not being discharged to home, and unplanned readmission; areas under receiver operator characteristic curves were calculated to assess predictive accuracy. Accelerated failure time models were used to analyze associations with LOS and compared using Harrell’s concordance index. Results: Predictive accuracy of SAS for SC was modest (AUC0.655) and not improved when controlling for ASA and wRVU (both of which had poor predictive accuracy for SC). Both wRVU (AUC 0.634) and SAS (AUC 0.663) had modest predictive accuracies for ROR, whereas the predictive accuracy of ASA (AUC 0.749) surpassed that of wRVU (AUC 0.630) for not being discharged to home. All 3 measures were poor at predicting readmission. In contrast, the predictive accuracy of ASA, wRVU, and SAS for LOS was highest when combined (AUC 0.699). Conclusions: Commonly used, simple measures of comorbidity/functional status and surgical complexity can help predict risk of ROR and not being discharged to home (respectively), whereas only SAS has sufficient (albeit modest) discriminatory ability to predict risk of SC. All three measures are too coarse to predict unplanned readmission, but when used in combination, can help predict LOS.
Phase I multicenter, open-label study to establish the maximum tolerated dose (MTD) of trifluridine/tipiracil (TAS-102) and oxaliplatin combination in patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Hollebecque Antoine , Calvo Aitana , Andre Thierry , Argiles Guillem , Cervantes Andres , Leger Catherine , Valette Aude , Amellal Nadia , Fougeray Ronan , Tabernero Josep
Published: January 2019

816

Background: Preclinical evidence suggests improved efficacy when combining trifluridine/tipiracil with oxaliplatin compared to each monotherapy (Nukatsuka, 2015). The primary objective was to determine the MTD and the safety profile of the doublet among mCRC pts who have progressed after at least one prior line of treatment. Methods: Using a 3+3 design, eligible pts received escalating trifluridine/tipiracil doses from 25, 30 to 35 mg/m² bid, days 1–5 q14, together with a fixed dose of oxaliplatin 85 mg/m² (day 1). An intermediate cohort with a lower dose of oxaliplatin (65 mg/m²) plus 35 mg/m² of trifluridine/tipiracil was also tested. Results: Fifteen of 17 enrolled pts were evaluable for DLTs. Median age was 61 years (range 32-74), 11 and 6 pts had an ECOG PS of 0 and 1, respectively; 76% received ≥2 lines including for 10 pts previous line with oxaliplatin. Pts received a median of four cycles (range 1–23). The MTD was defined at the maximal planned dose: trifluridine/tipiracil 35 mg/m² bid, oxaliplatin 85 mg/m². Combination was well tolerated and only one DLT was observed (grade 3 febrile neutropenia). The most common ( > 20%) non-hematologic adverse drug reactions (ADRs) included nausea, asthenia, vomiting, diarrhea and decreased appetite. Moderate-to-severe neutropenia occurred in 5 pts and thrombocytopenia in 4 pts (all grade 1); 1 pt experienced a grade 4 anemia at Cycle 4. Oxaliplatin-related neurotoxicity grade ≥2 was observed in 2 pts. ADRs were manageable with basic supportive care, with treatment delays or temporary interruptions. Best overall response includes partial response (n = 1, unconfirmed), stable disease (n = 7). Conclusions: At the MTD (trifluridine/tipiracil 35 mg/m² bid, oxaliplatin 85 mg/m²), incidence and severity of bone marrow suppression as well as gastrointestinal toxicities were similar to previously published data. A cohort of 6 additional pts will confirm the MTD. An expansion part combining the doublet with either nivolumab or bevacizumab evaluating the safety and preliminary antitumor activity of each triplet will start soon. Clinical trial information: NCT02848443.
FOLFIRI3-aflibercept as second- or later-line therapy in patients with metastatic colorectal cancer.
Authors: Carola Candice , Ghiringhelli Francois , Kim Stefano , Andre Thierry , Barlet Juliette , Bengrine Leila , Marijon Helene , Garcia Marie Line , Borg Christophe , Dainese Linda , Steuer Nils , Larsen Annette K , De Gramont Aimery , Chibaudel Benoist
Published: January 2019

817

Background: The efficacy of the standard FOLFIRI-aflibercept second-line therapy may be improved by the chemotherapy regimen in metastatic colorectal cancer (MCRC). FOLFIRI was optimized by splitting the dose of irinotecan on day 1 and day 3 and by removing the bolus of 5-FU in the FOLFIRI3 regimen. Methods: This is a retrospective multicentric cohort, evaluating efficacy and safety of the association of aflibercept with FOLFIRI3, in patients (pts) with previously treated MCRC. The primary endpoint was overall response rate (ORR). Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: From September 2014 to December 2016, 74 pts were treated in four French centers. Nine pts were excluded due to prior use of aflibercept (n = 3), more than one prior line of treatment in irinotecan-naïve pts (n = 3) and inadequate liver function (n = 3). In the cohort of irinotecan-naïve pts (n = 30), ORR and DCR were 43.3% and 76.7%. Median PFS and OS were 11.3 months (95% CI 6.1-29.0) and 17.0 months (95% CI 13.0-17.3). The most common ( > 5%) grade 3-4 adverse events were diarrhea (37.9%), neutropenia (14.3%), stomatitis and anemia (10.4%), hypertension (6.7%). In the cohort of pts previously treated with irinotecan (n = 35), 20 (57.1%) pts received ≥2 prior lines of treatment with various prior irinotecan regimen (FOLFIRINOX, n = 21; FOLFIRI, n = 10; FOLFIRI3, n = 4). ORR and DCR were 34.3% and 60.0%. Median PFS and OS were 5.7 months (95% CI 3.9-10.4) and 14.3 months (95% CI 12.8-19.5). In 4 patients refractory to irinotecan, FOLFIRI3-aflibercept led to one partial response, 2 stabilizations, and one patient not evaluable. Conclusions: A minimal modification of the FOLFIRI regimen led to a dramatically improvement of efficacy with FOLFIRI3-aflibercept, whatever prior use of irinotecan. Further randomized trial is planned.
Validation of the Mexican-Spanish version of the EORTC QLQ-INFO25 instrument in patients with gastrointestinal cancers.
Authors: Salas-Becerril Maricela , Allende-Perez Silvia R , Monroy Alejandra , Aiello-Crocifoglio Vincenzo , Onate-Ocana Luis F.
Published: January 2019

818

Background: Information received by the cancer patient is a main component of an evaluation of quality of care. The most frequently used instrument to do so is the EORTC QLQ-INFO25, and our aim is to validate its Mexican-Spanish version in patients with gastrointestinal cancer. Methods: This is a prospective study including patients who responded the QLQ-INFO25 instrument at a cancer referral center. Reliability and validity tests were performed, and the association of scale scores with clinical variables is shown. Results: One hundred thirty six patients were included, 70 female and 66 males. Mean age was 56.2 years; 111 corresponded to colorectal and 25 to gastroesophageal cancer. Questionnaire compliance rates were high and both instruments were well accepted; no missing values were found. Convergent item correlation in the QLQ-C30 ranged from 0.223 to 0.822 and in the QLQ-INFO25 from 0.008 to 0.768, respectively. Divergent item correlation ranged from 0.011 to 0.674 and from 0.014 to 0.662, respectively. Cronbach’s α coefficients of eight of nine multi-item scales of the QLQ-C30 and all four multi-item scales of the QLQ-INFO25 instruments were > 0.7 (range, 0.655–0.905). Selected scales of both instruments distinguished among esophagogastric or colorectal cancer. Conclusions: The Mexican-Spanish version of the QLQ-INFO25 questionnaire provides domains not covered by the generic instrument, it is reliable and valid to be used in clinical trials assessing patients’ appraisal on the received information by the health personnel.
Impact of primary tumour location (PTL) on outcomes in patients (pts) with metastatic colorectal cancer (mCRC) undergoing first-line panitumumab (Pmab) + FOLFIRI treatment .
Authors: Karthaus Meinolf , Van Den Eynde Marc , Mineur Laurent , Thaler Josef , Koukakis Reija , Berkhout Marloes , Gallego Javier
Published: January 2019

820

Background: Prognosis in pts with mCRC is affected by PTL; PTL may also affect the activity of the epidermal growth factor receptor inhibitor Pmab (+ FOLFIRI). Methods: In this phase II, single-arm study (NCT00508404), pts received first-line Pmab+FOLFIRI Q2W until disease progression (PD); primary endpoint: objective response rate (ORR). Analyses included pts with RAS wild-type (WT) mCRC (no mutations in KRAS/ NRAS exons 2, 3 and 4). Baseline demographics/disease characteristics were summarised by PTL and the effect of PTL on outcome was analysed. Early tumour shrinkage (ETS) was defined as a ≥30% reduction in the sum of the longest diameters of measurable target lesions at week 8. Depth of response (DpR) was the maximum % change from baseline to nadir in pts with shrinkage, or the change at PD in pts with no shrinkage. DpR was positive for shrinkage, negative for growth and zero for no change. Progression-free survival (PFS) was analysed by PTL and ETS status. There was no long-term follow-up of overall survival in this study. Results: PTL could be determined in 52/69 (75%) RAS WT pts; 45/52 (87%) had left (L)-sided disease. Pts with L- vs right (R)-sided disease were more likely to have BRAF WT mCRC (91% vs 71%), an ECOG performance status of 0 (56% vs 43%) and liver+other metastases (53% vs 29%). Pts with L- vs R-sided disease had longer median (95% CI) PFS (11.2 [7.6,17.0] vs 7.2 [1.1,19.1] months) and were more likely to experience ETS ≥30% (53% vs 29%). ORR (60% vs 57%), median (95% CI) duration of response (DoR; 13.2 [9.3,47.7] vs 14.3 [3.5,17.3] months), median DpR (61% vs 60%), and resection rates (any: 13% vs 14%; R0: 7% vs 14%) were similar for L- and R-sided pts. ETS ≥30% was associated with improved PFS irrespective of PTL (HR [95% CI] vs ETS < 30%: 0.53 [0.22,1.29] on L; 0.35 [0.03,3.54] on R). Conclusions: These post-hoc data are in line with larger previous studies suggesting improved ETS/PFS with Pmab treatment in RAS WT left-sided mCRC; ORR, DoR and DpR were similar regardless of PTL. No formal conclusions can be drawn regarding the activity of Pmab+FOLFIRI in right-sided mCRC due to the small pt numbers, but ETS may also predict PFS benefit in right-sided disease. Clinical trial information: NCT00508404.
Phase II dose titration study of regorafenib for patients with unresectable metastatic colorectal cancer that progressed after standard chemotherapy.
Authors: Kudo Toshihiro , Kato Takeshi , Kagawa Yoshinori , Sakai Daisuke , Satoh Taroh , Doki Yuichiro , Mori Masaki
Published: January 2019

821

Background: The CORRECT study showed significant overall survival (OS) improvement in the regorafenib (REG), compared with the placebo group in metastatic colorectal cancer (mCRC) which progressed after standard chemotherapy. In Japanese subgroup analysis, the hazard ratio of OS also indicated a tendency similar to overall population. The standard starting dose of REG is 160mg/body/d, and not adjusted according to body weight and height, race of the patients, or other parameters, however, some cases require dose reduction to 120mg/d or less due to adverse events (AE). Dose modification due to AE was observed frequently in Japanese compared with non-Japanese during the study (84.6% and 51.3%). Therefore, we performed this dose titration study to investigate efficacy and safety of REG. Methods: This single arm, multicenter phase II study evaluated lower initial dose of REG (120mg/d, for 21 days, followed by 7-day break) in mCRC progressed after standard chemotherapy. Dose escalation to 160mg was allowed in 2nd and subsequent cycle, if patients developed < grade 2 AE, except for liver toxicity. Patients underwent radiographic evaluation every 8 wks. The primary endpoint was disease control rate (DCR: CR+PR+SD ≥ 6 wks). The major secondary endpoints included progression free survival (PFS), OS and safety. Results: Between September 10, 2015, and March 7, 2017, total 60 patients were enrolled into the study. Median age was 68.5 (range: 30-84), and ECOG PS 0/1 were 70%/30%. DCR was 36.7% (22/60); 7% (4/60) have had SD for 6 months or longer. Median PFS was 2.3 months (95% CI: 1.8 - 2.8). 3.3% of patients (2/60) had protocol defined REG dose escalation to 160mg; one case was from the cycle 2, and the other case was from the cycle 4. 42% (25/60) had dose reduction to 80mg due to AE, and that dose reduction was needed in 10% (6/60) at the first cycle. Grade 3-4 adverse events were observed in 55% (33/60). Conclusions: Starting dose of REG 120mg appears to have comparable efficacy to 160mg. Adverse events were generally consistent with the known safety profile of REG in this setting. Final results with additional follow-up on efficacy and safety outcome measures will be provided at the meeting. Clinical trial information: UMIN000018968.
A phase Ib/II study of cetuximab and pembrolizumab in RAS-wt mCRC.
Authors: Boland Patrick McKay , Hutson Alan , Maguire Orla , Minderman Hans , Fountzilas Christos , Iyer Renuka V.
Published: January 2019

834

Background: Cetuximab is a chimeric IgG1 anti-EGFR monoclonal antibody approved in RAS-wt metastatic colorectal cancer (mCRC). Pre-clinical data have suggested that cetuximab triggers immunogenic cell death and support an immunologic basis of activity. Small clinical data sets demonstrate that EGFR-based therapy preferentially increases TILs in colorectal hepatic metastases. This Phase Ib/II study was designed to assess the safety and clinical activity of cetuximab and pembrolizumab in metastatic colorectal cancer. Methods: Eligible pts were those with RAS-wt mCRC, ECOG performance status (PS) 0-2, with at least 1 prior line of therapy for advanced stage disease, and no prior treatment with an anti-EGFR antibody. The phase Ib study was designed as a safety lead-in with a de-escalation design. Pembrolizumab was administered at a fixed dose of 200 mg q3week with standard cetuximab dosing (400 mg/m2 loading dose, followed by 250 mg/m2 weekly). DLTs were defined as any ≥ grade 3 clinically significant toxicity which is possibly related and occurs within the first 6 weeks of therapy. For rash and hypomagnesemia only ≥ grade 4 toxicities were considered DLTs. Correlative serial biopsies were performed at baseline and at 9 weeks. Results: 9 patients, ages 33-73, were enrolled onto the Phase Ib study between 8/10/16 and 11/2/16. No DLTs were observed. The most common AEs of any cause observed were xerosis, dermatitis acneiform rash, hypomagnesemia, vomiting, and fatigue. ≥ Grade 3 toxicities were uncommon, but included hypomagnesemia (3), rash (1), urticaria (1), hypocalcemia (1), alk phos elevation (1), and ascites (1). 6/9 patients achieved stable disease lasting ≥ 16 weeks. Conclusions: The combination of cetuximab and pembrolizumab is well-tolerated in this study and can be administered at full dosages. Though hypomagnesemia appears prominent, no additional emergent AEs have been observed during or following the DLT period. The associated ongoing phase II study will enroll an additional 33 patients to assess the true efficacy of this regimen with dual primary endpoints of ORR and 6 month PFS. Clinical trial information: NCT02713373.
miR-30a-5p as a tumor suppressor gene in gastric cancer.
Authors: Min Jimin , Han Tae-su , Choi Boram , Hur Keun , Yanagihara Kazuyoshi , Kim V Narry , Lee Hyuk-Joon , Yang Han-Kwang
Published: January 2019

84

Background: Gastric cancer (GC) is the second leading cause of cancer-related death. MicroRNAs (miRNAs) are an abundant class of negative gene regulator and regulate multiple gene targets. miRNAs control a wide range of biological functions such as cellular proliferation, differentiation and apoptosis. Moreover, many miRNAs are highly conserved, and their deregulation is often associated with human malignancies. The aims of this study are to determine the miR-30a functions as a tumor suppressor gene and to evaluate whether the miR-30a-5p is able to use the diagnostic or prognostic marker in GC. Methods: To identify the gastric tumor-associated miRNAs, miRNA microarray was performed using the gastric cancer tissues. qRT-PCR was employed to confirm the microarray results. Also, to determine the miR-30a-5p biological functions in GC, miR-30a-5p mimic or inhibitor was treated in GC cell lines. Results: In miRNA microarray data, miR-30a-5p was down-regulated in GC tissues compared to normal mucosa. When we performed qRT-PCR to confirm miR-30a-5p expression, it was frequently down-regulated in our GC cohort, (n = 30, P < 0.001). Furthermore, ectopic expression of miR-30a-5p decreased cell growth, migration capacity and colony formation in vitro. Conclusions: Taken together, the miR-30a-5p expression was frequently down-regulated in GC. In addition, the miR-30a-5p suppressed tumorigenesis. Therefore, we suggest that miR-30a-5p activation may be a useful strategy of GC patient therapy and it can serve as a diagnostic or prognostic marker for GC.