bluuebunny/crossref_metadata_2025 huggingface dataset:
Lymphocyte-to-monocyte ratio and neutrophil-to-lymphocyte ratio independently predict survival in resected small bowel adenocarcinoma.
Authors: Huffman Brandon M. , Patel Shruti , Yadav Siddhartha , Jin Zhaohui , Mahipal Amit
Published: January 2019

426

Background: Small bowel adenocarcinoma is a rare malignancy affecting approximately 2,000 patients per year. There is a paucity of evidence prognosticating patients with small bowel adenocarcinoma. We aimed to evaluate multiple factors in patients with resected small bowel adenocarcinoma to determine any association with survival outcomes. Methods: Ninety three patients who underwent resection for stage I-III small bowel adenocarcinoma were retrospectively identified utilizing the pathology database at a single tertiary referral institution. All patients had complete follow up data and were included in the survival analysis. JMP software was used for statistical analysis. Overall survival was performed utilizing Kaplan-Meier method, and log-rank tests were used for statistical comparisons. Cox proportional hazards were performed to control for age, gender, location of tumor, tumor size, tumor stage, and adjuvant therapy. Sensitivity analysis was performed to establish best cutoff points for continuous variables. All tests were two sided and a P value of < 0.05 was considered significant. Results: The median age at diagnosis was 65 years (range 32-90). 61% were male. Median tumor size was 4.5 cm. There were 20, 36, and 37 patients with stage I, stage II, and stage III disease, respectively. Median overall survival (OS) was 151 months, 104 months, and 44 months for stages I, II, and III disease. In a multivariate analysis, independent predictor factors included presurgical lymphocyte to monocyte ratio (LMR) > 4.0, with a Hazard Ratio (HR) 0.13 (95% CI 0.007-0.69, p = 0.01), presurgical neutrophil to lymphocyte ratio (NLR) < 8.0, HR 0.39 (95% CI 0.17-0.96, p = 0.04), and tumor size < 7.5 cm, HR 0.22 (95% CI 0.07-0.85, p = 0.03). Stage, age, T stage, and N stage influenced overall survival in univariate analysis, but were not statistically significant on multivariate analysis. Conclusions: LMR and NLR independently predict survival in patients with resected small bowel adenocarcinoma.
Phase I study of tramatinib combined with sorafenib in patients (pts) with advanced hepatocellular cancer (HCC).
Authors: Wang Emilie , Kim Dae Won , Mahipal Amit , Chen Dung-Tsa , Cao Biwei , Masawi Fadzai , Kim Richard D.
Published: January 2019

431

Background: RAS/RAF/MEK/ERK (MAPK) signaling pathway is associated with proliferation, progression, and survival of HCC. Preclinical data suggests that activation of MAPK pathway may be one of resistant mechanisms of sorafenib, and the combination of MEK inhibitor and sorafenib can induce synergistic anticancer activity in HCC. We evaluated the safety and efficacy of trametinib (MEK inhibitor) combined with sorafenib in HCC. Methods: This was a phase I single center study with standard 3+3 design for pts with treatment naïve advanced HCC. The primary endpoints are determining dose limiting toxicities (DLT) and maximum tolerated dose (MTD). Secondary endpoints include overall survival (OS), progression free survival (PFS), and disease control rate (DCR). Initial plan was to enroll pts in 4 escalating dose levels (dl)—trametinib 1mg daily (qd)/sorafenib 200mg twice daily (bid)(dl 1), trametinib 1.5mg qd/sorafenib 200mg bid (dl 2), trametinib 1.5mg qd/sorafenib 400mg bid (dl 3), trametinib 2mg qd/sorafenib 400mg bid (dl 4). Eligible pts had advanced unresectable HCC, ECOG PS 1, Child-Pugh Score 6, and adequate organ function. Results: 17 pts were treated in 3 different dl of trametinib and sorafenib (3 in dl 1, 8 in dl 2, and 6 in dl 3). Median age was 65 years (range 40-80) with 64.7% male. All pts were evaluated for toxicity, but only 15 were evaluable for DLT. 2 pts were replaced as they came off of study within 1 month (1 pt in dl 3 due to varices unrelated to the study drug, 1 pt in dl 2 for voluntary withdrawal due to side effects). DLT was noted in dl 3 with 2 pts (grade 4 hypertension (HTN) and grade 3 elevated (elev) of bilirubin/AST/ALT > 7 days). Most common grade 3/4 treatment related adverse events were elev AST (47.1%), HTN (23.5%), elev Alk Phos (17.6%), elev ALT (5.9%), elev bilirubin (5.9%), and diarrhea (5.9%). The median PFS was 4.0 months (mo), and median OS was 5.8 mo. 11 pts were evaluable for response after cycle 2 (8 stable disease (SD), 2 disease progression (PD), 1 partial response). 3 pts were evaluable for response after cycle 4 (1 SD, 2 PD). DCR was 63.6%. Conclusions: Trametinib and sorafenib can be safely administered up to trametinib 1.5mg qd and sorafenib 200mg bid for pts with advanced HCC. Clinical trial information: NCT02292173.
Outcomes for patients with borderline resectable (BR) and locally advanced (LA) pancreatic cancer (PC) treated with induction FOLFIRINOX (FFX) +/- radiation (RT) followed by surgery compared to induction FFX followed by consolidative RT.
Authors: Cecchini Michael , Miccio Joseph , Pahade Jay , Lacy Jill , Salem Ronald R , Johnson Skyler Bryce , Stein Stacey , Kortmansky Jeremy S. , Johung Kimberly
Published: January 2019

437

Background: Induction FFX for PC deemed either BR or LA at diagnosis provides an opportunity to downstage pts with the aim of an R0 surgery. The addition of RT after induction FFX may further downstage. However, there is a paucity of data regarding long-term survival for BR and LA patients successfully downstaged and resected. We performed a retrospective review of BR and LA PC treated with induction FFX +/- RT followed by surgery or consolidative RT at the Yale Cancer Center (YCC) to assess survival in these two cohorts. Methods: Clinical data was abstracted for pts with BR or LA PC who had surgery or received consolidative RT without surgery after induction FFX +/- RT at the YCC from 2010-2018. Surgical pts were re-reviewed by a radiologist to assess vascular involvement (BR vs. LA) using NCCN criteria. PFS and OS for surgery and consolidative RT were analyzed by the Kaplan-Meier method. Survival was compared via the log rank test. Results: 102 pts met inclusion criteria (BR=47, LA=55), 41 pts had surgery [BR=29/47 (62%) LA=12/55 (22%)] and 61 pts had consolidative RT [(BR= 18/47 (38%), LA= 43/55 (78%)] after induction FFX. 18 surgery pts received RT prior to resection and all surgery pts had R0 resection. Median follow up was 25 mo (range 5 – 97). Median PFS with surgery was 22 mo (95% CI 15 – 59) vs 14 mo (95% CI 10.9 – 20.1) with consolidative RT (p<0.001), while OS with surgery was 42 mo (95% CI 25-NR) vs 20 mo (95% CI 17-25) without surgery (p<0.001). For pts with ≥ 2 yr follow up, 12/22 (55%) surgery pts and 17/18 (94%) consolidative RT pts relapsed. For pts with ≥ 3 yr follow up, 6/12 (50%) surgery pts and 10/10 (100%) consolidative RT pts relapsed. 2 yr PFS and OS was 45% (95% CI 28-61) and 74% (95% CI 57 – 86) with surgery versus 15% (95% CI 7-27) and 40% (95% CI 26-53) with consolidative RT. Conclusions: Surgery was associated with a high R0 rate and prolonged PFS and OS compared to consolidative RT in pts with BR and LA PC after FFX +/- RT. However, survival benefit was not statistically significant when selecting only LA pts although numbers are limited.
Resection of primary tumor in liver only metastatic midgut neuroendocrine tumors.
Authors: Manguso Nicholas , Lee Jaewon , Hendifar Andrew Eugene , Tuli Richard , Gangi Alexandra
Published: January 2019

446

Background: Surgical management of metastatic midgut neuroendocrine tumors (NET) remains controversial. Resection of primary tumor only without liver resection is advocated only in select patients, frequently for palliation. Additionally, no standard algorithm exists, and the risk profile for these patients is not well documented in the literature. We evaluated these midgut NETs with liver metastasis in the National Cancer Data Base (NCDB) to determine if resection of the primary tumor only affected survival outcomes. Methods: The NCDB was queried to identify patients with liver only metastatic midgut NET tumors between 2010 and 2015. Patients who underwent surgery of their liver metastasis were excluded. The cohort was separated into two groups, those who underwent resection of the primary tumor and those who did not. Patient demographics, year of diagnosis, clinicopathologic tumor characteristics and Charlson/Deyo comorbidity index were compared among the two groups. The primary outcome was overall survival (OS). Kaplan-Meier estimates were used to predict OS. Results: One-thousand nine hundred fifty-two patients with median age of 63 were identified. Median tumor size was 2.4 cm. Of these, 1,295 (66.0%) patients underwent resection of the primary tumor and 667 (34.0%) did not. Patients undergoing resection were younger (median age 63 vs. 65, p < 0.001) and had smaller tumors (median 2.3 cm vs. 3.0 cm, p < 0.001). There was no difference between the groups with respect to sex, year of diagnosis or Charlson/Deyo Comorbidity Score. Median follow up time was 42.8 months (IQR 29.7). A total of 483 deaths occurred in the entire cohort with a 5-year OS of 60.8%. The 5-year OS for patients undergoing resection of the primary tumor was 65.9% and 49.3% for those not undergoing resection (p < 0.001). Conclusions: Patients with liver only metastatic midgut neuroendocrine tumors had an overall survival advantage when the primary tumor was resected. Patients with liver only metastatic midgut NET may benefit from surgical resection and should be evaluated for surgery at the time of diagnosis.
Local control following stereotactic body radiotherapy to adrenal oligometastases.
Authors: Figura Nicholas B , Oliver Daniel Eli , Johnstone Peter Anthony , Hoffe Sarah E. , Frakes Jessica
Published: January 2019

447

Background: The role and associated risks of stereotactic body radiotherapy (SBRT) for adrenal metastases remain unclear. We report our single institution experience and report novel techniques to selectively dose-escalate treatment while concurrently minimizing dose to nearby critical structures. Methods: We retrospectively reviewed patients with evidence of metastatic adrenal disease originating from any primary histology treated with SBRT from 2013 to 2018. The primary endpoint was local control (LC). Secondary endpoints were disease-free survival (DFS), overall survival (OS), and treatment-related toxicity. LC, DFS, and OS were calculated with Kaplan-Meier analysis. Univariable and multivariable analysis were performed with long-rank and Cox proportional analysis. Results: A total of 45 adrenal metastases in 41 patients received SBRT. The median age was 67 years (range 40-80). The most common primary histologies were non-small cell lung cancer (51%), renal cell carcinoma (24%), and small cell lung cancer (10%). The median gross internal and planned target volumes were 21.23cc (range, 3.1–124.7cc) and 31.68cc (range, 5.2–175.9cc), respectively. The median dose administered was 50 Gy with 30 (67%) lesions receiving ≥50 Gy and 14 (31%) receiving 60 Gy. Twenty-six (58%) lesions were selectively dose-painted. Of the 42 simulations, 26 (62%) were treated supine, 5 (12%) prone, and 11 (26%) in the left lateral decubitus position. At a median follow-up of 10.5 months, there were 3 local recurrences (LR). 12-month LC rate was 96% with a median LC of 35 months. All three LR were in the metachronous, oligometastatic patients. One patient developed a hypertensive crisis which required intravenous antihypertensives. Conclusions: Adrenal SBRT for oligometastatic disease is a reasonable, noninvasive option with excellent LC and minimal toxicity. Lesions in close proximity to radiosensitive organs may benefit from techniques, such as dynamic patient positioning and selective dose-painting, for further dose-escalation to optimize LC rates while simultaneously limiting associated toxicity risks.
FOLFIRI in advanced biliary tract cancers.
Authors: Mizrahi Jonathan , Gunchick Valerie , Mody Kabir , Xiao Lianchun , Surapaneni Phani Keerthi , Shroff Rachna T. , Sahai Vaibhav
Published: January 2019

451

Background: Gemcitabine plus platinum (GP) is the standard of care first-line treatment for advanced biliary tract cancers (BTC). There is no established second-line therapy, and retrospective reviews report progression-free survival (PFS) for second-line treatment to be < 3 months. 5-Fluorouracil plus irinotecan (FOLFIRI) is a commonly used regimen in patients (pts) with BTC who have progressed on GP, though there is a paucity of data regarding its efficacy in this population. Methods: We retrospectively evaluated pts with advanced BTC who were treated with FOLFIRI at MD Anderson, University of Michigan and Mayo Clinic in Jacksonville. Data were obtained on pt demographics, type of BTC, PFS, and overall survival (OS). Results: Ninety-eight pts were included of which 74 (76%) had metastatic disease at the time of treatment with FOLFIRI. The median age was 59 (range, 22 to 86) years. The number of pts with extrahepatic cholangiocarcinoma (CCA)/gall bladder (GB)/intrahepatic CCA were 10, 17, and 71. FOLFIRI was used as 1st, 2nd, 3rd or 4th – Nth lines in 8, 50, 36, and 4 pts, respectively. Of the 65 pts whose best responses were documented, 23 (35%) had stable disease and 7 (11%) had a partial response per RECIST v1.1. Median duration on FOLFIRI was 2.2 months. The median PFS and OS were 2.4 (95% CI 1.7 to 3.1) and 6.6 (95% CI 4.7 to 8.4) months, respectively. Median PFS for pts treated with FOLFIRI in 1st, 2nd, 3rd or 4th – Nth lines were 3.1, 2.5, 2.3 and 1.5 months, respectively. Eighteen pts received concurrent bevacizumab (13) or EGFR-targeted therapy (5) with FOLFIRI, and both of groups exhibited a median PFS of 2.7 months. Eastern Cooperative Oncology Group performance status (PS) of 0-1 was associated with improved OS (P = 0.006) compared to PS of 2-3. Conclusions: In this multi-institution retrospective review of 98 pts with BTC treated with FOLFIRI, efficacy of this regimen appears to be modest. While PFS and OS outcomes were similar to what has been previously reported, the 46% disease control rate in this group of predominantly pretreated pts is encouraging. Given the lack of other standard therapies, FOLFIRI may still have a role in this pt population, but these results emphasize the need for more effective treatment options for pts with advanced, pretreated BTC.
Neoadjuvant multimodal treatment of borderline resectable (BRPC) and locally advanced unresectable pancreatic cancer (LAPC) in Mexico.
Authors: Camargo Vanessa Rosas , Martos Armedáriz Edgar Omar , Cisneros Cordero Miriam Heidi , NIETO GARCIA ZULEYMA , Flores Balcázar Christian Haydeé , Meneses Medina Mónica Isabel , Chan Nuñez Carlos , Gamboa Dominguez Armando , Huitzil Melendez Fidel David
Published: January 2019

454

Background: Pancreatic cancer remains a highly lethal disease. There is no consensus on treatment sequences and chemotherapy (CT) regimen in BRPC and LAPC. Our aim was to describe the multimodal treatment and outcomes in our population. Methods: We retrospectively reviewed medical records of patients (pts) with BRPC/LAPC and histological diagnosis of adenocarcinoma evaluated at Instituto Nacional de Ciencias Médicas y Nutrición from January 2011-December 2016. Clinical and pathological variables at diagnosis and treatment were recorded. Overall survival (OS) was estimated using Kaplan-Meier method and compared by Log-rank test. Results: 69 pts were evaluated, 39% (27) did not receive treatment. We analyze 42 treated pts. BRPC 33%/LAPC 67%. Median age was 58.8 y/o, 54.8% were female. Symptoms at diagnosis: 79% abdominal pain, 76% weight loss, 55% jaundice. ECOG performance status (PS): 0 (17%), 1 (69%) and 2 (14%). Main location was pancreatic head (76%). Median laboratory values: total bilirubin 1.04 mg/dL (0.2-25), albumin 4.1 g/dL (2.4-5.1), CA 19.9 182.8 U/mL (0.8-4028). Laparotomy at diagnosis was performed in 21%. All pts received induction CT (iCT). FOLFIRINOX was the most common regimen (37%), followed by FOLFOX4 (34%). The best overall response with iCT was stable disease (62%), progressive disease was observed in 24%. iCT followed by chemoradiation (CRT) could be delivered to 48% (20/42). Capecitabine-based CRT was preferred (94%). Six pts (14%) underwent surgical resection after multimodal treatment (36% BRPC, 3.5% LAPC), 5 pts achieved R0 resection. The resection rate with single-agent iCT was 0% vs 20% with combination iCT. Median OS was 15.6 months (m): 14.4 m for BRPC and 15.5 m for LAPC. Median OS according iCT: gemcitabine 7.8 m, fluorouracil 13.7 m, FOLFOX4 15.5 m and FOLFIRINOX 24.6 m. Univariate analysis identified ECOG PS (0-1 vs 2, P = 0. 014) and age ( < 59 vs ³59, P = 0.002) as significantly associated with survival. Conclusions: Early administration of combination CT followed by CRT and/o surgical resection in selected pts improves oncological outcomes in pts with BRPC/LAPC. In pts with good PS, iCT with FOLFIRINOX is the preferred regimen given best results.
Retrospective, cohort study evaluating empiric dose-reduced nab-paclitaxel with gemcitabine in metastatic pancreatic adenocarcinoma: A single institution experience.
Authors: Olowokure Olugbenga Olanrele , Geraghty LeeAnn , Grate Lisa , Gesenhues Alicia , Lane Adam , Mueller Eric , Niu Alex , Yellu Mahender , Gupta Anumeha , Latif Tahir
Published: January 2019

456

Background: The phase III MPACT trial was conducted to assess OS in patients with metastatic pancreatic adenocarcinoma (mPAC) receiving nab-paclitaxel (nab-P) 125 mg/m2 + gemcitabine (G) 1000 mg/m2 on days 1, 8, and 15 every 28 days. Due to reported increased incidence of adverse events (AEs) at this dose, practice at UC Health outside the setting of a clinical trial is to empirically dose reduce (EDR) nab-P to 100 mg/m2. This study is a review of the efficacy of EDR nab-P + G in patients with mPAC compared to MPACT data. Methods: This retrospective, single-center, cohort study included patients ≥18 years of age with mPAC (by biopsy) receiving first line therapy with EDR nab-P + G from January 1, 2012 to March 31, 2017. Primary outcome is OS. Secondary outcomes include PFS, CA19-9 percent reduction, incidence of grade ≥ 3 AEs. Results: See table. Conclusions: In patients with mPAC, EDR nab-P plus G demonstrated a median OS of 10 months and PFS of 5 months. 53% of patients had a 20% CA19-9 reduction from baseline with a 1 year OS rate of 45%. The incidence of grade ≥ 3 AEs appeared to be acceptable. [Table: see text]
Effect of surgical approach on node harvest in gastrectomy: Analysis of the National Cancer Database.
Authors: Watson Michael David , Trufan Sally J , Gower Nicole Lee , Hill Joshua S. , Salo Jonathan C.
Published: January 2019

47

Background: Recent studies demonstrate significant surgical outcome advantages for patients undergoing minimally invasive versus open gastrectomy. Lymph node harvest at the time of gastrectomy is an indicator of adequate surgical resection and greater harvest is associated with improved staging and patient outcomes. Our aim is to evaluate lymph node harvest based on surgical approach. Our hypothesis is that a minimally invasive approach, particularly robot-assisted, will be associated with higher lymph node harvest. Methods: Patients undergoing gastrectomy for gastric adenocarcinoma in the period of 2010-2015 were identified using the National Cancer Database (NCDB). Data collected includes demographic data, institutional volume, approach, type of gastrectomy, tumor size, tumor location, pathologic T classification, year of diagnosis, Charlson-Deyo score and node harvest. Outcomes for patients undergoing open, laparoscopic, and robot-assisted gastrectomy were compared with univariate analysis and with a multivariate generalized linear mixed model (GLMM). Results: 19,555 patients were identified. There were 12,400 men (63.4%) and the mean age was 66.3 ± 12.5 years. 13,486 (69.0%) patients underwent open gastrectomy, 5,023 (25.7%) laparoscopic gastrectomy, and 1,046 (5.3%) robotic-assisted gastrectomy. Mean node harvest for open was 16.1 ± 11.5, laparoscopic was 15.1 ± 12.1, and robotic-assisted was 17.2 ± 13.3. Using a GLMM which controlled for the above listed covariates, robotic-assisted gastrectomy was associated with higher node harvest than both open (p = 0.041) and laparoscopic (p < 0.001) while open was associated with higher node harvest than laparoscopic (p < 0.001). There were 1582 operations with zero nodes harvested. In a sub-analysis of resections where at least one node was harvested (n = 17,973), the mean node harvest for open was 16.9 ± 11.1, laparoscopic was 17.5 ± 11.2, and robotic was 19.7 ± 12.3. Conclusions: This data suggests that a robot-assisted approach is associated with increased node harvest compared to laparoscopic and open approach in gastrectomy.
Lymphocyte-to-C-reactive protein ratio and score are clinically feasible biomarkers in gastric cancer patients.
Authors: Okugawa Yoshinaga , Toiyama Yuji , Yamamoto Akira , Shigemori Tsunehiko , Kusunoki Kurando , Kusunoki Yukina , Yin Chengzeng , Suzuki Akihiro , Fujikawa Hiroyuki , Yasuda Hiromi , Hiro Junichiro , Yoshiyama Shigeyuki , Ohi Masaki , Araki Toshimitsu , McMillan Donald C , Kusunoki Masato
Published: January 2019

48

Background: Systemic inflammation arising from complex host-tumor interactions is considered the seventh hallmark of cancer. The aim of this retrospective study was to assess the clinical feasibility of our newly developed ‘lymphocyte-to-C-reactive protein (CRP) ratio’ (LCR) and ‘lymphocyte CRP score’ (LCS) for predicting short- and long-term outcomes in patients with gastric cancer. Methods: In total, 551 patients who underwent gastrectomy for primary gastric cancer at our institution were enrolled in this study. Preoperative LCR was calculated as follows: lymphocyte count (number/µL)/CRP level (mg/dL), and scoring system (LCS) was devised based on the cut-off value of both lymphocytes (1 × 109/L) and CRP (0.3 mg/dL) from previous evidences. Results: Reduced pre-operative LCRs significantly correlated with all of the well-established clinicopathological factors for disease development, including advanced T stage, venous invasion, lymphatic vessel invasion, lymph node metastasis hepatic metastasis, peritoneal metastasis, distant metastasis, and advanced tumor-node-metastasis stage. In the short-term outcome, low pre-operative LCR was an independent predictive factor for post-operative surgical site infection (SSI: OR:1.82, 95.0% CI:1.06–3.12, P = 0.03). In the long-term outcome, low pre-operative LCR was an independent prognostic factor for disease-free survival (DFS: HR:1.53, 95.0% CI:1.01–2.32, P = 0.04) and overall survival (OS: HR:2.03, 95.0% CI:1.42–2.90, P < 0.001), and prognostic impact of pre-operative LCR were verified in patients with metastatic and non-metastatic gastric cancer using the same cut-off value. Furthermore, our developed scoring system using lymphocyte and CRP could also demonstrated all of clinical significance using same difinite cut-off value in GC patients (SSI: OR: 4.43, 95.0% CI:1.75–11.2, P = 0.002; DFS: HR: 3.82, 95.0% CI:1.81–8.06, P < 0.001; OS: HR:2.88, 95.0% CI:1.48–5.61, P = 0.002). Conclusions: Assessment of lymphocytes and CRP could aid physicians in determining surgical risk, and oncological risk, thus faciliating appropriate peri-operative and post-operative management of patients with gastric cancer.
A randomized, double-blinded, placebo-controlled multicenter phase II trial of adjuvant immunotherapy with tecemotide (L-BLP25) after R0/R1 hepatic colorectal cancer metastasectomy (LICC): Final results.
Authors: Schimanski Carl Christoph , Kasper Stefan , Hegewisch-Becker Susanna , Schroeder Jan , Overkamp Friedrich , Kullmann Frank , Bechstein Wolf Otto , Vöhringer Matthias , Oellinger Robert , Lordick Florian , Heinemann Volker , Geissler Michael , Schulz-Abelius Armin , Linz Bernhard , Bernhard Helga , Schoen Michael R. , Greil Richard , Smith-Machnow Victoria , Schmidtmann Irene , Moehler Markus Hermann
Published: January 2019

480

Background: Hepatic metastasectomy is the only potential curative treatment option for stage IV colorectal cancer (CRC) limited to liver metastases (LM). After R0 resection of LM the high recurrence rate remains a major challenge. L-BLP25 is an antigen-specific cancer vaccine targeting mucin 1 (MUC1). The LICC trial aimed to improve survival outcome in mCRC patients (pts) after R0/R1 LM resection. Methods: This LICC trial, a binational, multicenter, double-blinded, placebo controlled phase II trial, included pts with stage IV LM limited CRC after resection of primary tumor and LM (R0/R1) within the last 8 weeks, ECOG 0/1 and adequate organ function. Pts were 2:1 randomized to receive L-BLP25 or placebo. L-BLP25 930 µg was administered as 8 weekly subcutaneous doses followed by 6 week maintenance intervals until recurrence or a maximum of 2 years. Cyclophosphamide 300 mg/m2 (CP) or matching saline (NS) was given intravenously 3 days prior to first L-BLP25/placebo. Co-primary endpoints were recurrence-free survival (RFS) and 3-year overall survival (OS), secondary endpoints were RFS and OS in subgroups with different MUC1 expression and safety. Differences in RFS and OS were analyzed with exploratory log-rank tests on the intention-to-treat population. Results: Of 121 pts enrolled between Oct 2011 and Dec 2014, 79 pts received L-BLP25+CP, 42 placebo+NS. Baseline characteristics were well balanced. Median age was 60 years. Median RFS was 6.1 (90% CI: 5.8-8.8) vs. 11.4 months (90% CI: 5.0-20.3) and estimated 3-year OS rate 69.1% vs. 79.1% for L-BLP25 and placebo, respectively. Two-factorial Cox regression models showed no impact of MUC1 expression or treatment on RFS or OS. The most common L-BLP25-related grade 3/4 adverse events were diarrhea, anemia and back pain. There was one death in the L-BLP25 arm due to Merkel cell carcinoma assessed by the investigator as being potentially related to vaccination. Conclusions: The LICC trial failed to meet its primary endpoint of significantly improving RFS and OS with L-BLP25. MUC1 expression was not associated with outcome. Clinical trial information: NCT01462513 . Clinical trial information: NCT01462513.
CCTG CO.26 trial: A phase II randomized study of durvalumab (D) plus tremelimumab (T) and best supportive care (BSC) versus BSC alone in patients (pts) with advanced refractory colorectal carcinoma (rCRC).
Authors: Chen Eric Xueyu , Jonker Derek J. , Kennecke Hagen F. , Berry Scott R. , Couture Felix , Ahmad Chaudhary E. , Goffin John R. , Kavan Petr , Harb Mohammed , Colwell Bruce , Samimi Setareh , Samson Benoit , Abbas Tahir , Aucoin Nathalie , Aubin Francine , Koski Sheryl L. , Wei Alice Chia-chi , Magoski Nadine M , Tu Dongsheng , O'Callaghan Christopher J.
Published: January 2019

481

Background: D is a human monoclonal antibody (mAb) that inhibits binding of programmed cell death ligand 1 (PD-L1) to its receptor. T is a mAb against the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Targeting both PD-L1 and CTLA-4 may have additive/synergistic activity as the mechanisms of action of CTLA-4 and PD-L1 inhibition are non-redundant. This study evaluated whether combining PD-L1 and CTLA-4 inhibition would lead to improved pt survival vs BSC alone in rCRC. Methods: Pts with rCRC were randomized 2:1 to D+T vs BSC . Pts were eligible if they failed all standard regimens; containing a fluoropyrimidine, irinotecan and oxaliplatin (and an EGFR inhibitor if Ras wild type). Prior treatment (Tx) with anti-VEGF agents or TAS-102 was permitted but not mandatory. Tx consisted of D (1500 mg) D1 q 28 days and T (75 mg) D1 for first 4 cycles, and all appropriate supportive measures. Primary endpoint was overall survival (OS) and a two-sided p-value < 0.10 was considered statistically significant. Results: Between August 2016 and June 2017, 180 pts were enrolled and 179 treated as randomized. Pt baseline characteristics were balanced. 85% of pts received ≥ 90% of planned doses of D and T. No pts with known defective mismatch repair (dMMR) tumors were enrolled. With a median (med) follow-up of 15.2 months (mo), the med OS was 6.6 mo for D+T and 4.1 mo for BSC (p = 0.07; Hazard ratio (HR): 0.72, 90% confidence interval (CI): 0.54–0.97). Med progression free survival was 1.8 mo and 1.9 mo respectively (HR 1.01, 90% CI 0.76–1.34; p=0.97). Disease control rate was 22.7% for D+T and 6.6% for BSC (p = 0.006). Grade 3/4 abdominal pain, fatigue, lymphocytosis and eosinophilia were significantly higher in D+T. At 16 weeks, there was significantly less deterioration on EORTC QLQ-C30 physical function for D+T. Confirmation of MMR status is ongoing. Conclusions: D+T significantly prolonged OS in pts with rCRC and preserved quality of life. Adverse events were more frequent with D+T. This is the first study showing that combined PD-L1 and CTLA-4 inhibition prolongs survival in pts with advanced refractory CRC not selected for dMMR. Clinical trial information: NCT02870920.
Circulating tumor cell count from a blood sample for colorectal cancer (CRC) prevention: A 627-patient prospective study.
Authors: Tsai Wen-Sy , Watson Drew , Chang Ying , Hsieh Ben , Shao Hung-Jen , Wu Jen-chia , Lai Jr-Ming , Chang Shih-En , Javey Mana , Mei Rui , Nimgaonkar Ashish
Published: January 2019

485

Background: Up to 25% of patients with adenomas progress to having colorectal cancer. If detected early, adenomas can be removed with a diagnostic colonoscopy procedure, preventing cancer. Invasive colonoscopy is the only screening method with the sensitivity to accurately detect adenomas, but has a low compliance rate of 38% for screening. Available non-invasive tests (including stool-based multi-analyte tests) have very limited sensitivity for adenomas. Hence, there is an unmet need for a non-invasive test for adenoma detection. Methods: IRB-approved prospective study was conducted in 627 subjects 50 years or older- recommended for routine CRC screening- 405 subjects had adenoma or CRC, confirmed by colonoscopy with tumor biopsy. Two mL peripheral blood was processed using the CellMax biomimetic platform (CMx), which uses a microfluidic biochip to enumerate circulating tumor cells (CTCs). Nominal logistic regression was used to assess performance while proportional odds logistic regression and Cuzick’s trend test were used to determine association of CTC counts with cancer stage. Results: An increase in CTC count was significantly correlated with an increase in disease burden (Cuzick’s Test p-value < 0.0001). Furthermore, there was a significant association between CTC counts and stages of adenoma-carcinoma progression (Likelihood ratio p-value < 0.0001). The CTC enumeration was able to differentiate between healthy and diseased patients (adenoma + cancer). Conclusions: To the best of our knowledge, these are the first reported results for a blood test that has high accuracy for adenoma detection, and truly enables colorectal cancer prevention. This test can be administered in the primary care setting and drive high compliance.[Table: see text]
Immunoscore clinical utility to identify good prognostic colon cancer stage II patients with high-risk clinico-pathological features for whom adjuvant treatment may be avoided.
Authors: Galon Jerome , Hermitte Fabienne , Mlecnik Bernhard , Marliot Florence , Bifulco Carlo Bruno , Lugli Alessandro , Nagtegaal Iris D. , Hartmann Arndt , Van Den Eynde Marc , Roehrl Michael H. A. , Ohashi Pamela S , Zavadova Eva , Torigoe Toshihiko , Patel Prabhudas S. , Wang Yili , Kawakami Yutaka , Marincola Francesco , Ascierto Paolo Antonio , Fox Bernard A. , Pages Franck
Published: January 2019

487

Background: Immunoscore Colon is an IVD test predicting the risk of relapse in early-stage colon cancer (CC) patients, by measuring the host immune response at the tumor site. It is a risk-assessment tool providing independent and superior prognostic value than the usual tumor risk parameters and is intended to be used as an adjunct to the TNM classification. Risk assessment is particularly important to decide when to propose an adjuvant (adj.) treatment for stage (St) II CC patients. High-risk stage II patients defined as those with poor prognostic features including T4, lymph nodes < 12, poor differentiation, VELIPI, bowel obstruction/perforation can be considered for adj. chemotherapy (CT). However, additional risk factors are needed to guide treatment decisions. Methods: A subgroup analysis was performed on the St II untreated patients (n = 1130) from the Immunoscore international validation study (Pagès The Lancet 2018). The high-risk patients (with at least 1 clinico-pathological high-risk feature) were classified in 2 categories using pre-defined cutoffs: Low Immunoscore versus High Immunoscore and their five-year time to recurrence (5Y TTR) was compared to the TTR of the low-risk patients (without any clinico-pathological high-risk feature). Results: Among the patients with high-risk features (n = 630), 438 (69.5%) had a High Immunoscore with a corresponding 5Y TTR of 87.4 (95% CI 83.9-91.0), statistically similar (logrank pv not stratified p > 0.42, wald pv stratified by center p > 0.20) to the TTR 89.1 (95% CI 86.1-92.1) observed for the 500 low-risk patients (with no clinico-pathological feature). Furthermore, 5Y TTR for these patients were statistically similar to those of St II patients with high-risk features and a High Immunoscore (n = 438), who received adj. CT (n = 162) (5Y TTR of 83.4 (95% CI 77.6-89.9). Conclusions: These data show that despite the presence of high-risk features that usually trigger adj. treatment, when not treated with CT, a significant part of these patients (69.5%) have a recurrence risk similar to the low risk patients. Therefore, the Immunoscore test could be a good tool for adj. treatment decision in St II patients.
Epidemiological trends of HPV-related anal cancers amongst males globally: A systematic literature review.
Authors: Walia Anuj , Wang Xuan , Nicholson Martha , Sun Lucy , Wong Jessica R. , Eriksson Jennifer , Kothari Smita , Morais Edith
Published: January 2019

492

Background: Anal cancer is associated with human papillomavirus (HPV), a sexually transmitted infection, which can be prevented by the HPV vaccination. Few countries do recommend vaccination for the male population, but all males are at risk of contracting HPV. This study aimed to identify the latest evidence on the incidence of anal cancer and pre-cancer related to HPV in males globally and to analyze the epidemiological trends. Methods: A systematic literature search was performed using Medline and EMBASE. Studies containing original anal cancer incidence data in males published between January 1, 2008 and March 23, 2018 in English were included. Results: The global incidence of anal cancers and pre-cancers among the general male population was identified in 25 studies with observations ranging between 1968 and 2014. Incidence over time was reported in Australia and Europe. In an Australian national study, anal cancer incidence increased from 0.77 to 1.3 per 100,000 persons from 1982-2005, and in the UK from 0.79 to 1.06 per 100,000 persons from 1962-2002. In Denmark, the anal cancer range increased from 0.20-0.41 to 0.69-1.3 per 100,000 person-years (PYs) from pre-2000 to post-2000, and in France from 0.2 to 0.5 per 100,000 PYs from 1982-2012. In two national US studies, the mean incidence of pre-cancers was 1.5 in the period 1997-2009, and 0.41 from 1978-2007 per 100,000 PYs. The burden of anal cancers and pre-cancers increased the most among high-risk males reported in US studies. For HIV-positive males, mean incidence of cancer increased from 10.5 during 1980-1989 to 42.3 in 1996-2004 per 100,000 PYs, and for HIV-positive MSM, incidence increased from 47 to 270 per 100,000 PYs between 1984 and 2013. The mean pre-cancer incidence among HIV-positive males increased from 1.7 during 1980-1989 to 29.5 in 1996-2004 per 100,000 PYs. Conclusions: This systematic literature review demonstrates the increase in anal cancer and pre-cancer incidences over time in men, especially in high-risk male populations. The burden of anal cancers and pre-cancers increase over time in all male populations highlights the unmet medical need and the importance of preventative interventions such as HPV gender-neutral vaccinations.
Use of MLH1 methylation analysis versus BRAF V600E mutation testing to select patients for Lynch syndrome genetic testing in a Chinese population: A large consecutive cohort study.
Authors: Wang Wenmiao , Dong Lin , Zou Shuangmei , Lu Ning
Published: January 2019

493

Background: Within MLH1-deficient colorectal cancer (CRC), BRAF mutation and MLH1 promotor hypermethylation strongly suggest a sporadic origin, providing exclusion criteria for Lynch syndrome (LS). However, the prevalence of BRAF mutation in Chinese CRCs are lower than that reported in Western countries, leading to concerns on the specificity of BRAF mutation for LS screening. The aim of this study was to assess the clinical usefulness of BRAF V600E mutation tesing and MLH1 promoter hypermethylation analyses to improve the yield of the diagnostic algorithm for discriminating LS in Chinese population. Methods: 4104 consecutive patients who had undergone surgery for CRCs between December 2011 and December 2014 in Chinese National Cancer Center were reviewed. 169 patients with MLH1 deficiency were analyzed. The MLH1 methylation status was evaluated by methylation-specific PCR; the BRAF mutation status was assessed by real-time PCR. Germline mutation testing was performed on 28 patients with BRAF-negative staining/MLH1 hypermethylation and family cancer history. Results: 52.9% (89/169) of patients displayed MLH1 hypermethylation. However, the BRAF mutation was found in 17.2% (29/169) of patients, and only 29.2% (26/89) of CRCs displaying MLH1 promoter hypermethylation harbored BRAF mutation, much lower from that reported by the western countries. Somatic methylation was identified in five LS patients. A CRC history in at least one first-degree relative had an outstanding ability to select patients with MLH1 hypermethylation for germline mutation testing, with 100% sensitivity and 82.6% specificity. Conclusions: The prevalence of BRAF mutation in Chinese CRCs are lower than that reported in Western countries leading to a decreased efficacy on triage patients for germline mutation. On the countary, MLH1 methylation analysis can improve the diagostic yield of LS, therefore play an indispensable role in LS screening among Chinese population.
Population pharmacokinetics (popPK) of Sym004 to evaluate the effect of intrinsic and extrinsic factors on exposure in metastatic colorectal cancer (mCRC).
Authors: Alifrangis Lene , Schoemacker Rik , Skartved Niels Jorgen Ostergaard , Hald Rikke , Düring Maria , Montagut Clara , Argiles Guillem , Kopetz Scott , Horak Ivan David , Kragh Michael , Wade Janet R
Published: January 2019

496

Background: Sym004 consists of two anti-EGFR monoclonal antibodies (futuximab and modotuximab) directed against non-overlapping epitopes in the EGFR domain III. Sym004 induces rapid and efficient removal of the EGFR from the cancer cell surface by triggering EGFR internalization and degradation and has shown promising efficacy in mCRC patients. Based upon a post-hoc analysis of a Phase 2 study, a Phase 3 trial in genomically selected mCRC patients is in preparation. Methods: The aim was to establish a popPK model for Sym004 in order to i) evaluate impact of covariates (intrinsic and extrinsic factors) on Sym004 exposure and ii) provide exposure metrics for a PK/PD analysis. Sym004 serum concentrations were obtained from 330 patients with mCRC (n = 247) or advanced solid tumors (studies Sym004-01, Sym004-02, Sym004-05 and Sym004-06). Sym004 (0.4-18 mg/kg) was dosed by i.v. infusion weekly or every 2nd week, or as a 9 mg/kg loading dose followed by 6 mg/kg weekly (9/6 mg/kg weekly). Non-linear mixed effects modelling was done in NONMEM v7.3.0. Covariates evaluated included body weight, age, sex, race, albumin, renal function, hepatic function, tumor type and size, ECOG and previous anti-EGFR treatments. Results: The base popPK model was a 2-compartment model with linear and non-linear Michaelis-Menten-type elimination and a priori inclusion of body weight on CL, Vmax, V1 and V2. The model captured the non-linear PK well. The final covariate model retained covariates whose point estimates were outside the range of 0.8 to 1.25 and whose 90% confidence intervals did not overlap with the null value and included only body weight and albumin. Inter-individual variability was estimated for CL, Vmax and V1 and was in the range of 18-30%. Simulations were used to assess the clinical relevance of the covariates as judged by the magnitude of the change in exposure of the Phase 3 dose regimen of 9/6 mg/kg weekly. Conclusions: The popPK model described the Sym004 PK data well. No covariates were present that changed the Sym004 exposure in a clinically significant manner which would necessitate a dose modification. The model is suitable for simulating the Sym004 PK for PK/PD analyses. Clinical trial information: NCT01117428,NCT01417936,NCT02083653,NCT01955473.
Outcomes of younger patients diagnosed with locally advanced rectal cancer.
Authors: Habib Rosemary , Gebski Val , Toh James , Pathma-Nathan Nimalan , Khoury Toufic El , Ctercteko Grahame , Jayamohan Jayasingham , Wong Ka Yeung Mark , Wilcken Nicholas , Nagrial Adnan
Published: January 2019

500

Background: The incidence of rectal cancer is higher in the older population. In developed nations there has been a rise in incidence in young onset rectal cancer (yRC). We evaluated and compared the presentation and survival outcomes of treatments for locally advanced rectal cancer in yRC patients to that of older patients. Methods: All cases of rectal cancers referred to a large tertiary referral cancer centre in Western Sydney between 2009-2016 were examined. Patient demographics, presenting symptoms, treatment, clinico-pathological characteristics, progression free survival (PFS) and overall survival (OS) were obtained. Under 50 years old was used as the cut-off age for defining yRC. Results: One hundred sixty-two patients were identified, 33 in the yRC and 129 in the older patient group. The median age at diagnosis was 62 (24 – 92). Median follow-up was 40 months. There was no difference in presenting symptoms between the two groups, with per rectal bleeding being the most common symptom at presentation. 17.5% of yRC presented with stage IV disease, compared with 22.1% of older patients. yRC were more likely to complete neoadjuvant therapy (97% vs 81%; P=0.02). yRC were more likely to proceed to surgery (91% vs 72%, P=0.02). There were no significant differences in surgical outcomes, including complications and postoperative TNM staging. yRC were more likely to have microsatellite high tumours (18% vs 4%; P=0.01). No statistical differences were seen in survival outcomes (PFS 57.1 vs 62.9 months, P=0.26; OS 85.1 Vs 92.8 months, P=0.57) between older and yRC patients. Eight progressions (eight deaths) were observed in the yRC group and 40 progressions (36 deaths) were observed in the older patient group. Conclusions: 20% of rectal cancers were considered yRC. These patients were more likely to complete neoadjuvant therapy and proceed to surgery. In this cohort, median PFS and OS were longer compared to the older patient group, although this was not statistically significant. yRC were more likely to have MMR deficiency. Patients under 50 years with alarm symptoms including per rectal bleeding require vigilance in investigations to allow for earlier detection and appropriate management of rectal cancer.
Safety of compression therapy using newly developed gloves for oxaliplatin induced neuropathy prevention.
Authors: Koyama Yukinori , Morioka Michina , Tobaru Yuri , Sakura Yusuke , Fukumoto Mikiko , Nagamine Ayana , Hattori Kuniaki , Taira Itsuki , Shimada Norimitsu , Kawakami Koshi , Tsuyuki Shigeru , Kanazawa Akiyoshi
Published: January 2019

501

Background: Oxaliplatin (l-OHP) is a key drug commonly used in primary and metastatic colorectal cancer treatment. However, l-OHP is associated with non-hematological adverse effects, including peripheral neuropathy (PN). About 90% of patients who received l-OHP experience PN after single dose of l-OHP and PN is likely to be negatively associated with quality of life. There is no established effective prophylactic management for chemotherapy induced PN according to the 2014 American Society of Clinical Oncology (ASCO) guideline. Recently, compression of hands during injection of drugs has been reported to be effective for chemotherapy induced PN. We developed new gloves for compression therapy which are reusable and low cost. We prospectively analyzed the safety of the gloves. Methods: Patients who received l-OHP were eligible for this phase Ⅰ study. Wrist and hand size were measured and appropriate size of gloves were selected. The pressure of hands is estimated as 20-33 hPa. Patients start to wear the gloves on both hands, from 30 min before the injection of l-OHP until 30 min after the injection. Peripheral neuropathy was evaluated at each treatment cycle using common terminology criteria for adverse events (CTCAE) version 4.0. Results: Between October 2017 and August 2018, fourteen patients (median age 66 years [range 39– 79years], 7 male and 7 female) were enrolled and were evaluated. No patients withdrew from this study. No safety concerns were identified for any safety variables assessed during the trial. CTCAE grade 2 or higher sensory PN was observed in four (28.6%) patients. The average time until grade 1 or more neuropathy appeared was 27.8 days and average dose of l-OHP was 225mg. Conclusions: Compression therapy by the new gloves had no safety concerns, demonstrating a profile favorable for further development for prevention of oxaliplatin induced PN. Clinical trial information: 000029671.
Survival outcomes of left-sided versus right-sided colon cancer.
Authors: Gowarty Jasmine Lizette , Durham Charis , Wong Lucas , Chen Wencong
Published: January 2019

502

Background: Right-sided colon cancers (RCC) are defined up to the splenic flexure where as left-sided colon cancers (LCC) involve the descending, sigmoid, and rectosigmoid regions. The landmark CALGB/SWOG 80405 study concluded that sidedness was an independent prognostic factor for survival in stage IV adenocarcinoma of the colon or rectum, with a poorer prognosis in RCC. This raises the question as to whether or not stage of malignancy plays a role. We performed a retrospective analysis on survival for stage I to IV colon cancer treated at our institution in order to assess if tumor location is an independent prognostic factor as described in previous studies. Methods: Primary site of cancer, sex, age at diagnosis, vital status, and year of diagnosis for stage I, II, III, and IV colon cancer was collected from our institution’s tumor registry from 2007 to 2017. The inclusion criteria included those diagnosed with stage I to IV colon cancer at 18 years of age and above. Exclusion criteria included a diagnosis of both RCC and LCC and patients under age 18. The median of overall survival and time to recurrence between LCC and RCC were compared using Wilcoxon Rank Sum Test with two-sided significance level at 0.05. Results: Time to overall survival and time to recurrence was shown to have no significant difference between RCC and LCC (p = 0.3398 and 0.9467, respectively). Cox proportional hazards model adjusted for age and sex also support the claim (p = 0.1725 and 0.0633). There was a statistically significant difference in age between the two groups with the older mean age seen in RCC (68 versus 62). The distribution of recurrence was statistically significant with a higher recurrence in RCC (p = 0.0105). Conclusions: Unlike CALGB/SWOG 80405, our analysis included the transverse colon as part of RCC and examined stage I to IV colon cancer to ultimately conclude that there was no significant difference in overall survival or time to recurrence. Our study suggests that tumor location is not an independent prognostic factor on survival for all stages of colon cancer. However, a higher suspicion for recurrence may be needed for those diagnosed with RCC. Future investigations involving molecular subtypes and mutations are needed to further clarify prognosis and tumor sidedness.