bluuebunny/crossref_metadata_2025 huggingface dataset:
Nintedanib versus placebo in patients receiving mFOLFOX6 for metastatic, chemorefractory colorectal cancer: TRICC-C trial—Final results from the randomized phase II trial of the AIO.
Authors: Ettrich Thomas Jens , Berger Andreas Wolfgang , Decker Thomas , Hofheinz Ralf , Heinemann Volker , Hoffmann Thomas , Hebart Holger Frithjof , Herrmann Thomas , Hannig Carla Verena , Buechner-Steudel Petra , Guethle Melanie , Bartholomaeus Hanna , Beutel Alica , Perkhofer Lukas , Seufferlein Thomas
Published: January 2019

666

Background: Anti-VEGF agents plus chemotherapy improve PFS of patients with mCRC in the first- and second-line-setting. During this treatment tumour angiogenesis is driven by other factors but VEGF. Nintedanib, a triple angiokinase inhibitor of VEGFR-1-3, FGFR-1/-3 and PDGFR-α/-β, thereby additionally targets angiogenic escape mechanisms upon resistance to anti-VEGF treatment. The TRICC-C trial evaluates the combination of mFOLFOX6 plus Nintedanib. Final results of the randomized phase II trial are presented. Methods: Patients with mCRC having received one line of non-oxaliplatin containing palliative chemotherapy, with an ECOG-PS of 0/1 were randomized 1:1 in a double-blind design to receive: mFOLFOX6 plus Nintedanib (2 x 200 mg p.o./d, d1-d14) or placebo, respectively, repeated every 14 days. Primary endpoint was PFS. Secondary endpoints were ORR, OS and safety. Patients who received at least one dose of trial medication were included in the efficacy and safety analyses. Results: From 12/2012 to 5/2016 53 patients (scheduled n = 180) were randomized. The trial was terminated prematurely due to slow accrual. Compared to mFOLFOX6 plus placebo (F+P), the combination of mFOLFOX6 plus Nintedanib (F+N) improved mPFS (F+P: 4.6 vs. F+N: 8.1 mo.; HR 0.65; 95% CI 0.32-1.30; p = 0.2156), mOS (F+P: 9.9 vs. F+N: 17.1 mo.; HR 1.03, 95% CI 0.48-2.23; p = 0.9387) and DCR (F+P: 50 vs. F+N: 66,7%; p = 0.2709). ORR was comparable in both arms (F+N: 3.8 vs. F+P: 3.7%). Toxicity was low to moderate without major differences between both arms except G 3/4 neutropenia (F+N: 19%, F+P: 12%) and GI disorders (F+N: 23%, F+P: 15%). Conclusions: Final results suggest a PFS, OS and DCR benefit for mFOLFOX6 + Nintedanib in the second-line therapy of mCRC. Due to the premature termination of the trial there was no statistical significance demonstrable. Showing no clinically significant PFS-benefit in the first-line situation (mFOLFOX6 plus Nintedanib/Bevacizumab, Ann Oncol. 2015) or the last line as single agent, respectively (ESMO 2016) the TRICC-C results suggests that Nintedanib plus mFOLFOX6 could be an interesting therapeutic option for the second-line situation. Clinical trial information: NCT01362361.
Integrating geriatric assessment into routine gastrointestinal (GI) consultation: The Cancer and Aging Resilience Evaluation (CARE).
Authors: Williams Grant Richard , Kenzik Kelly , Parman Mariel , Rocque Gabrielle Betty , McDonald Andrew Michael , Paluri Ravi Kumar , Navari Rudolph M. , Nandagopal Lakshminarayanan , Smith Crystal Young , Robertson Matthew , Bhatia Smita
Published: January 2019

667

Background: Integrating Geriatric Assessment (GA) in the management of older adults with cancer is recommended, yet rarely practiced in routine oncologic care. In this report, we describe the feasibility of integrating the routine incorporation of GA in the management of older adults with GI malignancies and characterize GA impairments. Methods: CARE was adapted from the Cancer and Aging Research Group GA with modifications to create a completely patient-reported version. The CARE assesses self-reported functional status, physical function, nutrition, social support, anxiety/depression, cognitive function, comorbidities, and social activities. Patients ≥ 60yo referred for consultation to the GI Oncology clinic were asked to complete the CARE (paper/pencil) on their first visit. The completed CARE was collected during nurse triage and submitted to the clinical team prior to the physician encounter. Feasibility was defined as completion of the CARE by ≥ 80% of eligible patients during the initial consultation. Results: Between September 2017 and August 2018, 199 eligible new patients attended the GI Oncology Clinic, 192 (96.5%) were approached, and 181 (90.4%) completed the CARE. Most patients (79.6%) felt the length of time to complete was appropriate (median time of 10 minutes [IQR 10-15 minutes]). The mean age was 70y (range 60-96), 54.3% were male, and 75.1% were non-Hispanic white. Common tumor types included colon (27.8%), pancreatic (21.2%), and rectal (10.2%) cancer; predominately advanced stage diseases (stage III: 26.9%; stage IV: 40.0%). GA impairments were prevalent: 48.6% reported dependence in Instrumental Activities of Daily Living, 18.0% reported dependence in Activities of Daily Living, 22.5% reported ≥ 1 fall, 29.4% reported a performance status ≥ 2, 51.3% were limited in walking one block, 75.7% reported polypharmacy (≥ 4 medications), and 84.3% had ≥ 1 comorbidity. Conclusions: Performing a GA in the routine care of older adults with GI malignancies is feasible, and GA impairments are common among older adults with GI malignancies. A fully patient-reported GA such as the CARE may facilitate broader incorporation of GA in the routine clinic work flow.
Activated interferon-γ (IFN-γ) pathway associated with clinical benefit to programmed cell death protein-1 (PD-1)/PD ligand 1 (PD-L1)-based therapy in esophageal squamous cell carcinoma (ESCC).
Authors: Guo Jhe-Cyuan , Hsieh Min-Shu , Lin Chia-Chi , Huang Ta-Chen , Chang Chun-Jung , Hsu Chih-Hung
Published: January 2019

67

Background: Previous studies indicate a preexisting T cell response and the associated “adaptive immune resistance” are critical for the clinical efficacy of anti-PD-1/PD-L1 immunotherapy. The study explored the activated IFN-γ pathway and the expression of interferon regulatory factor 1 (IRF-1), as surrogates of preexisting T cell response, as potential biomarkers associated with clinical benefit (CB) for ESCC patients receiving anti-PD-1/PD-L1 therapy. Methods: Thirty-one ESCC patients treated with PD-1/PD-L1 blockade antibody, alone or in combination, were enrolled. Tumor response evaluation was made according to Response Evaluation Criteria in Solid Tumours 1.1, and CB was defined as complete response, partial response or stable disease at least 6 months. Formalin-fixed paraffin-embedded tissues from 31 patients were analyzed for the expression of PD-L1 and IRF-1 by immunohistochemistry; 13 tissues were analyzed for the expression of immune-related genes by NanoString nCounter Human PanCancer Immune Profiling. Results: Of 31 enrolled patients (M: F= 30: 1, median age of 58), 23 and 8 were of recurrent and de novo metastatic ESCC. Sixteen and 15 received PD-1/PD-L1 blockade alone and PD-1/PD-L1-based combination therapy, respectively; 13 had received at least 2 lines of systemic therapy for advanced disease. The response rate was 10%, and the CB rate was 16%. The median progression-free-survival (PFS) and overall survival are 1.8 and 5.6 months, respectively. The 25-gene IFN-γ signature was significant higher in patients with CB than in patients without CB ( P = 0.020). Neither PD-L1 expression on tumor cells (TC) nor on immune cells (IC) was associated with CB ( P = 0.489 and 0.646, respectively). However, the IRF-1 expression on TC or on IC was significantly associated with CB ( P < 0.001 and 0.005, respectively). Conclusions: Activated IFN-γ pathway determined by 25-gene IFN-γ signature and high IHC-expression of IRF-1 were associated with CB in advanced ESCC patients receiving anti-PD-1/PD-L1-based therapy. (Supported by the grant of MOST 105-2314-B-002 -186 -MY3).
The impact of multidisciplinary team (MDT) management on outcome of hepatic resection in liver-limited colorectal metastases.
Authors: Corallo Salvatore , Calegari Maria Alessandra , Zurlo Ina Valeria , Marchesani Silvio , Orlandi Armando , Dadduzio Vincenzo , Di Stefano Brunella , Camarda Floriana , Di Dio Carmela , Garufi Giovanna , Barbaro Brunella , Vellone Maria , Ardito Francesco , Giuliante Felice , Pozzo Carmelo , Cassano Alessandra , Barone Carlo Antonio , Bria Emilio , Basso Michele
Published: January 2019

671

Background: Hepatic resection is the gold standard treatment for pts with liver-limited mCRC with 5- and 10-yrs survival rates reaching up to 60% and 20%. Although multidisciplinary team (MDT) management might ensure a more accurate assessment of pts and a faster referral to surgeons, reports discussing the impact of MDTs on survival are controversial and to date there are no strong evidences supporting routinely MDT discussion. The aim of this study was to evaluate the benefit of MDT management in pts with liver-limited mCRC in our single institution experience. Methods: Clinical records of pts with liver-limited mCRC who underwent radical surgery at Fondazione Policlinico “A. Gemelli” - IRCCS from Jan-2006 to Dec-2016 were retrospectively analyzed. The objective of the analysis was to compare survivals of pts managed within our MDT (MDT cohort) to those of pts referred to surgery from other hospitals without MDT discussion (non-MDT cohort). Primary endpoints were DFS and OS. Differences in baseline characteristics and in post-operative morbidity were evaluated. Results: Of the 619 pts analyzed, 230 were included in the MDT cohort and 389 in the non-MDT cohort. No significant difference between the two groups was found in terms of DFS (12vs11 m; p 0.09) and OS (55vs51 m; p 0.68). Concerning baseline characteristics, in the MDT cohort compared to non-MDT cohort there was a statistically higher number of median metastases (4.5vs2.6; p < 0.0001) and a higher rate of synchronous metastases (61.7vs39.3%; p < 0.001). Despite pre-operative CT rate was higher in the MDT group (75.8vs70.7%), the median duration of CT before surgery was significantly lower in MDT pts (7 vs 8 cycle; p < 0.001). Moreover, post-operative morbidity was significantly lower in the MDT cohort (6.2vs19.2%; p < 0.00001). Conclusions: Our study does not demonstrate a survival benefit from MDT management of pts with liver limited mCRC. However, the analysis shows that MDT assessment allows to consider eligible for surgery pts with a more advanced disease. Moreover, MDT discussion seems to reduce the median duration of pre-operative CT with a consequent lower rate of post-operative morbidities. Our data warrant prospective validation.
Predictors of survival in rectal squamous cell carcinoma: An analysis from the National Cancer Database (NCDB).
Authors: Tella Sri Harsha , Kommalapati Anuhya , Goyal Gaurav , Mahipal Amit
Published: January 2019

672

Background: Rectal squamous cell carcinoma (RSCC) is a rare form of gastrointestinal malignancy. Using the NCDB, we determined the prognostic factors and survival outcomes of RSCC in the United States. Methods: We identified histologically confirmed cases of RSCC from the National Cancer Data Base (2004-2015). Univariate and multivariable methods were used to assess factors associated with survival. Kaplan-Meier method and log-rank test were used to perform overall survival (OS) analysis. Results: Of the 5,527 cases included in our analysis, 67% were female. Median age at diagnosis was 61 years and did not differ by sex. The proportion of patients with stage 1, 2, 3 and 4 diseases were 22%, 16%, 20%, and 11%, respectively (30% unknown stage). Among the ones who received surgical resection of primary tumor, 41%, 30%, 20% and 8% are of stages 1, 2, 3 and 4 respectively. The rate of R0 resection was 54%, 63%, 55% and 38% in stage 1, 2, 3 and 4, respectively. The R0 resection rate was much higher in patients who received neoadjuvant chemo or radiation therapy or both (87%, 78%, 74%, and 57% in stages I, 2, 3 and 4, respectively) as compared to that of their counterparts. On stage wise sub-group OS analysis, stage 1-3 patients had OS benefit from surgery (as compared to no-surgery) (145 vs 90 months, p<0.001) as opposed to 4 disease (16 vs 11 months, p=0.06). Adjuvant radiation therapy improved the median OS in stage 1-3 patients (as compared to no-adjuvant radiation) in patients with positive surgical margins (not reached vs 40 months, p<0.0001). Patients with stage 4 disease treated with radiation therapy had a better median OS than those without (16 vs 6 months, p<0.0001). On therapy wise sub-group analysis, the patients who received surgery only had a median OS of 145 months; surgery + chemoradiation (adjuvant and neoadjuvant) = not reached; whereas patients with chemoradiation only had median OS of 80 months. Conclusions: This is the largest registry-based study on RSCC to date. RSCC had a diverse OS varied significantly according to stage of the disease at presentation and therapy received. Surgical resection of primary tumor was associated with improved OS as compared to that of patients who received chemoradiation.
QoL from TASCO1: Health-related quality of life of trifluridine/tipiracil-bevacizumab and capecitabine-bevacizumab as first-line treatments in metastatic colorectal cancer patients not eligible for intensive chemotherapy—Results from the TASCO1 phase II study.
Authors: Moiseyenko Vladimir , Saunders Mark P. , Wasan Harpreet Singh , Argiles Guillem , Borg Christophe , Creemers Geert-Jan , Fedyanin Mikhail , Glynne-Jones Robert , Pfeiffer Per , Punt Cornelis J. A. , Stroyakovskiy Daniil , Ten Tije Albert J. , Van de Wouw Agnes W , Kanehisa Akira , Fougeray Ronan , Sabater Javier , Amellal Nadia , Van Cutsem Eric
Published: January 2019

676

Background: TASCO1 is a phase II study which evaluated the safety and efficacy of trifluridine/tipiracil + bevacizumab (TT-B) and capecitabine + bevacizumab (C-B) in first-line unresectable mCRC patients non-eligible for intensive therapy. Promising activity was shown on progression-free survival with TT-B (9.2 months) and C-B (7.8 months). Here we present the Quality of Life (QoL) analysis of the two treatment arms. Methods: In TASCO1, patients were randomized 1:1 to receive TT-B (n = 76) on a four-week cycle or C-B (n = 77) on a three-week cycle. QoL was assessed in TASCO1 at baseline and at each 12 weeks thereafter, until discontinuation of study treatment, using the QLQ-C30 and QLQ-CR29 questionnaires. Responses were described separately in each arm using descriptive statistics. Results: For QLQ-C30, 121 patients completed baseline questionnaire. No clinically relevant difference was observed on treatment in mean change of score from baseline for the global health status, functioning scales, and for most of the symptom scales, except for nausea/vomiting and diarrhoea (worsening in the TT-B group and stable in the C-B group for both symptoms), fatigue (stable in the TT-B group and worsening in the C-B), loss appetite (worsening in the two groups) and insomnia (improvement in the two groups). For QLQ-CR29, 117 patients completed baseline questionnaire. No clinically relevant difference on treatment was observed in mean change of score from baseline for most of items except for the following: hair loss, trouble with taste (worsening for both symptoms in the TT-B group while stable for hair loss and improvement for trouble with taste in the C-B group), sore skin, dry mouth (stable in the TT-B group and worsening in the C-B group for both symptoms), and anxiety (stable in the TT-B group and improvement in the C-B group). Conclusions: The Global Health Scale was maintained in Trifluridine/tipiracil+bevacizumab arm as well as in the capecitabine+bevacizumab arm. No clinically relevant difference from baseline was observed over time in both groups except for few sub-scales. Clinical trial information: NCT02743221.
Feasibility of using a fitness tracker to assess activity level and toxicity in colorectal cancer patients.
Authors: Ward William Harrell , Meeker Caitlin R. , Hill Maureen , Handorf Elizabeth A. , Hall Michael J. , Sigurdson Elin R. , Astsaturov Igor A. , Denlinger Crystal S. , Reddy Sanjay S. , Meyer Joshua E. , Zibelman Matthew R. , Madnick David , Moccia Matthew , Dotan Efrat , Farma Jeffrey M. , Vijayvergia Namrata
Published: January 2019

684

Background: Performance status (PS) is traditionally used to predict tolerance and morbidity associated with colorectal cancer (CRC) treatment. Monitoring activity level at the start of therapy using a wearable fitness tracker (Fitbit) may provide a more accurate estimate of overall patient (pt) PS and help predict treatment-related toxicity. Methods: With IRB approval, we prospectively enrolled CRC pts undergoing therapy into two cohorts: medical (M) and surgical (S). Our primary aim was to assess the feasibility of using Fitbit to assess activity level and toxicity. After documenting baseline ECOG PS, M and S pts wore Fitbit for four days while receiving chemotherapy or prior to surgery, respectively. Pts’ mean steps per day (SPD) were calculated, excluding days Fitbit was worn < 12 hours. To stratify the prediction of toxicity risk, a cutoff of 5,000 SPD was selected and any post-operative complication (S pts) or ≥ grade 3 toxicity (M pts) was counted as toxicity. The study is ongoing to accrue 80 pts. Results: On interim analysis, 43 pts were evaluated for the primary aim. Seventy nine percent (34/43) of pts had at least 3 days with ≥ 12 hours of Fitbit usage, meeting the 75% feasibility endpoint. Forty pts (25 M, 15 S) had at least 1 day with ≥ 12 hours of Fitbit usage and had data available for analysis. Mean SPD for PS 0 and PS 1 pts was 7,183 and 3,214, respectively (p=0.01), and overall was 6,290 (SD 4,416). Eight M pts and 2 S pts experienced toxicity (Table). The rate of toxicity was 23% (7/30) in pts with PS 0 and 33% (3/10) in pts with PS 1. With SPD as cutoff, the toxicity rate was 11% (2/19) in pts with > 5000, compared to 38% (8/21) in pts with < 5000. Conclusions: We observed high rates of compliance with a fitness tracker in CRC pts. SPD serves as a useful identifier for toxicity and may be a better predictor than traditional PS. These findings provide rationale to study SPD in lieu of PS for risk stratification of patients undergoing therapy and possibly incorporate pre-habilitation programs in high-risk groups, though validation in larger studies is needed. [Table: see text]
Evaluating the prognostic significance of lymphovascular invasion in stage II and III colon cancer.
Authors: Mutabdzic Dorotea , O'Brien Shalana BL , Handorf Elizabeth A. , Devarajan Karthik , Reddy Sanjay S. , Sigurdson Elin R. , Denlinger Crystal S. , Meyer Joshua E. , Farma Jeffrey M.
Published: January 2019

685

Background: Presence of lymphovascular invasion (LVI) is known to be a predictor of lymph node involvement in colon adenocarcinoma (CA). Lymph node involvement is associated with poorer prognosis necessitating adjuvant therapy. While some studies have suggested that LVI is a predictor of worse overall survival in early stage colon cancer, the significance of LVI on prognosis has not been tested in a comprehensive North American data set. Methods: Patients with stage II and III CA with LVI data available and those who received predefined standard of care treatment were identified from the National Cancer Data Base (NCDB) from 2011 to 2015. The relationship between LVI and overall survival was tested using Kaplan-Meier survival curves and Cox proportional hazards regression analysis after adjusting for relevant clinical and demographic variables. Hazard ratios and 95% confidence intervals are reported along with median overall survival (OS) where available. Results: The dataset included 93,070 patients with stage II and 66,701 patients with stage III CA. The proportion of patients with LVI was 13% in stage II and 47% in stage III CA. After adjusting for age, sex, gender, race, comorbidities, socioeconomic status, T, and N stage, LVI was associated with worse OS in stage II, HR 1.2 (1.15-1.25, p < 0.001), and in stage III, HR 1.25 (1.21-1.30, p < 0.001), CA. Median OS was 6.51 years with LVI versus. 6.85 years without LVI in stage II compared with 6.57 years with LVI versus not reached without LVI in stage III CA. Of the stage II patients with LVI, 20% received adjuvant chemotherapy (CT) and median OS was 6.91 years for those who did versus 6.07 years for those who did not receive CT. Conclusions: Our data suggest that LVI is an important predictor of OS in stage II and III CA. There is evidence that adjuvant chemotherapy improves OS in advanced CA but there remains uncertainty as to the benefit in stage II. Despite this uncertainty, guidelines suggest consideration of adjuvant CT in patients with high-risk stage II disease. Our data support the recommendation that LVI be considered a high-risk feature in stage II disease. Further studies are necessary to examine whether the type or duration of CT should differ for patients with CA and LVI.
Dose-finding and single-arm confirmatory study of definitive chemoradiotherapy (dCRT) with S-1/mitomycin-C (MMC) in patients (pts) with clinical (c) stage II/III squamous cell carcinoma of the anal canal (SCCA): JCOG0903.
Authors: Takashima Atsuo , Ito Yoshinori , Hamaguchi Tetsuya , Mizusawa Junki , Shimada Yasuhiro , Shiozawa Manabu , Kodaira Takeshi , Ohue Masayuki , Kinouchi Makoto , Murata Kohei , Fujita Fumihiko , Watanabe Masahiko , Moriya Yoshihiro , Iinuma Gen , Ishida Fumio , Saida Yoshihisa , Matsuda Takahisa , Katayama Hiroshi , Fukuda Haruhiko , Kanemitsu Yukihide ,   Colorectal Cancer Study Group of Japan Clinical Oncology Group
Published: January 2019

686

Background: dCRT with 5-FU/MMC is a standard treatment for cStage II/III SCCA. S-1 is an oral fluoropyrimidine and has a greater effect on radiosensitivity. We conducted this trial of dCRT with S-1/MMC to determine the recommended dose (RD) of S-1 in phase I part (P I) and to evaluate the efficacy and safety in phase II part (P II) for cStage II/III SCCA. When the primary endpoint in P II part is proven to be satisfactory, we can regard this combined treatment as the new standard treatment. Methods: Eligibility criteria included histologically proven SCCA, cStage II/III (UICC 6th), PS 0-1, and age 20-80 years. dCRT consisted of MMC (10 mg/m2 on days 1, 29) and S-1 (60 mg/m2/d in level 0 and 80 mg/m2/d in level 1 on days 1-14, 29-42) with concurrent 3-dimensional RT of 59.4 Gy/33fr. The P I adopted the 3+3 cohort design. The primary endpoint of P II was proportion of 3-year event-free survival (% 3-year-EFS). The sample size was 65 in the P II, with one-sided alpha of 5% and power of 80%, threshold and expected % 3-year EFS as 60% and 75%. Results: From Feb/2010 to Mar/2015, 69 pts (3 in level 0 and 66 [7 in P I and 59 in P II] in level 1) were enrolled. Pts’s backgrounds for level 1 were as follows: M/F, 12/54; Age, median 64 (range 33-80); cStage II/IIIA/IIIB, 29/9/28. Three in level 1 were ineligible and 63 eligible assigned to level 1 were included in efficacy analysis. In the P I, considering the details of DLTs, RD of S-1 was determined as 80 mg/m2/d. In the 63 eligible of level 1, %3-year EFS was 65.0% (90% CI 54.1-73.9%). % 3-year OS, PFS, and colostomy-free survival were 87.3% (95% CI 76.2-93.4%), 85.7% (74.3-92.3%), and 76.2% (63.7-84.9%), respectively. The complete response rate was 81% on central review. Among 65 pts receiving level 1 dCRT, common grade 3 or 4 acute toxicities were leukopenia (63.1%), neutropenia (40%), diarrhea (20%), radiation dermatitis (15.4%), and febrile neutropenia (3.1%). Only 6 (9.2%) showed grade 3 late toxicities. No treatment-related deaths were observed. Conclusions: Although dCRT with S-1/MMC showed acceptable toxicities and favorable 3-year survival, this study did not meet its primary endpoint. Clinical trial information: UMIN000003237.
Phase I study of preoperative capecitabine and lenvatinib with external radiation therapy in locally advanced rectal adenocarcinoma.
Authors: Frakes Jessica , Mehta Rutika , Hoffe Sarah E. , Imanirad Iman , Martinez Jimenez Maria E , Sanchez Julian , Malafa Mokenge Peter , Felder Seth , Dessureault Sophie , Kim Richard D.
Published: January 2019

694

Background: Despite routine use of neoadjuvant chemoradiation, patients with advanced rectal tumors experience significant rates of treatment failure and recurrence. Radiation resistance is a particular problem. Dual targeting of PDGF and VEGFR (Vascular endothelial cell growth factor receptor) in combination with radiation can enhance tumor response. Lenvatinib inhibits the kinase activities of VEGFR1-3, FGFR1-4, PDGFRα, KIT, and RET and in vivo results show that it effectively delays the growth of human colorectal xenografts. Methods: This is a phase I clinical trial of lenvatinib in combination with capecitabine administered with radiation. Patients with stage II or III rectal cancer confirmed by endoscopic ultrasound or MRI were eligible for the study. In this 3+3 phase I study with 3 cohorts, patients were treated with escalating doses of lenvatinib administered in combination with standard doses of capecitabine (850 mg/m2 PO BID D1-5 weekly for 5 ½ to 6 weeks) and external beam radiation therapy (180 cGY on D1-5 weekly for 5 ½ to 6 weeks). Patients underwent surgery 6-10 weeks after neoadjuvant therapy. Results: Nine patients have been enrolled in the 3 cohorts with the median age of 51 years. Lenvatinib dosing started at 14 mg PO daily (cohort 1) and was safely escalated to 20 mg PO daily (cohort 2) followed by 24 mg PO daily (cohort 3). There were no DLTs at the maximum tested dose of lenvantinib (24 mg). 5 patients have undergone low anterior resection and 4 have had abdominoperineal resection. The pathological complete response (pCR) rate was 33.33%, and downstaging was observed in 100% of patients. Median neoadjuvant rectal cancer score (NAR) was 8.7. Three pts had grade 3 events (2 hypertension (HTN), 1 lymphopenia) without any grade 4 events. Most common AEs were HTN and fatigue. No perioperative complications were observed. Tissues for all pts have been collected for planned correlative studies. Conclusions: This study shows that the combination of lenvatinib with capecitabine, and EBRT is well tolerated. NAR score and downstaging rates are encouraging. Currently we are enrolling 10 additional pts at the maximum tested dose of lenvatinib to further evaluate efficacy and safety. Clinical trial information: NCT02935309.
Stage II and III rectal adenocarcinoma outcomes related to lymphovascular invasion.
Authors: O'Brien Shalana BL , Mutabdzic Dorotea , Handorf Elizabeth A. , Devarajan Karthik , Reddy Sanjay S. , Sigurdson Elin R. , Denlinger Crystal S. , Meyer Joshua E. , Farma Jeffrey M.
Published: January 2019

698

Background: Lymphovascular invasion (LVI) has been shown to be associated with nodal involvement and higher rates of local recurrence in rectal cancer. In some studies, the presence of LVI has also been associated with worse overall survival; however, these have been mostly smaller, single institution studies or incomplete data sets. Our goal was to examine the effect of LVI on prognosis in a large and inclusive database. Methods: Outcomes of patients with clinical stage II and stage III rectal adenocarcinoma in the National Cancer Data Base (NCDB) from 2011 to 2015, in whom LVI data was available, were included. Exclusion criteria incorporated patients who did not receive neoadjuvant radiation and chemotherapy, neoadjuvant or adjuvant. Overall survival was compared in patients with and without LVI, controlling for age, sex, race, comorbidities, socioeconomic factors, and T and N stages using Kaplan-Meier survival curves and Cox proportional hazards regression analysis. Median overall survival and hazard ratios with 95% confidence intervals are reported where available. Results: The dataset included 9206 patients with stage II and 12640 patients with stage III rectal adenocarcinoma for which LVI data were available and who received the study’s previously defined standard of care. The proportion of patients with LVI was 11% in stage II and 16% in stage III rectal cancer. After adjusting for age, sex, race, T or N stage, and other clinical and demographic variables, LVI was associated with worse overall survival in stage II HR 1.87 (1.62-2.16, p < 0.001) and in stage III HR 1.8 (1.61-2.02, p < 0.001) rectal cancer. The median overall survival was not reached in stage II rectal cancer patients without LVI versus 5.73 years with LVI. In stage III rectal cancer, the median overall survival was 6.91 years without LVI versus 6.21 years with LVI. Conclusions: Lymphovascular invasion is an independent risk factor of mortality in stage II and III rectal cancer. Stage II rectal cancer patients without LVI have comparatively good survival of the groups studied, potentially identifying a group of patients that may benefit from de-escalated therapy. Further studies will be guided at identifying if benefits with chemotherapy are associated with LVI status.
Outcomes and utilization of adjuvant chemotherapy (AT) for stage II colon cancer (CC-II) in elderly population.
Authors: Barzi Afsaneh , Jiao Xiayu , Hay Joel W , Sadeghi Sarmad
Published: January 2019

701

Background: The use of AT in elderly patients (pts) with CC-II is controversial. We used Surveillance Epidemiology End Results (SEER) linkage with Medicare claims to explore the patterns of AT and survival in pts with CC-II diagnosed between 2004-2010. Methods: Colon cancer was identified using ICD-O-3 codes. TNM staging information was used to classify pts as stage II and its subgroups. We restricted our cohort to pts who had surgery within 4 months (mos) of the diagnosis using ICD-9 codes: 45.7x and 45.8x and excluded pts who died within 3 mos after the surgery as well as those who were enrolled on a health maintenance organization. We searched Medpar, outpatient facility, or carrier claims in the 4 mos after surgery to identify pts who received AT using ICD-9 diagnosis and procedure codes, HCPCS, and revenue center codes. Logistic regression was used to assess the relationship between demographics and clinical characteristics of pts in each group and receipt of AT. Kaplan-Meier method was used for survival analysis. We performed a flexible parametric survival analysis to estimate the 3-year overall survival benefit for AT while controlling for demographics and clinical characteristics. Results: A total of 15,310 pts were included in our study. Among those, 14% (n=2,168ss received AT of which 718 (33%) received oxaliplatin containing regimen. Pts and tumor characteristics are reported in the table. After adjusting for pts and tumor characteristics, probability of survival at 3 years was 72.9% for pts who received AT and 74.2% for those who did not, HR=1.06 (95% CI, 0.96-1.17), with P-value: 0.229. The AT use was declining over time. Conclusions: Although AT is used in healthier and higher risk elderly pts with colon cancer, it was not associated with significantly improved overall survival. [Table: see text]
Neoadjuvant treatment in a Mexican cohort of patients with locally advanced rectal cancer: Oncologic outcomes and prognostic factors.
Authors: NIETO GARCIA ZULEYMA , Martos Armendáriz Edgar Omar , Camargo Vanessa Rosas , Flores Balcázar Christian Haydeé , Meneses Medina Mónica Isabel , Salgado Nesme Noel , García Badiola Artemio , Licano Zubiate Mariana , Luna González Laura Esther , Garay Mora Juan Alberto , Gamboa Domínguez Armando , Huitzil Melendez Fidel David
Published: January 2019

704

Background: Preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME) and adjuvant chemotherapy (CT) is the standard of care for locally advanced rectal cancer (LARC). Total neoadjuvant therapy (TNT) consists of induction CT followed by CRT prior to surgery. This is an alternative strategy recommended in guidelines. Objective: To describe neoadjuvant strategies, oncologic outcomes and prognostic factors in a cohort of patients (pts) with LARC treated at a referral center in Mexico City. Methods: We retrospectively reviewed medical records from pts with LARC (T3-T4 or N+) treated with any neoadjuvant strategy at Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán” from January 2010 to December 2015. Clinical and pathological information was registered. Survival was estimated by Kaplan-Meier method. Univariate analysis for prognostic factors was performed and survival was compared by the log rank test. Results: 43 pts were included. Median age was 62 y/o (19-83), 51% were female. Clinical stage (CS) II 9% and CS III 91%. 36 pts were T3-4 and N+(86%). Localization was lower third 30%, middle third 56% and upper third 12%. 63% were moderately differentiated adenocarcinoma. 84% had TNT: induction CT with FOLFOX-4 regimen for 3 months followed by CRT (50.4 Gy in 28 fractions concurrently with fluoropyrimidines) and TME. Surgery: ultra-low anterior resection (AR) 48%, low AR 28% and abdominoperineal resection 24%. One patient did not accept surgery. Of the 32 pts with ultra-low and low AR, 94% had protective ileostomy. The pathologic complete response (pCR) ypT0ypN0 rate was 45% (19/42). Median follow-up was 48 months. There were 8/42 recurrences (19%): local-only 2.3%, systemic only 12% and both 5%. None of the pts with pCR recurred. All pts with residual nodal disease recurred (5/5). The 5-year relapse-free survival rate was 73%. There were 6 deaths, one patient died without disease. The 5-year overall survival rate was 83%. Conclusions: In pts with LARC the TNT is associated with high rates of pCR and favorable oncological outcomes. pCR and residual nodal disease after neoadjuvant therapy were strongly associated with recurrence and survival.
Impact of the prior chemotherapy with two different fluoropyrimidines on the efficacy of CapeIRI or FOLFIRI in metastatic colorectal cancer: An exploratory analysis of the phase III AXEPT trial.
Authors: Kim Tae Won , Muro Kei , Xu Rui-hua , Park Young Suk , Wang Wei , Han Sae-Won , Ota Mitsuyoshi , Ahn Joong Bae , Deng Yanhong , Akiyoshi Kohei , Cho Sang Hee , Ba Yi , Denda Tadamichi , Lee Keun-Wook , Zhang Tao , Matsuda Chu , Yamada Yasuhide , Morita Satoshi , Iwasa Satoru , Sakamoto Junichi
Published: January 2019

711

Background: Modified CapeIRI (irinotecan 200 mg/m2 on day 1, capecitabine 1600 mg/m2 on days 1–14 every 3 weeks) with or without bevacizumab (± BV) has shown non-inferiority of overall survival compared with FOLFIRI ± BV based on the phase III study, AXEPT, as second-line chemotherapy for patients with mCRC. In this exploratory analysis of the AXEPT trial, we evaluated the impact of the prior chemotherapy with two different fluoropyrimidine backbones (fluorouracil and leucovorin vs oral fluoropyrimidine) on the efficacy of CapeIRI and FOLFIRI. Methods: Patients were randomized to receive standard FOLFIRI ± bevacizumab or modified CapeIRI ± bevacizumab after failure to fluoropyrimidine-based chemotherapy in the AXEPT study. Prior fluoropyrimidine backbones were categorized into oral fluoropyrimidine-based (eg, capecitabine or S-1) regimen (oral 5-FU group) and fluorouracil and leucovorin-based regimen (infusional 5-FU group). Assessed endpoints included overall survival, progression-free survival, response rate, and safety. Results: Prior fluoropyrimidine backbone was available for 642 patients among all 650 randomized patients (oral 5-FU group in 291, and infusional 5-FU group in 351). Median overall survival was 17.0 and 16.7 months for FOLFIRI ± BV and CapeIRI ± BV in the prior oral 5-FU group, and 14.9 and 16.7 months for FOLFIRI ± BV and CapeIRI ± BV in the prior infusional 5-FU group. Median progression-free survival was 7.9 and 8.6 months for FOLFIRI ± BV and CapeIRI ± BV in the prior oral 5-FU group, and 6.8 and 8.3 months for FOLFIRI ± BV and CapeIRI ± BV in the prior infusional 5-FU group. Conclusions: There was no significant difference in the efficacy of CapeIRI or FOLFIRI regardless of prior fluoropyrimidine backbones. Therefore, CapeIRI ± BV could also be effective for patients after failure of oral fluoropyrimidine-based chemotherapy (eg, CapeOX ± BV). Clinical trial information: NCT01996306. [Table: see text]
Preprocedural prediction of non-curative endoscopic submucosal dissection for early gastric cancer.
Authors: Choi Cheol Woong , Kang Dae Hwan , Kim Su Jin
Published: January 2019

74

Background: Endoscopic submucosal dissection (ESD) has been accepted as the treatment of choice for early gastric cancer (EGC) without lymph node metastasis. However, additional surgical gastrectomy should be considered after non-curative endoscopic resection. We aimed to evaluate the predictive factors associated with non-curative endoscopic resection. Methods: Between November 2008 and June 2015, a retrospective study was conducted in a single, tertiary, referral hospital. A total of 596 EGC lesions resected by ESD were analyzed. Non-curative endoscopic resection was defined as the occurrence of lesions associated with piecemeal resection, positive resection margins, lymphovascular invasion, or lesions that did not meet the expanded indications for ESD. Results: The rate of non-curative endoscopic resection was 16.1%. The mean follow-up period was 35.3 ± 25.0 months. Associated predictive factors for non-curative endoscopic resection were female sex (OR, 2.470; p = 0.004), lesion size ≥ 20 mm (OR 3.714; p < 0.001), longer procedure time (OR 2.449, p = 0.002), ulceration (OR 3.538, p = 0.002), nodularity (OR 2.967, p < 0.001), depression (OR 1.806, p = 0.038), undifferentiated carcinoma (OR 2.825, p = 0.031) and lesion located in the mid or upper third of stomach (OR 7.135 and OR 4.155, p < 0.001, respectively). As the number of risk factors increased, the risk of non-curative ESD also increased. Conclusions: Prior to selection of ESD, the risks associated with non-curative ESD should be considered so that appropriate treatment modalities may be selected.
A phase II, open-label, randomized study to evaluate the efficacy and safety of andecaliximab combined with nivolumab versus nivolumab alone in subjects with unresectable or recurrent gastric or gastroesophageal junction adenocarcinoma.
Authors: Shah Manish A. , Metges Jean-Philippe , Cunningham David , Shiu Kai-Keen , Wyrwicz Lucjan , Thai Dung , Brachmann Carrie , Bhargava Pankaj , Catenacci Daniel V.T. , Wainberg Zev A.
Published: January 2019

75

Background: Andecaliximab (ADX) is a monoclonal antibody that inhibits matrix metalloproteinase 9 (MMP9). Preclinical studies suggest that MMP9 inhibition relieves immune suppression and promotes T-cell infiltration to potentiate checkpoint blockade. Methods: Phase 2, open-label, randomized study of the efficacy and safety of ADX + nivolumab (NIVO) vs. NIVO alone in patients with pre-treated metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. Patients were randomized to either ADX 800 mg IV + NIVO 3 mg/kg IV, or NIVO 3 mg/kg IV alone, and stratified by tumor PD-L1 status. Treatment was administered every 2 weeks. Re-staging CT scans were performed every 8 weeks to evaluate response. Primary endpoint: objective response rate (ORR). Secondary endpoints: progression-free survival (PFS), overall survival (OS), and adverse events (AEs). Results: Of the 144 patients randomized, 141 were treated, 109 (76%) completed tumor assessment. 81% of patients were white, with 69% male and a mean (SD) age of 59 (12) years. ORR (95% CI) was 11.1% (4.9–20.7%) in patients receiving ADX + NIVO, and 6.9% (2.3–15.5%) in those receiving NIVO alone, p = 0.6. Kaplan-Meier estimated median (95% CI) PFS was 1.8 (1.8–2.0) months in patients receiving ADX + NIVO, and 1.9 (1.7–1.9) months in those receiving NIVO alone, p = 0.2. Kaplan-Meier estimated median (95% CI) OS was 7.2 (5.2–9.1) months in patients receiving ADX + NIVO, and 5.9 (3.5–8.6) months in those receiving NIVO alone, p = 0.4. AEs leading to treatment discontinuation occurred in 1 patient in the ADX + NIVO group, and in 1 patient in NIVO-only group. PD-L1 and mismatch repair deficient subgroup analyses will be presented. Exploratory biomarker analyses will be submitted separately. Conclusions: Addition of ADX to NIVO did not improve ORR, PFS, or OS compared with NIVO alone in patients with pre-treated metastatic gastric or GEJ adenocarcinoma. Combination of ADX with NIVO had a favorable safety and tolerability profile. Clinical trial information: NCT02864381.
A comparison of elderly versus nonelderly patients in the CRITICS gastric cancer trial.
Authors: Slagter Astrid E , Tudela Benjamín , van Amelsfoort Romy , Sikorska Karolina , van Sandick Johanna W. , Van De Velde Cornelis J. H. , van Grieken Nicole C.T. , Lind Pehr A. , Nordsmark Marianne , Putter Hein , Meershoek – Klein Kranenbarg Elma , Jansen Edwin PM , Cats Annemieke , Verheij Marcel
Published: January 2019

81

Background: Although the proportion of elderly cancer patients (pts) increases, few randomized trials provide separate results on this group. Here, we present a sub-analysis of the CRITICS trial, comparing elderly with non-elderly pts. Methods: Preoperative (preop) chemotherapy (CT) included three cycles of epirubicin, cisplatin/oxaliplatin and capecitabine (ECC/EOC); pts were upfront randomized between postoperative (postop) CT (3x ECC/EOC) and chemoradiotherapy (CRT; 45Gy + cisplatin/capecitabine). Elderly pts were defined as age ≥ 70 years at the time of randomization. We present tolerability and outcomes for elderly versus non-elderly pts. Results: Details on baseline characteristics, preop treatment, surgery, postop treatment and survival are shown in Table 1. Tumor type and localization did not differ between both groups. Conclusions: Age had a significant impact on toxicity and tolerability of preop CT, but did not affect surgical resection rates and complications. Although less elderly pts started postop treatment and elderly pts received lower dose in de CT arm, there were no differences in treatment related toxicities. Survival was not significantly different. Clinical trial information: NCT00407186. [Table: see text]
A retrospective analysis of third-line treatment in advanced gastric cancer.
Authors: Ishizuka Yasunobu , Terazawa Tetsuji , Yukami Hiroki , Yamaguchi Toshifumi , Kuwakado Shin , Kii Takayuki , Goto Masahiro , Higuchi Kazuhide
Published: January 2019

83

Background: As a result of ATTRACTION2, nivolumab was added to the third line treatment in advanced gastric cancer (AGC), but the response rate was about 10%. As there is no predictive biomarker and no comparison with cytotoxic regimen, it is difficult to choice the regimen. Therefore, we examined the treatment outcome of cytotoxic regimen in third line treatment in the real world retrospectively. Methods: We retrospectively evaluated efficacy and safety of cytotoxic regimen as third-line treatment in patients with AGC between July 2015 and December 2017. Results: Among 138 patients received chemotherapy as first line, 29 patients (21%) received third line therapy. The characteristics were as follows; the median age, 70 years old (range 34-80); male/female, 19 (66%)/10 (34%); performance status (PS) 0/1/2, 7/18/4. The overall response rate was 19% and the disease control rate was 38%. The median overall survival (OS) was 6.6 months and the progression free survival was 3.8 months. The most common grade 3/4 hematological toxicities were neutropenia (27%), followed by anemia (27%) and febrile neutropenia (13.7%). Grade 3/4 nonhematological toxicities included anorexia (27.6%), diarrhea (10%), nausea (10%). Conclusions: Cytotoxic regimen as third line showed acceptable activity, but only 21% of patients could received the third line chemotherapy. The further investigation of predictive biomarker of nivolumab is expected.
Impact of tumor growth rate during preceding treatment on tumor response to nivolumab or irinotecan in advanced gastric cancer.
Authors: Kato Kyoko , Masuishi Toshiki , Fushiki Kunihiro , Nakano Shintaro , Kawakami Takeshi , Kawamoto Yasuyuki , Narita Yukiya , Tsushima Takahiro , Nakatsumi Hiroshi , Kadowaki Shigenori , Todaka Akiko , Yuki Satoshi , Tajika Masahiro , Machida Nozomu , Komatsu Yoshito , Muro Kei , Yasui Hirofumi
Published: January 2019

84

Background: Although nivolumab (NIVO) and irinotecan (IRI) are recognized as standard third-line and further treatments for patients (pts) with advanced gastric cancer (AGC), the drug that should be administered first remains unclear. Conversely, tumor growth rate (TGR) during preceding treatment was associated with tumor response to regorafenib or trifluridine/tipiracil in colorectal cancer. Methods: We retrospectively evaluated 212 pts with AGC treated with NIVO or IRI for the first time between January 2015 and June 2018 at three institutions. The main inclusion criteria were ECOG PS of 0–2, prior use of fluoropyrimidines and taxanes, and no prior use of NIVO or IRI. Pts were classified into slow- (SG) and rapid- (RG) growing groups according to TGR and presence or absence of new lesions (NL) during preceding treatment. TGR = (D1 − D0)/100D0 (CT1 − CT0), where CT1 is the date of CT at PD during preceding treatment, CT0 is the date of CT before CT1, and Dn is the sum of target lesion diameters at CTn. SG and RG were defined as NL− with low TGR and NL− with high TGR or NL+, respectively. TGR cut-off value was defined as a median TGR of 0.30%/day. Results: A total of 117 pts (RG/SG, 72/45; NIVO/IRI, 32/85) were eligible. Almost all baseline characteristics were similar between the NIVO and IRI groups among the RG or SG, whereas the proportion of pts with peritoneum metastases was higher in the NIVO group than in the IRI group among the RG. The response rate (RR) was significantly higher with NIVO than with IRI [31% vs. 3%, odds ratio (OR): 13.8, p = 0.01; adjusted OR (aOR): 52, p = 0.002] among the SG, whereas it was comparable between both drugs (5% vs. 8%, OR: 0.68, p = 0.73; aOR: 0.94, p = 0.96) among the RG. PFS was longer with NIVO than with IRI [median PFS (mPFS) 4.2 vs. 1.9 months (m), hazard ratio (HR): 0.50, p = 0.10] among the SG, whereas it was shorter with NIVO than with IRI (mPFS 1.6 vs. 2.1 m, HR: 1.37, p = 0.28) in the RG. Conclusions: RR was higher with NIVO than with IRI among slow growing tumors, whereas it was comparable between both drugs among rapid growing tumors. TGR during preceding treatment might be helpful for drug selection in pts with AGC who are considered for treatment with NIVO or IRI.