bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical outcome and prognosis of metastatic colorectal cancer (mCRC) patients (pts) on phase 1 trials: A single institution experience from 1999 to 2016.
Authors: Kam Audrey E. , Pendurti Gopichand , Shah Umang H. , Ghalib Mohammad Haroon , Chaudhary Imran , Viswanathan Sengottuvel , Mantzaris Ioannis , Goel Sanjay
Published: January 2019

828

Background: Pts with mCRC who progress on all standard therapies have a poor prognosis and limited therapy options. Phase 1 trials represent a valuable treatment option. Herein we report the characteristics and outcomes of mCRC patients treated at our institution. Methods: We reviewed records of pts with mCRC enrolled on phase I trials at our institution from January 1999 to December 2016. Treatment-related response, toxicity, and deaths were recorded. Prognostic factors for overall survival (OS) were calculated using univariate (UVA) and multivariable Cox PH analysis (MVA). Results: We observed 187 enrollments with 152 unique patients accrued on 37 phase I trials. Median age was 59 years (range 29-83) and median number of prior therapies was 3 (range 0-8). 144 patients were evaluable for response. The clinical benefit rate (SD+response, CBR) was 33.2% and the ORR was 4.3%. Grade 3/4 non-hematological and hematological AE were seen in 25.5% and 17.3% of patients, respectively. Treatment-related mortality was 0.5%. Median PFS was 1.7 mos and OS was 8.2 mos. In UVA, the following variables predicted a shorter OS: age (p = 0.049); PS > 1 (p < 0.01); sites of metastases > 2 (p = 0.04); LDH > ULN (p < 0.001); albumin < 3.5 (p < 0.001); direct bilirubin > ULN (p = 0.02); WBC > 5.2 (p = 0.001); anemia (p = 0.046). In MVA, age > 60 (HR 1.63, p < 0.004), albumin < 3.5 (HR 3.69, p < 0.001), direct bilirubin > ULN (HR1.69, p < 0.01), and WBC > 5.2 (HR 1.97, p < 0.001) were negative prognostic factors for OS, adjusted for race and sex. A risk score based on MVA revealed that patients with a score of 0-1 had an improved OS (12.5mos) compared to a score of 2 (9.1mos, p-value < 0.005) and 3 (3.2 mos, p-value < 0.001). Conclusions: Patients with mCRC enrolled on phase 1 trials had a CBR of 33.2% and median OS of 8.2 mos, which exceeds third line therapies including regorafenib and trifluridine/tipiracil. Negative prognostic factors for OS were: age > 60, albumin < 3.5, direct bilirubin > ULN, and WBC > 5.2. A risk score based on these parameters showed that patients with a higher score had a significantly shorter OS, which may be useful in selecting patients for phase 1 trials.
Clinical characteristics and outcomes of metastatic or recurrent gastric cancer with high progranulin expression in patients who had received palliative chemotherapy.
Authors: Koo Dong-Hoe , Do Ingu , Yoo Tae-Kyung , Oh Sukjoong , Lee Yun-Gyoo , Kim Kyungeun , Sohn Jin Hee , Park Jung Ho , Sohn Chong Il , Son Byung Ho , Serrero Ginette , Yoo Chang Hak
Published: January 2019

83

Background: Progranulin (PGRN), characterized as an autocrine growth and survival factor, is known to stimulate the tumorigenesis and proliferation of several cancer cell types. However, little is known about the prognostic role of PGRN in metastatic or recurrent gastric cancers (MRGCs). Methods: A retrospective analysis was performed on patients with MRGCs who had received palliative chemotherapy between January 2010 and March 2014. PGRN expression in tumor cells by immunohistochemical staining was calculated as the product of proportion (0 = none; 1 ≤ 25%; 26% ≤ 2 ≤ 50%; 3 > 50%) and intensity score (0, no staining; 1, weak; 2, moderate; 3, strong), and categorized as high expression (Score ≥ 4) or low expression ( < 4). Results: A total of 101 patients were analyzed with the median age of 57 years (range, 24–79) at first-line chemotherapy, and 66 patients (65%) were male. Twenty-three patients (23%) had high PGRN expression tumors, and they were almost younger patients (≤ 65 years, 96%). In terms of metastatic sites, the patients with high PGRN tumors had more liver metastasis (30% vs. 17%), and the patients with low PGRN had more bone metastasis (10% vs. 4%). There were no significant differences in the proportion of patients with a response to chemotherapy (32% vs 38%) between patients with high or low PGRN tumors. The median follow-up duration of surviving patients was 54.8 months (range 34.5-81.4 months). Overall, 90 patients (89%) died, and a median overall survival (OS) and progression free survival (PFS) were 13.1 months (95% CI, 9.5–16.8 months) and 5.6 months (95% CI, 4.7-6.5), respectively. The PFS and OS were not statistically different between patients with high PGRN tumors and those that were low PGRN (median PFS 5.2 vs 5.9 and OS 14.9 vs 13.0 months, P = 0.471 and 0.927, respectively). In addition, multivariate analysis showed that PGRN expression was not a prognostic factor in both PFS and OS after adjusting for possible confounding factors including sex, age, performance, histopathology and number of metastasis. Conclusions: There was no relationship between PGRN expression and response to chemotherapy or prognosis in patients with MRGCs.
Barriers for access to isolated liver metastasis treatment in colon cancer in the United States.
Authors: De Souza Andre Luiz , Rathore Ritesh , Mukkamalla Shiva Kumar Reddy
Published: January 2019

833

Background: Multidisciplinary treatment of stage IV colon cancer with isolated hepatic metastases implies patient’s access to quality healthcare. Here, we evaluate barriers for access to hepatic metastasectomy in the United States. Methods: The National Cancer Database was queried for stage IV colon cancer patients with isolated liver metastasis diagnosed from 2010-2014. Patient demographics, T and N staging, laterality and surgery were among the variables of interest. Pearson Chi square test was used for statistical analysis Results: A total of 3145 patients were identified for analysis. Moderately differentiated, T3 and N1 tumors were the most frequent tumors to be treated with perioperative and neoadjuvant chemotherapy. Neoadjuvant and perioperative chemotherapy correlated with age (p<0.0001) and year of diagnosis (p=0.0289). Left sided tumors were more likely to receive perioperative and neoadjuvant chemotherapy compared to right sided or transverse tumors (p<0.0001). Conclusions: With various degrees of utilization of perioperative and neoadjuvant chemotherapy based on demographic and clinical variables, there exists a great need to close the gap in access to chemotherapy and surgery for colorectal cancer isolated liver metastases. [Table: see text]
Qualitative analysis of Iowa rectal cancer patients’ decisions on where to receive surgery.
Authors: Charlton Mary E. , Shahnazi Ariana , Gribovskaja-Rupp Irena , Lin Chi , Hunter Lisa , Chrischilles Elizabeth A. , Lynch Charles F , Ward Marcia M
Published: January 2019

835

Background: Current literature suggests surgeons and hospitals that perform large volumes of rectal cancer care achieve superior outcomes, but only about half of rectal cancer resections are performed by high-volume surgeons in comprehensive hospitals. Little is known about considerations of patients with rectal cancer when deciding where to receive surgery. Methods: A purposive sample of stage II/III rectal adenocarcinoma survivors diagnosed 2013-2015 were identified through the Iowa Cancer Registry and interviewed by telephone about factors influencing decisions on where to receive rectal cancer surgery. Interviews were recorded and transcribed, and a thematic analysis was conducted. Results: Thematic saturation was reached after interviewing 15 survivors. Mean age was 63; 60% were male, 53% resided in non-metropolitan areas and 60% received surgery at low-volume centers. Recommendation from a trusted source, usually a physician, appeared to be a main driver of where patients received surgery. Patients who chose high-volume centers were directed by a trusted source to seek care there, whereas patients who chose low-volume centers described valuing hospitals that were closer to home, knowing individuals at the hospital and receiving prior care there, and being familiar with others who received care from a specific surgeon. Most considered surgeon volume and experience to be important determinants of outcomes, but few actually assessed it. Most characterized surgeon experience based on subjective assessments including interpersonal skills, ability to explain procedures and perceived surgeon confidence. Several reported not trusting online sources for treatment information. Conclusions: Most rectal cancer patients in our sample relied on physician referrals to decide where to receive surgery. Further research is needed to determine rectal cancer patients’ preferences for obtaining information about surgeon/hospital volume and experience since our findings suggest they are neither discussing these factors with their surgeon nor researching them on their own. Once preferences are determined, targeted interventions facilitating more informed decision-making by patients can be developed.
Mutational landscape of metastatic colorectal cancer: Aggregate insights from a molecular tumor board.
Authors: Lewis Mark Andrew , Haslem Derrick S. , Thota Ramya , Rhodes Terence Duane , Barker Tyler , Moulton Bryce , Abraham Tyler , Fulde Gail , Romero Robin , Christensen Bryce , Nadauld Lincoln
Published: January 2019

837

Background: The mutational landscape of metastatic colorectal cancer (CRC) is being elucidated by next-generation sequencing of both primary tumors and metastatic foci. In this study, we examined the results of all stage IV CRC cases submitted to our molecular tumor board (MTB). Methods: We performed a retrospective analysis of all patients who had next-generation sequencing performed between January 2015 and August 2017 on either their primary tumor and/or metastasis. Cases were presented at a MTB convened twice monthly. For the purposes of this study only pathogenic mutations were notated, not variants of unknown significance (VUS). Results: Eighty-seven unique patients had 97 specimens sequenced (28 primary tumors and 69 metastases). The primaries averaged 3 mutations per specimen (range: 1-6) whereas the metastases averaged 4 (range: 1-14, p=.25). The most common anatomic sites of submitted metastatic tissue were the liver (n=35, average mutations=4), followed by the lungs (n=10, average mutations=3) and the omentum/peritoneum (n=8, average mutations=3). Two patients had both a primary tumor and a metastasis sequenced, with a 33% rate of concordance in inter-specimen mutations. Five patients had multiple metastases sequenced, with a 53% rate of concordance in inter-specimen mutations; in every case of longitudinal sequencing, mutational burden increased in metastases over time. The most common mutation was apc (21% of all mutations), followed by p53 (16%) and then kras (13%). Candidacy for EGFR-directed therapy was found in 8 cases, and mismatch repair defects were detected in 5 cases. Conclusions: In stage IV CRC cases sent to our MTB, tissue from metastases was more commonly submitted for analysis than from the primary tumors. There is not necessarily concordance between mutations in primary tumors and metastases, nor among multiple metastases in the same patient. Sequencing at multiple time points in the disease course may allow observation of clonal evolution and dynamic adaptation of therapeutic targets.
Pemetrexed monotherapy as salvage treatment in metastatic colorectal cancer patients who failed standard chemotherapy: A phase II single-arm prospective trial.
Authors: Lim Sung Won , Cho Jangho , Lee Jeeyun , Park Se Hoon , Park Joon Oh , Park Young Suk , Lim Ho Yeong , Kang Won Ki , Kim Seung Tae
Published: January 2019

840

Background: We designed a single-arm, open label phase II study to determine the efficacy and toxicity of pemetrexed monotherapy with vitamin supplement in refractory colorectal (CRC) patients who failed standard treatments, including 5-FU, oxaliplatin, and irinotecan with or without biologic agents. Methods: Patients were treated with pemetrexed 500 mg/m2 on day 1, every 3 weeks, with folic acid and vitamin B12 supplementation. Patients began vitamin supplementation with B12 intramuscular injection (1000 mcg) every 9 weeks starting 1 week before the first pemetrexed dose, and patients received daily oral folic acid (1 mg) starting at least 5 days before the first pemetrexed dose. Treatment was continued until disease progression or intolerable toxicity was observed. Results: Between June 2016 and October 2016, 24 patients were enrolled in this study. One patient withdrew content, leaving a total of 23 patients to be evaluated. The median age of the patients was 54.0 years (range, 23.0 to 67.0), and the median ECOG performance status was 1 (1-2). The median number of previous systemic chemotherapies was 3 (range, 2 to 5). No complete response and no partial response were observed among the patients. Stable disease was observed in 10 patients (43.4%), and 7 patients had a response duration of 2 months or more. The median PFS was 1.6 months (95% CI, 1.1 to 2.0) and the median OS was 9.8 months (95% CI, 5.9 to 13.6). Only one patient experienced treatment-related toxicity of grade 3 or more. Neither hematologic toxicities nor dose reduction due to treatment-related toxicities were observed. There was no treatment-related death. Conclusions: Pemetrexed monotherapy showed moderate disease control and an acceptable toxicity profile as salvage therapy for refractory CRC. Clinical trial information: NCT02588781.
Laparoscopic resection followed by decompression with a drainage tube for obstructive colorectal cancer.
Authors: Kagawa Yoshinori , Murata Kohei , Naito Atsushi , Kawai Kenji , Takeda Yutaka , Takeno Atsushi , Masuzawa Toru , Ohmura Yoshiaki , Katsura Yoshiteru , Murakami Kohei , Sakamoto Takuya , Mori Ryota , Nose Yohei , Toya Keisuke , Yukawa Yoshiro , Takase Kouki , Kato Takeshi
Published: January 2019

844

Background: Obstructive colorectal cancer is an oncological emergency that requires emergency treatment. In Japan, laparoscopic resection after decompression with metallic-stent placement is becoming mainstream as a bridge to surgery (BTS). However, there are reports of worse prognoses due to stent placement, and the European Gastroenterology Society of Endoscopy guidelines do not recommend BTS. In our department, since 2011 the first choice of the treatment has been laparoscopic resection after decompression with a trans-anal or trans-nasal drainage tube. STo investigate the safety and short- and long-term results of laparoscopic resection after decompression with a drainage tube. Methods: Eighty-one cases of obstructive colorectal cancer that underwent surgery at our hospital from 2011 to 2016 were investigated with regards to the short- and long-term outcomes of treatment strategies for obstructive colorectal cancer. Results: The median age was 72 years old (39-94). The ratio of male to female was 46:29. The success rate of decompression was 86.7% (66 cases). Stages II, III and IV were involved in 25, 28 and 28 cases, respectively. The causes of the emergency operations were an inability to insert both the ileus tube and the stent (9.3%, 7 cases), and perforation (2.7%, 2 cases) when the trans-anal ileus tube was inserted. In the cases in which decompression was possible, the laparoscopic operation rate was 89.4% (56 cases) and the primary resection rate was 90.9% (59 cases). The median surgical time was 194 minutes (27-325), the median blood loss was 10 g (0-660 g),The median postoperative hospital stay was 14 days (5-147 days). The rate of anastomotic leak was 4.5%. There were no deaths within 30 and 90 days after surgery. The relapse free survival rate in Stage II and III were 72% and 67.9%, respectively. The median months of overall survival in Stage II, III and IV were 60.4, 56.3 and 18.7, respectively. Conclusions: A treatment strategy with laparoscopic resection followed by decompression with a drainage tube was performed feasibly and safely. At this time, the effects of a stent on oncological prognosis is unclear, and this strategy could be an effective treatment for obstructive colorectal cancer.
Social and contextual factors and their relationship with the use of palliative chemotherapy in patients with metastatic colorectal cancer (mCRC): A retrospective cohort study.
Authors: Ahmed Shahid , Iqbal Nayyer , Haider Kamal , Chalchal Haji I. , Le Duc , Alvi Riaz , Zaidi Adnan , Pahwa Punam
Published: January 2019

849

Background: Although there is evidence that social and contextual factors such as living alone are associated with outcomes in cancer patients, little is known about their influence on the use of palliative chemotherapy in mCRC. We previously reported various patient-and tumor-related factors that correlate with the use of palliative chemotherapy in mCRC (Oncology. 2015;88:289). In this study we examine social and contextual factors including marital status, having children and distance to cancer center for their association with the use of chemotherapy in patients with mCRC. Methods: A cohort of 569 patients with mCRC diagnosed from 2006-2010 in Saskatchewan was evaluated. Logistic regression analyses were performed to assess relationship between the use of chemotherapy and various variables. Results: Median age was 69 yrs (IQR 59-77) and M:F was 59:41. 326 (57%) patients received chemotherapy. Significant differences were noted between the chemotherapy vs. no chemotherapy groups with respect to median age (62 vs. 76 year, p < 0.001), WHO performance status (PS) > 1 (18 vs. 58%, p < 0.001), comorbid illness (24 vs 63%, p < 0.001), low albumin (61 vs. 89%, p < 0.001), anemia (61 vs. 87%, p < 0.001), elevated alkaline phosphatase (53 vs. 84% < 0.001), elevated creatinine (6 vs. 11%, p = 0.025), hyponatremia (20 vs. 14%, p = 0.03), primary tumor resection (61 vs 47%, p = 0.001), metastasectomy (21 vs. 9%, p < 0.001), mean distance to cancer center (98.7±113.6 vs. 127.8±124.6 km, p < 0.001), married/partnered (67 vs 33%, p < 0.001), and having children (64 vs. 36%, p < 0.001), respectively. On multivariate logistic regression analysis after adjustment of other variables, WHO PS > 1 (HR 5.1; 95%CI: 3.1-81.), not having children (3.3, 1.78-6.2, < 0.001), elevated alkaline phosphatase (HR 2.9; 95%CI: 1.8-4.8), and low albumin (HR 2.2; 95%CI: 1.2-3.8), were correlated with low rates of chemotherapy. Marital status or travel distance did not correlate with use of chemotherapy. Conclusions: Our results show that use of chemotherapy in patients with mCRC significantly varies in those with and without children. Future study are required to explore this difference.
Chemoradiation for the treatment of locoregional squamous cell carcinoma of the anal canal: A single center retrospective analysis in Japan.
Authors: Takahashi Ryo , Wakatsuki Takeru , Shinozaki Eiji , Taguchi Senzo , Fujimoto Yoshiya , Osumi Hiroki , Ota Yumiko , MATSUSHIMA TOMOHIRO , Ogura Mariko , Ichimura Takashi , Takahari Daisuke , Suenaga Mitsukuni , Chin Keisho , Oguchi Masahiko , Ueno Masashi , Yamaguchi Kensei
Published: January 2019

851

Background: Squamous cell carcinoma of the anal canal (SCCA) is a rare malignancy. In western countries, chemoradiotherapy (CRT) has become the standard treatment for locoregional SCCA according to National Comprehensive Cancer Network guidelines. But only some small amount case reports have been found about CRT for SCCA in Japan. We retrospectively evaluated the results of CRT for SCCA at a single center in Japan. Methods: We had treated 33 patients with the concurrent CRT at the Cancer Institute Hospital between 2007 and 2017. RT consisted of 45.0 to 59.4 Gy given in 5 to 7 weeks, with a daily dose of 1.8 Gy. Chemotherapy was given during RT: 1000mg/m2 daily fluorouracil (FU) as a continuous infusion on day 1 to 4 and 29 to 32, and a single dose of mitomycin C (MMC) 10mg/m2 administered on day 1 and 29. Data on relapse and deaths were obtained until August 2017. Results: Of 33 patients who were treated with CRT, the median age was 59 (range 35-82) years. Male to female sex ratio was 1:4.5. Patients who had Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 were 88% and patients who had ECOG PS 1 were 12%. The clinical stages before CRT were cStage I in 9 (27%), II in 4 (12%), IIIA in 6 (18%) and IIIB in 14 (42%). Although clinical complete response (CR) was observed in 29 patients of 33 (88%), 5 patients of 29 recurred. No patients recurred in cStage I and II. SCCA remained or recurred in 2 patients of 6 in cStage IIIA and 7 patients of 14 in cStage IIIB. 3-year disease free survival (DFS) was 71.3% (95%CI: 52.0-84.0%), and 3-year overall survival was 81.8% (95%CI: 55.1-92.8%). Conclusions: CRT for SCCA resulted in clinically meaningful impact on DFS and OS in our hospital. Therefore, CRT may be the standard of treatment also in Japan.
Variation in the use of adjuvant chemotherapy following neoadjuvant radiotherapy and surgery for rectal cancer in a publicly-insured health care system.
Authors: Bubis Lev , Mahar Alyson L. , Gupta Vaibhav , Jeong Yunni , Davis Laura , Li Qing , Karanicolas Paul Jack , Coburn Natalie
Published: January 2019

854

Background: The efficacy of routine administration of adjuvant chemotherapy following sequential neoadjuvant chemoradiotherapy and surgery for rectal cancer is uncertain. This uncertainty may lead to practice pattern variations, with significant downstream discrepancies in oncological outcomes, patient-centered outcomes, and healthcare costs. The objective of this study, therefore, was to evaluate patient, disease, and health system factors associated with receipt of adjuvant chemotherapy following neoadjuvant radiotherapy and proctectomy. Methods: A retrospective cohort study of patients diagnosed with rectal cancer undergoing preoperative radiotherapy prior to proctectomy from January 1, 2010 to December 31, 2014 was performed using linked administrative healthcare databases. We compared the rate of chemotherapy administration (≥ 1 billing record) within 180 days of index rectal resection by healthcare administrative region in Ontario, Canada (2014 population: 13.4 million). Multivariable logistic regression models were constructed to assess patient, disease, and health system factors associated with differences in receipt of adjuvant chemotherapy. Results: We studied 1668 patients treated with preoperative radiotherapy and proctectomy, of whom 67% received chemotherapy within 180 days after surgery. The rate of adjuvant chemotherapy administration varied among health regions from 54% to 93%. On multivariable analysis, health region of residence, younger patient age, lower baseline comorbidity burden, and pathological nodal involvement were significant predictors of receipt of adjuvant chemotherapy. Conclusions: There is significant variation in receipt of adjuvant chemotherapy for patients receiving preoperative radiotherapy followed by proctectomy in Ontario. This variability is associated with patient, disease, and health system-related factors. Identifying the drivers of variability in cancer care practice may help to provide a basis for understanding and addressing discrepancies in clinical, patient-centered, and economic outcomes in healthcare systems.
PROX: Primary resistance to oxaliplatin containing regimen in the first line treatment of metastatic colorectal carcinoma—Retrospective analysis.
Authors: Machado Larissa , Felismino Tiago , De Brito Sales Diogo , Morbeck Diogo , Karani Amanda , Diniz Lara Azevedo , Cunha Ingrid Hariman Fonseca , Souza Virgilio , Begnami Maria Dirlei , Macedo Mariana Petaccia , Carraro Dirce Maria , Mello Celso Lopes
Published: January 2019

855

Background: The rate of primary resistance to modern first line (FL) chemotherapy regimen in the treatment of metastatic colorectal cancer (mCRC) is low. Progression Disease (PD) to FOLFOX in the FL is less than 15% in most trials. Prognostic factors associated with worse outcome in mCRC have been identified. However, primary resistance to Oxaliplatin (PROX) containing regimen is not well understood, as well as the role of salvage therapy in further lines of treatment. The aim of the study was to analyze clinical and pathological characteristics of patients with PROX. Methods: A retrospective, single center study included patients that presented PD in the first response evaluation with an Oxaliplatin containing regimen in the FL treatment of mCRC. We also evaluated the Overall Survival (OS) and progression free survival (PFS) of these patients to second and third line. Clinical and pathological variables were analyzed and correlated with (OS). Results: A total of 55 patients were inclued. Median age these cohort was 57 years. Female/Male rate was 42%/58%. Mucinous component was 27%. Right and Left colon was 27% and 66%, respectively. BRAF mutation (2/16 pts). Wild type KRAS was 44%. Synchronic metastasis was 75%. Ressection of metastasis was performed in 20%. Liver limeted disease was found in 45%. Main chemotherapy regimen containing oxaliplatin was FOLFOX (78%) in first line. Bevacizumab, Cetuximab and Panitumumab were used in 21.8%, 9%, 1.8%, respectively. OS was 9.4 months. PFS in second line 3.8 months (47 pts) and third line 3.5 months (18 pts). The only variable associated with longer survival was resection of metastasis (25.6 x 8.6 months, p=0.039). Conclusions: No clinical and pathological variable were able to predict primary resistance to Oxaliplatin containing regimen. However, we found a higher proportion of mucinous subtype. Patients submitted to resection of metastasis had almost three fold the survival of patient that did not underwent surgery. Refractory patients have a very short survival. Further lines of treatment are not able to rescue these patients. Further studies focusing in patients with primary resistance to chemotherapy in first line are needed.
A phase II trial of first-line FOLFIRINOX for patients with advanced gastroesophageal adenocarcinoma.
Authors: Park Haeseong , Wang-Gillam Andrea , Suresh Rama , Rigden Caron E. , Amin Manik A. , Tan Benjamin R. , Pedersen Katrina , Lim Kian-Huat , Trikalinos Nikolaos , Navo Katherine , Morton Ashley , Schrumpf Lindsey , Marquez Samantha , Trinkaus Kathryn , Lockhart A. Craig
Published: January 2019

89

Background: Standard first-line regimens for patients with metastatic gastroesophageal adenocarcinomas have an approximate 40% objective response rate (ORR). FOLFIRINOX has been used in first line therapy in other GI cancers (i.e pancreatic and CRC) with impressive efficacy signals. Methods: This is a phase II study of first line combination chemotherapy with fluorouracil (5-FU), irinotecan, and oxaliplatin in patients with advanced gastric, esophageal, or gastroesophageal junction adenocarcinoma (NCT01928290). Starting doses were 5-FU 400mg/m2 bolus followed by 2400 mg/m2 over 46 hours with leucovorin 400 mg/m2, irinotecan 180 mg/m2, and oxaliplatin 85 mg/m2. Trastuzumab was administered as 6 mg/kg loading dose then 4 mg/kg every 14 days if patients had HER2+ cancer. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression free survival (PFS), overall survival (OS), time to progression (TTP), clinical benefit rate (CBR), and duration of response. Enrollment of 41 patients with HER2- disease was planned to reach one-sided = 0.10 and power 0.90 with goal of detecting true ORR60%. No enrollment goal was planned for HER2+. Results: From Nov 2013 to July 2017, 58 patients were enrolled, 25 out of 58 (43%) had HER2+ disease. Forty-nine patients were evaluable for response as they completed at least one restaging scan. ORR was 78% (38/49) in all patients, 67% (18/27) in HER2-, 91% (20/22) in HER2+. One patient (2%) had complete response, 37 (76%) had partial response, 7 (14%) had stable disease > 6 months; therefore, CBR was 92%. Median PFS is 11.9 months, median OS is 17.4 months and median follow up time 16.1 months. 41 (83.7%) had dose modification or delay during treatment. There were no unexpected toxicities. Conclusions: FOLFIRINOX with or without trastuzumab showed remarkable ORR and PFS in patients with advanced gastroesophageal adenocarcinoma in the first-line setting. This regimen may be a reasonable therapeutic option for patients with preserved performance status. Further investigation in larger population is warranted. Clinical trial information: NCT01928290.
Associations of PD-1 and PD-L1 expression with mismatch repair status and prognosis in chemoradiotherapy-naïve esophageal and gastric adenocarcinoma.
Authors: Svensson Maria , Borg David , Zhang Cheng , Hedner Charlotta , Nodin Bjorn , Uhlen Mathias , Mardinoglu Adil , Leandersson Karin , Jirstrom Karin
Published: January 2019

9

Background: Although neoadjuvant and/or adjuvant treatment enhances survival in patients with resectable esophageal and gastric (EG) cancer, the prognosis remains poor and there is a great need to identify novel treatment strategies and suitable biomarkers. Expression of programmed death ligand 1 (PD-L1) is, together with mismatch repair (MMR) status, a putative biomarker of response to immune-modulating therapies, but their prognostic value in EG cancer remains unclear. Therefore, the aim of this study was to examine the expression of PD-L1 in tumour cells (TC) and tumour-infiltrating immune cells (TIC), and the receptor PD-1 in TIC, in EG adenocarcinoma. Particular attention was given to their relationship with MMR status, and prognosis. Methods: PD-L1 and PD-1 expression in TC and/or TIC was assessed by immunohistochemistry (IHC) on tissue microarrays with primary tumours from a retrospective consecutive cohort of 174 patients with chemoradiotherapy-naïve resected EG adenocarcinoma. MMR status was determined by IHC. The prognostic value of PD-L1 and PD-1 was also examined at the mRNA level in 354 cases of gastric adenocarcinoma in The Cancer Genome Atlas. Results: PD-1 expression was not associated with MMR status, but PD-L1 expression in TC and TIC was significantly associated with MMR deficiency (p < 0.001 for both). Neither TC PD-L1 nor MMR status was prognostic. However, high PD-1 (10%) and PD-L1 ( > 50%) expression in TIC was significantly associated with a prolonged OS, the latter independently of other prognostic factors and MMR status (hazard ratio = 0.39, 95% confidence interval 0.15-0.99). Moreover, the prognostic value was only evident in MMR proficient tumours, and similar in esophageal and gastric tumours. At the transcript level, PD-L1 expression was not prognostic, but high PD-1 expression was significantly associated with a prolonged OS in gastric adenocarcinoma (p = 0.012). Conclusions: High expression of PD-L1 but not PD-1 is significantly associated with MMR deficiency in EG cancer. High PD-L1 expression in TIC but not in TC, or high PD-1 expression in TIC, signifies a prolonged survival, in particular in MMR proficient tumours.
Nivolumab safety profile in Asian and Western patients with chemotherapy-refractory (CTx-R) advanced gastric/gastroesophageal junction (adv G/GEJ) cancer from the ATTRACTION-2 and CheckMate-032 trials.
Authors: Chau Ian , Chen Li-Tzong , Kang Yoon-Koo , Satoh Taroh , Kato Ken , Chung Hyun Cheol , Kang Won Ki , Chao Yee , Chen Jen-Shi , Ott Patrick Alexander , Le Dung T. , Zhao Huanyu , Jimenez-Exposito Maria Jesus , Janjigian Yelena Yuriy , Boku Narikazu
Published: January 2019

90

Background: Nivolumab (NIVO) monotherapy demonstrated a survival benefit and durable responses in pts with CTx-R adv G/GEJ cancer (Boku N et al ESMO 2017; Janjigian Y et al ASCO 2017). Here we describe the safety profile of NIVO in Asian (A) and Western (W) pts with CTx-R adv G/GEJ who had received ≥ 2 prior CTx in the ATTRACTION-2 and CheckMate-032 trials, respectively. Methods: The safety population included pts who received ≥ 1 dose of study drug at the data cutoff of August 2016 for ATTRACTION-2 and March 2016 for CheckMate-032. TRAEs, serious TRAEs, and select TRAEs (sTRAE; with a potential immune-related etiology) were assessed. sTRAEs were managed using protocol-specified algorithms, which included corticosteroids as immune-modulating treatment (tx). Time to onset and resolution of sTRAEs were also assessed. Results: Median duration of NIVO tx was 1.9 mo in A and 2.3 mo in W pts. TRAEs (any grade) were reported in 43% of A and 64% of W pts; grade 3–4 TRAEs (A pts:10%; W pts:14%), serious TRAEs (A pts:10%; W pts:7%) and TRAEs leading to discontinuation (≤ 3% of pts in both groups) were infrequent. Most sTRAEs were grade 1–2 (Table) and occurred within the first 3 mo of NIVO tx. In A and W pts, median time to resolution of sTRAEs ranged from 3–19 wk. For those sTRAEs that required tx with immune-modulating agents, the median time to resolution of most sTRAEs ranged from 3–35 wk. Conclusions: NIVO demonstrated an acceptable safety profile in both A and W pts with CTx-R adv G/GEJ cancers with no clinically meaningful racial differences. Most sTRAEs were grade 1–2 in both cohorts and manageable using the recommended tx algorithms. Clinical trial information: NCT02267343 ATTRACTION-2 and NCT01928394 CheckMate 032. [Table: see text]
Postoperative chemotherapy in patients who are pN+ following neoadjuvant chemoradiation for locally advanced esophageal cancer.
Authors: Francis Samual , Nevala-Plagemann Christopher Duane , Cavalieri Courtney Christine , Lloyd Shane , Garrido-Laguna Ignacio
Published: January 2019

97

Background: Esophageal cancer survival rates have improved since the widespread adoption of neoadjuvant chemoradiation therapy (CRT) followed by esophagectomy for patients who present with locally advanced disease. Unfortunately, overall prognosis for these patients remains poor. In this study, we sought to assess the effect of additional adjuvant chemotherapy in patients who have positive lymph nodes (pN+) following surgery. Methods: Using the National Cancer Database we retrospectively identified all patients with locally advanced esophageal cancer who received neoadjuvant CRT from 2004 to 2014. We then identified patients within this dataset who were found to be pN+ following neoadjuvant chemoradiation and esophagectomy and categorized them as having received adjuvant chemotherapy versus no additional chemotherapy. Survival analysis was performed using Kaplan-Meier estimation and propensity score matching. Results: 2,045 patients were identified as being pN+ following neoadjuvant CRT. Within this group, 14% received adjuvant chemotherapy. The 1, 5, and 8 year overall survival (OS) of patients receiving adjuvant therapy was 87%, 30%, and 21% compared to 76%, 23%, and 16% in those receiving neoadjuvant therapy alone, respectively (p = 0.0017). After a propensity score matched analysis, median OS was found to be significantly longer in the those receiving neoadjuvant CRT plus adjuvant chemotherapy compared to neoadjuvant CRT alone (27.8 months vs 22.2 months; HR 0.78; 95% CI, 0.62 to 0.97; p = 0.032). Conclusions: While not currently the standard of care, our data suggests that adjuvant chemotherapy may improve survival in patients with locally advanced esophageal cancer who are found to be pN+ following surgery. Additional prospective studies are needed to confirm this finding.
Impact of adjuvant chemotherapy with S-1 on survival in patients with type 4 and large type 3 gastric cancer.
Authors: Omori Hayato , Kaji Sanae , Makuuchi Rie , Irino Tomoyuki , Tanizawa Yutaka , Bando Etsuro , Kawamura Taiichi , Terashima Masanori
Published: January 2019

98

Background: The prognosis of patients with linitis plastica (type 4) and large ulcero-invasive-type (type 3) gastric cancer is reported to be extremely poor. In stage II/III gastric cancer, adjuvant chemotherapy with S-1 is a standard treatment in Japan. However, the efficacy of postoperative chemotherapy with S-1 in these types of patients with dismal prognosis is unknown. The aim of this study is to evaluate the impact of adjuvant chemotherapy with S-1 on survival in type 4 and large type 3 gastric cancer patients. Methods: A total of 152 patients with clinically resectable type 4 and large type 3 gastric cancer who underwent R0 or R1 surgery from 2002 to 2014 were included. The survival outcome between patents with surgery alone and patients who received adjuvant S-1 was compared using a 1:1 propensity score matching method. Results: Patients with adjuvant S-1 were significantly younger (67 vs 74 y, p = 0.009), had higher incidence of T4 (90 vs 62%, p < 0.001), N2-3 (84 vs 63%, p = 0.008), and cytology positive (52 vs 29%, p = 0.006) than in surgery alone patients. Before matching, median survival time (MST) was not different in surgery alone (n = 52) and adjuvant S-1 (n = 100) (31.3 vs 35.8 months, p = 0.41). Propensity score matching yielded 48 patients (24 patients in each group). After matching, baseline characteristics were well balanced between the two groups. Survival in patients with adjuvant S-1 was significantly better than in surgery alone patients (MST: 50.3 vs 15.4 months, p = 0.002). Cox proportional hazard analysis revealed adjuvant S-1 treatment was selected as independent prognostic factor (HR: 0.38, 95%CI: 0.18-0.76, p = 0.006), as well as lavage cytology (HR: 3.9, 95%CI: 1.8-8.9, p < 0.001). Conclusions: Adjuvant chemotherapy with S-1 may have a strong impact on survival in type 4 and large type 3 gastric cancer patients. The efficacy of this treatment will be further demonstrated in the future clinical trials.
Survival of second-line irinotecan-based chemotherapy in early relapse patients with gastric cancer after adjuvant chemotherapy: Exploratory subgroup analysis of TRICS trial.
Authors: Nishikawa Kazuhiro , Murotani Kenta , Fujitani Kazumasa , Inagaki Hiroshi , Akamaru Yuske , Tokunaga Shinya , Takagi Masakazu , Tamura Shigeyuki , Sugimoto Naotoshi , Shigematsu Tadashi , Yoshikawa Takaki , Ishiguro Tohru , Nakamura Masato , Miyashita Yumi , Morita Satoshi , Tsuburaya Akira , Sakamoto Junichi , Tsujinaka Toshimasa
Published: January 2019

99

Background: Second-line chemotherapy (SLC) was reported to improve the survival of advanced gastric cancer (AGC). The TRICS trial which a randomized phase III study of second-line irinotecan plus cisplatin versus irinotecan alone in patients with AGC refractory to S-1 monotherapy, revealed that both irinotecan based chemotherapies were effective with favorable long-term survivals and generally well tolerated. Eligible patients included patients with recurrence within 6 months after the completion of adjuvant therapy with S-1 (early relapse cases), or patients with tumor progression after first-line S-1 for an advanced cancer (progressive cases), in this trial. However, it is unclear whether survivals in early relapse cases were different from these in progressive cases or not. Methods: A total of 168 patients registered to the TRICS trial were classified as early relapse group (n = 111) or progressive group (n = 57), and 168 (irinotecan plus cisplatin, early relapse 56/83, 67%; irinotecan alone, 55/85, 65%) and 163 (55/81, 68%; 53/82, 65%) patients were analyzed for survival. Adjusted OS and adjusted PFS were constructed adjusted Kaplan-Meier curve with inverse probability weight, and were estimated by inverse probability of treatment weighting method (IPTW). Results: In baseline characteristics, PS 0 were more frequently seen in early relapse group than in progressive group (86% vs 72%, p = 0.0328), and median age of early relapse group was younger than progressive group (66 vs 72, p = 0.0162). The median OS was 13.9 months in early relapse group and 10.0 months in progressive group (HR:0.746, p = 0.1019). The adjusted median OS was 14.0 months in early relapse group and 10.6 months in progressive group (IPTW HR:0.864, p = 0.1019). Early relapse group showed better trends in PFS compared to the progressive group (4.7M vs 3.6M, HR: 0.650, p = 0.0149). The adjusted median PFS was 4.8 months in early relapse group and 3.7 months in progressive group (IPTW HR:0.673, p = 0.0008). Conclusions: Irinotecan based chemotherapies were effective especially in early relapse cases after adjuvant therapy with S-1, in second-line setting of AGC.
CheckMate 649: A randomized, multicenter, open-label, phase III study of nivolumab (NIVO) + ipilimumab (IPI) or nivo + chemotherapy (CTX) versus CTX alone in patients with previously untreated advanced (Adv) gastric (G) or gastroesophageal junction (GEJ) cancer.
Authors: Moehler Markus H. , Janjigian Yelena Yuriy , Adenis Antoine , Aucoin Jean-Sebastien , Boku Narikazu , Chau Ian , Cleary James M. , Feeney Kynan , Franke Fabio A. , Mendez Guillermo Ariel , Schenker Michael , Li Mingshun , Hitre Erika , Couture Felix , Karamouzis Michalis , Etienne Pierre-Luc , Ajani Jaffer A.
Published: January 2019

TPS192

Background: Pts with adv G/GEJ cancer have an OS of ≈ 1 y, indicating an unmet medical need for new first-line treatments. Expression of PD-L1 is observed in up to 40% of pts with G/GEJ cancer and is associated with poor prognosis. In the randomized phase 3 ATTRACTION-2 study, NIVO demonstrated superior overall survival vs placebo with a 38% reduction of the risk of death (median OS, 5.3 vs 4.1 mo; HR, 0.62 P< 0.0001) and increased the OS rate at 12 mo (27% vs 12%; Boku N et al ESMO 2017) in pts with adv CTX-R (≥ 2 lines) G/GEJ cancer. In the phase 1/2 CheckMate-032 study in pts with CTX-R G/GEJ/esophageal cancer (79% ≥ 2 prior Tx lines), NIVO 1 mg/kg + IPI 3 mg/kg had a manageable safety profile and resulted in 24% ORR (40% ORR in pts with PD-L1+ tumors), a median OS of 6.9 mo, and a 35% OS rate at 12 mo (Janjigian Y et al ASCO 2017). In the phase 1 CheckMate-012 trial, NIVO + CTX had clinical activity and manageable safety in pts with NSCLC (Rizvi NA et al J Clin Oncol 2016). These positive results support investigation of NIVO, NIVO + IPI, and NIVO + CTX in earlier lines of treatment for G/GEJ cancer. The open-label, phase 3 CheckMate 649 trial will evaluate NIVO + IPI and NIVO + CTX vs CTX alone as first-line treatment for pts with adv G/GEJ cancer (NCT02872116). Methods: 1266 pts aged ≥ 18 y with untreated, inoperable adv/metastatic G/GEJ cancer (histologically confirmed adenocarcinoma) regardless of PD-L1 status will be randomized to receive either NIVO + IPI, NIVO + CTX (capecitabine/oxaliplatin [XELOX] or fluorouracil/leucovorin/oxaliplatin [FOLFOX]), or investigator choice of XELOX or FOLFOX. Tumor tissue for determination of PD-L1 status (Dako assay) must be provided from ≤ 6 mo before study treatment. No prior systemic treatment, including HER2 inhibitors, are allowed. Pts with known HER2+ status, suspected autoimmune disease, grade > 1 peripheral neuropathy, or active infection are excluded. Primary endpoint is OS in pts with PD-L1+ (≥ 1%) tumors. Other endpoints include OS in all pts; PFS and time to symptom deterioration in all pts and in pts with PD-L1+ tumors; and safety. Clinical trial information: NCT02872116.
A phase II study of chemotherapy and immune checkpoint blockade with pembrolizumab in the perioperative and maintenance treatment of locoregional gastric or GE junction adenocarcinoma.
Authors: Oberstein Paul Eliezer , Schrope Beth , Gonda Tamas , Sethi Amrita , Han Arnold , Schwartz Gary K. , Shah Manish A.
Published: January 2019

TPS197

Background: Gastric cancer is a prevalent worldwide disease for which surgical resection alone is insufficient to cure the majority of localized patients. Peri-operative chemotherapy is a standard of care approach that has demonstrated modest improved survival rates. Immune checkpoint therapy has proven efficacy in a subset of patients with refractory disease but it’s role in earlier stage disease and in combination with chemotherapy is not defined. By combining chemotherapy with immune checkpoint blockade utilizing pembrolizumab we hypothesize that we will obtain improved tumor response and prolonged disease control compared to chemotherapy alone. Tissue specimens will be obtained at baseline and at the time of surgery for novel correlative studies including single cell T cell receptor characterization and expression profiling. Methods: This Phase 2, multicenter study investigates the efficacy and safety of oxaliplatin/FU based chemotherapy plus pembrolizumab in the perioperative treatment of locally advanced, resectable gastric or GE junction adenocarcinoma. A total of 40 eligible patients with T2-4 and/or N1, M0 tumors on imaging or EUS will be treated with capecitabine, oxaliplatin and epirubicin (epirubicin can be omitted at investigator discretion) plus fixed dose pembrolizumab at 200mg for 3 cycles prior to surgery plus one additional dose of pembrolizumab alone before surgery. Following completion of post-operative chemotherapy with pembrolizumab, patients continue pembrolizumab for 1 year of maintenance therapy (17 cycles). The primary endpoint is disease free survival at 24 months (DFS 24) with an estimated 80% power to detect a clinically significant 24 month DFS rate of 65%. A key secondary endpoint is pathCR at surgery, additional endpoints include response rate (RECIST 1.1), 12 month DFS, and overall survival. Safety, including surgical outcomes, will be assessed. Multiple correlative analyses utilizing baseline and post-treatment tissue, PD-L1 staining, and serum samples will also be performed. Enrollment opened in March 2017. Clinical trial information: NCT02918162.
A phase I/II multi-center study of nivolumab and carboplatin/paclitaxel with radiation therapy (RT) for patients with locally advanced esophageal squamous cell carcinoma (ESCC).
Authors: Giuroiu Iulia , Ku Geoffrey Yuyat , Leichman Lawrence P. , Du Kevin Lee , Oh Philmo , Levinson Benjamin A. , Iqbal Syma , Thomas Charles R. , Wu Jennifer J.
Published: January 2019

TPS199

Background: ESCC comprises 80% of esophageal cancers worldwide. Preoperative chemoRT is a standard-of-care based on the CROSS trial ( N Engl J Med 2012;366:2074-2084), which reported encouraging pathologic complete response (pCR) and overall survival (OS). Surgery is often deferred in patients with clinical CR (cCR) based on lack of overall survival (OS) benefit ( J Clin Oncol 2005;23:2310-2317, J Clin Oncol 2007;25:1160-1168). Nivolumab has activity in advanced ESCC ( Lancet Oncol 2017;18:631-639), and adding it to chemoRT may improve outcomes. ESCC has a high somatic mutation rate and treatment with chemoRT may augment the abscopal effect. Methods: Our trial aims to establish the safety and tolerability (phase I), as well as the efficacy (phase II) of nivolumab added to a standard chemoRT backbone for patients with TanyN1-3 or T3-4N0M0 ESCC. Phase I will enroll up to 12 patients and phase II, up to 44, per an optimal two-stage design. The phase I primary endpoint is unacceptable toxicity at 28 days after the last dose of chemotherapy. Phase II primary endpoints are cCR (endoscopy + PET/CT), pCR for patients undergoing surgery, and median progression-free survival and OS, which will be estimated via Kaplan Meier curves. Extensive tumor and blood immune correlative studies are planned. Clinical trial information: NCT03278626. [Table: see text]