bluuebunny/crossref_metadata_2025 huggingface dataset:
Cryotherapy in addition to chemotherapy for palliation of inoperable esophageal cancer: A multicenter prospective study.
Authors: Kachaamy Toufic , Sharma Neil R. , Pannala Rahul , Weber Jeffrey , Gorsuch Kimberly , Young Yashika , Salas Christina , Zelt Christina M. , Werling Heather , Gupta Digant , Vashi Pankaj G.
Published: February 2020

342

Background: Palliation of dysphagia (Dys) in patients with inoperable esophageal cancer (EC) can be challenging. The major goal of palliation therapy is to improve patient’s quality of life (QoL) and Dys and allow adequate caloric intake. The most commonly used palliative modalities for Dys are radiation therapy (RT) and esophageal stenting. However, RT is limited by total dose and adverse events (AE) in patients receiving systemic therapy (ST), and stenting suffers from a high rate of AE including reflux and chest pain. A relatively new modality of liquid nitrogen endoscopic spray cryotherapy (cryo) has been reported in retrospective studies to improve Dys in patients receiving systemic therapy. We prospectively evaluated Dys and QoL of patients with inoperable EC undergoing cryo in addition to ST for palliation. Methods: A prospective multicenter study of 24 adult inoperable EC patients undergoing cryo and ST for palliation at 4 specialized cancer centers from Sep 2017 to Aug 2019. QoL was assessed using a modified EORTC QLQ-OES18 questionnaire (score 18 to 72, with higher scores indicating worse QoL). Dys was measured using a 4-point Likert scale: 0, no Dys; 1, Dys to solids; 2, Dys to semi-solids; 3, Dys to liquids; 4, Dys to saliva. Paired t-test was used to evaluate change in QoL and Dys between pre- and post-cryo. Results: There were 19 males and 5 females (17 stage IV, 5 stage III, and 2 stage II at diagnosis). Among 24 patients, a total of 71 cryo were performed, with a mean of 2.9 treatments per patient. After a median follow-up of 2 months, the mean EORTC score improved significantly from 35.4 at baseline to 25.5 at last follow-up ( p < 0.001). Similarly, the Dys score improved significantly from 2.0 at baseline to 0.87 at last follow-up ( p < 0.001). Grade 3 or higher AE were seen in only one patient (4%) who had GI bleeding 2 weeks after cryo and was diagnosed with bleeding from severe reflux esophagitis related to gastric outlet obstruction. Conclusions: The analysis of this multicenter prospective study shows that cryo in addition to ST for palliation of EC is well tolerated with significant improvement in Dys and QoL.
Correlation of heart dose with lymphopenia in esophageal cancer patients treated with chemoradiation.
Authors: Post Amber , Bowen Stephen R. , Nguyen Bao-Ngoc , Logan William , Zeng Jing , Apisarnthanarax Smith
Published: February 2020

346

Background: Lymphopenia has been associated with survival and disease progression in esophageal cancer patients treated with chemoradiation (cRT). We previously published on our posterior-only proton therapy approach that maximally spares the heart and lungs, but at the cost of increased dose to the bone marrow in the vertebral bodies (VBs). We assessed hematologic toxicity in proton (PT) and IMRT treated patients and studied dosimetric parameters associated with hematologic toxicity. Methods: 35 patients treated with PT and 46 patients treated with IMRT for esophageal cancer between 2011-2018 were analyzed. Most patients were treated concurrently with carboplatin/paclitaxel to a median dose of 50.4 Gy. Lymphocyte, neutrophil and total leukocyte values while under treatment were recorded and graded per the CTCAE v4.03 toxicity scale, and the neutrophil-to-lymphocyte ratio (NLR) was computed. Mean dose and volumes (cc) receiving 5-50 Gy were calculated for the heart and VBs. A receiver-operator characteristic analysis was performed for univariate correlation between incidence of grade ≥3 hematotoxicity and dose-volume parameters. Results: Median follow-up was 36.1 months for all patients and the overall survival at 3 years was 57.5%. The rates of grade 3 or 4 hematologic toxicity in the PT group were 37.1% (leukopenia), 22.9% (neutropenia), and 80.0% (lymphopenia) versus 41.3%, 15.2% and 87.2%, respectively, for IMRT patients. There was a significant correlation between grade 4 lymphopenia and the heart V5, V10 and V20, but no significant correlation between VB doses with any hematotoxicity. Median NLR values and heart dose were higher in the IMRT group (9.17 vs 3.86 with PT, p = 0.0048; 10.5 vs 23.5Gy, p< 0.0001, respectively). There was a correlation between survival and NLR with a hazard ratio of 1.025 (CI 1.006 - 1.044). Conclusions: Low doses to the heart mediate severe lymphopenia in esophageal cancer patients treated with cRT. These data confirm the safety of the posterior-only proton approach without concern for increased hematologic toxicity despite higher vertebral body doses compared to IMRT. They also suggest that the blood pool is more important as a source of severe lymphopenia.
Prognostic impact of immune-related adverse events with nivolumab in patients with advanced gastric cancer: A multicenter retrospective analysis.
Authors: Ohya Yuno , Ando Takayuki , Ueda Akira , Ogawa Kohei , Motoo Iori , Kajiura Shinya , Tsukada Kenichiro , Hara Takuo , Suzuki Nobuhiro , Nakada Naokatsu , Takatori Shunsuke , Horikawa Naoki , Fujii Tsutomu , Yasuda Ichiro
Published: February 2020

347

Background: Nivolumab was established as one of the standard treatments for previously treated advanced gastric cancer (AGC). The aim of this study is to evaluate the frequency of immune-related adverse events (irAEs) with Nivolumab and its impact on treatment efficacy in clinical practice. Methods: We performed multicenter retrospective analysis, which included 90 patients with advanced gastric cancer who received Nivolumab treatment between October 2017 and September 2019. The frequency of irAEs and its treatment outcome were evaluated, and survival was compared during Nivolumab treatment. Results: The characteristics of 90 patients in this analysis were as follows: median age (range), 68 (36-85); male/female, 56/34; ECOG PS 0-1/≥2, 62/28; number of metastatic sites 1/≥2, 36/56; treatment line 3/≥4, 63/27. Median treatment cycle of nivolumab treatment was 3 (range 1-26). The overall response in 68 patients with target lesions was 6.3% (4/68), and the median PFS and OS was 1.5 and 4.3 months, respectively. IrAEs were observed in 8 patients (8.8%), including grade 4 pneumonitis, grade 2 or 3 adrenal insufficiency, and grade 2 hypothyroidism, encephalitis, and immune thrombocytopenia. Median time to onset of irAEs was 1.3 (range 0.6-10.5) months. Six were treated with systemic corticosteroid therapy, and all irAEs were relieved. The median PFS and OS were 4.7 months (95%CI, 1.2-9.3) and 12.2 months (95% CI, 3.2-not reached) in patient with irAEs, and 1.4 months (95%CI, 1.1-1.9) and 4.1 months (95%CI, 2.6-6.6) in those without, respectively. There was significant difference in the PFS (p=0.005) and OS (p=0.03). Conclusions: Nivolumab was effective and well tolerated even in clinical practice. Development of irAEs may be associated with better outcome of Nivolumab in patients with AGC.
Analysis of weight loss as a prognostic factor in patients (pts) with advanced gastric cancer from REGARD, RAINBOW and RAINFALL phase III studies.
Authors: Mansoor Wasat , Roeland Eric , Chaudhry Aafia , Wei Ran , Chatterjee Anindya , Knoderer Holly , Abada Paolo , Klempner Samuel J.
Published: February 2020

348

Background: Maintaining weight (wt) and adequate nutrition during systemic treatment in advanced gastric cancer (G/GEJ) therapy remains a challenge. We investigated the impact of early wt-loss on survival in three phase 3 studies of ramucirumab (R); REGARD (RG), RAINBOW (RB), and RAINFALL (RF) in G/GEJ. Methods: ITT pts were categorized into 2 groups based on their body wt change from start to end of cycle 1 (C1; C = 28 days in RG, RB; C = 21 days in RF): wt-loss < 3% vs ≥3%. Univariate Cox PH models were performed in each individual study to evaluate the effects of body wt change from the start to end of C1 on OS. A pooled meta-analysis stratified by study and a sensitivity analysis of the subgroup of responders was also performed. Results: A total of 311 (RG: 212 in R+BSC; 99 in Placebo (PB)+BSC), 591 (RB: 306 in the R+Paclitaxel (P); 285 PB+P), and 562 (RF: 279 in R+Cape/Cis (CC); 283 in PB+CC) pts with body wt data during C1 were evaluated. The number of pts with wt-loss of ≥3% and < 3% are shown in Table. Pts with wt-loss < 3% during C1 experienced longer OS compared to those with wt-loss ≥3%, irrespective of treatment arms across studies (Table). In pooled treatment arms within each study, the HR for wt-loss group ( < 3% vs ≥3%) was 0.359 (95% CI = 0.254, 0.507), 0.632 (0.497, 0.804), 0.752 (0.608, 0.930) in RG, RB, RF, respectively. In the meta-analysis that combined the 3-studies, univariate Cox PH model stratified by study showed consistent effect of early wt-loss on OS regardless of treatment arm, HR ( < 3% vs ≥3%) = 0.632 (0.546, 0.732). Conclusions: Analysis from three phase 3 studies demonstrates early wt-loss ≥3% during C1 is an important negative prognostic factor for survival in gastric/GEJ cancer. Prospective studies of the relationship of weight preserving nutritional interventions on OS are warranted. Clinical trial information: NCT00917384, NCT01170663, NCT02314117.

[Table: see text]
Predictors of outcome following local excision for T1 rectal adenocarcinoma: A contemporary analysis.
Authors: Jayakrishnan Thejus Thayyil , Abel Stephen , Reichstein Ari , Fortunato Richard , Nosik Stanislav , McCormick James , Finley Gene Grant , Monga Dulabh K. , Kirichenko Alexander V. , Wegner Rodney E.
Published: February 2020

35

Background: Local excision (LE) alone is a standard treatment option for appropriately selected early stage rectal adenocarcinoma patients. Guidelines for this therapeutic approach are based upon retrospective single institution data, some of which dates back 30 years. We thus sought to use the National Cancer Database (NCDB) to examine outcomes in a large cohort of patients with early stage rectal adenocarcinoma treated with LE and to identify/confirm predictors of outcome. Methods: We queried the NCDB for patients with pT1N0M0 rectal adenocarcinoma treated with local excision alone. Baseline characteristics were tabulated and included lymphovascular invasion (LVI), perineural invasion (PNI), grade, and size all of which have been recorded in the NCDB since 2010. Multivariable Cox regression was used to identify predictors of overall survival. Kaplan Meier curves were generated to compare survival based upon significant factors found on multivariable analysis. Results: Using the above criteria, we identified 887 patients eligible for analysis across 2010-2014. The median age was 67 and 57% of patients were male. The median tumor size was 1.5 cm (IQ range: 0.9-2.5 cm). A minority of patients had grade 3 tumors (5%), LVI (8%), or PNI ( < 1%). Median follow up was 36 months (1-83). On multivariable Cox regression, predictors of worse survival included: size > 4 cm, age > 67, higher comorbidity score, and presence of LVI. On Kaplan Meier analysis, 5 year OS was 75% vs. 74% for patients without and with LVI, respectively (p = 0.0115). In terms of size, the 5 year OS was 74% vs. 51%for size < 4cm and size > 4cm (p = 0.0138). Conclusions: Our large contemporary series demonstrates excellent survival outcomes in patients with early stage rectal adenocarcinoma treated with LE alone. LVI remains a predictor of outcome, while grade and perineural invasion were not significant in this analysis. This finding is likely due to a small number of patients with those characteristics.
A phase I/II study of nivolumab, paclitaxel, and ramucirumab as second-line in advanced gastric cancer.
Authors: Hironaka Shuichi , Kadowaki Shigenori , Izawa Naoki , Nishina Tomohiro , Yamanaka Takeharu , Minashi Keiko , Muro Kei , Sunakawa Yu , Kajiwara Takeshi , Hayashi Yuichiro , Kawakami Yutaka , Nakajima Takako Eguchi
Published: February 2020

352

Background: Synergistic anti-tumor effect induced by simultaneous blockade of PD-1 and taxanes, and PD-1 and VEGFR-2 has been reported. A phase I/II study was conducted to investigate the safety and efficacy of nivolumab (Nivo) with paclitaxel (PTX) plus ramucirumab (Ram), which is the standard treatment as the second-line treatment for advanced gastric cancer (AGC). Methods: AGC patients (pts) with measurable lesions, ECOG PS 0-1, and disease progression on the first-line chemotherapy with fluoropyrimidine and platinum were eligible. Pts received Nivo (3 mg/kg on days 1 and 15) combined with PTX (80 mg/m2 on days 1, 8 and 15) and Ram (8 mg/kg on days 1 and 15) (Level 1), every 4 weeks. After feasibility was evaluated in 6 pts (phase I part), additional 37 pts were enrolled in a phase II part with the primary endpoint of 6-month progression-free survival (PFS) rate. The combined positive score (CPS) is defined as the number of PD-L1 positive cells (tumor cells, macrophages, and lymphocytes) divided by the total number of viable tumor cells. Results: Fourty-three AGC pts were enrolled: median age, 66 years; ECOG PS 1, 48.8%; and CPS ≥1, 60.5%. Dose limiting toxicities were observed in 2 pts in the phase I part and recommended dose was determined as Level 1. ORR was 37.2% (95%CI, 23.0-53.5%): 46.2% (95%CI, 26.6-66.6%) in CPS≥1 pts and 30.8% (95%CI, 9.1-61.4%) in CPS < 1 pts. With a median follow-up time of 16.8 months, 6-month PFS rate was 46.4% (80% CI, 36.4-55.8%) ( P= 0.067): 57.7% (95%CI, 36.8-73.9%) in CPS≥1 pts and 38.5% (95%CI, 14.1-62.9%) in CPS < 1 pts. Median PFS was 5.1 months (95%CI, 4.5-6.5 months). Median survival time was 13.1 months (95%CI, 8.0-16.6 months): 13.8 months (95%CI, 8.0-19.5 months) in CPS≥1 pts and 8.0 months (95%CI, 4.8-24.1 months) in CPS < 1 pts, and 18-months survival rate was 32.1% (95%CI, 18.2-46.8%). Conclusions: Nivo with PTX plus Ram demonstrated promising antitumor activity as the 2nd-line treatment for AGC pts with manageable toxicities. Clinical trial information: UMIN000025947.
Low-grade gastric mucosa-associated lymphoid tissue lymphoma: Clinicopathological factors associated with Helicobacter pylori eradication and tumor regression.
Authors: Shim Hyun Ik , Lee Dong Ho , Cho Jae Ho , Shin Cheol Min , Yoon Hyuk , Park Young Soo , Kim Nayoung
Published: February 2020

353

Background: Eradication of Helicobacter pylori is widely accepted as the initial therapy for low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma. The aim of this study was to assess the remission and relapse rates of low-grade gastric MALT lymphoma after H. pylori eradication and to identify the clinical factors affecting remission. Methods: We retrospectively analyzed 151 patients diagnosed with gastric MALT lymphoma from May 2003 to December 2018. Results: Of the 151 patients, 112 (74.2%) had an H. pylori infection. Total regression rates with eradication was 90.2% (101/112) in H. pylori-positive patients and 55% (11/20) in H. pylori-negative patients. Age, sex, tumor location, endoscopic findings, and the severity of mononuclear lymphocytes were not related to achieving successful initial H. pylori eradication and remission. However, patients with a smaller H. pylori burden ( p=0.030) and less neutrophil infiltration ( p=0.003) were more likely to achieve a successful initial H. pylori eradication. H. pylori ( p<0.001) and the burden ( p=0.020) were significantly related to remission of MALT lymphoma. Conclusions: The results show that H. pylori burden and neutrophil infiltration were inversely related to the success of the initial H. pylori eradication procedure and that the H. pylori burden was inversely related to the remission of MALT lymphoma.
DKN-01 in combination with pembrolizumab in patients with advanced gastroesophageal adenocarcinoma (GEA): Tumoral DKK1 expression as a predictor of response and survival.
Authors: Klempner Samuel J. , Bendell Johanna C. , Villaflor Victoria Meucci , Tenner Laura LaNiel , Stein Stacey , Naik Girish S. , Sirard Cynthia A. , Kagey Michael , Chaney Marya F. , Strickler John H.
Published: February 2020

357

Background: Dickkopf-1 (DKK1) modulates Wnt signaling and contributes to an immune suppressive tumor microenvironment. DKN-01 (D), a neutralizing DKK1 antibody + pembrolizumab (P) has demonstrated safety and clinical activity in advanced GEA. We report response and survival outcomes in anti-PD-1/anti-PD-L1 naïve GEA patients by high/low tumoral DKK1 expression. Methods: We enrolled advanced anti-PD-1/PD-L1 naïve GEA patients (pts) in a Phase 1b/2a study of D + P (NCT02013154). Tumoral DKK1 mRNA expression was assessed by an in situ hybridization RNAscope assay. Objective response rate (ORR), disease control rate (DCR), progression free survival (PFS) and overall survival (OS) were compared between DKK1 high and low groups. Kaplan-Meier method and Cox-PH model was used for survival analysis and logistic regression was used for clinical benefit/response outcome. Results: 34 GEA pts were enrolled to receive 300 mg D + P. 31 GEA pts had DKK1 expression available (25 response-evaluable/RE) and 27 had both DKK1 and PD-L1 expression available (22 RE). In RE pts, DKK1 high (H-score ≥ upper-tertile [≥35]) had an ORR of 50% (5 PR/10), DCR of 80% (8/10) while DKK1 low ( < upper-tertile) had an ORR of 0% (0/15) and DCR of 20% (3/15); DKK1 high (vs. low) had an OR of 16 (95%CI: 2.2, 118.3; n = 25) and adjusted (for PD-L1 CPS ≥10 vs. < 10) OR of 17.6 (95%CI:1.6, 194.4; n = 22) for clinical benefit/response (PR/SD vs. PD). Median PFS was 22.1 weeks in DKK1 high (n = 11) vs. 5.9 weeks in DKK1 low (n = 20); HR of 0.23 (95%CI: 0.082, 0.66; n = 31). Adjusted (for PD-L1 expression) HR for DKK1 high was 0.20 (95%CI: 0.061,0.68; n = 27) for PFS. DKK1 high (n = 11) had a median OS of 31.6 weeks vs. 17.4 weeks in DKK1 low (n = 20); HR of 0.45 (95%CI: 0.16, 1.3; n = 31) and adjusted HR of 0.62 (95%CI: 0.2,1.9; n = 27). Conclusions: High levels of tumoral DKK1 expression identify advanced anti-PD-1/PD-L1 naïve GEA pts with the greatest benefit from D + P. Improvements in response/clinical benefit and PFS were observed independent of PD-L1 expression. Tumoral DKK1 as a potential predictive biomarker for DKN-01 treated GEA pts will be evaluated in future studies. Overall survival follow-up is ongoing. Clinical trial information: NCT02013154.
Postoperative adjuvant chemotherapy with S-1 versus SOX/XELOX regimens for pStage III gastric cancer: A cohort study.
Authors: Tsuchiya Nobuhiro , Kunisaki Chikara
Published: February 2020

358

Background: Adjuvant chemotherapy following curative gastrectomy is recommended for patients with pStage II or III, except pT3 (ss), N0 gastric cancer in Japan. This study aimed to compare the efficacy of postoperative adjuvant chemotherapy with S-1 versus SOX/XELOX for pStageIII gastric cancer. Methods: Between January 2015 and December 2018, 51 patients with pStage III gastric cancer underwent curative gastrectomy. The combination therapy group received a combined SOX and XELOX regimen as follows: (1) SOX regimen: 130 mg/m2 of oxaliplatin on day 1 every 3 weeks combined with 40 mg/m2 of S-1 twice daily on days 1–14 every 3 weeks; (2) XELOX regimen: 130 mg/m2 of oxaliplatin on day 1 every 3 weeks combined with 1000 mg/m2 of capecitabine twice daily on days 1–14 every 3 weeks. We evaluated their hospital records retrospectively. The indication of SOX/XELOX regimens was based on PS and intent of patients. Results: The S-1 group comprised 28 cases (pStage III A/B/C: 12/8/8), while the SOX/XELOX group comprised 23 cases (pStage III A/B/C: 4/10/9). There was no difference in age, sex, comorbidity, prognostic nutritional index and stage between two groups. The 2-year DFS of the S-1 group and the SOX/XELOX group were 58.6% and 71.7%, respectively (p = 0.367). Subgroup analysis showed that the 2-year DFS of patients with pStage IIIC gastric cancer in the S-1 group was significantly lower than the SOX/XELOX group (S-1 vs. SOX/XELOX: 25.9% vs. 78.7%, p = 0.041). As concerns adverse effects (CTCAE ver 4.0), peripheral sensory neuropathy was significantly higher in the SOX/XELOX group than in the S-1 group (S-1: grade I/II 3.6%/0% vs. SOX/XELOX: grade I/II 21.7%/34.8%, p < 0.001), although the other adverse effects did not differ between the two groups. Conclusions: SOX/XELOX therapy may be more useful than S-1 therapy for more advanced tumors among pStage III gastric cancers.
Is splenectomy for dissecting splenic hilar lymph nodes justified in scirrhous type of gastric cancer?
Authors: Hayashi Tsutomu , Yoshikawa Takaki , Kamiya Ayako , Date Keichi , Wada Takeyuki , Otsuki Sho , Yamagata Yukinori , Katai Hitoshi , Nishida Toshirou
Published: February 2020

359

Background: Splenectomy for dissecting splenic hilar nodes (#10) should be avoided for most gastric cancer considering high morbidity and no survival benefit, while that is often selected in scirrhous type of gastric cancer because this special type frequently invades the whole stomach and the #10 nodes. Splenectomy is necessary for dissecting #10, however, survival benefit of dissecting #10 is unclear. Methods: Patients who had scirrhous gastric cancer and underwent D2 total gastrectomy with splenectomy in National Cancer Center Hospital, Japan, between 2000 to 2011 were retrospectively analyzed. The therapeutic value index was calculated by multiplying the metastatic rate of each nodal station and the 5-year survival of patients who had metastasis to each node. Results: In total, 144 patients were eligible for the present study. The most frequent metastatic site was the nodes along the lessar curvature (#3, 57%), followed by the nodes along the right gastro-epiploic artery (#4d, 45%), the right nodes located at the cardia (#1, 34%), the nodes along the left gastro-epiploic artery (#4sb, 23%), the inferior nodes at the pyloric ring (#6, 22%), the nodes along the left gastric artery (#7, 21%), the nodes along the short gastric artery (#4sa, 18%), the nodes along the cardiac branched artery (#2, 15%), the nodes around the spleen (#10, 15%), the distal nodes along the splenic artery (#11d, 15%), the proximal nodes along the splenic artery (#11p, 13%), the nodes around the celiac artery (#9, 13%), and the nodes along the common hepatic artery (#8a, 10%). These lymph nodes had a metastatic rate of more than 10%. The node with the highest index was #3(18), followed by #4d(13.4), #1(9.59), #4sa(5.85), #4sb(5.75), #10(4.86), #7(4.16), #11d(4.16), #11p(3.87), #2(3.07), #8a(2.08), and #9(1.39). The index of #10 was exceeded that of #2, #7, #8a, and #9 which are the key nodes dissected in D2. Conclusions: The metastatic rate of splenic hilar nodes was relatively high, and the therapeutic index was the sixth highest in the fifteen regional lymph nodes included in D2 dissection. Splenectomy for dissecting splenic hilar nodes would be justified in scirrhous type of gastric cancer considering its survival benefit.
Safety and tolerability of oxaliplatin based pressurized intraperitoneal aerosol chemotherapy (PIPAC) for patients with peritoneal carcinomatosis: A phase I dose-finding study in Asian patients.
Authors: Sundar Raghav , Kim Guo Wei , Tan Hon Lyn , Wang Lingzhi , Chue Koy Min , Tai Chia Hui , Teo Siok Chin , Jang Clarisse , Chee Corissa , Lieske Bettina , Chee Cheng Ean , Shabbir Asim , So Jimmy Bok Yan , Yong Wei-Peng
Published: February 2020

360

Background: PIPAC is a novel, laparoscopic intraperitoneal chemotherapy delivery technique which aims to improve on hyperthermic intraperitoneal chemotherapy (HIPEC), ameliorating drug distribution and tissue penetration. Thus far, PIPAC has been conducted with oxaliplatin chemotherapy in Europe, at an arbitrary dose of 92mg/m2; 150mg/m2 was found to be intolerable. We conducted a dose-escalation phase 1 study to establish the safety, tolerability and recommended phase 2 dose (RP2D) for PIPAC in Asian patients. Methods: This phase 1 study of oxaliplatin administered via PIPAC was designed as a traditional 3+3 dose escalation study for patients with predominant peritoneal metastasis from a gastrointestinal primary tumor, after failure of standard therapies. Dose levels were planned at 45, 60, 90 and 120mg/m2. Repeat doses of PIPAC were permitted, 6 weeks apart. Dose limiting toxicities (DLT) were defined as any clinically relevant grade 3 adverse events occurring within 28 days after PIPAC. Results: This study included 16 patients (25 PIPAC procedures; 8 gastric, 4 colorectal and 1 gallbladder, pancreas and appendix cancer each). Median age was 62 years, with a median peritoneal carcinomatosis index (PCI) score of 17 (range 1 - 39). Two patients developed pancreatitis (grade 2 and 3) on day 6 and day 9 after PIPAC administration at the dose cohort of 45mg/m2, necessitating cohort expansion to 6 patients. One patient was noted to have asymptomatic grade 3 hyperamylasemia (90mg/m2 cohort). There were no other DLTs and all 3 patients in the highest dose cohort (120mg/m2) tolerated PIPAC well. Nine patients who underwent a 2nd PIPAC procedure had a decrease in PCI score from 18.4 to 15.5; one patient at 120mg/m2 had an improvement in PCI from 30 to 12. Conclusions: The RP2D of PIPAC with oxaliplatin is 120mg/m2. Single agent PIPAC is well tolerated, and future studies with PIPAC must consider a bi-directional approach with the incorporation of systemic therapy, with either chemotherapy or immunotherapy to improve efficacy. Clinical trial information: NCT03172416.
Enhanced efficacy of anti-VEGFR2/taxane therapy after progression on immune checkpoint inhibition (ICI) in patients (pts) with metastatic gastroesophageal adenocarcinoma (mGEA).
Authors: Kankeu Fonkoua Lionel Aurelien , Chakrabarti Sakti , Sonbol Mohamad Bassam , Kasi Pashtoon Murtaza , Starr Jason Scott , Liu Alex J , Bois Melanie C. , Pitot Henry C. , Ross Helen J. , Wu Tsung-Teh , Graham Rondell P. , Markovic Svetomir , Dong Haidong , Yoon Harry H.
Published: February 2020

362

Background: Most pts with mGEA do not respond to ICI or ramucirumab/paclitaxel (RAM/TAX). Emerging data suggest that ICI may potentiate subsequent therapy (Tx). In KN059 we unexpectedly observed durable responses in 2 pts on RAM/TAX after ICI (PMID 29674442). We examined if ICI impacts efficacy of subsequent RAM/TAX in a larger cohort and explored alterations in the tumor microenvironment. Methods: All pts with mGEA at Mayo Clinic (MN, AZ, FL) who received RAM/TAX (2014-19) were included. We compared best objective response rate (ORR: complete [CR] or partial response [PR]) per RECIST1.1 and overall survival (OS) in pts who received RAM/TAX with (Group A) vs without (Group B) immediately preceding PD-1 blockade. Chi square and multivariate logistic and Cox regression were used. We adjusted for total lines of Tx received and the line of Tx in which RAM/TAX was given, to control for potential differences in the biology of heavily treated pts or those receiving RAM/TAX as 2nd vs 3rd line Tx. We also adjusted for age and ECOG PS. Results: In total 87 pts met inclusion criteria. In the 19 pts (Group A) who received RAM/TAX (usually as 3rd line Tx) after progression on ICI, there was a 77% relative risk reduction of death after initiation of RAM/TAX compared to the 68 pts (Group B) who received RAM/TAX (usually as 2nd line) without preceding ICI (median OS 15.0 vs 7.6 mo; HR 0.23; P < .001). The ORR was also significantly higher (58% vs 18%; P < .001) including the CR rate (16% vs 1%; P = .006). Two CRs in Group A are ongoing (10 - 34 mo). Of note, 95% of Group A pts did not respond to ICI, and all had irRECIST progression on ICI. Immunofluorescent analysis from a responder showed 65-fold reduction (post vs pre-Tx) in intratumoral density of immunosuppressive FOXP3+ Tregs, with preserved density of antitumor CD8+ T cells. Conclusions: Higher than expected efficacy was observed on RAM/TAX when immediately preceded by ICI, suggesting ICI may enhance efficacy of subsequent anti-VEGFR/taxane therapy. This serial immunotherapy combination may be a novel option for pts with primary resistance to ICI and will be tested prospectively in a new randomized phase 2 trial (NCT04069273).
Refusal of surgery results in inferior survival in esophageal cancer.
Authors: Parsons Matthew , Tao Randa , Lloyd Shane , Johnson Skyler Bryce , Scaife Courtney L. , Garrido-Laguna Ignacio , Varghese Thomas
Published: February 2020

364

Background: Trimodality therapy with chemoradiation followed by surgery is the standard of care for non-metastatic esophageal cancer. Some patients refuse surgery and this information is captured in the National Cancer Database (NCDB). We sought to understand factors associated with refusal of surgery in these patients and to compare their survival rates with those who undergo surgery. Methods: Data from the NCDB for patients with pathologically proven non-metastatic esophageal cancer from 2006 to 2013 were pooled and screened. Patients with T1N0M0 disease were excluded. Pearson’s chi-squared test and multivariate logistic regression analyses were used to assess the distribution of demographic, clinical, and treatment factors. After propensity-score matching with inverse probability of treatment weighting, overall survival (OS) was compared between patients who refused surgery and those who had surgery using Kaplan Meier analyses and doubly-robust estimation with multivariate Cox proportional hazards modeling. Results: We found 890 of 18,942 patients (4.6%) refused surgery. Older patients, females, those with squamous histology, patients insured by Medicare and those who received radiation therapy (RT) were more likely to refuse. Patients who had N1 disease, high incomes, those who received chemotherapy and those who lived farther from care were more likely to have surgery. The initial 6 month OS was not significantly different between patients who refused surgery and those who had surgery (93.5% vs 95.1% P= 0.064). However, five-year OS was significantly lower in patients who refused (16.4% vs. 38.4% P< .01). This survival decrement was observed uniquely in patients with both adenocarcinoma and squamous cell carcinoma histology. Among those who refused surgery, the OS decrement was mitigated by increasing RT doses. In those who received over 54 Gy of RT, there was no statistical difference in OS between the groups (HR = 0.84, 95% CI 0.65-1.09). Conclusions: We identified a number of patient characteristics that are related to the refusal of surgery in esophageal cancer. Refusal of surgery was related to a decrease in OS in propensity weighted cohorts. This survival decrement may be mitigated by RT in a dose dependent fashion.
A phase II study of nab-paclitaxel plus ramucirumab for the second-line treatment of patients with metastatic gastroesophageal cancer.
Authors: Bendell Johanna C. , Percent Ivor John , Weaver Robert Waide , Chua Cynthia Coo , Xiong Henry Q. , Cohn Allen Lee , Zakari Ahmed , Singh Jaswinder , Kozloff Mark , Lietman Caressa , Lane Cassie Michelle , Jones Suzanne Fields , Finney Lindsey H. , Carmody Sean , Womack Mark Sanders
Published: February 2020

365

Background: Nab-paclitaxel (NP) is a protein-stabilized formulation of paclitaxel, US FDA approved for treatment of metastatic breast cancer, advanced/metastatic non-small cell lung cancer and metastatic adenocarcinoma of the pancreas. Ramucirumab (R) is an antibody targeting vascular epithelial growth factor receptor 2 (VEGFR-2) approved for treatment of gastric or gastroesophageal (GE) adenocarcinoma in combination with paclitaxel as 2nd line treatment. This phase II study evaluated the efficacy of NP and R for pts with metastatic GE cancer. Methods: Pts with metastatic GE adenocarcinoma were treated with 125 mg/m2 NP on days 1, 8, and 15, and 8 mg/kg R on days 1 and 15 of each 28-day cycle. Pts continued study treatment (tx) until intolerable toxicity, disease progression (PD), or withdrawal of consent. Restaging occurred every 2 cycles. The primary objective was progression-free survival (PFS); secondary objectives were response rate (RR), time to progression (TTP), overall survival (OS) and toxicity. Results: 65 pts were enrolled between 05/15 and 12/18: median age 63 yrs (35-86), 75% male, 71% ECOG 1. Primary tumor sites were stomach (37%), GE junction (35%), and esophagus (28%). 83% were stage IV at initial diagnosis. 29% were HER2+ at study entry. 57% had 1st line chemo, 40% chemo + targeted agent and 3% chemo + immunotherapy. Median tx duration was 13 weeks (.1-55) for NP and 12 weeks (.1-54) for R; at data cutoff 2 pts remained on tx.60% discontinued due to PD; 17% due to AE. 43% and 23% had AE-related dose reductions of NP and R, respectively; 8% and 6% were on day 15. 58% had dose interruptions of R due to AE; 42% on day 15. Median PFS was 3.8 months (CI 95% 3.4, 4.8); median TTP 4.5 months (CI 95% 3.5, 6.3); and median OS 8.8 months (CI 95% 6.1, 11.3). RR was 15% (CI 95% 6.6, 24.2); disease control rate was 68% (CI 95% 56.3, 79.1). Most common tx related AEs were neutropenia (55%), fatigue (40%), peripheral neuropathy (37%), anorexia and mucositis (26% each). Conclusions: There were no unexpected toxicity findings with NP and R in pts with GE cancers. Compared to historical controls, outcomes in this study were similar to those seen in the Western population of pts who received paclitaxel plus R. Clinical trial information: NCT02317991.
Endoscopic versus surgical resection for mucosal esophageal squamous cell carcinoma: Treatment outcomes and factors affecting survival.
Authors: Kim Ga Hee , Song Ho June , Na Hee Kyong , Ahn Ji Yong , Lee Jeong Hoon , Jung Kee Wook , Kim Do Hoon , Choi Kee Don , Lee Gin Hyug , Jung Hwoon-Yong
Published: February 2020

368

Background: Mucosal esophageal squamous cell carcinoma (T1a EC) is treated with endoscopic (ER) or surgical resection (SR). The data regarding prognosis of T1a EC and the associated factors are still lacking. This study aimed to compare the treatment outcomes of T1a EC in ER and SR groups, and to investigate the factors affecting long-term survival. Methods: We retrieved data for 263 patients with T1a EC who underwent ER (n = 200) or SR (n = 63). Relevant clinical and tumor-specific parameters were reviewed. Underlying comorbidity was scored using Charlson co-morbidity index (CCI). Significant factors affecting survival were determined by Cox regression analysis. Results: The mean age of the patients was 64.5±8.0 years. During a mean follow-up of 54.4±20.4 months, the 5-year overall survival (OS) of all T1a EC patients was 85.7% (86.8% in ER and 82.4% in SR group; p = 0.631). In multivariate analysis, CCI was a significant factor affecting survival (p < 0.001). The 5-year OS was 60.2% in patients with CCI > 2 and 88.2% in patients with CCI ≤2 (p < 0.001). The 5-year cumulative incidence of primary EC recurrence was 1.9% and metachronous EC recurrence was 15.1% in ER group (0% in SR group). Incidence of subsequent second primary cancers was 9% in ER and 9.5% in SR. The 5-year cumulative incidences of all cases of cancer recurrence in ER and SR groups were 27.5% and 10.8%, respectively (p = 0.037). The procedure-related adverse events occurred in 10.0% in ER and 41.3% in SR (p < 0.001). Among the 24 (12.0%) and 10 (15.9%) deaths in ER and SR group, respectively, primary EC-specific death was not reported. The major causes of death were second primary cancers in ER group (75%), and post-operative complications or organ failure in SR group (70%). Conclusions: Long-term survival was excellent in patients undergoing ER or SR for T1a EC. The prognosis of T1a EC was significantly associated with underlying comorbidity. Attention should be paid to metachronous cancer recurrence in ER group and operation-related adverse events in SR group.
Association between postoperative pneumonia and prognosis of patients with esophageal cancer.
Authors: Atsumi Yosuke , Aoyama Toru , Tamagawa Ayako , Tamagawa Hiroshi , Ju Mihwa , Koumori Keisuke , Maezawa Yukio , Kano Kazuki , Kazama Keisuke , Murakawa Masaaki , Numata Masakatsu , Sato Tsutomu , Yukawa Norio , Masuda Munetaka , Rino Yasushi
Published: February 2020

370

Background: We examined the association between postoperative pneumonia and prognosis of patients with esophageal cancer after curative surgery. Methods: We enrolled 122 patients who underwent curative resection for esophageal cancer between 2008 and 2018. The patients who had postoperative pneumonia were categorized into the pneumonia group, while those without postoperative pneumonia were classified into the non-pneumonia group. We identified the risk factors for the recurrence-free survival (RFS) and the overall survival (OS). Postoperative pneumonia was defined using the revised Uniform Pneumonia Score. Results: Thirty-four of the 122 patients (27.9%) had postoperative pneumonia. The 5-year OS rate after surgery in the pneumonia group was significantly lower than that in the non-pneumonia group (28.2% versus 55.1%, p = 0.006). Although not significant, the 5-year RFS rate after surgery in the pneumonia group tended to be lower than that in the non-pneumonia group (18.9% versus 49.2%, p = 0.061). A multivariate analysis identified postoperative pneumonia as a significant independent risk factor for the OS (hazard ratio = 2.15; 95% confidence interval, 1.25 to 3.68; P = 0.006). Conclusions: Our analysis showed postoperative pneumonia was an independent risk factor for worse overall survival in patients who underwent curative resection for esophageal cancer. This finding suggests that we should plan the surgical procedure, perioperative care and surgical strategy to prevent postoperative pneumonia.
Loss of body weight during neoadjuvant chemotherapy with docetaxel, cisplatin, and fluorouracil as predictive of poor survival of patients with esophageal squamous cell carcinoma.
Authors: Ito Munehiro , Kato Ken , Yamamoto Shun , Imazeki Hiroshi , Aoki Masahiko , Oshima Kotoe , Hirano Hidekazu , Okita Natsuko , Shoji Hirokazu , Honma Yoshitaka , Iwasa Satoru , Takashima Atsuo , Kanamori Jun , Oguma Junya , Daiko Hiroyuki , Boku Narikazu
Published: February 2020

371

Background: Though neoadjuvant chemotherapy with docetaxel/cisplatin/5-fluorouracil (DCF) showed a promising efficacy in patients (pts) with resectable esophageal squamous cell carcinoma (ESCC), grade 3 anorexia during the course and body weight loss (BWL) were frequently experienced. BWL is considered as a factor for poor survival in operable cancer pts, however, there is rarely reported of the relationship of BWL during neoadjuvant therapy and survival. Methods: We retrospectively evaluated pts of ESCC withclinical stage II or III, excluding T4, who had received neoadjuvant DCF and esophagectomy (R0 resection) at our institution between April 2010 and December 2018. We define the cut-off level at more than 3% weight reduction (BWL3 group) between before and after of first cycle of DCF. Results: Among the 77 pts who were selected for this analysis, 13 patients showed BWL > 3% (BWLS group), and other 64 pts did not (no-BWL group). The median age, proportions of performance status of 0, cT3 stage, cN2-3 stage and serum albumin lower than normal level in no-BWL and BWL3 group were 65 and 67y.o, 59 and 77%, 88 and 54%, 75 and 69%, 34 and 31%, respectively. There was no significant difference inhistological therapeutic effect (grade 2-3) with 50% in no-BWL and 62% in BWL3 group (P = 0. 549). The incidence of postoperative grade 2 or higher pneumoniawas same in both group (23% vs 17%, P = 0. 695). The median overall survival (OS) was not reached in non-BWL group and 39.5 m in BWL3 group (P = 0.048), respectively. The median progression free survival (PFS) was not reached in non-BWL group and 39.5 m in BWL3 group (P = 0.382), respectively. In multivariate analysis, BWL is independent prognostic factor for OS (hazard ratio [HR] = 11.5, 95%CI: 2.45-53.8, P = 0.002). Conclusions: Our exploratory study demonstrated that body weight loss during first course of neoadjuvant DCF therapy for ESCC patients may be a prognostic factor for survival.
Continuous fluropyrimidine (FP) with platinum (P) based chemotherapy (CT) versus maintenance FP after induction therapy in advanced gastric (G) and gastroesophageal (GE) cancer.
Authors: Walden Daniel , Sonbol Mohamad Bassam , Buckner Petty Skye , Borad Mitesh J. , Bekaii-Saab Tanios S. , Ahn Daniel H.
Published: February 2020

375

Background: Combination FP with P CT have become the standard of care for advanced G/GEJ cancer. Clinical trials in conjunction with practice, have adopted induction FP and P CT for 3-4 months (mos). In other GI malignancies, induction CT followed by maintenance CT (MTC) has been shown to improve patient (pt) outcomes compared to observation, with a decrease in treatment (trmt) related toxicities with induction therapy. However a maintenance approach in G/GEJ cancer has not been investigated in clinical trials. We investigated pt outcomes with metastatic G/GEJ cancer who received continuous induction (CTX) versus induction followed by MTC. Methods: A retrospective analysis of pts with metastatic G/GEJ adenocarcinoma treated with (FP+ P)-based CT between 2007 to 2017 from three centers of a single institution was performed. Metastatic G/GEJ cancer pts who achieved at least stable disease after initial induction trmt were included. Pts were categorized into the CTX group if they received greater than 16 weeks or 8 cycles of combined CT and assigned to the MTC group if they received maintenance FP monotherapy after 8 or less cycles of combined induction CT. Data was extracted from the medical record to determine progression free survival (PFS), overall survival (OS), and toxicities. Results: Sixty-four pts that met criteria and were evaluated, thirty-four received CTX and thirty received MTC. No significant difference in PFS (12.1 vs 8.0 mos p = .72, HR=1.10 95%CI .66-1.83) was observed between the CTX and MTC groups, additionally there was no significant difference in OS. A significant decrease in trmt related toxicities were observed, with a higher proportion of thrombocytopenia (84.8% vs 50.0% p = .004), and grade 3 neuropathy (39.4% vs 13.8% p =.024) in CTX pts (Table). Conclusions: MTC following induction FP/P CT is associated with an improved toxicity profile and appears to be effective compared to CTX in metastatic G/GEJ cancer. Prospective randomized studies confirming its potential benefits compared with continuous induction CT are warranted.

[Table: see text]
Relationship of lymphopenia to overall survival and progression-free survival in rectal cancer patients receiving neoadjuvant chemoradiation.
Authors: Howell Jackson Neal , Nelson Bailey , Cady David , Kharofa Jordan
Published: February 2020

39

Background: Pelvic radiation and myelosuppressive chemotherapy can lead to lymphopenia during the course of preoperative chemoradiation when treating rectal cancer. Lymphopenia during chemoradiation has been associated with higher risks of recurrence in other cancers, possibly due to decreased immunosurveillance. The effect in rectal cancer is not well described. We hypothesize that high-grade lymphopenia is associated with worse progression-free survival (PFS) and overall survival (OS) in rectal cancer patients undergoing preoperative chemoradiation. Methods: All patients treated at our institution with neoadjuvant chemoradiation between 2013 and 2019 were reviewed (n = 99). The study was limited to patients with Stage II – IV (AJCC 8th edition) rectal adenocarcinoma. Patients were excluded if they had prior systemic therapy (n = 13) or if lymphocyte data was unavailable (n = 30). Lymphopenia which arose during or within 30 days of completion of chemoradiation was graded by the CTCAE v.4.0. Neoadjuvant Rectal (NAR) scores, indicators of pathologic response, were calculated for each surgical patient. Kaplan-Meier analysis was used to calculate PFS and OS. Two-tailed t-tests (a=0.05) were used to detect differences between subgroups. Results: Fifty-six patients met inclusion criteria. Grade 2 (G2) or higher lymphopenia occurred in 43 (76.8%) patients (G2 = 22, G3 = 20, G4 = 1). In patients with G2 vs G3-4 lymphopenia, there were no differences in baseline, treatment, or demographic characteristics. The median PFS for these patients was 20.0 months. Patients with G3-4 lymphopenia had significantly worse 2-year PFS compared to those with G2 lymphopenia (83.3% vs 59.3% p = 0.03). The two-year OS did not differ between groups (100% vs 60.3%, p = 0.10). Lymphocyte nadir did not correlate with pathologic response, as measured by the NAR score (r = -0.28, p = 0.07). Conclusions: In this study, G3-4 lymphopenia was associated with worse PFS in rectal cancer patients treated with neoadjuvant chemoradiation, despite a small sample size. The prognostic implications of lymphopenia in rectal cancer should be confirmed in larger cohorts and the underlying mechanisms explored.
Preliminary analysis of total neoadjuvant therapy for patients with locally advanced gastric (G) and gastroesophageal (GE) adenocarcinoma.
Authors: Roeland Eric , Kanter Katie , Wo Jennifer Yon-Li , Fish Madeleine , Nipp Ryan David , Van Seventer Emily E. , Parikh Aparna Raj , Allen Jill N. , Giantonio Bruce J. , Blaszkowsky Lawrence Scott , Keane Florence , Klempner Samuel J. , Ryan David P. , Auchincloss Hugh G. , Ott Harald , Lanuti Michael , Morse Christopher , Mullen John Thomas , Hong Theodore S.
Published: February 2020

393

Background: Nearly half of patients with G/GE cancer do not receive or complete post-operative chemotherapy and/or chemoradiation (CRT). Total neoadjuvant therapy (TNT) is as an emerging alternate treatment strategy. We have previously reported a 28% pCR with FOLFIRINOX followed by CRT. However, TNT outcomes with FLOT or FOLFOX followed by CRT are lacking. Methods: We retrospectively analyzed patients after resection of locally advanced G/GE after receiving TNT. Patient received neoadjuvant FOLFOX or FLOT x 8 cycles, CRT (G 45 Gy, GE 50.4 Gy) with concurrent chemotherapy (5FU, carboplatin/paclitaxel). The primary aim was to explore TNT completion rates. Secondary aims included pCR and toxicity. We performed descriptive statistics, t-test, chi-squared, and Fisher’s exact tests as appropriate. Results: From 12/2015 to 8/2019, 57.1% (40/70) completed TNT and resection (15.7% active treatment, 15.7% progressive disease, 11% treated elsewhere). Median age was 66.0 (range:27-79) and 73% male. Tumor locations included 57.5% G, 30.0% GE, and 12.5% overlapping. Neoadjuvant chemotherapy included FLOT 22.5% (n = 9) or FOLFOX 77.5% (n = 31). Overall we found a 25% pCR without significant differences between type of neoadjuvant chemotherapy. Conclusions: TNT followed by resection is feasible with acceptable rates of treatment completion and toxicity. Notable limitations include the retrospective analysis, small sample size, and heterogenous treatment. The pCR rate is promising and warrants further prospective study to optimize TNT approaches. [Table: see text]