bluuebunny/crossref_metadata_2025 huggingface dataset:
Distinct genomic landscape in colorectal mucinous carcinoma via comprehensive genomic profiling.
Authors: Huang Liang , Luo Shuangling , Xue FangQin , Xiao Yi , Wang Ziqiang , Lai Sicong , Liu Zhanzhen , Hu Huanxin , Zeng Ziwei , Lin Tengjiao , Zhang Shiyue , Wang Jian , Wang Kai , Chen Gong , Kang Liang
Published: February 2020

222

Background: Mucinous carcinoma (MC), accounting for 10-15% of colorectal cancer (CRC), has long been associated with an inferior response to treatment. MC as an unfavorable prognostic factor in early stage CRC remains questionable. In this study, we used a large CRC cohort to define the genomic landscape of MC and identify prognostic and clinically actionable information. Methods: The 1226 CRC patient cohort included 997 adenocarcinomas (AC), 129 MC, and 110 adenocarcinomas with mucous composition (AMC). All of the pathological sections were verified by an experienced pathologist. FFPE tumor samples and matched peripheral blood were sequenced using a 450-cancer-related gene panel. Results: MC was significantly associated with right colon (p<0.001) and regional lymph node metastasis (p=0.004) compared to AC. We found a higher mutation rate of BRAF V600E (10.9% vs. 3.3%), PIK3CA (28.7% vs. 19.2%), SMAD4 (34.1% vs. 19.1%), BRCA1/2 (16.3% vs. 6.8%) and homology recombination pathway (40.3% vs. 22.7%), and a lower rate of TP53 (53.5% vs. 79.5%), APC (46.5% vs. 75.1%,), and HER2 amplification (0% vs. 2.1%,) in MC than in AC. MC had a significantly higher proportion of microsatellite instability-high (MSI-H) tumors (22.5% vs. 6.8%, p<0.001). Furthermore, in tumors with MSI stable, POLE mutation was more frequent in MC than in AC (7.0% vs. 2.6%, p=0.094) and resulted in dramatic elevated tumor mutational burden (TMB, range 79.5-591.5 muts/Mb), indicating up to 30% of MC patients may benefit from immunotherapy. MSI-H was associated with better prognosis (5-y DFS, MSI-H 86.7% vs. MSS 56.7%) in stage II/III CRC patients with MC. Importantly, AMC mimicked the genomic features of MC rather than AC. Conclusions: For the first time, comprehensive genomic analysis revealed that MC had distinct molecular features, indicating promising clinically application for both immunotherapy and targeted therapy. Early stage MC had a diverse prognosis due to MSI status and should be interpreted differently. The similarity of molecular profile between AMC and MC suggested the possible usage of MC, but not AC, clinical strategy for AMC.
Vascular endothelial growth factor (VEGF)-D and clinical outcomes in metastatic colorectal cancer (mCRC) patients (pts) treated with second-line FOLFIRI plus bevacizumab (Bev): A biomarker study of the WJOG 6210G trial.
Authors: Izawa Naoki , Shitara Kohei , Masuishi Toshiki , Denda Tadamichi , Yamazaki Kentaro , Moriwaki Toshikazu , Okuda Hiroyuki , Kondoh Chihiro , Nishina Tomohiro , Makiyama Akitaka , Baba Hideo , Yamaguchi Hironori , Nakamura Masato , Sunakawa Yu , Akiyoshi Kohei , Sato Mikio , Yonesaka Kimio , Yoshino Takayuki , Yamanaka Takeharu , Muro Kei
Published: February 2020

226

Background: The WJOG 6210G trial demonstrated a similar efficacy between FOLFIRI plus Bev and FOLFIRI plus panitumumab (Pani) at 2nd-line treatment in pts with KRAS exon2 wild-type mCRC (Shitara K, et al, Cancer Sci 2016). Recently, angiogenesis biomarker studies of clinical trials have identified VEGF-D as a potential predictor for angiogenesis inhibitors in mCRC. We evaluated whether VEGF-D level are associated with clinical outcomes in the WJOG 6210G trial. Methods: Plasma samples which were collected at pre-treatment were analyzed. VEGF-D level in plasma was measured by means of magnetic bead panel (G & G SCIENCE CO., LTD.). The correlations of VEGF-D level with progression-free survival (PFS) and overall survival (OS) were evaluated by cox regression analyses. Results: Ninety-nine pts were evaluable for VEGF-D level (Bev, n = 51; Pani, n = 48) among 121 pts enrolled in the WJOG6210G. The median VEGF-D level was 441 pg/ml (range 60-1570). VEGF-D level was not affected by the period from last administration of 1st-line Bev to start of 2nd-line treatment. When the median VEGF-D level was adopted as cut-off value, pts with high VEGF-D achieved a shorter PFS and OS than pts with low VEGF-D in the Bev arm [HR: 0.58 (95%CI 0.32-1.07), p = 0.08; HR: 0.62 (95%CI 0.34-1.11), p = 0.10]. In pts with high VEGF-D, the Bev arm tended to have a shorter OS and PFS compared to Pani arm [median: 12.4 m vs. 17.5 m, HR: 1.58 (95%CI 0.87-2.88); median: 4.7 m vs. 5.5 m, HR: 1.31 (95%CI 0.72-2.40)]; whereas, comparable OS and PFS in pts with low VEGF-D [median: 18.9 m vs. 16.5 m, HR: 1.08 (95%CI 0.59-2.01); median: 5.9 m vs. 7.2 m, HR: 1.10 (95%CI 0.62-1.99)]. OS was stratified by VEGF-D level quartile, then OS of Bev arm in each quartile was compared with that of Pani arm (Table). Clinical trial information: UMIN000031621. Conclusions: Our study suggests clinically meaningful association between VEGF-D level and clinical outcomes in mCRC pts treated with 2nd-line FOLFIRI plus Bev.

[Table: see text]
Overall survival of cetuximab administered every two weeks versus weekly in real-world data of U.S. patients with metastatic colorectal cancer.
Authors: Pescott Chris , Batech Michael , Boutmy Emmanuelle , Ronga Philippe , Lamy Francois-Xavier
Published: February 2020

23

Background: Cetuximab (CET) administered weekly (q1w) at 250 mg/m², after an initial dose of 400 mg/m², is approved in combination with chemotherapy (CT) for the treatment of (K) RAS wild-type metastatic colorectal cancer (mCRC). The use of CET 500 mg/m2 administered with CT every 2 weeks (q2w) is according to US clinical practice guidelines and observed routinely. In this study, we compared q2w vs q1w regimens on overall survival (OS) in a presumed first-line (1L) treatment subcohort and present updated data on the noninferiority of q2w vs q1w in line-agnostic (1L+) treatment using US real-world data. Methods: Using IBM MarketScan, a large US insurance claims database, we classified a cohort of mCRC patients treated between 07/2010 and 12/2016 with CET+CT as q1w or q2w based on observed infusion patterns. Absence of mCRC-related treatment claims preceding CET initiation date (defined as the index date) qualified as CET treated in 1L. A validated algorithm was used to determine patient death. Confounding was accounted for using high-dimensional propensity scoring (hdPS) with inverse probability of treatment weights. OS was compared using Cox proportional hazards regression. Imbalanced confounders after hdPS were added to the Cox model. In 1L+, noninferiority of the q2w regimen was tested with a margin hazard ratio (HR) of 1.25. However, noninferiority could not be tested in 1L due to the small sample size; a test for difference was used instead. Results: Of 2,730 CET-exposed mCRC patients (updated), 1,779 (65.2%) and 951 (34.8%) were classified in q1w and q2w groups, respectively, among which 557 (31.3%) and 316 (33.2%) received CET in 1L. The HR (95% CI) for OS of q2w vs q1w in 1L was 1.10 (0.92-1.31; crude), and 1.05 (0.86-1.29; adjusted; p for difference: 0.625). In 1L+, crude and adjusted HRs were 1.05 (0.94-1.18) and 0.94 (0.85-1.03), respectively, rejecting the inferiority hypothesis at p < 0.001. Conclusions: Only a third of patients received CET in 1L in this study. OS was statistically noninferior in q2w vs q1w in 1L+, and adjusted results in 1L suggest no differences between both treatment schedules. However, more data would be needed to formally test the noninferiority hypothesis in 1L.
Clinical utility of targeted next generation sequencing (NGS) to predict response to neoadjuvant therapy (NT) in rectal cancer (RC).
Authors: Carroll Kristen , Burns Michael C. , Jones Ryan , Kocherginsky Masha , Burdett Kirsten Bell , Yang Guang-Yu , Benson Al Bowen , Mahalingam Devalingam
Published: February 2020

237

Background: NGS analysis has identified molecular alterations that have predictive and prognostic implications in advanced RC. However, its role in identifying predictive signatures of chemoradiotherapy response in RC remains largely unexplored. Neoadjuvant rectal cancer (NAR) score, a composite score available after resection, is a validated short-term surrogate endpoint for long-term outcomes. Herein, we identified gene alterations in early stage RC with NGS analysis and correlated mutations with tumor response using the NAR scoring system. Methods: Patients (pts) with stage I-III RC completing NT followed by resection (2011-2018) had their tumor prospectively sequenced by an ion torrent targeted 22 gene NGS panel ( AKT1, ALK, BRAF, CTNNB1, DDR2, EGFR, ERBB2/4, FBXW7, FGFR1/2/3, KRAS, MAP2K1, MET, NOTCH1, NRAS, PIK3CA, PTEN, SMAD4, STK11, TP53). NAR scores were calculated based on clinical and pathologic staging data input, yielding 3 cohorts: low (score < 8, pCR or near CR), intermediate (8-16), or high ( > 16, poor or no response) NAR scores. Associations were drawn using Two-sided Fisher’s exact. Both unadjusted (p) and Benjamini & Hochberg adjusted (BHp) p-values are shown. Results: 51 pts with RC were analyzed: median age 59 (24-81), male (59%), clinical stage I (6%), II (25%) and III (69%). Pathological mutations were found in 94% of pts, including TP53 (76%), KRAS (49%), PIK3CA (10%), NRAS (6%), FGFR3 (4%), MET (4%). Post NT 8 (16%) pts had low NAR scores, including 6 (12%) cases with pCR, 26 (51%) intermediate, and 17 (33%) high NAR scores. Gene alterations in FGFR3 (p =0.022, BHp = 0.15) and NRAS (p =0.026, BHp = 0.15) were associated with NAR score, while no differences were observed with mutations in TP53 or KRAS. Additionally, 17 (33%) pts had recurrences [13% of pts with low NAR scores, 31% intermediate, 47% high], with metastases primarily to lung (53%) and/or liver (35%). Conclusions: This study suggests that pts with RC who derived favorable responses to standard NT could have a targeted molecular profile, namely alterations in FGFR3 and NRAS. Conversely, pts that lack this profile may benefit from novel therapeutic approaches to improve NAR scores and long-term outcomes.
Effect size as a tool to identify subpopulations with improved clinical outcomes in metastatic colorectal cancer.
Authors: Fricke Stephanie Leigh , Kratz Jeremy D. , LoConte Noelle K. , Lubner Sam Joseph , Mulkerin Daniel , Matkowskyj Kristina A. , Eickhoff Jens C. , Deming Dustin A.
Published: February 2020

252

Background: ASCO defined meaningful trial endpoints in colorectal cancer (CRC) to include OS HR ≤0.67 (Ellis, JCO 2014). This measure is limited in identifying treatment benefit for subgroups from heterogeneous populations. Effect size (Glass’s Δ) calculates the absolute difference in median clinical outcomes normalized to the control group standard deviation. We hypothesized that durable effect sizes ≥2 would be useful in predicting which trials possess subgroup populations of clinical significance despite a HR > 0.67. Methods: Prospective phase II-III trials in metastatic CRC from the ASCO Meeting Library (2016-2019) were cataloged by clinical outcomes of PFS and OS. Effect size was calculated from trials reporting confidence intervals and compared with absolute difference in clinical outcome, hazard ratio and therapeutic intervention. Trials with an indeterminant HR, yet effect size > 2 were reviewed in subgroup analyses. Results: 385 abstracts were reviewed with 99 clinical analyses available for effect size calculation. Absolute difference in PFS correlated with effect size (R = 0.64) and was inversely proportional to HR (R = -0.63). The absolute difference in OS correlated with effect size (R = 0.69) and was inversely proportional to HR (R = -0.57). When stratified by clinically significant HR (defined ≤0.67), median effect size for PFS was 13.7±13.3 (SD) which was significantly different from HR > 0.67 with median effect size 1.0±3.8 (p < 0.001). Median effect size for OS when stratified by HR ≤0.67 was 3.7±2.5 which was significantly different when compared to endpoints with HR > 0.67 with median effect size 0.9±1.4 (p < 0.003). Subgroup populations with survival benefit included combination checkpoint blockade durvalumab/tremelimumab vs supportive care with effect size 3.1 (HR 0.72; NCT02870920). First-line PFS benefit was predicted in KRAS wildtype liver-limited CRC treated with FOLFOX+cetuximab vs FOLFOX+bevacizumab by effect size of 3.2 (HR 0.80; NCT01836653). Conclusions: Effect size holds potential as a measure to delineate improved clinical outcomes from heterogeneous populations and could identify those trials for which further subgroup analysis should be explored.
Is mucinous histology a prognostic marker in early and advanced colorectal cancer?
Authors: Habib Rosemary , Gebski Val , Micklethwaite Kenneth , McLeod Duncan , Toh James , Pathma-Nathan Nimalan , El-Khoury Toufic , Ctercteko Grahame , Gowrishankar Kavitha , Wilcken Nicholas , Wong Mark , Nagrial Adnan
Published: February 2020

253

Background: In early and advanced colorectal cancer (CRC), there is limited data comparing the influence of mucinous (MAC) with non-mucinous adenocarcinoma (NMAC) histology on clinical outcomes. We investigated the association between histological type and outcomes in CRC. Methods: Medical records of patients with stage II, III and IV CRC referred to a tertiary centre in Western Sydney between 2009-2016 were examined and demographic and clinical information extracted. Key prognostic factors were modeled using log rank tests and proportional hazards (PH) regression methods in multivariate analyses. Results: Data on 686 patients was extracted. Median age was 70 years (19 – 94). Median follow up was 38.4 months. 98 patients (12%) had MAC and no differences in stage were observed at presentation between MAC and NMAC (p = 0.16). MAC was associated with increased prevalence of microsatellite instability (36% v 11% p < 0.01), high grade tumours (51% v 18% p < 0.01), female gender (61% v 45% p < 0.01) and right sided primary (65% v 40% p < 0.01). In stage II/III, MAC had comparable relapse free survival (RFS) versus NMAC (median 79 vs 97 months; P = 0.21). However, in the adjuvant chemotherapy group, a poorer RFS was seen for MAC (52 Vs 82 months, HR = 0.52, P = 0.03). In all patients with relapsed disease, MAC was more likely to be associated with peritoneal carcinomatosis (51% vs 26%; P < 0.01), and less likely to be associated with liver metastases (45% Vs 70%, P < 0.01) than NMAC. PH analysis of the MAC cohort revealed poorer RFS for LVI (HR 2.85; p = 0.03), T4 stage (HR 3.15, p = 0.01) and adjuvant chemotherapy (HR 5.49, p < 0.01). On multivariate analysis, T4 remained significant for poorer RFS. No differences were seen in OS in early stage CRC between MAC and NMAC. However, right sided and female gender with stage IV MAC had poorer OS (Right colon: HR 6.6; P = 0.03) (Female: HR 4.90, P = 0.03). Conclusions: MAC is associated with poorer RFS in early stage CRC irrespective of sidedness, and with poorer OS in right sided CRC. Given their poor response to adjuvant chemotherapy, novel adjuvant treatments should be considered for early MAC CRC. In the palliative setting, novel therapies and clinical trials are required for patients with MAC, particularly with right sided primaries.
End-to-side versus side-to-side anastomosis after laparoscopic right hemicolectomy for colon cancer: Short-term outcomes of a randomized controlled trial.
Authors: Kim Min Hyun , Cho Jung Rae , Oh Heung-Kwon , Kim Duck-Woo , Kang Sung-Bum
Published: February 2020

27

Background: A standard anastomotic configuration after right hemicolectomy is not well established, although short-term benefits of end-to-side anastomosis have been reported. This study was designed to assess the superiority of end-to-side anastomosis compared to side-to-side anastomosis after laparoscopic right hemicolectomy for colon cancer under an enhanced recovery program. Methods: Between September 2016 and August 2019, 130 patients (18–80 years) scheduled for laparoscopic right hemicolectomy were randomly assigned (1:1) to undergo end-to-side ( n = 65) or side-to-side ( n = 65) anastomosis. All patients underwent an enhanced recovery program with early diet and mobilization. The primary outcome was the cumulative recovery rate 7 days after surgery, defined as the percentage of patients who met all of the following recovery criteria: tolerated diet for 24h, analgesic-free, safe ambulation, and afebrile status without major complications. Results: The cumulative recovery rate did not differ between end-to-side (92.3%, 60/65) and side-to-side anastomosis (92.3%, 60/65) ( P = 1.000). Both approaches had similar cumulative recovery rates at 4, 5, and 6 days (end-to-side vs. side-to-side: 41.5% vs. 35.4%, P = 0.589; 73.8% vs. 63.1%, P = 0.257; 86.2% vs. 81.5%, P = 0.634; respectively) The median recovery time [interquartile range (IQR)] in the end-to-side and side-to-side groups was 105 [90-124] hours and 113 [84-139] hours, respectively ( P = 0.474), showing no significant difference. Length of stay [IQR] was similar in the end-to-side and side-to-side groups (5 [5–7] vs. 6 [5–7] days; P = 0.376). The 30-day complication rate (16.9% vs. 12.3%, P = 0.620), enhanced recovery program failure rate (10.8% vs. 7.7%, P = 0.763), and 30-day readmission rate (4.6% vs. 3.1%; P = 1.000) were not significantly different between the groups. Conclusions: This is the first randomized controlled trial showing that end-to-side anastomosis is not superior to side-to-side anastomosis in terms of short-term outcomes after laparoscopic right hemicolectomy. Clinical trial information: NCT02897531.
Performance of a blood-based test for the detection of multiple cancer types.
Authors: Wolpin Brian M. , Richards Donald A. , Cohn Allen Lee , Chen Xiaoji , Bredno Joerg , Kurtzman Kathryn N. , Yecies Jessica , Shaknovich Rita , Zhang Nan , Tummala Mohan K. , Spigel David R. , Cosgrove David , Wilks Sharon , Siegel Robert D. , Fung Eric T. , Jamshidi Arash , Aravanis Alex , Hartman Anne-Renee , Liu Minetta C. , Klein Eric A.
Published: February 2020

283

Background: Cancers of the esophagus, stomach, pancreas, gallbladder, liver, bile duct, colon and rectum will account for 17% of incident cancer diagnoses and 26% of cancer-related deaths in the US in 2019. We developed a methylation-based cfDNA early multi-cancer detection test that also can predict the tissue of origin (TOO) of these and other cancers types; performance of this test for gastrointestinal (GI) tract cancers is reported here. Methods: The Circulating Cell-free Genome Atlas (CCGA; NCT02889978) study is a prospective, multi-center, observational, case-control study with longitudinal follow-up, enrolling individuals with cancer ( > 20 cancers, all stages, newly diagnosed) and without cancer. Plasma cfDNA was subjected to a cross-validated targeted methylation (TM) sequencing assay. Methylation fragments were combined across targeted genomic regions and assigned a probability of cancer and a predicted TOO. GI cancer classes were upper GI (esophagus/stomach, n = 67), pancreas/gallbladder/extrahepatic bile duct (n = 95), liver/intrahepatic bile duct (n = 29), and colon/rectum (n = 121). Results: Detection across all GI cancers was 82% (95% CI 77-86) at a > 99% pre-set specificity. Overall predicted TOO accuracy was 92% (88-95) among the samples for which TOO was predicted (6/255 had indeterminate predicted TOO). The table shows performance by GI cancer type. Conclusions: Simultaneous detection at high specificity ( > 99%) of multiple cancer types, including GI cancers across stages at high sensitivity (82%), was shown using TM analysis of cfDNA. Accurate (92%) localization of cancers to specific regions of the GI tract was also achieved. Detection of multiple GI cancers from a single noninvasive blood test could be a practical method for detecting GI and other cancers, and may facilitate diagnostic work-ups. Clinical trial information: NCT02889978.

[Table: see text]
The short-term outcomes from TOP-G trial: Ramdomized phase II noninferiority trial comparing gastrectomy with omentectomy and omentum preserving gastrectomy for advanced gastric cancer.
Authors: Yamada Takanobu , Murakami Hitoshi , Taguri Masataka , Hasegawa Shinichi , Yamanaka Takeharu , Rino Yasushi , Mushiake Hiroyuki , Oshima Takashi , Matsukawa Hiroshi , Tani Kazuyuki , Suzuki Yoshihiro , Ozawa Yukihiro , Tanabe Hiroyasu , Sato Tsutomu , Tamagawa Hiroshi , Yukawa Norio , Yoshikawa Takaki , Imada Toshio , Masuda Munetaka , Yamamoto Yuji
Published: February 2020

285

Background: A complete resection of the omentum has been believed as a standard procedure for advanced gastric cancer. However, there was no evidence for survival significance of omentectomy. Therefore, we conduct the Phase II trial (TOP-G trial) comparing gastrectomy with omentectomy and omentum preserving gastrectomy. Here, we present the short-term outcomes which was a secondary endpoint of TOP-G trial. Methods: Enrollment criteria included histologically confirmed cT2-4a and N0-2 gastric adenocarcinoma. The extent of nodal dissection was performed based on the Gastric Cancer Treatment Guidelines in Japan. All procedure was performed through laparotomy. Laparoscopic approach was not accepted. Surgical outcomes morbidity, and mortality were compared between gastrectomy with omentectomy group (group A) and omentum preserving gastrectomy group (group B). Postoperative complication was evaluated with Clavien-Dindo classification. Results: A total of 251 patients were randomly assigned to group A (n = 125) or group B (n = 126) between April 2011 and October 2018. After excluding patients who received bypass or no surgery, 246 patients were analyzed as actual treatment group. There was no difference between two groups in patient characteristics and pathological findings. There was no difference in operation time (median 244 vs 204 min, p = 0.156) and in blood loss (median 260 vs. 210 ml, p = 0.371). Median number of totally retrieved lymph nodes was similar (median 36 vs. 37, p = 0.758). There was no difference in the incidence of any postoperative complication (28.9% vs. 25.8%, p = 0.584). There was no mortality in both groups. Conclusions: Omentum preserving gastrectomy for advanced gastric cancer was similar short-term outcomes with gastrectomy with omentectomy. Clinical trial information: UMIN000005421.
Is D2 surgery necessary for clinical T1 gastric cancer with nodal swelling?
Authors: Wada Takeyuki , Yoshikawa Takaki , Kamiya Ayako , Date Keichi , Hayashi Tsutomu , Otsuki Sho , Yamagata Yukinori , Katai Hitoshi , Nishida Toshirou
Published: February 2020

288

Background: D2 surgery is required for clinical T1 gastric cancer with nodal swelling, however, D2 has a higher risk for morbidity than D1/D1+. Moreover, previous study demonstrated that the false positive rate for nodal diagnosis in clinical T1 was very high. To select optimal surgery with high probability, we explored risk factors for false positivity in clinical T1 disease. Methods: Patients who underwent radical gastrectomy for clinical T1 gastric cancer between April 2015 and June 2019 were enrolled. Accuracy, sensitivity, specificity, positive predictive value, and negative predictive values for nodal diagnosis were retrospectively investigated. The risk factors for false positivity were also analyzed by the following factors; age, sex, histological type, tumor size, tumor depth, location, tumor type, presence of ulcer, and timing of CT that is (1) the patients who underwent primary endoscopic mucosal dissection (ESD) but resulted in non-curative resection, then received CT to proceed to surgery (delayed CT group) or (2) the other patients who had received CT before primary surgery or before non-curative ESD (primary CT group). Results: A total of 679 patients were examined in the present study. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 83.5% (567/679), 14.3% (13/91), 94.2% (554/588), 27.7% (13/47), and 87.7% (554/632), respectively. The false positive rate was 72.3% (34/47). In univariate analysis, differentiated tumor ( p= 0.012) and delayed CT (p < 0.001) were associated with the false positivity. Multivariate analysis revealed that delayed CT (OR, 4.534; p < 0.001) was a sole significant risk factor for false positivity. False positive rate was 100% (13/13) in the delayed CT group and 61.8% (21/34) in the primary CT group ( p= 0.009). Conclusions: False positive rate was high in clinical T1 disease, especially when the patients received delayed CT after non-curative ESD. D2 surgery would be unnecessary even though nodal swelling was detected in CT after non-curative ESD.
Impact of intraoperative staging of gastric cancer on long-term survival.
Authors: Koumori Keisuke , Kano Kazuki , Watanabe Hayato , Shimoda Yota , Fujikawa Hirohito , Yamada Takanobu , Rino Yasushi , Masuda Munetaka , Oshima Takashi , Ogata Takashi
Published: February 2020

302

Background: The preoperative stage and intraoperative stage of gastric cancer were unified as the clinical stage in the 8th edition of the TNM classification (UICC). Although there are some reports about the relationship between preoperative stage and prognosis, the relationship between intraoperative stage and prognosis remains unclear. The aim of this study was to clarify the impact of intraoperative diagnosis and staging on long-term survival. Methods: Overall survivals were examined in 915 patients who underwent curative resection for gastric adenocarcinoma between April 2011 and March 2019 in our hospital. Results: The median age of the patients was 69 years (27-90 years), including 585 male and 330 female. The median follow-up period was 33.6 months (0.1-86.7 months). The number of the patients according to intraoperative stage were 641(70.1 %) in stageI, 15(1.6%) in stageIIA, 135(14.8%) in stageIIB, 111(12.1%) in stageIII, 12(1.3%) in stageIVA and 1(0.1%) in stageIVB. The hazard ratios of intraoperative stage for overall survival were as follows (ref: StageI); StageIIA, 6.990 (95% CI: 2.473-19.760, p < 0.001), StageIIB, 2.234 (95% CI: 1.220-4.092, p = 0.009), StageIII, 4.091 (95% CI: 2.416-6.928, p < 0.001), StageIVA, 6.061 (95% CI: 2.150-17.080, p < 0.001), StageIVB, 14.92 (95% CI: 2.035-109.3, p = 0.008). Conclusions: The survival of intraoperative StageIIA was poorer than StageIIB/III. Intraoperative positive lymph node metastasis could be negative impact of survival, even if tumor invasion was T1 or T2.
A nationwide population-based study comparing survival in unresectable advanced or synchronous metastatic esophageal and gastric adenocarcinoma.
Authors: Pape Marieke , Vissers Pauline A.J. , Bertwistle David , McDonald Laura , Van Laarhoven Hanneke W.M. , Verhoeven Rob H. A.
Published: February 2020

308

Background: Similarities between esophageal and gastric adenocarcinomas have been identified in terms of genomic characteristics. There is however no consensus on the combined or stratified inclusion of esophageal adenocarcinoma (EAC) within gastric cancer (GC) clinical trials. The aim of our study was to compare patient and tumor characteristics, first-line treatment regimens and overall survival (OS) of patients with EAC and GC. Methods: We selected patients with unresectable advanced and/or synchronous metastatic EAC (n = 1554) or GC (including junction tumors; n = 2095) diagnosed in the period 2015-2017 from the nationwide Netherlands Cancer Registry. Patients with a positive HER2 test result and/or receiving trastuzumab as a first-line treatment were excluded. Data on OS were analyzed using Kaplan-Meier curves with Log-Rank test. Results: The EAC patient population had significantly more male patients (83% vs 66%), lower median age (68 vs 71 years) and higher median BMI (25.4 vs 24.5). Significant differences in location of metastases were identified, with higher percentages in non-regional lymph nodes (48% vs 28%), liver (50% vs 35%), lung (21% vs 9%) and bone (19% vs 7%) and lower in peritoneum (5% vs 42%), in EAC versus GC patients respectively. EAC patients more often received any type (supportive or active systemic) of treatment (76% vs 60%). Median OS was longer in EAC than GC patients (EAC: 4.8 vs GC: 4.1 months; p < 0.01). The percentages of patients receiving first-line systemic treatment were equal in both groups (43%). The number of patients receiving CapOx or FOLFOX was not significantly different (43% vs 47%). Carboplatin+paclitaxel was more frequently given in EAC versus GC (34% vs 3%), while EOX or ECC was given less frequently (12% vs 30%). No significant difference was observed in median OS between EAC and GC patients receiving first-line active systemic treatment (8.0 vs 7.6 months; p = 0.28). Conclusions: Patient characteristics, tumor characteristics, treatment regimens and OS differ between EAC and GC patients. Despite these differences, in patients receiving first-line active systemic treatment no significant differences in OS were found.
Relationship between perioperative change of total psoas muscle area and cancer prognosis in esophageal carcinoma.
Authors: Matsui Kazuaki , Kawakubo Hirofumi , Matsuda Satoru , Mayanagi Shuhei , Irino Tomoyuki , Nakamura Rieko , Fukuda Kazumasa , Wada Norihito , Kitagawa Yuko
Published: February 2020

314

Background: As surgery for esophageal carcinoma in the elderly people has been increasing, sarcopenia is a severe problem not only in complications, but also in long-term prognosis. However, the relationship between perioperative skeletal muscle loss especially in the early postoperative period and long-term prognosis has not been clarified. Methods: This study retrospectively analyzed 152 patients with thoracic esophageal carcinoma who had underwent radical esophagectomy in our institution from April 2008 to March 2015 (Patients with postoperative hospital stay longer than 6 weeks were excluded). As an index of perioperative sarcopenia, total psoas muscle area (TPA) was measured before surgery (as baseline), at postoperative day (POD) 7 and postoperative month (POM) 6 from CT images. We investigated the correlation between the change of TPA and the postoperative survival. Results: Of 152 patients, 52 (34.2%) showed a TPA decrease from baseline to POD 7, and 98 (64.5%) showed a TPA decrease from baseline to POM 6. At the time of POD 7, overall survival (OS) decreased significantly in a TPA decrease group (P = 0.008, 5-year survival rate: non-decrease group 82.3% / decrease group 56.8%). Recurrence free survival (RFS) was also significantly decreased in a TPA decrease group (P < 0.001, 5-year recurrence free survival rate: non-decrease group 73.7% / decrease group 44.9%). On the other hand, at the time of POM 6, OS and also RFS had no significant difference between decrease and non-decrease groups. In univariate analysis for OS, pStage ≥3 and TPA decrease at POD 7 had poor prognosis. In multivariate analysis for OS, pStage ≥3 (HR:5.516, P < 0.001, 95%CI:2.634-11.551) and TPA decrease at POD 7 (HR:2.036, P = 0.047, 95%CI:1.010-4.103) were also independent poor prognostic factors. In the univariate analysis for RFS, pStage ≥3, TPA decrease at POD 7 and age ≥60 years had poor prognosis. In multivariate analysis, pStaeg ≥3 (HR:3.831, P < 0.001, 95%CI:2.182-6.728) and TPA decrease at POD 7 (HR:1.942, P = 0.021, 95%CI:1.104-3.416) were independent poor prognostic factors. Conclusions: Our findings suggest that the TPA decrease early in a postoperative period has poor prognosis on OS and also RFS.
Helicobacter pylori‐negative gastric cancer in Guatemala: Incidence, clinical characteristics, treatment modalities, and outcomes.
Authors: Ramirez Rixci , Rosales Lopez Daniel Estuardo , Godinez Francisco Javier , Camey Carolina , Gramajo Marisol
Published: February 2020

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Background: Gastric cancer (GC) in Guatemala is the second most common cancer diagnosis and the second leading cause of cancer death in both sexes. It is difficult to determine the exact incidence rate of H. pylori infection‐negative gastric cancer (HPIN‐GC) because H. pylori detection rates decrease with the progression of gastric atrophy and intestinal metaplasia. The aim of this study was to evaluate the incidence, clinicopathologic characteristics, treatment modalities and outcomes. Methods: A retrospective review of the medical records of 210 pts with histological diagnosis of gastric cancer evaluated at the General Hospital of Diseases from the Guatemalan Social Security Institute (IGSS) from January 2010 to December 2018. Helicobacter pylori infection status was evaluated by histology, a rapid urease test Current H. pylori infection was defined as positive results from histology. Overall survival was estimated by Kaplan Meier method and compared by Log-rank test. P value < 0.05 was considered significant. Results: The rate of HPIN‐GC occurrence was 36% (n = 76). Sex, age, location of the tumor, Lauren’s classification and treatment modalities were not different according to H. pylori infection status. However, HPIN‐GC had a more advanced pT classification (T3/T4; 58 vs 28%, p=.019) and a more advanced stage (more than stage I; 64 vs 44%, p=.033) than H. pylori‐positive gastric cancer. Treatment modalities: 22% gastrectomy, 24% palliative care, 54% systemic chemotherapy at any time of disease course, 33% initial palliative surgery (derivative o gastrectomy), gastrectomy at any time in 16% (n 7). For those patients who received systemic chemotherapy (n 113) objective response rate was 38% and disease control rate 66%.Median OS was 26 months: 47 m for localized, 18 for locally advanced, and 8 m for advanced disease ( P=.0001). Only 17% of patients received second line chemotherapy and 4% a third line. Conclusions: At least 36% cases of gastric cancer were H. pylori negative. HPIN‐GC looks like to have a poorer prognosis than H. pylori‐positive cases. Chemotherapy can be offered to less than a half of patients. the earliest stages are associated with better survival.
Impact of postoperative complications on recurrence in pathological stage II/III gastric cancer patients who received curative resection followed by adjuvant S-1 chemotherapy.
Authors: Watanabe Hayato , Hayashi Tsutomu , Koumori Keisuke , Kano Kazuki , Shimoda Yota , Fujikawa Hirohito , Yamada Takanobu , Rino Yasushi , Masuda Munetaka , Ogata Takashi , Oshima Takashi
Published: February 2020

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Background: Postoperative complications increased recurrence in gastric cancer (GC) patients. However, there was no study evaluating impact of postoperative complication among patients receiving adjuvant chemotherapy. The aim of present study was to investigate the impact of postoperative complications in pStage II/III GC patients who received adjuvant S-1 chemotherapy. Methods: The present study retrospectively examined GC patients who received curative gastrectomy followed by adjuvant S-1 chemotherapy between January 2000 and December 2011 at Kanagawa Cancer Center. The patients with postoperative complications were classified into PC group, and those without postoperative complications were into NC group. Clinicopathological characteristics and recurrence-free survival (RFS) were compared between the groups. Results: 226 patients were included in this study. Postoperative complication occurred in 30 patients (13.3%). Age (Median, range) is significantly higher in NC group (64, 24-86) than in PC group (59, 36-82) (p = 0.033). Total gastrectomy was predominant type of surgery in the PC group (73.3%) than in NC group (52.0%) (p = 0.031). There was no difference in gender, ASA score, tumor location, pathological stage (TNM 7th) and pathological type between two groups. Conclusions: Postoperative complications were an independent risk factor for RFS in pStage II/III GC patients who received curative gastrectomy followed by adjuvant S-1 chemotherapy.
Should signet-ring cell histology alter the treatment approach for clinical stage I gastric cancer?
Authors: Turgeon Michael K. , Gamboa Adriana C. , Rupji Manali , Lee Rachel M. , Switchenko Jeffrey M. , Russell Maria C. , Cardona Kenneth , Kooby David A. , Staley Charles A. , Maithel Shishir K. , Shah Mihir M.
Published: February 2020

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Background: Upfront surgery is standard of care for stage I gastric cancer. Despite this, many clinicians administer preoperative therapy for clinical stage I disease with signet ring cell histology, given its aggressive biology. We aimed to assess the validity of this practice. Methods: The National Cancer Database (2004-2015) was reviewed for pts with non-metastatic signet ring cell gastric cancer who underwent treatment with surgery alone, perioperative chemotherapy, neoadjuvant therapy, or adjuvant therapy. Analysis was stratified by preoperative clinical stage and pathologic stage. Primary outcome was overall survival (OS). Results: Of 3000 pts, median age was 61 (IQR: 51-70). 34% were clinical stage I (n = 1018) of which 53% received surgery alone (n = 542), 5% perioperative chemotherapy (n = 47), 12% neoadjuvant therapy (n = 125), and 30% adjuvant therapy (n = 304). Median follow-up was 26 mos. For clinical stage I disease, surgery alone was associated with improved median OS (108 mos) when compared to perioperative chemotherapy (80 mos), neoadjuvant therapy (41 mos), or adjuvant therapy (73 mos, all p < 0.001). For pathologic stage I, surgery alone had equivalent survival to perioperative and adjuvant therapy (5-yr OS: 81 vs 82 vs 79%, p = 0.22). Concordance between clinical and pathologic stage I was 56%, specifically, 41% of clinical stage I pts were upstaged to pathologic stage II (44%) and stage III (56%). Adjuvant therapy for these pts was associated with improved median OS compared to pretreatment (perioperative chemotherapy / neoadjuvant therapy) for those upstaged to pathologic stage II (122 vs 37mos, p < 0.001) or stage III (40 vs 18mos, p < 0.001) disease. Conclusions: Our stage-stratified study demonstrates improved survival with upfront surgery for clinical stage I signet ring cell gastric cancer. Despite 41% of clinical stage I pts being upstaged to stage II or III on final pathology, adjuvant therapy offers a favorable rescue strategy, with improved outcomes compared to those treated preoperatively. Surgery alone also affords similar survival for pathologic stage I disease compared to multimodal therapy. This study challenges the intrinsic bias to over-treat stage I signet ring cell gastric cancer.
Efficacy and safety of nab-paclitaxel plus ramucirumab versus paclitaxel plus ramucirumab as second-line treatment for patients with advanced gastric cancer: A single institutional experience.
Authors: Okunaka Mashiro , Kotani Daisuke , Demachi Ken , Kawazoe Akihito , Yoshino Takayuki , Shitara Kohei
Published: February 2020

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Background: Nanoparticle albumin-bound (nab)- paclitaxel (PTX) was non-inferiority to solvent-based paclitaxel as second-line for advanced gastric cancer (AGC) with fewer infusion-related reactions and a trend toward improved overall survival (OS) in patients (pts) with peritoneal metastasis (PM) or ascites in ABSOLUTE trial (Shitara K et al. Lancet Gastroenterol Hepatol. 2017). Furthermore, safety and efficacies of nab-PTX plus ramucirumab (RAM) was reported in a phase II trial (Bando H, et al. EJC 2018), although no randomised trial with PTX plus RAM is reported so far. Methods: We retrospectively reviewed consecutive pts with AGC receiving nab-PTX plus RAM or PTX plus RAM as second-line chemotherapy from June 2015 to January 2019 at the National Cancer Center Hospital East. Adverse events were evaluated using Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Progression-free survival (PFS) was calculated using the Kaplan-Meier method, and the differences were evaluated using the log-rank test. Results: A total of 257 pts were included for analysis with 118 pts treated with nab-PTX plus RAM and 139 pts with PTX plus RAM. 151 pts (59%) had peritoneal metastasis and 76 pts (30%) were associated with moderate or massive amounts of ascites. Objective response rates were similar between two groups (nab-PTX plus RAM 34.1% vs. PTX plus RAM 28.0%, p = 0.36). There were no significant differences in PFS (median 3.9 vs. 3.9 months, log-rank p = 0.34; hazard ratio [HR] = 1.14). HR of PFS was 0.96 in pts with PM and 0.79 in pts with moderate or massive ascites. The major grade 3 or higher adverse events were neutropenia (nab-PTX plus RAM 55.1% vs. PTX plus RAM 55.4%), leucopenia (28.8 vs. 35.3%), thrombocytopenia (5.1 vs. 2.9%), and febrile neutropenia (5.1 vs 9.4%). Conclusions: Efficacy and safety of nab-PTX plus RAM were comparable to those of PTX plus RAM in pts with AGC in clinical practice. nab-PTX plus RAM is a treatment option as second-line treatment in pts with AGC.
Clinicopathological features and treatment outcomes of young patients with gastric and esophageal cancers.
Authors: Beck Lauren Amanda , Ma Lucy Xiaolu , Espin-Garcia Osvaldo , Suzuki Chihiro , Jiang Di Maria , Liu Geoffrey , Chen Eric Xueyu , Knox Jennifer J. , Wong Rebecca , Brar Savtaj Singh , Swallow Carol Jane , Yeung Jonathan , Darling Gail Elizabeth , Conner James , Elimova Elena , Jang Raymond Woo-Jun
Published: February 2020

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Background: Gastric and esophageal (GE) cancers most commonly occur in older adults in their 60’s. There are inconsistent reports about prognosis in adolescent and young adult (AYA) pts, and treatment patterns and outcomes in this population have not been well characterized. Methods: A retrospective analysis was performed for AYA (age < 40) pts with GE cancers who presented to Princess Margaret Cancer Centre from 2008 to 2016. The Kaplan-Meier method was used to analyze progression free (PFS) and overall survival (OS). Results: We identified 57 AYA GE cancer pts (30 gastric, 27 esophageal). Features at diagnosis included: median age 35, 51% female (70% in gastric, 30% in esophageal), 82% with performance status 0-1, 83% Charlson Comorbidity Index 0, 54% stage IV. For gastric pts, 53% had diffuse histology and 47% had signet ring adenocarcinoma. There was a negative family history of gastric or esophageal cancer in 77% of pts. Curative intent treatment was used in 23 pts, palliative in 34. In curative pts, 48% had neoadjuvant therapy, 52% had upfront surgery. Of pts who underwent surgery, 57% had T3 or T4a disease and 38% had N2 or N3 disease. Median OS in curative pts was 39.9 months (95% CI 19.7-69.9), with a 5-year OS rate of 37% (95% CI 20-67). Of the palliative pts, 91% had chemotherapy. First line chemotherapy was a triplet regimen in 80%, doublet in 13%. The median number of treatment cycles on first line chemotherapy was 6, with a median PFS of 7.4 months (95% CI 5.4-10.5). At progression, 14 pts had second line treatment, 3 pts had third line and only 1 pt was treated beyond third line. Median OS in palliative pts was 12.1 months (95% CI 8-21.3). Conclusions: Consistent with the literature, our gastric AYA pts had increased female predominance and diffuse histology. Many AYA pts had advanced disease at diagnosis, with over half of pts presenting with metastatic disease. In both the curative and palliative setting, AYA pts did not have better survival outcomes despite being young with few comorbidities, suggesting they may have more aggressive biology.
Senior resident versus fellow participation during complex cancer operations.
Authors: de Geus Susanna W. L. , Kasumova Gyulnara G , Eskander Mariam F. , Ng Sing Chau , McAneny David B. , Tseng Jennifer F. , Sachs Teviah E.
Published: February 2020

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Background: Teaching hospitals that train both general surgery residents and fellows in complex general surgical oncology have become more common. Despite ACGME dictums, attending surgeons may favor either residents or fellows assisting on operations of greater complexity, depending upon a variety of factors, including local surgical culture. This study investigates whether participation of a senior resident versus a fellow impacts outcomes of complex cancer surgery. Methods: Patients who underwent esophagectomy, or gastrectomy with assistance from either a senior resident (PGY-4 or 5) or a fellow (PGY-6 to 8) were identified from the American College of Surgeon’s National Surgical Quality Improvement Program (2007-2012). Analyses were performed separately for each operation. Propensity-scores were created for the odds of undergoing the operation assisted by a fellow. Patients were matched based on propensity score, and outcomes were compared after matching. Results: In total, 1,160 esophagectomies and 2,432 gastrectomies were identified. Senior resident participation was reported in 60.2% and 86.6%, respectively. Resident involvement was associated with non-white race (17.0% vs. 13.8%; p < 0.001), and lower rates of neoadjuvant chemotherapy (6.4% vs. 11.7%; p < 0.001). After matching, rates major complication rates were slightly higher for patients who underwent esophagectomies involving a resident compared to fellow (38.1% vs. 31.8%; p = 0.0447). However, major complications rates were similar for gastrectomy (21.2% vs. 22.1%; p = 0.775). In addition, operative time was shorter for gastrectomy (212 vs. 232 min; p = 0.009) involving a resident compared to a fellow, but comparable for patients who underwent esophagectomy (327 vs. 337 min; p = 0.310). Conclusions: The results of this study suggest that senior resident participation in complex cancer operations does not negatively impact operative time or outcomes, compared to involvement of a surgical oncology fellow. Although confounding by operative autonomy may exist, these findings indicate that senior residents should be given the same opportunities as fellows to participate in these potentially more challenging operations.
First-line chemotherapy versus chemoradiation for resectable distal esophageal adenocarcinoma.
Authors: de Geus Susanna W. L. , Hirji Sameer , Ng Sing Chau , Sachs Teviah E. , Tseng Jennifer F.
Published: February 2020

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Background: Multiple randomized controlled trials have shown that both neoadjuvant chemotherapy (CT) and chemoradiation (CRT) convey survival benefit as compared to upfront surgery in patients with esophageal adenocarcinoma. However, international practice remains variable. Therefore, the present study compares the outcomes of first-line CT to CRT for patients with adenocarcinoma arising from the distal esophagus. Methods: Patients with clinical stage T2-T3, N0-N+ esophageal adenocarcinoma originating from the distal esophagus who received first-line CT or CRT were identified from the National Cancer Data Base (2006-2014). Propensity-score were created for the odds of receiving CRT. Patients were matched 1:1 based on propensity score. Subset analysis was performed in patients who underwent esophagectomy. Pathological complete response was defined as ypT0N0M0. Results: In total, 709 and 8,877 patients who received first-line CT and CRT were identified, respectively. CT was associated with stage cT2 (27.2% vs. 23.3%; p = 0.017), and treatment at a high-volume center (27.2% vs. 20.2%; p < 0.001). After matching, resection rates were comparable for patients who received first-line CT and CRT (62.2% vs. 63.7%; p = 0.545). However, median overall survival was slightly lower for patients who receive CT compared to CRT (23.7 vs. 28.4 months; p = 0.044). Among patients who underwent esophagectomy, time to surgery (135 vs. 134 days; p = 0.689) and median overall survival (37.0 vs. 40.5 months; p = 0.630) was similar between matched cohorts. However, complete response (15.8% vs. 25.8%; p < 0.001) and negative margin (94.3% vs. 88.9%; p = 0.004) rates were significantly lower after CT compared to CRT. Conclusions: In patients with esophageal adenocarcinoma, first-line CRT results in significantly higher pathological complete response rates, negative resection margins rates, and improved survival. These findings suggest that first-line CRT is preferable over CT when tolerated in patients with esophageal adenocarcinoma.