Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial

Cats, Annemieke; Jansen, E.P.M.; Grieken, Nicole C.T. van; Sikorska, Karolina; Lind, Pehr; Nordsmark, Marianne; Kranenbarg, Elma Meershoek-Klein; Boot, H.; Trip, Anouk Kirsten; Swellengrebel, HA A. Maurits; Laarhoven, Hanneke W. M. van; Putter, Hein; Sandick, Johanna W. van; Henegouwen, Mark I. van Berge; Hartgrink, Henk H.; Tinteren, Harm van; Velde, Cornelis J.H. van de; Verheij, Marcel; Coevorden, Frits van; Vanhoutvin, Steven; Hulshof, Maarten C.C.M.; Loosveld, Olaf; Tije, Albert J. ten; Erdkamp, Frans; Warmerdam, Fabienne; Peet, Donald L. van der; Verheul, Henk M.W.; Boerma, Djamila; Los, Maartje; Slot, Annerie; Houtsma, Danny; Portielje, Johanneke E.A.; Blaisse, Reinoud J B; Bilgen, Ernst Jan Spillenaar; Polée, Marco B.; Geenen, Maud M.; Braak, Jeffrey P.B.M.; Neelis, Karen J.; Slingerland, Marije; Jansen, R. L. H.; Buijsen, J.; Beeker, Aart; Eijsbouts, Q. A. J.; Riel, Johanna Mgh van; Rozema, Tom; Spronsen, Dick Johan van; Terwogt, Jetske M. Meerum; Tanis, Bea C.; Torren-Conze, Adelheid Me Van der; Hilligersberg, Richard van; Koopman, Miriam; Boer, Marien O den; Creemers, Geert-Jan; Sangen, M.J.C. van der; Rentinck, Marjolein Em; Berg, H. Pieter van den; Jonkers, G. J. P. M.; Grootenboers, D.A.R.H.; Vulink, Annelie Je; Hovenga, Sjoerd; Mijle, Huub Cj Van der; Baars, Arnold; Haringhuizen, A.; Appels, Marije Ie; Rietbroek, Ron C.; Hendriksen, Ellen M.; Legdeur, Marie-Cecile; Huinink, Daan ten Bokkel; Dobbenburgh, O Aart van; Smit, J. M.; Bochove, Aart van; Veldhuis, Gerrit-Jan; Müller, E; Bonenkamp, Johannes J.; Braam, P.M.; Boer, Jaap de; Halteren, Henk K. van; Valster, F.A.A.; Imholz, Alex L.T.; Dijk, Marjan A. van; Gaast, Ate van der; Otten, Julia; Ceha, Heleen M.; Glimelius, Bengt; Lagerbäck, Cecillia; Perman, Mats; Johnsson, Anders; Borg, David; Nielsen, Niels Hilmer; Piwowar, Andrzej; Elmlund, Mattias; Hörberg, Helene; Edlund, Per; Johansson, Bengt; Flygare, Petra; Jespersen, Marie Louise

doi:10.1016/s1470-2045(18)30132-3

Cited by 437 publications

(325 citation statements)

References 24 publications

Supporting

Mentioning

292

Contrasting

Unclassified

Order By: Relevance

“…Preoperative chemoradiation for gastric cancer has been evaluated in the single‐arm, phase 2 setting . The CRITICS study (ChemoRadiotherapy after Induction chemoTherapy In Cancer of the Stomach) demonstrated no survival advantage to the addition of postoperative RT to POC in patients with gastric and GEJ cancers . Because optimizing preoperative approaches may be more useful, it accordingly has been the subject of growing interest.…”

Section: Introductionmentioning

confidence: 99%

“…5 The CRITICS study (ChemoRadiotherapy after Induction chemoTherapy In Cancer of the Stomach) demonstrated no survival advantage to the addition of postoperative RT to POC in patients with gastric and GEJ cancers. 6 Because optimizing preoperative approaches may be more useful, it accordingly has been the subject of growing interest. Preoperative chemoradiotherapy with adjuvant chemotherapy (PCRT) is one strategy currently under investigation.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Survival outcomes in patients with gastric and gastroesophageal junction adenocarcinomas treated with perioperative chemotherapy with or without preoperative radiotherapy

Tian

Jiang

Madden

et al. 2019

Cancer

View full text Add to dashboard Cite

Background Perioperative chemotherapy (POC) is one standard approach for the treatment of resectable cancers of the stomach and gastroesophageal junction (GEJ), whereas there has been growing interest in preoperative therapies. The objective of the current study was to compare survival between patients treated with preoperative chemoradiotherapy and adjuvant chemotherapy (PCRT) with those receiving POC using a large database. Methods The National Cancer Data Base was queried for patients diagnosed between 2004 and 2013 with American Joint Committee on Cancer clinical group stage IB to stage IIIC (excluding T2N0 disease) adenocarcinoma of the stomach or GEJ. Patients treated with definitive surgery and POC with or without preoperative radiotherapy of 41 to 54 Gy were included. Overall survival (OS) was defined from the date of definitive surgery and estimated using the Kaplan‐Meier method. A total of 14 patient and treatment variables were used for propensity score matching (PSM). Results A total of 1048 patients were analyzed: 53.2% received POC and 46.8% received PCRT. The primary tumor site was the GEJ in 69.1% of patients and stomach in 30.9% of patients. The median age of the patients was 60 years, and the median follow‐up was 25.8 months. The use of PCRT was associated with a greater pathologic complete response rate of 13.1% versus 8.2% (P = .01). POC was associated with a decreased risk of death in unmatched groups (hazard ratio [HR], 0.83; P = .043). Using PSM cohorts, POC decreased the risk of death with a median OS of 45.1 months versus 31.4 months (HR, 0.70; P = .016). The 2‐year OS rate was 72.9% versus 62.5% and the 5‐year OS rate was 40.7% versus 33.1% for POC versus PCRT, respectively. Survival favored POC in PSM gastric (HR, 0.41; P = .07) and GEJ (HR, 0.77; P = .08) patient subgroups. Conclusions The addition of preoperative radiotherapy to POC appears to be associated with an increased risk of death in patients with resectable gastric and GEJ cancers.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Survival outcomes in patients with gastric and gastroesophageal junction adenocarcinomas treated with perioperative chemotherapy with or without preoperative radiotherapy

Tian

Jiang

Madden

et al. 2019

Cancer

View full text Add to dashboard Cite

show abstract

“…Gastric cancer is one of the most lethal malignancies worldwide 1. Many patients with gastric cancer, in particular in developing countries, are diagnosed at a late stage, which leads to a low rate of complete resection.…”

Section: Introductionmentioning

confidence: 99%

Depletion of death-associated protein-3 induces chemoresistance in gastric cancer cells through the β-catenin/LGR5/Bcl-2 axis

Jia

Cheng

et al. 2019

Journal of Investigative Medicine

View full text Add to dashboard Cite

Previously, we demonstrated that death-associated protein-3 (DAP3) loss drives chemoresistance in gastric cancer cells. In the present study, we aimed to determine the underlying molecular mechanism. The effect of DAP3 silencing on β-catenin signaling was assessed. The direct mediator of DAP3 silencing-induced chemoresistance was identified. Depletion of DAP3 stimulates nuclear accumulation of β-catenin and enhances β-catenin-dependent transcriptional activity in gastric cancer cells. However, the protein kinase B , , extracellular regulated protein kinase and signal transducer and activator of transcription 3 signaling pathways remain unaffected by DAP3 loss. We found that the downstream target gene LGR5 (leucine-rich G-protein coupled receptor 5) is upregulated in DAP3-depleted gastric cancer cells. Moreover, knockdown of LGR5 resensitizes DAP3-depleted gastric cancer cells to 5-fluorouracil (5-FU) and oxaliplatin. We also observed that ectopic expression of LGR5 reduces apoptosis in gastric cancer cells on treatment with 5-FU and oxaliplatin, which is accompanied by prevention of caspase-3 cleavage. The antiapoptotic protein Bcl-2 is identified as a key mediator of LGR5-induced apoptosis resistance in gastric cancer cells. The present findings indicate that DAP3 deficiency-induced chemoresistance in gastric cancer is at least partially mediated through the β-catenin/LGR5/Bcl-2 axis. Targeting LGR5 may provide a novel strategy to overcome chemoresistance in DAP3-deficient gastric cancer cells.

show abstract

“…1 Surgical excision, perioperative chemotherapy and/or postoperative chemoradiotherapy are the main therapeutic regimens for GC. [3][4][5] EphA2 is a key member of the erythropoietin-producing hepatocellular (Eph) receptors, which is the largest subfamily of receptor tyrosine kinases (RTKs). 2,3 Currently, there are no established biomarkers that predict GC response to targeted agents, and the GC patients do not yet benefit from molecularly directed therapies.…”

Section: Introductionmentioning

confidence: 99%

“…2,3 Currently, there are no established biomarkers that predict GC response to targeted agents, and the GC patients do not yet benefit from molecularly directed therapies. [3][4][5] EphA2 is a key member of the erythropoietin-producing hepatocellular (Eph) receptors, which is the largest subfamily of receptor tyrosine kinases (RTKs). Accumulating evidence suggests that EphA2 is overexpressed in various neoplasms, including glioma, 6 lung cancer, 7 GC, 8 renal cell carcinoma 9 and colorectal cancer.…”

Section: Introductionmentioning

confidence: 99%

EphA2‐to‐YAP pathway drives gastric cancer growth and therapy resistance

Huang

Yuan

Chen

et al. 2019

Intl Journal of Cancer

View full text Add to dashboard Cite

Yes‐associated protein (YAP) is a transcriptional coactivator that promotes cell proliferation, stem cell maintenance and tissue homeostasis. The YAP activity is primarily regulated through an inhibitory phosphorylation by the serine/threonine kinases of Hippo pathway. Here, we show that receptor tyrosine kinase (RTK) erythropoietin‐producing hepatocellular receptor A2 (EphA2) interacts with and phosphorylates YAP protein, leading to stabilization, nuclear translocation and activation of YAP in gastric cancer (GC) cells. EphA2 induces chemotherapy‐resistance by increasing YAP stability and nuclear YAP protein. Knockdown of YAP blocks EphA2‐induced tumor growth in GC xenograft mouse models. Importantly, the coactivation of EphA2 and YAP is manifested in clinical human GC, and is related to GC recurrence. Thus, our results establish a novel EphA2‐to‐YAP pathway that drives GC growth, progression and therapy‐resistance, targeting this pathway would be an efficient way for the treatment of GC, particularly chemotherapy‐resistant GC.

show abstract

Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial

Cited by 437 publications

References 24 publications

Survival outcomes in patients with gastric and gastroesophageal junction adenocarcinomas treated with perioperative chemotherapy with or without preoperative radiotherapy

Survival outcomes in patients with gastric and gastroesophageal junction adenocarcinomas treated with perioperative chemotherapy with or without preoperative radiotherapy

Depletion of death-associated protein-3 induces chemoresistance in gastric cancer cells through the β-catenin/LGR5/Bcl-2 axis

EphA2‐to‐YAP pathway drives gastric cancer growth and therapy resistance

Contact Info

Product

Resources

About