Definitive chemoradiation is a curative treatment option for patients with locoregional esophageal squamous cell carcinoma (ESCC) who are not suitable for surgical resection, but many tend to develop local recurrence. The purpose of the study was to investigate factors affecting local recurrence of the tumor. Seventy-two patients with stage II–III thoracic ESCC who received definitive concurrent chemoradiation (CRT) and completely responded to the treatment were enrolled into this study. The case patients were 49 patients who recurred locally within 24 months after definitive CRT and 23 patients who did not have a local recurrence within 24 months were considered as controls. We investigated whether dysregulation of apoptosis-related genes was associated with early tumor recurrence. Quantitative real-time polymerase chain reaction showed upregulation of BCLAF1 and downregulation of BAG4, CARD6, IGF1R, and TNF in the tissues of case patients, as compared with controls. Among the patients with recurrent ESCC, those with tumors which exhibited more than twofold upregulated BCLAF1 and more than twofold downregulated BAG4 and TNF had a decreased time interval to local recurrence. Three gene pairs of the downregulated genes showed a significant correlation with local recurrence: BAG4 and CARD6, BAG4 and TNF, CARD6, and TNF. The patients with T3–4 disease and those with tumor >3 cm in length had a trend toward early local recurrence, though the associations were not reached statistical significance. Upregulation of BCLAF1 and downregulation of BAG4 and TNF was independently associated with early local recurrence in multivariate analysis (P < 0.05). This study supports the involvement of apoptosis-related genes in early tumor recurrence after definitive chemoradiation in patients with stage II–III thoracic ESCC.
Chemoradiation Squamous cell carcinoma Esophageal cancer Recurrence Prognostic factor
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This work was supported by the National Natural Science Foundation of China (No: U1204816) and Henan Provincial Science and Technology Bureau.
Gwynne S, Hurt C, Evans M, Holden C, Vout L, Crosby T. Definitive chemoradiation for oesophageal cancer—a standard of care in patients with non-metastatic oesophageal cancer. Clin Oncol (R Coll Radiol). 2011;23:182–8.CrossRefGoogle Scholar
Bedenne L, Michel P, Bouche O, Milan C, Mariette C, Conroy T, et al. Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol. 2007;25:1160–8.CrossRefPubMedGoogle Scholar
Stahl M, Stuschke M, Lehmann N, Meyer HJ, Walz MK, Seeber S, et al. Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus. J Clin Oncol. 2005;23:2310–7.CrossRefPubMedGoogle Scholar
Minsky BD, Pajak TF, Ginsberg RJ, Pisansky TM, Martenson J, Komaki R, et al. INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol. 2002;20:1167–74.CrossRefPubMedGoogle Scholar
Rodriguez-Nieto S, Zhivotovsky B. Role of alterations in the apoptotic machinery in sensitivity of cancer cells to treatment. Curr Pharm Des. 2006;12:4411–25.CrossRefPubMedGoogle Scholar
Melet A, Song K, Bucur O, Jagani Z, Grassian AR, Khosravi-Far R. Apoptotic pathways in tumor progression and therapy. Adv Exp Med Biol. 2008;615:47–79.CrossRefPubMedGoogle Scholar
Lauber K, Munoz LE, Berens C, Jendrossek V, Belka C, Herrmann M. Apoptosis induction and tumor cell repopulation: the yin and yang of radiotherapy. Radiat Oncol. 2011;6:176.CrossRefPubMedPubMedCentralGoogle Scholar
Denham JW, Steigler A, Kilmurray J, Wratten C, Burmeister B, Lamb DS, et al. Relapse patterns after chemo-radiation for carcinoma of the oesophagus. Clin Oncol. 2003;15:98–108.CrossRefGoogle Scholar
Ishihara R, Yamamoto S, Iishi H, Takeuchi Y, Sugimoto N, Higashino K, et al. Factors predictive of tumor recurrence and survival after initial complete response of esophageal squamous cell carcinoma to definitive chemoradiotherapy. Int J Radiat Oncol Biol Phys. 2010;76:123–9.CrossRefPubMedGoogle Scholar
Welsh J, Settle SH, Amini A, Xiao L, Suzuki A, Hayashi Y, et al. Failure patterns in patients with esophageal cancer with definite chemoradiation. Cancer. 2012;118:2632–40.CrossRefPubMedGoogle Scholar
Kenjo M, Uno T, Murakami Y, Nagata Y, Oguchi M, Saito S, et al. Radiation therapy for esophageal cancer in Japan: results of the patterns of care study 1999–2001. Int J Radiat Oncol Biol Phys. 2009;75:357–63.CrossRefPubMedGoogle Scholar
Greene F, Page D, Fleming I, Fritz A, Balch C, Haller D, et al. American Joint Committee on Cancer. AJCC cancer staging manual. 6th ed. Philadelphia: Lippincott-Raven; 2002.CrossRefGoogle Scholar
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001;25:402–8.CrossRefPubMedGoogle Scholar
Sarras H, Alizadeh Azami S, McPherson JP. In search of a function for BCLAF1. The Scientific World J. 2010;10:1450–61.CrossRefGoogle Scholar
Ozawa F, Friess H, Zimmermann A, Kleeff J, Büchler MW. Enhanced expression of silencer of death domains (SODD/BAG-4) in pancreatic cancer. Biochem Biophys Res Commun. 2000;271:409–13.CrossRefPubMedGoogle Scholar
Eichholtz-Wirth H, Sagan D. IkappaB/NF-kappaB mediated cisplatin resistance in HeLa cells after low-dose gamma-irradiation is associated with altered SODD expression. Apoptosis. 2000;5:255–63.CrossRefPubMedGoogle Scholar
Kim SS, Ahn CH, Kang MR, Kim YR, Kim HS, Yoo NJ, et al. Expression of CARD6, an NF-kappaB activator, in gastric, colorectal and oesophageal cancers. Pathology. 2010;42:50–3.CrossRefPubMedGoogle Scholar
Clayton PE, Banerjee I, Murray PG, Renehan AG. Growth hormone, the insulin-like growth factor axis, insulin and cancer risk. Nat Rev Endocrinol. 2011;7:11–24.CrossRefPubMedGoogle Scholar