Purpose: Epigenetic silencing of tumor suppressor genes (TSGs) is an acquired abnormality observed in cancer and is prototypically linked to DNA methylation. We postulated that pre-treatment (priming) with 5-azacitidine would increase the efficacy of chemotherapy by reactivating TSGs. This study was conducted to identify a tolerable dose of 5-azacitidine prior to EOX (epirubicin, oxaliplatin, capecitabine) neoadjuvant chemotherapy in patients with locally-advanced esophageal/gastric adenocarcinoma (EGC). Experimental Design: Eligible patients had untreated, locally-advanced, resectable EGC, ECOG 0-2 and adequate organ function. 5-azacitidine (V, 75mg/m2) was given subcutaneously for 3 (dose level, DL 1) or 5 (DL 2) days prior to each 21-day cycle of EOX (E 50 mg/m2, O 130 mg/m2, X 625 mg/m2 BIDx21 d). Standard 3+3 methodology guided V dose escalation. DNA methylation at control and biomarker regions was measured by digital droplet, bisulfite qPCR in tumor samples collected at baseline and at resection. Results: All subjects underwent complete resection of residual tumor (R0). Three of the 12 patients (25%) achieved a surgical complete response and five had partial responses. The overall response rate was 67%. The most common toxicities were gastrointestinal and hematologic. Hypomethylation of biomarker genes was observed at all dose levels and trended with therapeutic response. Conclusions: Neoadjuvant VEOX was well-tolerated with significant clinical and epigenetic responses, with preliminary evidence that priming with V prior to chemotherapy may augment chemotherapy efficacy. The recommended phase II trial schedule is 5-azacitidine 75 mg/m2 for 5 days followed by EOX chemotherapy every 21 days.
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