RESUMEN
BACKGROUND: Chemoradiotherapy (CRT) is currently performed for patients with esophageal squamous cell carcinoma (SCC). Some reports have revealed that patients who responded well to CRT had favorable outcomes, whereas poor responders conversely showed a worse prognosis. The aim of this study was to identify molecular markers predicting sensitivity to CRT. METHODS: We reviewed 62 patients with T(3-4), N-any, and M-any esophageal SCC treated with definitive CRT. The regimen comprised protracted 5-fluorouracil infusion and a 2-h infusion of cisplatinum combined with radiation therapy (2 Gy/day) at a total radiation dose of 60 Gy. The expressions of epidermal growth factor receptor (EGFR), vascular endothelial growth factor, cyclin D1, and proliferating cell nuclear antigen were investigated immunohistochemically in biopsy specimens obtained before treatment from all 62 patients. The immunoreactivities were compared with responsiveness to CRT, as evaluated by endoscopy. RESULTS: The complete response rate of the primary tumor estimated by endoscopy was 62% (13/21) in patients in the EGFR-positive group. The difference in the CR rate between EGFR-positive and -negative groups was significant (p = 0.037). The immunoreactivities of the other molecular markers did not show a significant correlation with the responsiveness of the primary lesion to CRT. Multiple logistic regression analysis revealed that positive immunostaining for EGFR was significantly correlated with primary CR for CRT in esophageal SCC. CONCLUSION: Among 62 patients with esophageal SCC, differences in the responsiveness of primary lesions to CRT were correlated with EGFR immunoreactivity assessed in the biopsy specimens. These results suggest that EGFR may help to predict the response of primary sites to definitive CRT in esophageal SCC, although the results should be confirmed in a larger, more homogeneous series.
Asunto(s)
Biomarcadores de Tumor/análisis , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Receptores ErbB/análisis , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/inmunología , Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/patología , Quimioterapia Adyuvante , Receptores ErbB/inmunología , Neoplasias Esofágicas/química , Neoplasias Esofágicas/patología , Femenino , Humanos , Inmunohistoquímica , Modelos Logísticos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Radioterapia Adyuvante , Sensibilidad y EspecificidadRESUMEN
PURPOSE: To evaluate the association between dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) levels in primary gastric tumors and clinical response to S-1 or S-1 plus irinotecan in patients with unresectable advanced gastric cancer, and to investigate the molecular mechanism of augmented antitumor activity of the combination using human gastric cancer xenografts with high TS activity. MATERIALS AND METHODS: TS mRNA expression and DPD mRNA expression were measured by reverse transcription polymerase chain reaction in initial primary cancer biopsy specimens in 29 patients with advanced gastric cancer who had received S-1 alone (n=18) or in combination with irinotecan (n=11). In an experimental study, antitumor effects of S-1, irinotecan, and the combination were assessed in mice bearing human gastric tumors with high TS expression (4-1-ST and AZ-521 tumors) and low TS expression (SC-2 tumors), and activities of 5-fluorouracil-metabolizing enzymes were measured. RESULTS: In the clinical study, a strong statistical association between high TS expression and clinical resistance to S-1 alone was found (P = .009). In the experimental studies, S-1 plus irinotecan showed augmented antitumor activity against tumors with high TS activity (P < .01) compared with either agent alone. A potential mechanism for this effect was suggested by the significant reduction in TS activity observed following irinotecan administration in tumors with high TS activity. CONCLUSION: This study suggests that, via down-regulation of TS by irinotecan treatment, combination chemotherapy with S-1 and irinotecan could be effective in gastric cancer patients with high TS levels.
RESUMEN
S-1 Combined with Weekly Paclitaxel in Patients with Advanced Gastric Cancer: Masahiro Gotoh, Shin-ichiro Kawabe and Hiroya Takiuchi (Dept. of Gastroenterology, Osaka Medical College) Summary Both paclitaxel and S-1 have been identified as an effective agent for the treatment of gastric cancer. Furthermore, weekly paclitaxel was found to have a better toxicity profile and to be as effective as an equivalently dosed conventional schedule of delivery every 3 weeks. Osaka Gastrointestinal Cancer Chemotherapy Study Group (OGSG) conducted the phase I/II study of weekly paclitaxel combined with S-1. S-1 was given orally at a fixed dosage of 40 mg/m2 bid for 14 consecutive days, followed by a week rest. Paclitaxel was scheduled to be given intravenously on days 1 and 8. The MTD of paclitaxel was presumed to be 60 mg/m2 because 50.0% of patients (2/4) developed DLTs (mainly grade 3 anorexia). Therefore, the RD of paclitaxel was estimated to be 50 mg/m2. This combination treatment was demonstrated to exhibit a tolerable toxicity profile with a high antitumor activity of 48% (14/29) and MST of 417 days. This regimen is investigated in a randomized phase II trial and may yet become a test arm in future phase III trials.