Cervical cancer is a public health problem and the molecular mechanisms underlying radioresistance are still poorly understood. Here, we evaluated the modulation of key molecules involved in cell proliferation, cell cycle and DNA repair in cervical cancer cell lines (CASKI and C33A) and in malignant tissues biopsied from 10 patients before and after radiotherapy. The expression patterns of epidermal growth factor receptor (EGFR), excision repair cross-complementation group 1 (ERCC1) and p53 were evaluated in cancer cell lines by quantitative PCR and western blotting, and in human malignant tissues by immunohistochemistry. The mutation status of TP53 gene was evaluated by direct sequencing. Among cell lines, absent or weak modulations of EGFR, ERCC1 and p53 were observed after exposure to 1.8 Gy. Conversely, increased expressions of p53 (5/10 patients; P=0.0239), ERCC1 (5/10 patients; P=0.0294) and EGFR (4/10 patients; P=0.1773) were observed in malignant tissues after radiotherapy with the same radiation dose. TP53 mutations were found only in one patient. Here we show that a single dose of radiotherapy induced EGFR, ERCC1 and p53 expression in malignant tissues from cervical cancer patients but not in cancer cell lines, highlighting the gap between in vitro and in vivo experimental models. Studies on larger patient cohorts are needed to allow an interpretation that an upregulation of p53, EGFR and ERCC1 may be part of a radioresistance mechanism.

P001 - Sepsis impairs the capillary response within hypoxic capillaries and decreases erythrocyte oxygen-dependent ATP efflux

5033 Background: Concurrent cisplatin (C) based chemoradiotherapy (CRT) is the standard treatment for locally advanced cervical cancer (LACC). New strategies that increase the complete response (CR) rates may lead to longer progression-free(PFS) and overall survival(OS). Pre-clinical data indicates that inhibition of the epidermal growth factor receptor (EGFR) potentiates the effect of RT. We previously reported a phase I trial of the tyrosine kinase EGFR inhibitor erlotinib (E) administered concurrently with standard CRT for LACC that confirmed the safety of E at 150mg/day and preliminary efficacy data on the phase II. Methods: Eligibility - stage IIB to IIIB squamous cell cervical carcinoma; no prior therapy; ECOG PS 0-2; adequate end-organ function. Patients (pts) received E 150mg/day one week before and combined with C (40mg/m2, weekly, X 5) and RT (external beam - 4500cGy in 25 fractions, followed by 4 fractions/600cGy/weekly of brachytherapy). Pre and post treatment tumor tissue was obtained for molecular analysis.Response was assessed after a 3 month-interval with MRI, CT, PET and biopsy. Results: Patient characteristics: median age 44 (27-68), stage IIB 22 (57.9%), IIIA 1 (2.6%) and IIIB 15 (39.5%). 41 pts were enrolled and 3 excluded. 38 patients were available for toxicity. Two pts did not complete planned treatment (one presented Raynaud's Syndrome and had C interrupted and one presented grade 4 hepatotoxicity). Of 36 pts who completed E+CRT, median duration of treatment was 77 (64-129) days and median follow-up was 39.4 months(m) (IC95%35.5-43.3). Overall E+CRT was well tolerated. Most common grade 3 toxicity was skin rash (13%). Of 36 evaluable for response, 34 pts, (94.4%-IC 95% 79.99- 99.03) had CR and two pts had partial response. Cumulative OS and PFS survivals were 91.7% and 80.6% at 24m, and 80% and 73.8%, respectively, at 36m of follow-up, superior to historical control. Conclusions: In this cohort of LACC patients the combination of E+CRT is efficacious and feasible, with a CR rate of 94.4%. This combination is worth exploring in a randomized clinical trial. Molecular correlative studies will be presented at the meeting.