BACKGROUND: Cisplatin-based chemoradiation (CRT) is the standard treatment for patients with locally advanced cervical cancer. Epidermal growth factor receptor (EGFR) is frequently overexpressed in cervical cancer, and EGFR inhibition itself has antitumor effects and potentiates CRT. Results of a previous phase 1 trial of the EGFR inhibitor erlotinib combined with cisplatin-based CRT (E 1 CRT) recommended a phase 2 erlotinib dose of 150 mg/day. METHODS: Eligibility criteria included International Federation of Gynecology and Obstetrics stage IIB to IIIB epidermoid cervical cancer, no prior therapy, and an Eastern Cooperative Oncology Group performance status of 0 to 2. Patients received erlotinib at a dose of 150 mg/day 1 week before and in combination with cisplatin (40 mg/m 2 administered weekly for 5 cycles) and radiotherapy (4500 centigrays in 25 fractions), followed by brachytherapy (4 fractions at a dose of 600 centigrays weekly). RESULTS: A total of 36 patients completed treatment with E 1 CRT. The median duration of therapy was 77 days and the median follow-up period was 59.3 months. The therapy was well tolerated overall, and 34 patients (94.4%) achieved a complete response. The 2-year and 3-year cumulative overall and progression-free survival rates were 91.7% and 80.6% and 80% and 73.8%, respectively. CONCLUSIONS: Treatment with E 1 CRT appears to be safe and exerts significant activity against locally advanced cervical cancer. To the best of the authors' knowledge, this is the first study to date to demonstrate that a target agent has promising activity against locally advanced cervical cancer. Cancer 2014;120:1187-93.

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This retrospective study has demonstrated that paclitaxel-carboplatin is an active and well-tolerated regimen for the treatment of advanced cervical cancer.

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Background: Cervical cancer (CC) represents the second most commonly diagnosed cancer in women. The combined treatment involving C and R has been the standard treatment for stages IIB-IIIB. However the results are still disappointing with 5-year survival rates lower than 50%. There is a great need to explore new strategies in order to improve the prognosis of these patients. E inhibits the mammalian target of rapamycin (mTOR). The high aberrant activity of mTOR complexes is part of the underlying cause of carcinogenesis in CC. Further E inactivates the oncoprotein E7 (essential in the carcinogenesis of HPV) and inhibits its proliferation. Preclinical models have suggested that mTOR inhibitors sensitize tumoral cells and vasculature to C and R effects. Therefore mTOR inhibition may represent a promising treatment approach in CC. Methods: The primary objective of this trial is to evaluate the safety, toxicity (according to NCI CTCAE 3.0) and the maximum tolerated dose (MTD) of E in association to C and R in the treatment of locally advanced CC. The secondary objectives are to quantify PK and PD parameters, and to evaluate the response rate (using RECIST 1.1). In a modified Fibonacci design the trial aims to evaluate three cohorts of at least three patients treated with daily escalating doses of E (2.5/5/10 mg) in association with C (40 mg/m2 of body surface per week, for 5 weeks during teletherapy) and R (teletherapy - 4.500 cGy in 25 fractions, followed by 4 fractions of 600 cGy weekly of brachytherapy - B) in squamous cell cervical carcinoma patients stage IIB to IIIB. Patients are treated with E from day -7 to day 0 (one week before the C+R starting) up to the last day of B. Results: As of December 01, 2013, 13 patients were enrolled, 6 in the cohort #1, 3 in the cohort #2 and 4 in the cohort #3. Two patients did not completed the planned schedule, one at dose level of 2,5 mg presented grade 4 acute renal failure interpreted as dose limiting toxicity (DLT) and one at dose level of 10 mg with disease progression. Grade 3 toxicity occurred in cohorts #1 and #2 as follows: lymphopenia in 6 patients, neutropenia in 3 patients and leukopenia in 1 patient. Three patients in the cohort #3 are still on treatment. PK and PD studies will be performed together, after collection of the entire set of samples. Conclusions: The end of treatment of the last cohort is due to February 2014, when the MTD will be established. To the best of our knowledge this is the first study of everolimus, cisplatin and pelvic radiotherapy combination. Citation Format: Carlos Gil Ferreira, Flávia V. Guerra Alves, Rachele Grazziotin, Felipe Erlich, Giulliana Moralez, Michel P. Carneiro, Mariane Fontes Dias, Andréia C. de Melo. A Phase I study of oral administration of mTOR inhibitor everolimus (E) in association with cisplatin (C) and radiotherapy (R) for the treatment of locally advanced cervix cancer (LACC) - PHOENIX I. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT403. doi:10.1158/1538-7445.AM2014-CT403

Squamous cell carcinoma is the main histological tumor type in the upper aerodigestive tract (UADT), including the esophagus (ESCC) and the head and neck sites, as well as the oral cavity (OCSCC), larynx (LSCC) and oropharynx (OPSCC). These tumors are induced by alcohol and tobacco exposure, with the exception of a subgroup of OPSCC linked to human papillomavirus (HPV) infection. Few genes are frequently mutated in UADT tumors, pointing to other molecular mechanisms being involved during carcinogenesis. The F-box and leucine-rich repeat protein 7 (FBXL7) is a potential tumor-suppressing gene, one that is frequently hypermethylated in pancreatic cancer and where the encoded protein promotes the degradation of AURKA, BIRC5 and c-SRC. Thus, the aim of this study was to evaluate the methylation and expression profile of FBXL7 in the UADT and the gene’s association with the clinical, etiological and pathological characteristics of patients, as well as the expression of its degradation targets. Here we show that the FBXL7 gene’s body is hypomethylated in the UADT, independently of histology, but not in virus-associated tumors. FBXL7 body methylation and gene expression levels were correlated in the ESCC, LSCC, OCSCC and OPSCC. Immunohistochemistry analysis showed that FBXL7 protein levels are not correlated with the levels of its degradation targets, AURKA and BIRC5, in the UADT. The high discriminatory potential of FBXL7 body hypomethylation between non-tumor and tumor tissues makes it a promising biomarker.

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