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Endometrial cancer (EC) is the most frequent gynecologic malignancy in the world. Metastatic and recurrent disease confers a worse prognosis, and the side effects of the current cytotoxic agents are the main cause of treatment disruption. Recently, the genetic alterations that facilitate the start, development and progression of EC have been elucidated, reclassifying the disease in distinct subtypes with different mechanisms of carcinogenesis. Targeted therapy aims to interfere specifically these mechanisms causing less toxicity, therefore opening new perspectives for a tailored treatment and improvement of response and survival rates for heavily treated recurrent disease. Treatment with hormone therapy was not addressed in this review because it is an extensively discussed issue and would divert the discussion about molecular-targeted therapy. The purpose of this paper was to review the available literature data regarding the main genetic abnormalities related to the carcinogenesis and evaluate the safety and efficacy of the molecular-targeted agents in the treatment of metastatic and recurrent EC.

Cervix cancer (CC) represents the fourth most common cancer in women. Treatment involving cisplatin and radiotherapy has been the standard for locally advanced disease. Everolimus inhibits the aberrant activity of mTOR that is part of carcinogenesis in CC. Further everolimus inactivates the HPV E7 oncoprotein and inhibits its proliferation. Preclinical models have suggested that everolimus sensitizes tumoral cells and vasculature to cisplatin and radiotherapy. In a 3 + 3 design, the trial aimed to treat three dose levels of at least three patients with daily doses of everolimus (2.5, 5 and 10 mg/day), cisplatin and radiotherapy delivered in a 9-week interval in CC patients, stage IIB, IIIA or IIIB. Patients received everolimus from day −7 up to the last day of brachytherapy. Primary objective was to evaluate safety, toxicity and the maximum-tolerated dose (MTD) of everolimus in association with cisplatin and radiotherapy. Pharmacokinetic (PK) parameters and response rates were analyzed as secondary objectives. Thirteen patients were enrolled, 6 at 2.5 mg, 3 at 5 mg and 4 at 10 mg. Four patients did not complete the planned schedule, 1 at 2.5 mg presented grade 4 acute renal failure interpreted as dose-limiting toxicity (DLT) and 3 at 10 mg: 1 with disease progression, and 2 with DLTs—1 grade 3 rash and 1 grade 4 neutropenia. PK results were characterized by dose-dependent increases in AUC and C max. The MTD of everolimus in combination with cisplatin and radiotherapy has been defined as 5 mg/day. The data regarding safety and response rates support further studies.

Cervical cancer represents the third most commonly diagnosed cancer and the fourth cause of cancer death in women worldwide. Developing countries carry the biggest burden with approximately 76–85 % of cervical cancer. The most important factor for the development of this neoplasia is persistent human papillomavirus (HPV) infection and the incidence of cervical cancer is related to the prevalence of HPV in the population. Squamous cell cervical cancer represents approximately 80 % of all cervical cancers and adenocarcinoma and its variations accounts for approximately 20 %. Staging is essentially a clinical evaluation. The FIGO staging procedures include colposcopy, biopsy; cystoscopy, proctosigmoidoscopy and chest radiograph, accordingly to the symptoms. The treatment for early-stage cervical cancer is either surgery or radiation therapy. Surgery is reserved for stages IA, IB1 and selected IIA1. Chemoradiation is the treatment of choice for stage IB2 to IVA and for patients who are not candidates for hysterectomy. For patients with metastatic disease (stage IVB), platinum-based chemotherapy is usually the first choice. Immunization against HPV is expected to prevent specific HPV cancer in women and more effective screening in developing countries will contribute for a significant decline in incidence and mortality of cervical cancer.

Ovarian cancer (OC) is the sixth most common cancer worldwide among women, and, in developed countries, it is the leading cause of mortality among gynecological malignancies. With an overall cure rate of

e17009Background: Cervical cancer (CC) is a major public health problem, especially in developing countries as Brazil. Viral hepatitis B and C, as well HIV infection are sexually transmitted diseas...

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

Aim: Cervical cancer is the third most commonly diagnosed cancer and the fourth leading cause of cancer deaths in women around the world. Human papilloma virus (HPV) infection is considered necessary factor for the development of cervical cancer and it is identified in 99.7% of cases. The main route of HPV transmission is sexual, and factors such as multiple partners and early onset of sexual activity favors infection and transmission. The incidence of cervical cancer in HIV-positive women is high and it is a defining disease of immunodeficiency syndrome (AIDS). These women also have more aggressive disease that is less responsive to the standard therapy. Viral hepatitis B and C, as well as HIV infection, are sexually transmitted diseases and they share similar risk factors to those of cervical cancer. In the case of hepatitis, they have great importance to public health because of their high prevalence, incidence and possible complications of acute and chronic forms. The objective of this study is to evaluate the prevalence of HIV, hepatitis B and C infection in patients with cervical cancer. Methods: A retrospective search of the database at the Brazilian National Cancer Institute was performed, and all patients diagnosed with cervical cancer between October 2009 and December 2012 and the results of serological tests for HIV, hepatitis B and C infection were analyzed. Results: A total of 1659 women were enrolled. Squamous cervical cancer was diagnosed in 78.6%, adenocarcinoma in 16.8% and less frequent histological subtypes in 4.6%. The median age for first sexual intercourse was 17 years. Number of sexual partners (median) was 3. Positivity for HIV infection was identified in 0.98% (12 patients in 1222 tested). Between patients tested for hepatitis B (n = 1342), positivity for anti-HBc-IgG was 13.85% (n = 186), indicating previous contact with hepatitis virus B. For hepatitis C, 2.18% (n = 31) of the group tested (n = 1422) had anti-HCV positive, and hepatitis C was identified in 15 cases by a confirmatory test. Conclusions: Although the low prevalence of HIV infection, and hepatitis B and C in the cohort analyzed, the possibility of such co-infections should always be evaluated, since those diseases share routes of transmisson and prognosis could be influenced. Disclosure: All authors have declared no conflicts of interest.