A Fanucchi

Polycystic ovary syndrome and gynecological cancers: Is there a link?

Polycystic ovary syndrome [PCOS] is the most common endocrinopathy of women in reproductive age. An association between PCOS and type-1 endometrial cancer has often been reported in the literature. The prolonged anovulation with consequent continued secretion of estrogen unopposed by progesterone may enhance the development and growth of this malignancy, particularly in young women. Hypersecretion of luteinizing hormone [LH], chronic hyperinsulinemia and increased serum insulin-like growth factor [IGF]-I levels may represent risk factors for endometrial cancer. However, data available in the literature do not allow a meta-analysis to be carried out to calculate an estimate of the relative risk of endometrial cancer in women with PCOS. Anecdotal cases of low-grade endometrial stromal sarcoma and carcinosarcoma have been reported in association with prolonged unopposed estrogen stimulation, and in particular with PCOS. A few studies have addressed the possibility of an association between PCOS and epithelial ovarian cancer risk, and the results are conflicting but generally reassuring, and similarly the few available data appear to exclude a strong association between PCOS and breast cancer.

Molecular target therapies in endometrial cancer: from the basic research to the clinic.

Molecular targeted therapies represent an interesting field of pharmacological research in endometrial cancer. The loss of PTEN (phosphatase and tensin homolog deleted on chromosome 10) function, with consequent activation of the PI3K (phosphatidylinositol-3-kinase)–AKT (serine/threonine-specific protein kinase)–mTOR (mammalian target of rapamycin) signaling pathway, occurs in 32–83% of endometrioid-type endometrial carcinomas, thus suggesting a role for mTOR inhibition in this malignancy. Some analogues of rapamycin (CCI-799, RAD-001, AP-23573) have been developed and tested in different tumors including endometrioid-type endometrial carcinoma. For example, AP-23573 achieved a clinical benefit response in 33% of 27 heavily pretreated patients, and CCI-799 obtained a 26% partial response rate and a 63% stable disease rate in 19 patients. Overexpression of ErbB-2 (epidermal growth factor type II receptor) has been detected in 18–80% of uterine papillary serous carcinomas (UPSCs), thus providing a biological rationale for the use of trastuzumab in these aggressive tumors. UPSC often overexpresses claudin-3 and claudin-4, which represent the epithelial receptors for Clostridium perfringens enterotoxin (CPE). CPE-mediated therapy might be a novel treatment modality for UPSC resistant to chemotherapy. A better understanding of the signaling transduction pathways that are dysregulated in endometrioid-type endometrial carcinoma and UPSC will allow the development of novel molecular targeted therapies.

First-line chemotherapy with epidoxorubicin, paclitaxel, and carboplatin for the treatment of advanced epithelial ovarian cancer patients

OBJECTIVE A combination of carboplatin (CBDCA) and paclitaxel (TAX) is the standard treatment in advanced ovarian cancer (AOC) patients. Epidoxorubicin (EDX) is an active treatment in AOC and exhibits nonoverlapping toxicities with CBDCA and TAX; moreover, when added to platinum-based chemotherapy, it improves long-term survival. We have therefore conducted a phase II study to evaluate the tolerability and antitumor activity of an EDX/TAX/CBDCA (ETC) triplet in AOC patients. METHODS Patients with histologically confirmed suboptimal stage III-IV ovarian cancer who had not previously received cytotoxic drugs were treated with TAX (175 mg/m(2) in a 3-h iv infusion), CBDCA (AUC 6, Calvert formula), and EDX (75 mg/m(2) iv bolus) all given on day 1 every 28 days for a maximum of six courses on an outpatient basis. EDX dosage was chosen after a pilot phase I study. RESULTS Fifty-five patients were registered, of whom 5 were determined ineligible bacause of age. Forty-two of the 50 are evaluable for response; 27 (64%) achieved a clinical complete response (CR) and 9 (21%) a partial response (PR) for a response rate of 86% (95% CI 71-94%). Thirty-three patients underwent a secondary debulking procedure after a median of 6 courses (range 2-6). Pathological CR and PR were observed in 9 (27.3%) and 21 (63.6%), respectively; among patients with persistent disease a successful cytoreduction (<1 cm) was obtained in 53.8% of patients. At a median follow up of 35.6 months (range 0-55.5) median progression-free survival is 19.5 months and median overall survival is 36 months. The most common adverse effects were G3-4 leukopenia and thrombocytopenia which occurred in 59 and 37% of patients, respectively. CONCLUSIONS The ETC combination given according to the outlined doses and schedule is highly active in AOC patients with poor prognostic factors and deserves further study.

Serum soluble interleukin-2 receptor assay in epithelial ovarian cancer.

Preoperative serum soluble interleukin-2 receptor (sIL-2R) and CA 125 levels were measured in 183 patients with ovarian masses undergoing laparotomy. Serum sIL-2R levels were higher in the 54 patients with epithelial ovarian cancer than in the 129 patients with benign ovarian diseases (p < 0.0001). Elevated serum levels of sIL-2R (> or = 71 U/ml) and CA 125 (> or = 83 U/ml) were found in 79.6 and 77.8% of patients with epithelial ovarian cancer, respectively. Serum sIL-2R and CA 125 positivity rates correlated with the FIGO stage (p = 0.0033 and p = 0.0001, respectively). Raised serum levels of sIL-2R and CA 125 were detected in 11.6 and 7.0% of patients with benign ovarian diseases, respectively. The combination sIL-2R or CA 125 had a sensitivity of 88.9%, and the association sIL-2R and CA 125 had a specificity of 98.4% for epithelial ovarian cancer. As for the 16 patients with this malignancy who were serially monitored during and after chemotherapy, changes in sIL-2R and CA 125 levels correlated with the clinical course of disease in 62.3 and 94.3% of 53 instances, respectively. In conclusion, the serum sIL-2R assay could represent a useful adjunctive tool for the differential diagnosis of ovarian masses, while it seems to be of limited benefit for monitoring the response to chemotherapy and follow-up of patients with epithelial ovarian cancer.

Dose individualization can minimize nephrotoxicity due to carboplatin therapy in patients with ovarian cancer.

Carboplatin (Carbo-Pt), an alkylating agent cleared from the plasma through glomerular filtration, is commonly used for the treatment of ovarian cancer. When administered at high dosage or to patients with reduced renal function, Carbo-Pt may be nephrotoxic. The dose of Carbo-Pt is calculated with Calvert formula, using the value of 24-hour creatinine clearance (24h Ccr) as an estimate of glomerular filtration rate (GFR). The aim of this study was to evaluate the possibility of individualizing the dose of Carbo-Pt using an alternative method to estimate GFR, based on body composition analysis, and then to assess the nephrotoxicity of Carbo-Pt therapy individualized with this new method. First, we evaluated the agreement between GFR (renal clearance of diethylene triamine pentaacetic acid (99mTc-DTPA)), 24h Ccr, and the new estimate of GFR (BCMGFR) calculated on the basis of individual values of body cell mass (BCM) and plasma creatinine. BCMGFR gave a better estimate of GFR than 24h Ccr. Then, we evaluated the nephrotoxicity of a combination chemotherapy based on Carbo-Pt (AUC5-6) in 23 patients affected by ovarian cancer. The dose of Carbo-Pt was adjusted to residual renal function of patients, evaluated as BCMGFR. No case of acute renal failure was observed with this treatment regimen. Urinary excretion of proteins (albumin, β2-microglobulin, and retinol-binding protein) and tubular enzymes, measured as markers of tubular damage, increased significantly and transiently only in the first days after chemotherapy, whereas no evidence of chronic nephrotoxic effect was documented. Dose individualization, using the value of BCMGFR, may minimize nephrotoxicity due to Carbo-Pt therapy.