Gabriella Parma

Management of Ovarian Stromal Cell Tumors

PURPOSE To describe the clinical management of ovarian stromal cell tumors, which are a heterogeneous group of neoplasms that develop from the sex cords and the ovarian stroma. DESIGN We reviewed the current evidence on the clinical management of these relatively rare ovarian malignancies, which are typically detected at an early stage and may recur as late as 30 years following the initial treatment. The overall prognosis is favorable with a long-term survival ranging from 75% to 90% for all stages. Adult granulosa cell tumor (GCT) is the most common malignancy among these tumors. RESULTS Surgery is the cornerstone of initial treatment. In women of childbearing age and with disease limited to one ovary, a fertility-sparing surgery can be a reasonable approach. Tumor stage represents the most important clinical parameter of prognostic relevance. The value of postoperative adjuvant therapy for high-risk patients has not been proven by prospective randomized studies. Platinum-based chemotherapy is used currently for patients with advanced stages or recurrent disease, with an overall response rate of 63% to 80%. Taxane and platinum combination chemotherapy seems to be a reasonable candidate for future trials. Little evidence exists for the use of radiation or hormonal therapy, and these modalities should be restricted to selected cases. Given the propensity of GCT for late relapse, prolonged follow-up is required. CONCLUSION Surgery remains the most effective treatment for ovarian stromal tumors and, whenever feasible, for relapsing disease. Platinum-based chemotherapy is currently used in metastatic or recurrent tumors.

A randomized comparison of continuous versus interrupted mass closure of midline incisions in patients with gynecologic cancer

Objective To address the incidence of deep wound dehiscence and incisional hernia formation with two types of mass closure after vertical midline laparotomy performed in patients with gynecologic cancer. Methods Continuous and interrupted mass closures were compared randomly in 632 patients. Both methods were performed with absorbable material. Of the 614 subjects who could be evaluated, 308 underwent a continuous, nonlocking closure with looped polyglyconate suture, and 306 were closed with interrupted polyglycolic acid according to the Smead-Jones technique. Results Three (1%) subjects with the continuous closure and five (1.6%) with the interrupted closure had an abdominal wound infection (P = .50). One patient whose incision was closed with continuous suturing had a deep wound dehiscence (without evisceration). The follow-up period was 6 months to 3 years. No patient had evidence of chronic sinus drainage. Thirty-two (10.4%) of the patients who had the continuous closure and 45 (14.7%) of those who were closed with the interrupted method had evidence of incisional hernia (P = .14). No hernia developed in any patient with a wound infection. Four (1.3%) hernias after the continuous closure and eight (2.6%) after the interrupted closure required surgical repair because of patient discomfort (P = .38). Conclusion The interrupted closure was not superior to the continuous closure for short- and long-term wound security. The continuous method was preferable because it was more cost-efficient and faster.

A Phase I-II Preoperative Biomarker Trial of Fenretinide in Ascitic Ovarian Cancer

Purpose: To evaluate study feasibility, toxicity, drug concentrations, and activity of escalating doses of the synthetic retinoid fenretinide [N-(4-hydroxyphenyl)retinamide (4-HPR)] in ovarian cancer by measuring serum CA125 and cytomorphometric biomarkers in cancer cells collected from ascitic fluid before and after treatment. Methods: Twenty-two naive patients with ascitic ovarian cancer were treated with escalating doses of 4-HPR at 0, 400, 600, and 800 mg/d for 1 to 4 weeks before surgery. Changes in the proportion of proliferating cells expressed by Ki67 and computer-assisted cytomorphometric variables (nuclear area, DNA index, and chromatin texture) were determined in ascitic cells. Drug levels were measured by high-performance liquid chromatography. Results: Doses up to 800 mg/d were well tolerated, and no adverse reactions occurred. There was no effect of 4-HPR on changes in serum CA125, Ki67 expression, which were assessed in 75% of subjects, and cytomorphometric variables, which were assessed in 80% of subjects. Plasma retinol levels were significantly lower in affected women than healthy donors. 4-HPR plasma concentrations increased slightly with increasing doses and attained a 1.4 μmol/L concentration with 800 mg/d. Drug levels in malignant ascitic cells and tumor tissue were higher than in plasma but were 50 and 5 times lower, respectively, than in carcinoma cells treated in vitro with 1 μmol/L 4-HPR. Conclusions: Cell biomarkers can be measured in ascitic cells to assess drug activity. Under our experimental conditions, 4-HPR did not show activity in advanced ovarian cancer cells. However, clinical evidence supports further investigation of fenretinide for ovarian cancer prevention. (Cancer Epidemiol Biomarkers Prev 2006;15(10):1914–9)

Randomized Phase III Clinical Trial Evaluating Weekly Cisplatin for Advanced Epithelial Ovarian Cancer

This randomized, open label, phase III clinical trial (1988-1992) compared the efficacy and safety of a dose-dense regimen of single-agent cisplatin with a standard 3-weekly schedule in first-line chemotherapy for advanced epithelial ovarian cancer. Two hundred eighty-five patients were randomly assigned to the experimental dose-dense arm (cisplatin 50 mg/m(2) weekly × nine cycles) or to the control (standard treatment) arm (cisplatin 75 mg/m(2), administered on day 1 every 21 days × six cycles). The primary outcome was progression-free survival (PFS). Secondary outcomes were overall survival (OS), overall response to chemotherapy, and toxicity. Toxicity and response to treatment were compared with the χ(2) test using trend or exact correction. PFS and OS were estimated by Kaplan-Meier analyses and treatment hazard ratios (HRs) with the Cox proportional hazards model. All statistical tests were two-sided. After a median follow-up of 16.8 years, no differences were observed between the two treatments in PFS (experimental arm: 17.2 months; control arm: 18.1 months; HR = 1.08, 95% confidence interval [CI] = 0.83 to 1.40; P = .57) and in OS (experimental arm: 35 months; control arm: 32 months; HR = 0.97, 95% CI = 0.75 to 1.26; P = .97). Thus, increasing dose intensity of cisplatin does not improve PFS or OS compared with standard chemotherapy.

An open-label phase 2 study of twice-weekly bortezomib and intermittent pegylated liposomal doxorubicin in patients with ovarian cancer failing platinum-containing regimens

Background Pegylated liposomal doxorubicin (PLD) is an established treatment for relapsed ovarian cancer. Preclinical and clinical evidences in other tumor types suggest that the proteasome inhibitor bortezomib can act synergistically with PLD. Methods Patients with relapsed ovarian cancer (N = 58), previously treated with platinum (100%) and taxane (95%), received bortezomib, 1.3 mg/m2 intravenous (days 1, 4, 8, and 11), and PLD, 30 mg/m2 intravenous (day 1), every 3 weeks. Tumor responses were assessed using Response Evaluation Criteria In Solid Tumors and Gynecologic Cancer Intergroup criteria. An optimal 2-stage design was implemented. Gene expression profiling in peripheral blood was characterized before and during treatment in 10 platinum-sensitive patients enrolled in stage 2 of the study. Results Median number of bortezomib-PLD cycles was 3.5. Of 38 patients in the platinum-sensitive group, 9 responses were observed (median duration, 4.8 months). The platinum-resistant group was closed at stage 1 owing to lack of response. Toxicity was moderate and mainly consisted of hematologic, gastrointestinal, and mucositis events. Of the total 58 patients, peripheral neuropathy was reported in 9 patients (none were grade 3). Transcription profiling identified the prevalence of genes associated with ribonucleoprotein complexes, RNA processing, and protein translation. The gene expression changes were more robust in patients who responded or had stable disease compared with patients who had progressive disease. Conclusions The combination of bortezomib and PLD was well tolerated, but the antitumor activity is insufficient to warrant further investigation in ovarian cancer.