Radoslav Chekerov

Prognostic value of residual tumor size in patients with epithelial ovarian cancer FIGO stages IIA-IV: analysis of the OVCAD data.

Objective The objective of the study was to evaluate the prognostic impact of residual tumor size after cytoreductive surgery in patients with epithelial ovarian cancer. Methods In this prospective, multicenter study, 226 patients with epithelial ovarian cancer (International Federation of Gynecology and Obstetrics stages IIA–IV) were included. Patients were treated with cytoreductive surgery and adjuvant platinum-based chemotherapy. Univariate and multivariable survival analyses were performed to investigate the impact of residual tumor size on progression-free and overall survival. Results In 69.4% of patients, surgery resulted in complete tumor resection; minimal residual disease (≤1 cm) was achieved in 87.2% of patients. Advanced tumor stage was associated with a lower rate of complete tumor resection (P < 0.001). After cytoreductive surgery, 3-year overall survival rates were 72.4%, 65.8%, and 45.2% for patients without, with minimal, and with gross residual disease (>1 cm), respectively (P < 0.001). Multivariable survival analysis revealed residual tumor size (P = 0.04) and older patient age (P = 0.02) as independent prognosticators for impaired overall survival. Complete cytoreduction was predictive for a higher rate of treatment response (P = 0.001) and was associated with prolonged progression-free and overall survival (P < 0.001 and P = 0.001). Conclusions The size of residual disease after cytoreduction is one of the most crucial prognostic factors for patients with ovarian cancer. Patients after complete cytoreduction have a superior outcome compared with patients with residual disease. Leaving no residual tumor has to be the aim of primary surgery for ovarian cancer; therefore, patients should receive treatment at centers able to undertake complex cytoreductive procedures.

Monitoring of IL-10 in the serum of patients with advanced ovarian cancer: Results from a prospective pilot-study

OBJECTIVESnThe fact that ovarian cancer remains confined to the peritoneal cavity even in advanced stages has allowed us to surmise that local immunosuppressive factors could be involved in the tumor biology of ovarian cancer. In this context, IL-10 can be one of the key factors. By studying the kinetics of IL-10 concentrations prior to and after surgery, this study attempts to reveal once more the ability of tumor micro-environment to produce IL-10. Some studies indicate that IL-10 concentration correlates with the tumor burden and can thus predict the surgical outcome. Data concerning this aim from patients with ovarian cancer do not seem to exist.nnnMETHODSnIn this prospective study, serum blood was collected from 27 patients, one day prior to surgery as well as 24h, 4 and 8 days after surgery. The concentration of IL-10 was determined using ELISA.nnnRESULTSnWhile IL-10 levels rise within the first day post-OP, they are found to be reduced significantly when measured at later time points. IL-10 levels also correlate statistically significantly with the tumor grade, with lower IL-10 levels observed in well-differentiated and higher IL-10 levels in undifferentiated or only poorly differentiated tumors.nnnCONCLUSIONnIL-10 expression levels appear to be a good surrogate marker for tumor grading. If validated, this may in future contribute to the understanding of the biology stage cancers.

Efficient Prevention Strategy against the Development of a Palmar-Plantar Erythrodysesthesia during Chemotherapy

Background: Pegylated liposomal doxorubicin (PLD) is a highly efficient chemotherapeutic; however, it induces dermal side effects such as palmar-plantar erythrodysesthesia (PPE) in up to 80% of cases, probably by being emitted with the sweat onto the skin surface. Aim: The aim of the present study was to examine whether a topically applied ointment containing antioxidants with a high radical protection factor is able to prevent the formation of PPE. Methods: Twenty patients suffering from ovarian carcinoma and treated with PLD were observed. Results: 60% of the patients tolerated the regular application of the cream and developed no PPE. The remaining 40% interrupted the application. Six of them developed PPE and resumed ointment application thereafter. In these cases the PPE disappeared or was strongly reduced. Conclusion: The results of the observation clearly demonstrate that topical application of the ointment is an efficient strategy against the development of PPE during chemotherapy with PLD.

Randomized, Phase II, Placebo-Controlled, Double-Blind Study With and Without Enzastaurin in Combination With Paclitaxel and Carboplatin As First-Line Treatment Followed by Maintenance Treatment in Advanced Ovarian Cancer

PURPOSEnEnzastaurin is an oral serine/threonine kinase inhibitor antitumor agent. Our phase II trial tested the efficacy and safety of enzastaurin added to a standard carboplatin/paclitaxel chemotherapy regimen in patients with newly diagnosed advanced ovarian cancer.nnnPATIENTS AND METHODSnThis was a randomized, placebo-controlled study in patients with International Federation of Gynecology and Obstetrics stage IIB to IV ovarian, fallopian tube, or peritoneal epithelial carcinoma. Patients were randomly assigned to six cycles of chemotherapy (paclitaxel/carboplatin ± enzastaurin [PCE/PC]) followed by maintenance therapy (enzastaurin/placebo). Primary end point was progression-free survival (PFS). Secondary measures included response rate, safety assessment, and translational research.nnnRESULTSnA total of 142 patients were randomly assigned to PCE (n = 69) or PC (n = 73). Patients in the PCE group had a 3.7-month longer median PFS compared with patients in the PC group; this was not statistically significant (hazard ratio [HR], 0.80; 95% CI, 0.50 to 1.29; P = .37). Safety profiles of the treatment arms were comparable. Frequency of discontinuation because of adverse events was similar (PCE, 11.9%; PC, 9.7%). Multivariate analyses confirmed the importance of optimal debulking with regard to PFS (debulking optimal v suboptimal: HR, 0.51; 95% CI, 0.30 to 0.85; P = .009). HR for covariate stage (stage IIB to IIIB v IIIC to IV) was not statistically significant (0.75; 95% CI, 0.38 to 1.47; P = .40). Translational research of immunohistochemistry protein assays did not identify any markers significantly associated with treatment difference regarding PFS.nnnCONCLUSIONnThe PCE combination increased PFS, but it was not significantly superior to PC in this phase II study.

Genetic Versus Epigenetic BRCA1 Silencing Pathways: Clinical Effects in Primary Ovarian Cancer Patients

Objectives The aim of the present study was to assess in a large cohort of primary epithelial ovarian cancer patients the incidence and the clinical effect of BRCA1 genetic and epigenetic silencing mechanisms. Methods A total of 188 primary epithelial ovarian cancer patients, treated between 2000 and 2011 at the Charité University Hospital of Berlin, were included. The patients tumor and blood samples were obtained from the Tumor Bank Ovarian Cancer Network (www.toc-network.de). Direct sequencing of BRCA1 exon 11 was performed to detect germline mutations, whereas tumor samples were assessed for BRCA1 promoter hypermethylation by bisulphite-converted methylation-specific polymerase chain reaction. Basing on their BRCA1 status, patients were compared regarding clinicopathological variables and survival. Results Twenty-one patients (11.2%) showed hypermethylation in BRCA1 promoter (HMB), and 18 patients (9.6%) presented germline mutations in BRCA1 exon 11 (GMB). Patients with HMB showed a significantly younger age at diagnosis compared with BRCA1 wild type (BWT) patients (54 vs 61 years, P = 0.045), and both GMB and HMB patients were more likely to have high-grade serous ovarian cancer (76.2% and 77.8% vs 52.7%, P = 0.043 and P = 0.043). Positive family history of breast or ovarian cancer (OC) was more frequently reported among GMB patients with respect to BWT patients (44.4% vs 13.5%, P = 0.003); GMB, HMB, and BWT patients did not show significant differences in terms of tumor dissemination pattern, surgical outcomes, platinum response or survival; neither mutational nor hypermethylation BRCA1 status was found to be an independent prognostic factor for OC patients. Conclusions Hypermethylation in BRCA1 is associated with earlier occurrence of OC. In addition, the coexistence of both GBM and HMB is an infrequent event, occurring in 0.5% of OC cases. Silencing of BRCA1 through mutation and hypermethylation confers to distinct clinical characteristics of OC patients but similar clinical outcome with respect to BWT patients.

Impact of Body Mass Index (BMI) on Chemotherapy-associated Toxicity in Ovarian Cancer Patients. A Pooled Analysis of the North-Eastern German Society of Gynecological Oncology (NOGGO) Databank on 1,213 Patients

Background/Aim: Chemotherapy-associated toxicity is one of the limiting factors regarding treatment efficacy, patient outcome and quality of life in this collective. Underweight or obese patients represent a major group in which the therapy seems to be more challenging. The aim of this analysis was to evaluate the impact of BMI on the toxicity in patients undergoing chemotherapy. Patients and Methods: The data of three prospective phase II/III studies (‘Tower’, ‘Topotecan phase III’ and ‘Hector’) of the North-Eastern German Society of Gynecological Oncology including 1,213 patients with recurrent ovarian cancer were retrospectively analyzed. The study was performed using logistic regression and Cox regression analysis. Results: The median age at diagnosis was 59 years. Sixty-seven (5.5%) patients had BMI <20 and 272 (22.4%) patients had BMI >30. Preterm termination of the chemotherapy was associated with lower BMI (p=0.017). Moreover, non-hematological toxicity grade III/IV was mainly observed in underweighted women as well (p<0.001). Patients with higher BMI more often presented with grade III/IV anemia (p=0.019) and as a consequence required blood transfusions more frequently (p=0.005). The overweight group was also associated with a higher number of co-medications. However, no difference in survival regarding BMI was observed in our study. Conclusion: Fewer chemotherapy cycles and preterm discontinuation were more frequent in patients with lower BMI. Hematological toxicity and higher medication intake appeared more often in patients with higher BMI.