Recurrent Ovarian Carcinoma Patients Research Articles

The progression-free survival ratio as outcome measure in recurrent ovarian carcinoma patients: Current and future perspectives

ObjectiveClinical efficacy of cytostatic anticancer agents can be determined with the progression-free survival (PFS) ratio. This outcome measure compares PFS achieved by a new treatment (PFS2) to the PFS of the most recent treatment on which the patient has experienced progression (PFS1). Clinical benefit has been defined as a PFS-ratio (PFS2/PFS1) > 1.3. However, in order to demonstrate significant benefit, trial designs require an assumption on the proportion of patients who reach this ratio during palliative options. For ovarian carcinoma, data is lacking to support this assumption. Therefore in this study, we assess the PFS-ratio in recurrent ovarian carcinoma patients treated with current palliative options. MethodsWe included 67 patients with recurrent high-grade serous (HGSC, 73.1%) or low-grade (LGOC, 26.9%) ovarian carcinoma. We determined the median PFS-ratio and investigated the association with clinicopathological characteristics. ResultsOverall, we observed a median PFS-ratio of 0.69. The proportion of patients with a PFS-ratio > 1.3 was 22.4%. For HGSC patients, the median PFS-ratio was significantly lower than for LGOC patients (respectively, 0.58 and 1.26, p = 0.007). Multivariate logistic regression analysis revealed that the LGOC subtype and CA125 tumor marker concentration were independent factors related to a PFS-ratio > 1.3. ConclusionsAlthough the PFS-ratio represents a meaningful outcome measure in studies investigating cytostatic anticancer agents, we conclude that it is influenced by tumor histology and biological behavior. In future research, these factors should be taken into account when determining thresholds for clinical benefit in trial designs.

Abstract B79: Translational study of tumor treating fields in combination with paclitaxel in ovarian cancer.

Abstract Tumor Treating Fields (TTFields), a clinically active anticancer modality, are based on low intensity intermediate frequency alternating electric fields that exert their cytotoxicity by disrupting mitosis. The present study examines whether concomitant paclitaxel and TTFields have a beneficial impact on ovarian cancer growth both in vitro and in vivo. Moreover, on the basis of the preclinical observations, an open-label pilot clinical study evaluating the effect of the combined modalities in 30 patients with recurrent ovarian cancer was initiated. Preclinical studies: To investigate the inhibitory effect of TTFields on ovarian cancer cell growth in vitro and determine optimal therapeutic frequency of TTFields in ovarian cancer, human ovarian cancer cell lines were treated with TTFields (100-400 kHz) for 72 hours using the inovitro system (Novocure, Haifa, Israel). To assess whether adding TTFields to paclitaxel increases the response of ovarian cancer cells to paclitaxel, we treated these cell lines with paclitaxel alone and in combination with TTFields. In vivo efficacy of the combined treatment was tested in female C57Bl/6 mice, orthotopically implanted with MOSE-L FFL luciferase positive cells. The feasibility of effective regional delivery of TTFields therapy to the ovaries, pelvis and abdomen of human subjects was examined using Finite Element Mesh (FEM) simulations performed using the Sim4life software. The FEM simulations demonstrated effective distribution of fields at intensities of 1-2 V/cm, which is above the minimal threshold required for TTFields response. The INNOVATE Trial (NCT02244502): Based on positive preclinical studies demonstrating the combined efficacy of TTFields and paclitaxel in different ovarian cancer models, a pilot clinical trial was initiated to evaluate this therapeutic combination in recurrent ovarian carcinoma patients. In this prospective, pilot, single arm study, 30 patients will receive bi-directional TTFields at 200 kHz applied to the ovaries and surrounding intra-abdominal tissues using 4 transducer arrays located on the surface of the lower abdominal region. In addition, patients will receive concomitant paclitaxel at a standard regimen and dose. The combined treatment will be administered until further radiological progression. Inclusion criteria include ECOG score of 0-1 and no serious co-morbidities. The trial's primary endpoint is adverse events frequency and severity. The study will also collect preliminary efficacy data through the analysis of progression-free survival, 1-year survival rate and overall survival. Compliance data will be analyzed as an additional secondary endpoint. The INNOVATE study started to enroll patients in October 2014, and is currently accruing patients in Switzerland, Belgium and Spain. So far the trial has enrolled half of the planned 30 patients. In summary, we present the first preclinical evidence in ovarian cancer of the combined efficacy of paclitaxel and TTFields, a new anticancer treatment modality. Our results suggest that it may represent a novel, effective therapeutic strategy against ovarian cancer. Pilot clinical testing is ongoing. Citation Format: Mijal Munster, Roni Blat, Paul C. Roberts, Eva M. Schmelz, Moshe Giladi, Rosa S. Schneiderman, Yaara Porat, Zeev Bomzon, Noa Urman, Aviran Itzhaki, Tali Voloshin, Shay Cahal, Eilon D. Kirson, Uri Weinberg, Yoram Palti. Translational study of tumor treating fields in combination with paclitaxel in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B79.

Phase II study on the combination carboplatin-celecoxib in heavily pre-treated recurrent ovarian carcinoma patients

15009 Background: Cyclooxygenase-2 (COX-2) has been shown to be involved in several steps of ovarian onset and progression and its overepression is associated with a poor chance of response to chemotherapy and poor prognosis in ovarian cancer. Celecoxib, an orally active selective COX-2 inhibitor, has been tested for its ability to potentiate the activity of carboplatin in treatment of heavily pretreated recurrent ovarian cancer patients. Methods: A phase II study was planned, considering the regimen active if at least 12 responses were observed among the 43 enrolled patients. Celecoxib (400 mg/die), and carboplatin (5 AUC) q28 were administered, until progression or unacceptable toxicity. Response was assessed by RECIST and also by Rustin criteria. Results: 34 pts (median age: 60 yrs, range 28–74) and an ECOG performance status (0/1/2) of (21/12/1), were enrolled. 58.8% of patients were platinum resistant (progressing during or < 6 months from primary treatment). Median number of previous chemotherapy regimens was 3 (range 2–6). Currently 27 patients are evaluable for response. The overall response rate (CR and PR) was 25.9% (2 CR, 5 PR) with stabilization of disease in 8 patients (29.6%). Four responses occurred in platinum sensitive and 3 in platinum resistant group Median time to response was 11 weeks (range 9–19) and median duration of response was 23 weeks (range 12–39). According to Rustin criteria 10 patients out of 25 (40%) were considered responsive to treatment (return of CA125 levels to normal level or >50% reduction). Overall, 143 cycles were administered with a median value of 3 cycles (range = 1–10). Moderate/severe toxicities were as follows: G3 anemia occurred in 2.3% cycles, G3 neutropenia in 4.6% cycles, G3 thrombocytopenia in 1.5% cycles, G3/4 gastrointestinal toxicity occurred in 4.6% cycles. Cutaneous diffuse erithema was observed in 2 patients, in both cases recovered with a short period of antihistaminic treatment; 2 cases of hypertension were documented, G2 hypersensitivity reactions during carboplatin infusion were observed in 4 cases. Conclusions: Celecoxib combined with carboplatin is well tolerated and has promising activity as salvage treatment in heavily pretreated recurrent ovarian cancer patients. No significant financial relationships to disclose.

A Phase II Study of Liposomal Doxorubicin in Recurrent Epithelial Ovarian Carcinoma

We conducted a phase II trial to evaluate the efficacy and safety of liposomal formulation of doxorubicin in recurrent ovarian carcinoma patients. Thirty patients were included in the study after having obtained an informed consent. Their main characteristics were: median age, 64 years (range, 45-80), ECOG performance status 0 in 17 patients (56%), 1 in 11 patients (36%) and 2 in 2 patients (6.6%). Eighteen patients had metastatic disease and 12 locally advanced disease. All patients were pretreated with a platinum-based chemotherapy: 3 were considered refractory to platinum (progression or stable disease), 2 were platinum resistant (relapse < 12 months), and 7 were platinum sensitive (relapse > or = 12 months). Treatment consisted of liposomal doxorubicin, 50 mg/m2 every 4 weeks. The overall response rate was 26.6%, with 2 complete responses and 6 partial responses lasting 3.5 months. The incidence of grade 3-4 toxicity was 23.3% for neutropenia, 10% for mucositis and 10% for plantar-palmar erythrodysesthesia. Median survival was 12+ months (range, 2-26+). Liposomal doxorubicin appears to be a moderately active drug in pretreated patients, and its activity seems to be similar to that reported for other active regimens in terms of response rate. The toxicological profile of liposomal doxorubicin suggests that it may be combined with other drugs in the treatment of patients with ovarian cancer.