Recurrent Ovarian Carcinoma Research Articles

Outcomes of robotic secondary cytoreductive surgery for recurrent ovarian carcinoma

Objectives: To evaluate surgical and survival outcomes in patients with recurrent ovarian cancer undergoing robotic secondary cytoreduction.

Selective cardiac surveillance in patients with gynecologic cancer undergoing treatment with pegylated liposomal doxorubicin (PLD)

ObjectiveThe study objective was to examine the safety and cost savings of selective cardiac surveillance (CS) during treatment with pegylated liposomal doxorubicin (PLD). MethodsA retrospective, dual institution study of women receiving PLD for the treatment of a gynecologic malignancy was performed. The study period was 2002–2014. At both institutions, a selective strategy for CS was implemented in which only high-risk women with a cardiac history or with symptoms suggestive of cardiac toxicity during PLD treatment underwent a cardiac evaluation. Patient demographics, clinical and treatment history were evaluated. Cost analyses were performed utilizing professional/technical fee rates for echocardiogram and multi-gated acquisition scan for each state. ResultsPLD was administered in 184 women. The mean patient age was 62.7years, and 79% were treated for recurrent ovarian or peritoneal carcinoma. The median cumulative administered dose of PLD was 300mg/m2; 24 received >550mg/m2. The median follow-up time was 20months. Of the 184 patients, the majority (n=157, 85.3%) did not undergo either an initial cardiac evaluation or surveillance during or post-PLD treatment. Fifty-three patients considered high risk for anthracycline-induced cardiotoxicity underwent CS. Only three patients (1.6%) in the entire cohort developed CHF that was possibly related to PLD treatment; all had significant pre-existing cardiac risk factors. Selective instead of routine use of CS in the study population resulted in a cost savings of $182,552.28. ConclusionUtilizing cardiac surveillance in select women undergoing PLD treatment for gynecologic malignancies resulted in significant health care cost savings without adversely impacting clinical outcomes.

Molecular alterations in endometrial and ovarian clear cell carcinomas: clinical impacts of telomerase reverse transcriptase promoter mutation

Recently, mutations of telomerase reverse transcriptase (TERT) promoter were found in several types of cancer. A few reports demonstrate TERT promoter mutations in ovarian clear cell carcinomas but endometrial clear cell carcinoma has not been studied. The aims of this study were to compare differences of molecular alterations and clinical factors, and identify their prognostic impact in endometrial and ovarian clear cell carcinomas. We evaluated mutations of the TERT promoter and PIK3CA, expression of ARID1A, and other clinicopathological factors in 56 ovarian and 14 endometrial clear cell carcinomas. We found that TERT promoter mutations were present in 21% (3/14) of endometrial clear cell carcinomas and 16% (9/56) of ovarian clear cell carcinomas. Compared with ovarian clear cell carcinomas, endometrial clear cell carcinomas showed older mean patient age (P<0.001), preserved ARID1A immunoreactivity (P=0.017) and infrequent PIK3CA mutation (P=0.025). In ovarian clear cell carcinomas, TERT promoter mutations were correlated with patient age >45 (P=0.045) and preserved ARID1A expression (P=0.003). In cases of endometrial clear cell carcinoma, TERT promoter mutations were not statistically associated with any other clinicopathological factors. In ovarian clear cell carcinoma patients with early FIGO stage (stages I and II), TERT promoter mutation was an independent prognostic factor and correlated with a shorter disease-free survival and overall survival (P=0.015 and 0.009, respectively). In recurrent ovarian clear cell carcinoma patients with early FIGO stage, TERT promoter mutations were associated with early relapse within 6 months (P=0.018). We concluded that TERT promoter mutations were present in endometrial and ovarian clear cell carcinomas. Distinct molecular alteration patterns in endometrial and ovarian clear cell carcinomas implied different processes of tumorigenesis in these morphologically similar tumors. In ovarian clear cell carcinoma of early FIGO stage, patients with TERT promoter mutation require close follow-up during the initial 6 months following chemotherapy.

Clinical observational study of conformal radiotherapy combined with topotecan chemotherapy in patients with platinum-resistant recurrent ovarian cancer.

This retrospective study aimed to observe the cura-tive effect and adverse reactions of three-dimensional conformal radiotherapy combined with topotecan chemotherapy in patients with platinum-resistant recurrent epithelial ovarian carcinoma. The chemoradiotherapy group (N = 22) received 15 mv X-rays with 1.8 to 2.0 Gy/f/d radiation, 5 times per week. The total dose was 45 to 65 Gy; the median dose was 52.5 Gy. Topotecan chemotherapy (2.0 mg/m(2)) was administered after the first week of radiotherapy on days 1, 8, and 15; it was repeated every 28 days. The only che-motherapy group (N = 20) received topotecan chemotherapy (4.0 mg/m(2)) in the first week, and the dose was administered on days 1, 8, and 15; it was repeated every 28 days. The median follow-up times were 18.5 months (2 to 37.7) and 10.8 months (1.5 to 29.6) in the chemoradiotherapy and in the only chemotherapy groups, respectively. The total response rates were 42.1% (8/19) and 11.1% (2/18), respectively. The clinical benefit rates were 68.4% (13/19) and 22.2% (4/18), respectively, with significant difference (P < 0.05). The median disease progression-free periods were 9.8 and 6.6 months, respectively, with significant difference (P < 0.001). The median survival times were 19.7 and 12.5 months, respective-ly, with significant difference (P < 0.05). The degrees of digestive tract reaction rates were 26.3% (5/19) and 16.7% (3/18), whereas the hematology toxicity rates were 21.1% (4/19) and 22.2% (4/18), respectively, with no significant difference (P > 0.05). As three-dimensional conformal radiotherapy combined with topotecan che-motherapy had good curative effect on platinum-resistant recurrent epithelial ovarian cancer, with mild adverse reactions, this tech-nique can be used as a remedial measure.

Efficacy of permanent iodine-125 seed implants and gemcitabine chemotherapy in patients with platinum- resistant recurrent ovarian carcinoma.

The aim of this study was to explore the efficacy and adverse reactions of CT-guided radioactive 125I-seed implantation treatment combined with chemotherapy for platinum-resistant recurrent ovarian carcinoma. From September 2010 to December 2012, 23 patients with platinum-resistant recurrent ovarian carcinoma were enrolled. All the patients refused, could not bear, or were not suitable for surgery. They all had no more than 3 lesions, which were detected and could also be measured by CT. All were clarified as single-lesion or multiple-lesion groups. A total of 41 lesions underwent implantation of from 8 to 106 125I seeds (median=43). Multi-plane implanting was adopted and 125I-seeds of (0.4-0.7)mCi were placed at intervals of (0.5-1.0) cm. After implantation treatment, all patients underwent 4 cycles of chemotherapy with gemcitabine 800 mg/m2 (days 1, 8 and 15). The outcome was evaluated with CT 3 weeks and every 3 months after implantation treatment. After 6 months, the volume of 32 out of 41 lesions (78.0%) was reduced at least 30%, within which 9 lesions completely disappeared(22.0%). Complete response was observed in 7 cases (30.4%), with a partial response in 4 cases (17.4%),4 cases stable(17.4%)and 8 cases showing progression (34.8%). The total clinical remission rate was 47.8% (11/23). The clinical remission rate was 77.8% (7/9) in the single-lesion group and 28.6% (4/14) in the multiple-lesion group with a significant difference between the two(P=0.036). The common side effects observed were mild gastrointestinal reactions. 125I-seed implantation combined with chemotherapy applies an effective way in the treatment of platinum-resistant recurrent ovarian epithelial carcinoma with the advantages of high local control rates, good short-term effects, little trauma and less side effects.

Differential expression of argininosuccinate synthetase in serous and non‐serous ovarian carcinomas

The current standard of care for epithelial ovarian cancer does not discriminate between different histologic subtypes (serous, clear cell, endometrioid and mucinous) despite the knowledge that ovarian carcinoma subtypes do not respond uniformly to conventional platinum/taxane‐based chemotherapy. Exploiting addictions and vulnerabilities in cancers with distinguishable molecular features presents an opportunity to develop individualized therapies that may be more effective than the current ‘one size fits all' approach. One such opportunity is arginine depletion therapy with pegylated arginine deiminase, which has shown promise in several cancer types that exhibit low levels of argininosuccinate synthetase including hepatocellular and prostate carcinoma and melanoma. Based on the high levels of argininosuccinate synthetase previously observed in ovarian cancers, these tumours have been considered unlikely candidates for arginine depletion therapy. However, argininosuccinate synthetase levels have not been evaluated in the individual histologic subtypes of ovarian carcinoma. The current study is the first to examine the expression of argininosuccinate synthetase at the mRNA and protein levels in large cohorts of primary and recurrent ovarian carcinomas and ovarian cancer cell lines. We show that the normal fallopian tube fimbria and the majority of primary high‐grade and low‐grade serous ovarian carcinomas express high levels of argininosuccinate synthetase, which tend to further increase in recurrent tumours. In contrast to the serous subtype, non‐serous ovarian carcinoma subtypes (clear cell, endometrioid and mucinous) frequently lack detectable argininosuccinate synthetase expression. The in vitro sensitivity of ovarian cancer cell lines to arginine depletion with pegylated arginine deiminase was inversely correlated with argininosuccinate synthetase expression. Our data suggest that the majority of serous ovarian carcinomas are not susceptible to therapeutic intervention with arginine deiminase while a subset of non‐serous ovarian carcinoma subtypes are auxotrophic for arginine and should be considered for clinical trials with pegylated arginine deiminase.

A phase II study of lenalidomide in platinum-sensitive recurrent ovarian carcinoma

Lenalidomide has dual antiangiogenic and immunomodulatory properties and confirmed antitumor activity in hematologic malignancies. A phase II study investigating the safety and efficacy of continuous lenalidomide in recurrent ovarian cancer patients was initiated. Patients with histologically confirmed epithelial ovarian, fallopian tube or primary peritoneal carcinoma, with asymptomatic recurrence 6 months after prior therapy were treated with continuous oral lenalidomide (20 mg/day). The primary end point was to evaluate efficacy according to the rate of disease control at 4 months. Secondary objectives were progression-free survival (PFS) and safety. Most of the 45 patients enrolled and treated had serous histology (78%) and a single line of prior chemotherapy (73%). Median platinum-free interval (PFI) was 11.3 months (range 6.9-56.8). Clinical benefit at 4 months was 38% [95% confidence interval (CI) 23% to 53%]. A 59% disease control rate was reported in patients with a PFI >12 months versus 24% with PFI of 6-12 months (P = 0.023). Four patients had RECIST partial responses and 21 had stable disease. CA125 responses were reported in eight patients, including one complete response. Median PFS was 3.4 months (95% CI 2.4-4.4). Most frequent toxicity was hematologic, notably grade 3-4 neutropenia in 29% of patients, along with fatigue (69%), gastrointestinal toxicity (constipation 53%, abdominal pain 49%, diarrhea 38%, nausea/vomiting 36%) and thrombosis (11%). Eight patients withdrew due to related toxicity. Lenalidomide shows interesting efficacy in late recurrent ovarian cancer patients. Toxicity was mainly hematologic, gastrointestinal and venous thrombosis. Future studies will evaluate combination of lenalidomide with chemotherapy agents. NCT01111903.

The natural history of pericardial tamponade secondary to recurrent ovarian carcinoma — A case report and review of the literature

•We report a case of malignant cardiac tamponade secondary to ovarian carcinoma•We emphasize the quick and fatal outcome of such a complication•It seems that aggressive treatment offers the longest overall survival.

Whole-body diffusion-weighted MRI versus CT for detection, restaging and operability assessment of recurrent ovarian carcinoma

Methods Fifty-one women suspected for recurrent ovarian cancer underwent 3-Tesla WB-DWI/MRI using 2 b-values (b=0-1000 s/mm2), T2and contrast T1-weighted sequences in addition to CT. WB-DWI/MRI and CT were compared for per-patient detection of recurrence, per-site detection of disease extent including peritoneal, serosal, retroperitoneal, periportal and distant metastases and for detecting disease extent according to institutional operability criteria. Imaging findings were correlated with surgical/pathological findings or imaging follow-up for at least 6 months.

Abstract CT339: Prospective molecular identification of ovarian cancer patients benefiting from PARP inhibitor (PARPi, rucaparib) maintenance therapy - reaching beyond germline BRCA mutations

Abstract Background: PARP inhibitors are thought to be effective therapy for cancers with homologous recombination (HR) deficiency, best shown to date in patients (pts) with a germline BRCA (gBRCA) mutation. The Cancer Genome Atlas (TCGA) estimated ∼ 50% of high-grade serous ovarian carcinoma (OC) pts have an HR defect (HRD) due to a BRCA mutation (germline or somatic), other HR gene mutation, or another mechanism, e.g., BRCA1 promoter methylation. A randomized maintenance trial of olaparib in recurrent OC demonstrated a clinical benefit in both gBRCA-mutated and gBRCA-wild-type pts. Currently, the best molecular predictors of PARPi response (other than a BRCA mutation) are not known. Platinum sensitivity, often used as a surrogate predictive indicator for PARPi response, is inadequate. A better technique, such as molecular analysis of tumor tissue, could be a superior method for selection of pts for PARPi therapy. Methods: The rucaparib development plan in OC employs a unique strategy of conducting the key trials in parallel, allowing the Phase 2 (ARIEL2) to complete first so that a molecular HRD signature, associated with sub-groups most likely to benefit, can be prospectively applied to the final analysis of the Phase 3 pivotal trial (ARIEL3). ARIEL2 is an ongoing, single-arm, open-label biomarker study designed to refine the molecular signature associated with a response to rucaparib. Eligible pts (n=180) have relapsed, platinum-sensitive, high-grade OC and measurable disease. All pts undergo a pre-dose biopsy and provide archival tumor tissue. Tumor tissue HR status is assessed using Foundation Medicine's next generation sequencing (NGS) platform and University of Washington's BROCA-HR panel, with the current HRD algorithm developed using in vitro/in vivo and TCGA (and similar) bioinformatic data. The key efficacy analyses to be correlated with tumor HR status are response by RECIST v1.1, GCIG-defined CA-125 response, and PFS. The number of gBRCA pts is limited to maximize non-gBRCA response predictors. Exploratory biomarkers include assessment of tissue NHEJ competency (candidate predictive biomarker) and circulating tumor DNA (candidate efficacy surrogate). The optimized algorithm will then be tested prospectively in ARIEL3 (n=540), an international, randomized (2:1), double-blind, placebo-controlled maintenance trial in platinum-sensitive OC in remission after platinum-based therapy. The primary endpoint of ARIEL3 is PFS in molecularly-defined HRD subgroups as determined by NGS analysis of archival tumor tissue using the optimized algorithm, refined (as required) through ARIEL2.Conclusion: This pair of clinical trials seeks to determine prospectively the appropriate population, among all women with platinum-sensitive OC, who derive a meaningful benefit from PARPi treatment in the maintenance setting. Citation Format: Elizabeth Swisher, Iain McNeish, Robert L. Coleman, James D. Brenton, Scott H. Kaufmann, Andrew Allen, Mitch Raponi, Heidi Giordano, Lara Maloney, Jeffrey Isaacson, Jonathan A. Ledermann. Prospective molecular identification of ovarian cancer patients benefiting from PARP inhibitor (PARPi, rucaparib) maintenance therapy - reaching beyond germline BRCA mutations. [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 CT339. doi:10.1158/1538-7445.AM2014-CT339

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for recurrent ovarian carcinoma: analysis of 30-day morbidity and mortality.

The aim of this study was to evaluate morbidity and mortality associated with cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with ovarian, fallopian tube, and primary peritoneal cancer. A retrospective review of patients undergoing cytoreductive surgery plus HIPEC from 1 January 2007 to 29 July 2013 at two academic medical centers was performed. Grade 3/4 complications (National Cancer Institute's Common Toxicity Criteria version 4.0) from day of surgery until 30days postoperatively were recorded. Thirty-two patients were identified, with 27 cases of ovarian cancer, three primary peritoneal cancers, and two fallopian tube cancers. Indications included 24 at the time of cancer recurrence, six at interval surgical resection, and two in the consolidative setting. Hyperthermic chemotherapeutic regimens included carboplatin (n=21), cisplatin (n=4), oxaliplatin (n=2), oxaliplatin+intravenous 5-fluorouracil (n=1), doxorubicin (n=1), and cisplatin+doxorubicin (n=1). Infusion time ranged from 30 to 90min, with a maximum temperature range of 41-43°C. The combined grade 3/4 morbidity rate was 65.6%, and the most frequent morbidities included grade 3 anemia (40.6%), infection (15.6%), and pleural effusion (12.5%). Six patients required readmission (18.8%), and two patients required reoperation (6.2%). Full-thickness diaphragm resection/peritoneal stripping had a significant association with grade 3/4 pleural effusions (p=0.0007). Cytoreductive surgery plus HIPEC is feasible in patients with ovarian cancer with 65.6% grade 3/4 morbidity and no deaths. Balancing these complications with potential survival benefits is important in centers considering implementing HIPEC protocols.

Outcomes analysis of an alternative formulation of PEGylated liposomal doxorubicin in recurrent epithelial ovarian carcinoma during the drug shortage era.

BackgroundIn response to the critical shortage of Doxil®, the US Food and Drug Administration (FDA) allowed temporary importation of non-FDA-approved second-generation liposomal doxorubicin, Lipo-Dox®. Lipo-Dox utilizes a different liposomal particle than Doxil and demonstrates different pharmacokinetic properties. Its use has never been evaluated in a North American population. The objective of this study was to evaluate the efficacy and tolerability of Lipo-Dox at Magee-Womens Hospital, University of Pittsburgh Medical Center, for patients with recurrent epithelial ovarian cancer who were treated during the Doxil shortage.MethodsPatients treated with Lipo-Dox from January 2012 to December 2012 were identified retrospectively. Disease response was defined radiographically by RECIST (Response Evaluation Criteria in Solid Tumors) or biochemically by CA-125 level if measurable disease was not present. Survival was defined from the start date of Lipo-Dox until the date of progression or death. Toxicity was assessed by the Gynecologic Oncology Group common toxicity criteria.ResultsEighteen patients with recurrent epithelial ovarian cancer who received Lipo-Dox were identified. These patients had a median of three prior treatment regimens. The median number of Lipo-Dox cycles given was 3.5 (range 1–8). No patients had a complete or partial response. Two patients had stable disease over a mean follow-up of 144.5 days. Fourteen patients had progressive disease, with a median time to progression of 82 days. Progression was based on CA-125 in four patients and RECIST in the remainder. Nine patients died from the disease.ConclusionAlthough this represents a small, pretreated population, there were no clinical responses to Lipo-Dox, raising the question as to whether it is an equivalent substitute for Doxil. Further evaluation is needed, but if confirmed, these findings raise concerns regarding the use of current stocks of Lipo-Dox, as well as the prudence of managing future drug shortages with pharmacologically similar, but clinically untested drugs.

Abstract number 17: Robotic and open cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) in the management of recurrent ovarian carcinoma

Abstract number 17: Robotic and open cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) in the management of recurrent ovarian carcinoma

A phase II study of ramucirumab (IMC-1121B) in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma

ObjectiveVascular endothelial growth factor (VEGF) receptor-mediated signaling contributes to ovarian cancer pathogenesis. Elevated VEGF expression is associated with poor clinical outcomes. We investigated ramucirumab, a fully human anti-VEGFR-2 antibody, in patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. Primary endpoints were progression-free survival at 6months (PFS-6) and confirmed objective response rate (ORR). MethodsWomen who received ≥1 platinum-based chemotherapeutic regimen and had a platinum-free interval of <12months with measurable disease were eligible. Patients received 8mg/kg ramucirumab intravenously every 2weeks. ResultsSixty patients were treated; one patient remained on study as of September 2013. The median age was 62years (range: 27–80), and median number of prior regimens was 3. Forty-five (75%) patients had platinum refractory/resistant disease. Thirty-nine patients (65.0%) had serous tumors. PFS-6 was 25.0% (n=15/60, 95% CI: 14.7–37.9%). Best overall response was: partial response 5.0% (n=3/60), stable disease 56.7% (n=34/60), and progressive disease 33.3% (n=20/60). The most common treatment-emergent adverse events possibly related to study drug were headache (65.0%; 10.0% Grade ≥3), fatigue (56.7%; 3.3% Grade ≥3), diarrhea (28.3%; 1.7% Grade ≥3), hypertension (25.0%; 3.3% Grade ≥3), and nausea (20.0%; no Grade ≥3). Two patients experienced intestinal perforations (3.3% Grade ≥3). Pharmacodynamic analyses revealed changes in several circulating VEGF proteins following initial ramucirumab infusion, including increased VEGF-A, PlGF and decreased sVEGFR-2. ConclusionsAlthough antitumor activity was observed, the predetermined efficacy endpoints were not met.

Analysis and comparison of somatic mutations between primary and recurrent ovarian carcinomas: A study in serial samples

Objectives: The objective of this study was to determine the frequency and types of point somatic mutations in epithelial ovarian cancer using a mutation detection protocol called OncoMap that employs mass spectrometric-based genotyping technology.

A cost-effectiveness analysis of four chemotherapy regimens used in the treatment of platinum-sensitive recurrent epithelial ovarian carcinoma

A cost-effectiveness analysis of four chemotherapy regimens used in the treatment of platinum-sensitive recurrent epithelial ovarian carcinoma

Radiation therapy for recurrent clear cell ovarian carcinoma

Objectives: Given the relative chemoresistant nature of clear cell gynecologic cancers, radiation therapy (RT) has been explored as an adjuvant treatment. We investigated the utility of radiation to treat recurrent clear cell carcinoma of the ovary.

The role of secondary cytoreduction in patients with recurrent low-grade serous ovarian carcinoma

The role of secondary cytoreduction in patients with recurrent low-grade serous ovarian carcinoma

Nanoparticle albumin-bound (nab) paclitaxel therapy in patients with primary and recurrent ovarian, fallopian tube, and primary peritoneal carcinoma

Nanoparticle albumin-bound (nab) paclitaxel therapy in patients with primary and recurrent ovarian, fallopian tube, and primary peritoneal carcinoma

Robotic and open cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) in the management of recurrent ovarian carcinoma

Robotic and open cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) in the management of recurrent ovarian carcinoma