Ovarian Peritoneal Metastasis Research Articles

Long‐term outcomes and survival analysis of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy in patients with pseudomyxoma peritonei at a newly established peritoneal malignancy centre in Japan

AbstractBackgroundCytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is established in the management of pseudomyxoma peritonei (PMP), selected cases of peritoneal mesothelioma, and resectable colorectal or ovarian peritoneal metastases in Western countries. However, the efficacy and feasibility of these techniques are not well established in the Asian population, and little has been reported on long‐term survival outcomes for surgically resected PMP patients.Materials and MethodsRetrospective analysis of a prospective database of short‐ and longer‐term outcomes of consecutive patients who underwent CRS and HIPEC for PMP in a newly established peritoneal malignancy unit in Japan between 2010 and 2016.ResultsA total of 105 patients underwent CRS and HIPEC and 57 maximal tumor debulking (MTD) for pseudomyxoma peritonei. In the CRS group, the primary tumor was appendiceal in 94 patients (90%) followed by ovarian and colorectal. Major postoperative complications occurred in 22/105 patients (21%) with one in‐hospital mortality (0.9%). The 5‐year overall and disease‐free survival rates for the CRS group were 74.2% and 50.1%, respectively. Multivariate analysis revealed unfavorable histology to be the significant predictor of reduced overall and disease‐free survival. Completeness of cytoreduction, CA19‐9, and CA125 were also associated with disease‐free survival.ConclusionsThis is the first report on long‐term outcomes and survival analysis of CRS and HIPEC for PMP in the Asian population. CRS and HIPEC can be conducted with reasonable safety and favorable survival in a new center. Complete tumor removal and histological type are the strongest prognostic factors for both overall and disease‐free survival.

Abstract A23: Ultrarapid total abdominal FLASH irradiation in a preclinical model of ovarian cancer

Abstract Introduction: Ultrahigh dose-rate irradiation (FLASH RT) is rapidly emerging as new strategy to enhance the therapeutic index of radiotherapy by protecting normal tissues from radiation-induced toxicity while maintaining tumor control. In mice, FLASH has been shown to protect the lung, skin, and brain against radiation-induced toxicity. A recent study has utilized FLASH radiotherapy in preclinical models of lung cancer to demonstrate that FLASH RT radiotherapy achieves similar tumor control to conventional RT. While these findings identify an important role for FLASH RT in the protection of multiple tissues, the role of FLASH in enhancing the therapeutic index of abdominal and pelvic tumors located near the highly radiosensitive intestine is not known. For this purpose, we have developed an experimental platform using a clinical linear accelerator that enables total abdominal FLASH RT where rapid delivery of a single fraction of high-dose radiotherapy is performed in less than one second (200 Gy/sec). Methods: For the tumor model, ID8 cells were injected intraperitoneally into female mice. Radiation was delivered 10 days post-ID8 injection. Tumor burden was assessed at 28 days following tumor injection. Flow cytometry was used to profile infiltrating immune cells. Normal tissue toxicity was assessed through survival, total body weight, solid stool production, complete blood count, and histologic analysis. Results: In ID8 tumor-bearing mice, 14 Gy FLASH promotes GI function with a 2-fold increase in solid stool production at 5 days post-TAI. Both modalities extended median overall survival in the ID8 model by 5 days and reduced tumor burden by 50% relative to unirradiated controls. Irradiated cohorts also demonstrated an increase in the number of proliferating CD8+ and CD4+ T cells present in the ascites. Conclusion: We demonstrate that FLASH RT protects the gastrointestinal (GI) tract from lethal radiation-induced toxicity, improves epithelial integrity and GI function, enhances crypt survival, and provides efficient tumor control in a preclinical model of ovarian peritoneal metastasis. Here we present the first data supporting the potential for tumor control and GI protection using FLASH-TAI in a syngeneic orthotopic preclinical model of ovarian cancer. Citation Format: Karen Levy, Jinghui Wang, Joshua Eggold, Suchitra Natarajan, Peter Maxim, Bill Loo, Erinn Rankin. Ultrarapid total abdominal FLASH irradiation in a preclinical model of ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A23.

Abstract AP25: TOTAL ABDOMINAL ULTRA-RAPID FLASH IRRADIATION DEMONSTRATES DECREASED GASTROINTESTINAL TOXICITY COMPARED TO CONVENTIONAL TOTAL ABDOMINAL IRRADIATION IN MICE

Abstract OBJECTIVE: Ovarian cancer is the most common cause of gynecologic cancer-related death in the United States. The majority of patients diagnosed with ovarian cancer present with stage III or IV disease in which the tumor has disseminated beyond the ovaries and pelvic organs to the peritoneum and mesothelial lining of abdominal organs. Despite advances in ovarian cancer treatments including maximal cytoreductive surgery, chemotherapy and checkpoint-blockade immunotherapy, recurrence is common and prognosis remains poor. Ovarian cancer is a radiosensitive tumor; however, use of total abdominal irradiation (TAI) has fallen out of favor in the past 15 years due to high toxicity, particularly of the gastrointestinal (GI) tract. In prior studies, ultra-rapid FLASH radiation spares normal tissues, such as the lung and skin, from toxic effects of radiation. This suggests that FLASH may be an effective strategy to reduce complications of radiotherapy while maintaining antitumor control. We developed a FLASH irradiation system for mice using a linear accelerator that generates 16 MeV electrons at a high beam current and delivers large doses of radiation in a single beam in <500ms. Conventional radiotherapy delivers a dose-rate of 3-4 Gy/minute, while FLASH radiotherapy delivers a dose-rate of >40 Gy/second. Our objective is to develop a method for delivering TAI using FLASH and assess toxicity. METHODS: Female C57BL/6 mice received TAI using FLASH and conventional (CONV) radiation in increasing doses: 8.5 Gy, 10.5 Gy and 12 Gy. Normal tissue toxicity was determined by measuring total body weights, stool counts, histological analysis, and survival. RESULTS: Seven cohorts of mice were analyzed: five unirradiated controls, eight received 8.5Gy, five received 10.5Gy and five received 12 Gy of either TAI-FLASH or TAI-CONV. Stool counts were unchanged from controls in TAI-FLASH mice 5 days post-irradiation at all doses. In the TAI-CONV cohort, a 50% stool quantity decrease was noted after 8.5Gy and a 63% stool quantity decrease was noted after 12Gy at 5 days post-TAI. Histological analysis of the duodenum post-irradiation demonstrated that TAI-FLASH has a protective effect on the mucosal architecture. Weights remained unchanged across all groups. The survival analysis was most notable for all of the TAI-CONV mice having died by day 9 whereas all of the TAI-FLASH mice survived. CONCLUSIONS: These data demonstrate FLASH protects against death from TAI and improves the epithelial integrity of the lower GI tract following TAI compared to conventional radiation in a preclinical model. Our discovery that FLASH is a safe strategy to deliver effective doses of total abdominal radiation potentially identifies a new opportunity to utilize TAI-FLASH for treatment of ovarian peritoneal metastases. Citation Format: Karen Levy MD, Joshua Eggold BA, Marjan Rafat PhD, Emil Schuler PhD, Hussein Shehade PhD, Daniel Fregoso BS, Jose Vilches-Moure DVM PhD, Albert Koong MD PhD, Peter Maxim PhD MSc, Billy W Loo MD PhD, Erinn Rankin PhD. TOTAL ABDOMINAL ULTRA-RAPID FLASH IRRADIATION DEMONSTRATES DECREASED GASTROINTESTINAL TOXICITY COMPARED TO CONVENTIONAL TOTAL ABDOMINAL IRRADIATION IN MICE [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr AP25.

Preclinical testing of ultra-rapid FLASH total abdominal irradiation demonstrates survival benefit and decreased gastrointestinal toxicity compared to conventional external beam radiation.

3092 Background: Total abdominal irradiation (TAI) is not widely used in the treatment of ovarian cancer due to high abdominopelvic toxicity. Ultra-rapid FLASH irradiation has been shown to spare the lung, skin and brain from radiation toxicity in preclinical models. Conventional radiotherapy delivers a dose-rate of 3-4 Gy/minute, while our small animal FLASH system uses a linear accelerator to generate a dose-rate of 200 Gy/second. Our data demonstrates that use of FLASH-TAI in a preclinical model protects against death from irradiation and confers gastrointestinal (GI) protection when compared to conventional external beam irradiation. Ongoing studies are evaluating the potential for tumor control in an ID8 mouse model of ovarian cancer. Methods: Female C57BL/6 mice received TAI using FLASH and conventional (CONV) radiation at increasing doses: 8.5 Gy, 10.5 Gy and 12 Gy. Unirradiated controls and irradiated cohorts were analyzed at 5-days and 12 months post-irradiation. Normal tissue toxicity was determined by measuring total body weights, stool counts, laboratory analysis, histological analysis, immunohistochemistry, immunofluorescence microscopy and survival. Results: Solid stool production was preserved in FLASH mice, whereas a 50-63% decrease was observed in the CONV cohorts. Histology demonstrated that FLASH preserves small intestinal architecture. TUNEL analysis demonstrated an increase in apoptosis throughout the small intestine of only the CONV cohort. Exploratory necropsy of all surviving cohorts at 12 months post-irradiation was notable for secondary transmural proximal duodenal adenocarcinomas within the radiation field in 25% of only the aged CONV cohorts. There was no laboratory evidence of long-term hematopoietic, liver or kidney toxicity at 12 months. Survival analysis was notable for death of all 12 Gy CONV mice by 9 days post-irradiation whereas 75% of the 12 Gy FLASH mice were alive at 11 months. Conclusions: FLASH protects against death from TAI, improves small intestine epithelial integrity following TAI, protects against radiation-induced apoptosis and may protect from secondary gastrointestinal tumors in the radiation field. Our discovery that FLASH is a safe strategy to deliver effective doses of total abdominal radiation potentially identifies a new opportunity to utilize FLASH-TAI for treatment of ovarian peritoneal metastases.

Establishment of a rat ovarian peritoneal metastasis model to study pressurized intraperitoneal aerosol chemotherapy (PIPAC)

Backgroundpressurized intraperitoneal aerosol chemotherapy (PIPAC), with or without electrostatic precipitation (ePIPAC), was recently introduced in the treatment of peritoneal metastases (PM) from ovarian cancer (OC). Preliminary clinical data are promising, but several methodological issues as well the anticancer efficacy of PIPAC remain unaddressed. Here, we propose a rat ePIPAC model that allows to study these issues in a clinically relevant, reproducible, and high throughput model.Methodslaparoscopy and PIPAC were established in healthy Wistar rats. Aerosol properties were measured using laser diffraction spectrometry based granulometric analyses. Electrostatic precipitation was accomplished using a commercially available generator (Ultravision™). A xenograft model of ovarian PM was created in athymic rats using intraperitoneal (IP) injection of SKOV-3 luciferase positive cells. Tumor growth was monitored weekly by in vivo bioluminescence imaging.ResultsPIPAC and electrostatic precipitation were well tolerated using a capnoperitoneum of 8 mmHg. All rats survived the (e)PIPAC procedure and no gas or aerosol leakage was observed over the entire procedure. With an injection pressure of 20 bar, granulometry showed a mean droplet diameter (D(v,0.5)) of 47 μm with a flow rate of 0.5 mL/s, and a significantly lower diameter (30 μm) when a flow rate of 0.8 mL/s was used. Experiments using IP injection of SKOV-3 luciferase positive cells showed that after IP injection of 20 × 106 cells, miliary PM was observed in all animals. PIPAC was feasible and well supported in these tumor bearing animals.Conclusionswe propose a reproducible and efficient rodent model to study PIPAC and ePIPAC in OC xenografts with widespread PM. This model allows to characterize and optimize pharmacokinetic and biophysical parameters, and to evaluate the anti-cancer efficacy of (e)PIPAC treatment.

Pressurized IntraPeritoneal Aerosol Chemotherapy vs. intravenous chemotherapy for unresectable peritoneal metastases secondary to platinum resistant ovarian cancer - study protocol for a randomized control trial.

BackgroundDespite optimal surgery and appropriate first-line chemotherapy, ∼70–80 % of patients with epithelial ovarian cancer will develop disease relapse. The prognosis is poor especially for women with Platinum resistant ovarian cancer. The standard treatment for these groups of patients is non-platinum-containing chemotherapy like taxanes, anthracyclines, gemcitabine, topotecan, and trabectedin. These drugs in various combinations and sequences provide modest survival or symptomatic benefit but with significant side effects. Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) is a minimally-invasive drug-delivery technique specifically addressing limited tissue penetration and poor drug distribution with promising results. PIPAC is a novel method of delivering normothermic chemotherapy into the abdominal cavity as an aerosol under pressure. This concept seems to enhance the effectiveness of intra peritoneal chemotherapy by taking advantage of the physical properties of gas and pressure by generating an artificial pressure gradient and enhancing tissue uptake and distributing drugs homogeneously within the closed and expanded peritoneal cavity. Thus, due to the high local bioavailability during PIPAC, the chemotherapy dosage can be reduced which in turn largely prevents systemic side effects and organ toxicity.MethodsThe study aims to investigate the therapeutic efficacy measured as objective tumour response according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria, of PIPAC in comparison with conventional Intravenous chemotherapy for women with recurrent platinum resistant ovarian cancer with peritoneal metastasis (PM). Consecutive patients diagnosed with PM secondary to platinum-resistant ovarian cancer will be randomized to PIPAC group or IV chemotherapy group. The primary objective of this study is to determine the efficacy after three cycles of PIPAC with cisplatin and doxorubicin in comparison with six cycles of systemic chemotherapy. The secondary outcome measures include morbidity and mortality, overall survival and disease specific survival. Analysis is by intention to treat.AimAssess the objective tumour response of PIPAC in comparison with systemic intravenous chemotherapy for women with platinum-resistant ovarian cancer.Study typeProspective randomized control intervention trial.Intervention modelIV Chemotherapy group (Control group) PIPAC group (Experimental group)MaskingOpen label.Primary purposeTreatment.Sample sizeCalculated sample size is 97 and rounded to 100. For each treatment group sample size of 50 will be considered.Primary outcome criteriaObjective tumour response according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria version 1.1.Secondary outcome criteriaMorbidity;Disease-specific survival (months between inclusion and death due to ovarian cancer);OS (months between inclusion and death due to any cause);CA 125 levels.DiscussionPIPAC in women with platinum resistant ovarian PM has good response owing to superior tissue penetration and better drug distribution. The procedure is safe and well tolerated owing it to its minimal invasiveness. Typical side-effects of systemic chemotherapy, such as alopecia, peripheral neurotoxicity, nausea and myelosuppression are absent. We expect reduction of ascites with symptomatic relief and CA 125 levels. PIPAC is a novel technique for selected patients with platinum resistant ovarian PM and further investigation in comparative clinical trials with conventional chemotherapy will establish its role as a good palliative treatment option.Ethics committee approvalObtained.StatusRecruiting.Trial registration numberREF/2018/08/021223 Registered on Clinical Trials Registry – India (CTRI); www.ctri.nic.in

ROBO1 Expression in Metastasizing Breast and Ovarian Cancer: SLIT2-induced Chemotaxis Requires Heparan Sulfates (Heparin).

The members of the slit homolog (SLIT) and roundabout homolog (ROBO) families have emerged as important signaling molecules in tumor metastasis. This study analyzed their role in regulating breast cancer (BC) cell motility and chemotaxis and assessed expression of ROBO1 in brain metastases (BMs) of breast, lung, and colon cancer, and in peritoneal metastases (PMs) of ovarian cancer. The BC cell line MDA-MB231 was subjected to scratch, motility, and chemotaxis assays using heparin and a purified recombinant N-terminal SLIT2 fragment. Protein expression was assessed in primary tumors and metastases by immunohistochemistry. Exposure to SLIT2 induced MDA-MB231 cell motility, but no significant chemotaxis without the presence of heparin. ROBO1 was expressed in 4/5 primary BC and in 18/21 BC-derived BM samples; 7/9 BM primary lung cancer samples also stained positive. In contrast, BMs from colorectal cancer were negative for ROBO1. Primary ovarian cancer and ovarian PM showed ROBO1 expression in 0/6 and in only 2/6 samples, respectively, whereas SLIT2 was observed in 1/6 primary cancer and in 6/6 PMs samples. SLIT2 can induce BC cell motility and chemotaxis, but the latter requires the presence of heparin. BM expression of ROBO1 is a common feature of some, but not all cancer types. SLIT2 expression appears to be a general feature of ovarian cancer-derived PMs.

Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) as an outpatient procedure.

BackgroundPressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) is a drug-delivery method for patients with peritoneal metastasis (PM). The study objective was to investigate whether PIPAC is possible in an outpatient setting.MethodsData was extracted from the prospective PIPAC-OPC2 study (ClinicalTrials.gov NCT03287375). Patients with PM were treated by cisplatin and doxorubicin (PIPAC C/D), except patients with colorectal PM, who were treated by oxaliplatin (PIPAC OX). Patients were evaluated concerning the suitability for carrying out the PIPAC procedure in an out- patient setting. The preconditions for outpatient surgery were that the patient should be (1) freely mobilized, (2) adequately pain-relieved, (3) have untroubled urination and (4) without anxiety or discomfort caused by leaving the hospital.ResultsDuring the study period, 106 PIPAC procedures (79 PIPAC C/D, 27 PIPAC OX) were performed in 41 patients with gastrointestinal or ovarian PM. Ninety percent (37/41) of the patients were pretreated with systemic chemotherapy. Eight patients (20%) received bidirectional chemotherapy. Twenty-four percent (10/41) of the first PIPAC procedures were completed in an outpatient setting, which increased to 65% (13/20) in PIPAC no 3 (p=0.008). In the PIPAC C/D cohort, 28% and 80% of the PIPACs were performed in the outpatient setting at PIPAC 1 and 3 respectively, contrasting to only 11% and 20% in the PIPAC OX group. No readmissions after outpatient care. Postoperative morphine administration was more frequent in the PIPAC OX group.ConclusionsThe PIPAC procedure can be performed in an outpatient setting. The critical component for success is pain control.

Hyperthermic intraperitoneal chemoperfusion as a component of multimodality therapy for ovarian and primary peritoneal cancer.

The role of hyperthermic intraperitoneal chemoperfusion (HIPEC) in the multimodality treatment of ovarian peritoneal metastases (OPM) and primary peritoneal cancer (PPC) remains controversial. We hypothesized that cytoreductive surgery (CRS) and HIPEC would provide meaningful survival benefit without excessive morbidity. We reviewed clinicopathologic and perioperative data following 96 CRS-HIPEC procedures for primary or recurrent OPM and PPC. Kaplan-Meier survival curves and multivariate Cox-regression models identified prognostic factors affecting oncologic outcomes. CRS-HIPEC was mostly performed for recurrent disease (56.3%) and high-grade serous carcinoma (72.9%). Platinum-based systemic chemotherapy was administered to 89.5% of patients, with 75.5% having platinum-sensitive disease at CRS-HIPEC. Complete macroscopic resection was achieved in 70.8% of patients. Clavien-Dindo grade 3/4 morbidity occurred in 23.4% of patients; three patients died within 60-days postoperatively. Median overall survival from diagnosis of peritoneal metastases and CRS-HIPEC was 78 and 38 months, respectively. Completeness of cytoreduction, pathologic subtype, and 30-day morbidity were independent predictors of survival in multiple regression analysis. Our study demonstrates promising survival data and supports the role of HIPEC in the multimodality treatment algorithm for primary or recurrent OPM and PPC. However definite indications and timing of HIPEC need to be clarified by prospective studies.

Cachexia-anorexia syndrome in patients with peritoneal metastasis: an observational study.

Background: Little is known about the nutritional status of patients with peritoneal metastasis (PM), in particular about the evolution of the so-called anorexia-cachexia syndrome in these patients. The objective of the study was to assess nutritional status in PM patients at the end of life, including metabolic aspects. Methods: Observational study. Prospective nutritional status assessment in 87 PM patients, including Subjective Global Assessment: (SGA), physical examination (body mass index [BMI], bioelectrical impedance analysis [BIA], anthropometry and blood chemistry). Results: 85 % patients had received previous chemotherapy. Peritoneal carcinomatosis index was 16±11, Karnofsky 81±14 % and ascites volume 1,000±1,690 ml. SGA was reduced with 22.0±9.6 points, BMI normal with 25.3±5.8 kg/m2 and resting metabolism was 1,527±248 kcal/day. Serum total protein and albumin were at the inferior normal limit (6.5±0.8 g/dl, respectively 3.7±0.8 g/dl) and C-reactive protein (CRP) was elevated (2.9±4.1 g/dl). Serum levels of protein (p=0.05), albumin (p=0.003) and transferrin (p=0.001) were higher in gastrointestinal than in ovarian PM patients. When patients were grouped according to time from first assessment to death, serum protein and albumin decreased until end of life, whereas ascites volume, resting metabolism and CRP increased. Conclusion: Both increased resting metabolism and decreased caloric intake contribute to the development of the cachexia-anorexia syndrome in PM patients. End of life is caused by energetic dysbalance and exhaustion.

A folate-targeted photosensitizer to improve specificity of intraperitoneal photodynamic therapy of ovarian peritoneal metastasis

A folate-targeted photosensitizer to improve specificity of intraperitoneal photodynamic therapy of ovarian peritoneal metastasis

Assessment of the specificity of a new folate-targeted photosensitizer for peritoneal metastasis of epithelial ovarian cancer to enable intraperitoneal photodynamic therapy. A preclinical study

BackgroundOvarian cancer’s prognosis remains dire after primary therapy. Recurrence rate is disappointingly high as 60% of women with epithelial ovarian cancer considered in remission will develop recurrent disease within 5 years. Special attention to undetected peritoneal metastasis during surgery is necessary as they are the main predictive factors of recurrences. Folate Receptor α (FRα) shows promising prospects in targeting ovarian cancerous cells and intraperitoneal photodynamic therapy (PDT) could be a solution in addition to macroscopic cytoreductive surgery to treat peritoneal micrometastasis. The aim of this preclinical study is to assess the specificity of a folate-targeted photosensitizer for ovarian peritoneal micrometastasis. MethodsWe used the NuTu-19 epithelial ovarian cancer cell line to induce peritoneal carcinomatosis in female Fischer 344 rats. Three groups of 6 rats were studied (Control (no photosensitizer)/Non-conjugated photosensitizer (Porph)/Folate-conjugated photosensitizer (Porph-s-FA)). Four hours after the administration of the photosensitizer, animals were sacrificed and intraperitoneal organs tissues were sampled. FRα tissue expression was evaluated by immunohistochemistry. Tissue incorporation of photosensitizers was assessed by confocal microscopy and tissue quantification. ResultsFRα is overexpressed in tumor, ovary, and liver whereas, peritoneum, colon, small intestine, and kidney do not express it. Cytoplasmic red endocytosis vesicles observed by confocal microscopy are well correlated to FRα tissue expression. Photosensitizer tissue quantification shows a mean tumor-to-normal tissue ratio of 9.6. ConclusionWe demonstrated that this new generation folate-targeted photosensitizer is specific of epithelial ovarian peritoneal metastasis and may allow the development of efficient and safe intraperitoneal PDT procedure.

Evaluation of Folate-targeted ChemoRad Nanoparticle as Intraperitoneal Chemoradiotherapy for Ovarian Cancer

Ovarian peritoneal metastasis is the leading cause of morbidity and mortality in ovarian cancer patients. While intraperitoneal (IP) chemotherapy and IP radioisotope therapy have shown favorable clinical results, both lead to significant toxicities. Chemoradiotherapy has been shown to be superior to either therapy alone in many cancers, but has not yet been evaluated in ovarian cancer due to concerns of toxicity. Advances in nanotechnology have enabled the development of biologically targeted nanoparticle (NP) therapeutic carriers.

Folate-targeted nanoparticle delivery of chemo- and radiotherapeutics for the treatment of ovarian cancer peritoneal metastasis

Peritoneal metastasis is a major cause of morbidity and mortality in ovarian cancer. While intraperitoneal chemotherapy and radiotherapy have shown favorable clinical results, both are limited by their non-targeted nature. We aimed to develop a biologically targeted nanoparticle therapeutic for the treatment of ovarian cancer peritoneal metastasis. Folate-targeted nanoparticles encapsulating chemotherapy and/or radiotherapy were engineered. Paclitaxel (Ptxl) was used as the chemotherapeutic and yittrium-90 ( 90Y) was employed as the therapeutic radioisotope. Folate was utilized as the targeting ligand as most ovarian cancers overexpress the folate receptor. Nanoparticle characterization studies showed monodispersed particles with controlled Ptxl release. Folate targeting ligand mediated the uptake of NPs into tumor cells. In vitro efficacy studies demonstrated folate-targeted NPs containing chemoradiotherapy was the most effective therapeutic compared to folate-targeted NPs containing a single therapeutic or any non-targeted NP therapeutics. In vivo efficacy studies using an ovarian peritoneal metastasis model showed that folate-targeted NP therapeutics were significantly more effective than non-targeted NP therapeutics. Among the folate-targeted therapeutics, the NP containing chemoradiotherapy appeared to be the most effective. Our results suggest that folate-targeted nanoparticles containing chemoradiotherapy have the potential as a treatment for ovarian peritoneal metastasis.

Abstract 382: Evaluation of folate-targeted ChemoRad nanoparticle as intraperitoneal chemoradiotherapy for ovarian cancer

Abstract Approximately 15,000 women die of ovarian cancer in the U.S. each year. One of the most common causes of mortality in these patients is peritoneal metastases. While intraperitoneal (IP) chemotherapy and IP radioisotope therapy have shown favorable clinical results, both lead to significant toxicities. Chemoradiotherapy has been shown to be superior to either therapy alone in many cancers, such as head and neck cancer, cervical cancer and rectal cancer. However it has not been evaluated in ovarian cancer due to concerns of toxicity. Advances in nanotechnology have enabled the development of biologically targeted nanoparticle (NP) therapeutic carriers. These NPs allow preferential delivery of therapeutics to tumors, which in turn increases efficacy and minimizes toxicity. Our laboratory was the first to develop a nanoparticle platform, the ChemoRad NP, which can deliver both chemotherapy and radiotherapy. We hypothesized that a ChemoRad NP targeted against ovarian cancer cells can be a novel and effective treatment for ovarian peritoneal metastases. In this study, we engineered a folate-targeted ChemoRad NP encapsulating paclitaxel and Y90 for IP chemoradiotherapy of ovarian cancer. The NP was evaluated using the SKOV-3 ovarian carcinoma cell line and a murine model of ovarian peritoneal metastases. Folate was utilized as a targeting ligand as most ovarian cancers overexpress the folate receptor. Paclitaxel (Ptxl), a first-line chemotherapy for ovarian cancer, was used as the model drug. Y90 was employed as the therapeutic radioisotope based on its high-energy emission and low toxicity. The folate-targeted ChemoRad NP was formulated by a nanoprecipitation method. The resulting NPs have a hydrophobic polymeric core where Ptxl is encapsulated. The NP surface is covered by a self-assembled monolayer of lipid and lipid-polymer. Metal chelators were incorporated into the sub-surface layer for the chelation of Y90. Characterization of the NPs showed particle size of 70+/−5 nm and 60% Ptxl encapsulation efficiency. Drug release study showed controlled release with more than 95% of Ptxl released at 24 hrs. We demonstrated folate mediated cellular uptake of targeted NP Ptxl Y90 by SKOV-3 cells. An in vitro efficacy study showed the folate-targeted NP Ptxl Y90 (T-NP Ptxl Y90) is more effective than that of non-targeted NP Ptxl Y90. We then validated our folate NP containing Ptxl and Y90 in vivo. Peritoneal xenograft metastases were induced by injecting SKOV-3 cells IP in nude mice. Therapeutics were given IP at 3 weeks post tumor implantation. We were able to demonstrate that T-NP Ptxl Y90 is more effective than T-NP Ptxl, T-NP Y90, and non-targeted NPs containing either or both therapeutic agents. In conclusion, we have demonstrated that folate-targeted NP Ptxl Y90 is a biologically targeted chemoradiotherapy for ovarian cancer. It represents a potential novel treatment for ovarian peritoneal metastases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 382. doi:10.1158/1538-7445.AM2011-382