[Case of Long-Term Response to Radiotherapy for Intramedullary Spinal Cord Metastasis from Ovarian Cancer after Surgery].

Intramedullary spinal cord metastasis(ISCM)often causes spinal cord neuropathy and should be treated as an oncologic emergency. However, it recurs in most cases after treatment, ISCM is a disease with a very unfavorable prognosis. Herein, we report a successfully treated case of ISCM with emergent and high-dose radiotherapy. A 53-year-old woman had difficulty walking without assistance 2 years after surgery for ovarian cancer. She received emergent radiotherapy at a total dose of 50 Gy in 25 fractions. Her neurological symptoms dramatically improved over 3 weeks after radiotherapy. ISCM has been controlled using the imaging tests at 5 years after radiotherapy. We believe that both emergent and high-dose radiotherapy were effective for ISCM.

Gadolinium-Based Nanoparticles Sensitize Ovarian Peritoneal Carcinomatosis to Targeted Radionuclide Therapy.

Ovarian cancer (OC) is the most lethal gynecologic malignancy (5-y overall survival rate, 46%). OC is generally detected when it has already spread to the peritoneal cavity (peritoneal carcinomatosis). This study investigated whether gadolinium-based nanoparticles (Gd-NPs) increase the efficacy of targeted radionuclide therapy using [177Lu]Lu-DOTA-trastuzumab (an antibody against human epidermal growth factor receptor 2). Gd-NPs have radiosensitizing effects in conventional external-beam radiotherapy and have been tested in clinical phase II trials. Methods: First, the optimal activity of [177Lu]Lu-DOTA-trastuzumab (10, 5, or 2.5 MBq) combined or not with 10 mg of Gd-NPs (single injection) was investigated in athymic mice bearing intraperitoneal OC cell (human epidermal growth factor receptor 2-positive) tumor xenografts. Next, the therapeutic efficacy and toxicity of 5 MBq of [177Lu]Lu-DOTA-trastuzumab with Gd-NPs (3 administration regimens) were evaluated. NaCl, trastuzumab plus Gd-NPs, and [177Lu]Lu-DOTA-trastuzumab alone were used as controls. Biodistribution and dosimetry were determined, and Monte Carlo simulation of energy deposits was performed. Lastly, Gd-NPs' subcellular localization and uptake, and the cytotoxic effects of the combination, were investigated in 3 cancer cell lines to obtain insights into the involved mechanisms. Results: The optimal [177Lu]Lu-DOTA-trastuzumab activity when combined with Gd-NPs was 5 MBq. Moreover, compared with [177Lu]Lu-DOTA-trastuzumab alone, the strongest therapeutic efficacy (tumor mass reduction) was obtained with 2 injections of 5 mg of Gd-NPs/d (separated by 6 h) at 24 and 72 h after injection of 5 MBq of [177Lu]Lu-DOTA-trastuzumab. In vitro experiments showed that Gd-NPs colocalized with lysosomes and that their radiosensitizing effect was mediated by oxidative stress and inhibited by deferiprone, an iron chelator. Exposure of Gd-NPs to 177Lu increased the Auger electron yield but not the absorbed dose. Conclusion: Targeted radionuclide therapy can be combined with Gd-NPs to increase the therapeutic effect and reduce the injected activities. As Gd-NPs are already used in the clinic, this combination could be a new therapeutic approach for patients with ovarian peritoneal carcinomatosis.

Study protocol for prospective multi-institutional phase III trial of standard of care therapy with or without stereotactic ablative radiation therapy for recurrent ovarian cancer (SABR-ROC).

BACKGROUND: Efforts have been made to investigate the role of salvage radiotherapy (RT) in treating recurrent ovarian cancer (ROC). Stereotactic ablative radiation therapy (SABR) is a state-of-the-art therapy that uses intensity modulation to increase the fractional dose, decrease the number of fractions, and target tumors with high precision. METHODS: The SABR-ROC trial is a phase 3, multicenter, randomized, prospective study to evaluate whether the addition of SABR to the standard of care significantly improves the 3-year overall survival (OS) of patients with ROC. Patients who have completed the standard treatment for primary epithelial ovarian cancer are eligible. In addition, patients with number of metastases ≤ 10 and maximum diameter of each metastatic site of gross tumor ≤ 5 cm are allowed. Randomization will be stratified by (1) No. of the following clinical factors met, platinum sensitivity, absence of ascites, normal level of CA125, and ECOG performance status of 0-1; 0-3 vs. 4; (2) site of recurrence; with vs. without lymph nodes; and (3) PARP inhibitor; use vs. non-use. The target number of patients to be enrolled in this study is 270. Participants will be randomized in a 1:2 ratio. Participants in Arm 2 will receive SABR for recurrent lesions clearly identified in imaging tests as well as the standard of care (Arm 1) based on treatment guidelines and decisions made in multidisciplinary discussions. The RT fraction number can range from 1 to 10, and the accepted dose range is 16-45 Gy. The RT Quality Assurance (QA) program consists of a three-tiered system: general credentialing, trial-specific credentialing, and individual case reviews. DISCUSSION: SABR appears to be preferable as it does not interfere with the schedule of systemic treatment by minimizing the elapsed days of RT. The synergistic effect between systemic treatment and SABR is expected to reduce the tumor burden by eradicating gross tumors identified through imaging with SABR and controlling microscopic cancer with systemic treatment. It might also be beneficial for quality-of-life preservation in older adults or heavily treated patients. TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov (NCT05444270) on June 29th, 2022.

Preclinical studies of a PARP targeted, Meitner-Auger emitting, theranostic radiopharmaceutical for metastatic ovarian cancer.

Advanced ovarian cancer currently has few therapeutic options. Poly(ADP-ribose) polymerase (PARP) inhibitors bind to nuclear PARP and trap the protein-inhibitor complex to DNA. This work investigates a theranostic PARP inhibitor for targeted radiopharmaceutical therapy of ovarian cancer in vitro and PET imaging of healthy mice in vivo. METHODS: [77Br]RD1 was synthesized and assessed for pharmacokinetics and cytotoxicity in human and murine ovarian cancer cell lines. [76Br]RD1 biodistribution and organ uptake in healthy mice were quantified through longitudinal PET/CT imaging and ex vivo radioactivity measurements. Organ-level dosimetry following [76/77Br]RD1 administration was calculated using RAPID, an in-house platform for absorbed dose in mice, and OLINDA for equivalent and effective dose in human. RESULTS: The maximum specific binding (Bmax), equilibrium dissociation constant (Kd), and nonspecific binding slope (NS) were calculated for each cell line. These values were used to calculate the cell specific activity uptake for cell viability studies. The half maximal effective concentration (EC50) was measured as 0.17 (95 % CI: 0.13-0.24) nM and 0.46 (0.13-0.24) nM for PARP(+) and PARP(-) expressing cell lines, respectively. The EC50 was 0.27 (0.21-0.36) nM and 0.30 (0.22-0.41) nM for BRCA1(-) and BRCA1(+) expressing cell lines, respectively. When measuring the EC50 as a function of cellular activity uptake and nuclear dose, the EC50 ranges from 0.020 to 0.039 Bq/cell and 3.3-9.2 Gy, respectively. Excretion through the hepatobiliary and renal pathways were observed in mice, with liver uptake of 2.3 ± 0.4 %ID/g after 48 h, contributing to estimated absorbed dose values in mice of 19.3 ± 0.3 mGy/MBq and 290 ± 10 mGy/MBq for [77Br]RD1 and [76Br]RD1, respectively. CONCLUSION: [77Br]RD1 cytotoxicity was dependent on PARP expression and independent of BRCA1 status. The in vitro results suggest that [77Br]RD1 cytotoxicity is driven by the targeted Meitner-Auger electron (MAe) radiotherapeutic effect of the agent. Further studies investigating the theranostic potential, organ dose, and tumor uptake of [76/77Br]RD1 are warranted.

Efficacy and Safety of Stereotactic Body Radiation Therapy in Oligometastatic Uterine Cancer (MITO-RT2/RAD): A Large, Real-World Study in Collaboration With Italian Association of Radiation Oncology, Multicenter Italian Trials in Ovarian Cancer, and Mario Negri Gynecologic Oncology Group Groups.

PURPOSE: This retrospective, multicenter study analyzes the efficacy and safety of stereotactic body radiation therapy in a large cohort of patients with oligometastatic/persistent/recurrent uterine cancer. METHODS AND MATERIALS: Clinical and radiation therapy data from several radiation therapy centers treating patients by stereotactic body radiation therapy between March 2006 and October 2021 were collected. Objective response rate was defined as complete and partial response, and clinical benefit included objective response rate plus stable disease. Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer and Common Terminology Criteria for Adverse Events scales were used to grade toxicities. Primary endpoints were the rate of complete response to stereotactic body radiation therapy, and the 2-year actuarial local control rate "per-lesion" basis. Secondary endpoints were progression-free survival and overall survival, as well as toxicity. RESULTS: In the study, 157 patients with oligometastatic/persistent/recurrent uterine cancer bearing 272 lesions treated by stereotactic body radiation therapy at 14 centers were analyzed. Lymph node metastases (137, 50.4%) were prevalent, followed by parenchyma lesions (135, 49.6%). Median total dose was 35 Gy (10-75.2), in 5 fractions (range, 1-10). Complete and partial responses were 174 (64.0%), and 54 (19.9%), respectively. Stable disease was registered in 29 (10.6%), and 15 (5.5%) lesions progressed. Type of lesion (lymph node), volume (≤13.7 cc) and total dose (BED10 >59.5 Gy) were significantly associated with a higher probability of achieving complete response. Patients achieving complete response (CR) "per-lesion" basis experienced a 2-year actuarial local control rate of 92.4% versus 33.5% in lesions not achieving complete response (NCR; P < .001). Moreover, the 2-year actuarial progression-free survival rate in patients with CR was 45.4%, and patients with NCR had a 2-year rate of 17.6% (P < .001). Finally, patients who had a CR had a 2-year overall survival rate of 82.7%, compared with 56.5% for NCR patients (P <.001). Severe acute toxicity was around 2%, including one toxic death due to gastric perforation, and severe late toxicity around 4%. CONCLUSIONS: The efficacy of stereotactic body radiation therapy in this setting was confirmed. The low toxicity profile and the high local control rate in complete responder patients encourage the wider use of this approach.

The Significance of Radiotherapy in Ovarian Clear Cell Carcinoma: A Systematic Review and Meta-Analysis.

OBJECTIVE: To assess the response rate and survival effect of adjuvant radiotherapy (RT) or chemoradiotherapy (CRT) during ovarian clear cell carcinoma (OCCC). METHODS: We searched Web of Science, PubMed, Cochrane library electronic databases, Clinical Trials, WanFang Data and Chinese National Knowledge Infrastructure (CNKI) up to October 2022. We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of included studies. RESULTS: We identified a total of 4259 patients from 14 studies met the inclusion criteria. The pooled response rate of residual tumors for RT/CRT was 80.0%, the pooled 5-year progression-free survival (PFS) ratio during RT/CRT group was 61.0%, and the pooled 5-year overall survival (OS) ratio during RT/CRT group was 68.0%; heterogeneity tests demonstrated significant difference between studies (I2 >50%). Cumulative results suggested adjuvant RT/CRT improved 5-year PFS ratio of OCCC patients (OR: 0.51 (95% CI: 0.42-.88), I2 = 22%, P = .009), had no impact on 5-year OS ratio (OR: 0.52 (95% CI: 0.19-1.44), I2 = 87%, P = .21); meta-regression of studies before and after 2000 found consistent results. Sub-analysis observed that adjuvant RT/CRT had no impact on 5-year OS ratio of early-stage (stage I + II) OCCC patients (OR: 0.67 (95% CI: 0.25-1.83), I2 = 85%, P = .44), but might improve 5-year OS ratio of advanced and recurrent OCCC patients (OR: 0.13(95% CI: 0.04-.44), P = .001). CONCLUSION: This analysis suggested that adjuvant RT/CRT might improve oncologic outcomes of OCCC, especially for advanced and recurrent cases. Due to the inherent selective biases of retrospective studies enrolled in the meta-analysis, more convincing evidences based on prospective randomized controlled trials (RCTs) are urgently needed.

Proposed Risk Stratification and Patterns of Radioactive Iodine Therapy in Malignant Struma Ovarii.

Introduction: Malignant struma ovarii (MSO) is a rare thyroid cancer arising within an ovarian teratoma. While surgical excision of the primary tumor is widely accepted as standard of care, recommendations for adjuvant treatment of MSO-whether or not to administer radioactive iodine (RAI)-are based largely on case reports and remain debated. In this study, we aimed to propose a risk stratification and analyze RAI utilization patterns in MSO cases. Methods: The National Cancer Database (NCDB) was queried for patients with MSO between 2004 and 2016. Demographic, oncological, and clinicopathologic data were compared between groups using Fisher's exact test. Kaplan-Meier curves were used to estimate overall survival (OS), and variables associated with OS were assessed via univariate Cox regression. We adapted the 2015 American Thyroid Association risk guidelines for MSO patients. We stratified patients into low-, intermediate-, and high-risk groups using metastasis, extraovarian extension, lymphovascular invasion, lymph node status, surgical margins, tumor size, and grade. Risk stratification, demographic, oncological, and clinicopathologic data were compared between the groups receiving and not receiving RAI therapy. We then queried the Surveillance, Epidemiology, and End Results (SEER) 18 registry for patients with MSO between 2000 and 2018 to confirm our risk stratification analysis. Results: In the NCDB analysis, a total of 158 patients were identified, and 19 received RAI. RAI therapy was associated with distant metastasis (p = 0.005) and lymph node status (p = 0.012). Twenty-one NCDB patients were stratified as high risk, and 30% of high-risk patients received RAI. High-risk stratification was associated with decreased OS via univariate Cox regression (hazard ratio = 4.0 [95% confidence interval 1.11-14.26], p = 0.034). In our subsequent analysis using the SEER registry, there were 95 MSO patients, and 18 received RAI. Again, the majority of high-risk patients did not receive RAI, with only 41% of high-risk patients receiving RAI. Conclusions: MSO is a rare malignancy with apparently variable and inconsistent patterns of postoperative RAI administration. The risk stratification described here provides a framework to identify patients potentially at risk for mortality, and utilization of RAI in this group should be studied further.

Clinical Dose Preparation of [177Lu]Lu-DOTA-Pertuzumab Using Medium Specific Activity [177Lu]LuCl3 for Radioimmunotherapy of Breast and Epithelial Ovarian Cancers, with HER2 Receptor Overexpression.

Background: The overexpression of human epidermal growth factor receptor 2 (HER2) is commonly associated with metastatic breast cancer and epithelial ovarian cancer. The U.S. Food and Drug Administration (FDA) has approved Trastuzumab as an anti-HER2 agent for the metastatic breast and epithelial ovarian cancer. However, Trastuzumab has severe limitations in the treatment of metastatic breast cancer associated with ligand-dependent dimerization of HER2 receptor at the extracellular domain-II (ECD-II) region. The therapeutic approach in combination of pertuzumab and trastuzumab is found to be effective in preventing HER2 dimerization at the ECD-II region. The radioimmunotherapeutic approach, utilizing both these anti-HER2 agents (trastuzumab/pertuzumab), radiolabeled with [177Lu]Lu3+, has proved to be clinically efficacious with promising potential. Toward this, the formulation for clinical doses of [177Lu]Lu-DOTA-pertuzumab has been optimized using medium specific activity (0.81 GBq/µg) [177Lu]LuCl3. Materials and Methods: Preconcentrated pertuzumab was conjugated with p-NCS-benzyl-DOTA. Purified DOTA-benzyl-pertuzumab conjugate was radiolabeled with carrier-added [177Lu]LuCl3. Quality control parameters were evaluated for the [177Lu]Lu-DOTA-pertuzumab. In vivo biodistribution was carried out at different time points postadministration. Specific cell binding, immunoreactivity, and internalization were investigated by using SKOV3 and SKBR3 cells. Results: In this study, the authors reported a consistent and reproducible protocol for clinical dose formulations of [177Lu]Lu-DOTA-pertuzumab, with a radiochemical yield of 86.67% ± 1.03% and radiochemical purity (RCP) of 99.36% ± 0.36% (n = 10). Preclinical cell binding studies of [177Lu]Lu-DOTA-pertuzumab revealed specific binding with SKOV3 and SKBR3 cells up to 24.4% ± 1.4% and 23.2% ± 0.8%, respectively. The uptakes in SKOV3- and SKBR3-xenografted tumor in severe combined immunodeficiency mice were observed to be 25.9% ± 0.8% and 25.2% ± 1.2% ID/g at 48 and 120 h postinjection, respectively. Conclusions: A protocol was optimized for the preparation of ready-to-use clinical dose of [177Lu]Lu-DOTA-pertuzumab, in hospital radiopharmacy settings. The retention of RCP of the radiopharmaceutical, on storage in saline and serum, at -20°C, up to 120 h postradiolabeling, confirmed its in vitro stability.

Lactobacillus reuteri Releasing IL-22 (LR-IL-22) Facilitates Intestinal Radioprotection for Whole-Abdomen Irradiation (WAI) of Ovarian Cancer.

Oral administration (gavage) of a second-generation probiotic, Lactobacillus reuteri (L. reuteri), that releases interleukin-22 (LR-IL-22) at 24 h after total-body irradiation (TBI) mitigates damage to the intestine. We determined that LR-IL-22 also mitigates partial-body irradiation (PBI) and whole-abdomen irradiation (WAI). Irradiation can be an effective treatment for ovarian cancer, but its use is limited by intestinal toxicity. Strategies to mitigate toxicity are important and can revitalize this modality to treat ovarian cancer. In the present studies, we evaluated whether LR-IL-22 facilitates fractionated WAI in female C57BL/6 mice with disseminated ovarian cancer given a single fraction of either 15.75 Gy or 19.75 Gy or 4 daily fractions of 6 Gy or 6.5 Gy. Mice receiving single or multiple administrations of LR-IL-22 during WAI showed improved intestinal barrier integrity (P = 0.0167), reduced levels of radiation-induced intestinal cytokines including KC/CXCL1 (P = 0.002) and IFN-γ (P = 0.0024), and reduced levels of plasma, Eotaxin/CCL11 (P = 0.0088). LR-IL-22 significantly preserved the numbers of Lgr5+GFP+ intestinal stem cells (P = 0.0010) and improved survival (P < 0.0343). Female C57BL/6MUC-1 mice with widespread abdominal syngeneic 2F8cis ovarian cancer that received LR-IL-22 during 6.5 Gy WAI in 4 fractions had reduced tumor burden, less intestinal toxicity, and improved 30-day survival. Furthermore, LR-IL-22 facilitated WAI when added to Paclitaxel and Carboplatin chemotherapy and further increased survival. Oral administration (gavage) of LR-IL-22 is a potentially valuable intestinal radioprotector, which can facilitate therapeutic WAI for widespread intra-abdominal ovarian cancer.

Awake Surgery for Local Recurrence of Brain Metastasis in the Precentral Gyrus After Fractionated Stereotactic Radiotherapy: A Technical Case Report.

BACKGROUND: To avoid permanent neurologic deficits and preserve brain function, intraoperative electrical stimulation mapping (IESM) is essential for surgical resection. CASE REPORT: A 59-year-old right-handed woman with ovarian cancer who had undergone stereotactic radiotherapy for brain metastasis two years before, was introduced due to progressive left upper paresis. Magnetic resonance imaging showed a recurrence of the lesion. We performed awake surgery using IESM. Thus, the sensorimotor site was elicited on the precentral and postcentral gyrus. However, IESM elicited no disturbance of motor function on the surface of the posterior part of the precentral gyrus. We made a safe corticotomy on it, and performed the resection of recurrent BM. Preserving the motor and sensory function, we achieved the resection of BM. After surgery, she experienced a significant improvement in motor function. CONCLUSION: IESM is a useful tool to make a safe approach via the precentral gyrus avoiding permanent sensorimotor deficits.

Efficacy and safety of stereotactic body radiotherapy (SBRT) in oligometastatic/persistent/recurrent ovarian cancer: a prospective, multicenter phase II study (MITO-RT3/RAD).

BACKGROUND: Stereotactic body radiotherapy (SBRT) has shown promising results in the clinical setting of oligometastatic, persistent, or recurrent disease in several malignancies including ovarian cancer. PRIMARY OBJECTIVE: The MITO-RT3/RAD trial is a prospective, multicenter phase II study aimed at identifying potential predictors of response and clinical outcome after SBRT treatment. STUDY HYPOTHESIS: Radiotherapy delivered by pre-defined SBRT treatment schedules and shared constraints could improve the rate of complete response. TRIAL DESIGN: All patients accrued will be treated with a radiotherapy dose in the range of 30-50 Gy by 1, 3, or 5 SBRT daily fractions to all sites of active metastatic disease according to diagnostic imaging. Schedules of treatment and dose prescription have been established before considering target sites and healthy organ dose constraints. Follow-up and monitoring of side effects will be carried out every 3 months for the first year with imaging and clinical evalutation, and every 4 months within the second year; thereafter, surveillance will be carried out every 6 months. The best response on a per lesion basis will be evaluated by computed tomographic (CT) scan, positron emission tomography/CT, or magnetic resonance imaging in case of brain lesions, every 3 months. MAJOR INCLUSION/EXCLUSION CRITERIA: The study includes patients with oligometastatic, persistent, or recurrent ovarian cancer for which salvage surgery or other local therapies are not feasible due to any relative contra-indication to further systemic therapy because of serious co-morbidities, previous severe toxicity, unavailability of potentially active systemic therapy, or patient refusal. PRIMARY ENDPOINT: The primary endpoint of the study is the clinical complete response rate to SBRT by imaging on a per lesion basis. SAMPLE SIZE: Approximately 205 lesions will be treated (90 lymph nodes and 115 parenchyma lesions). ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Fifty-two centers have expressed their intention to participate. Enrollment should be completed by March 2023 and analysis will be completed in September 2023. TRIAL REGISTRATION: NCT04593381.

Ultrasound-stimulated microbubbles enhances radiosensitivity of ovarian cancer.

BACKGROUND: Radiation therapy is regarded as an effective treatment for early ovarian cancer (OC). However, due to radiation resistance caused by DNA double-strand breaks (DSBs) and angiogenesis, the efficacy of radiotherapy for advanced OC is limited and controversial. PURPOSE: To explore whether ultrasound-stimulated microbubbles (USMBs) can enhance the radiosensitivity of OC. MATERIAL AND METHODS: OC cells (ES-2) were respectively irradiated with 5-Gy and 10-Gy radiation doses with or without exposure to USMB. Methyl thiazolyltetrazolium (MTT) and colony-formation assays were conducted to detect the viability and proliferation of ES-2 cells after USMBs and ionizing radiation (IR) treatment. Immunofluorescence assays were conducted to examine levels of gamma-H2A histone family member X (γ-H2AX), an indicator for DSBs. Flow cytometry analyses were carried out to assess the apoptosis of ES-2 cells. The angiogenic activity of human umbilical vein endothelial cells (HUVECs) was measured by tube formation assays. RESULTS: USMBs enhanced IR-induced suppressive effect on the viability and proliferation of OC cells. The protein levels of phosphorylated γ-H2AX and CHK1 were significantly upregulated after IR treatment and further enhanced by USMBs. In addition, USMBs enhanced the promotion of IR-mediated OC cell apoptosis. The inhibitory effect of IR on angiogenesis was further enhanced by USMBs, and protein levels of AT1R, VEGFA, and EGFR were downregulated by IR in a dose-dependent way and then enhanced by USMB treatment in HUVECs. CONCLUSIONS: USMB exposure significantly enhances the radiosensitivity of OC by suppressing cell proliferation, promoting OC cell apoptosis, and inhibiting angiogenesis.

Phase I Trial of Stereotactic MRI-Guided Online Adaptive Radiation Therapy (SMART) for the Treatment of Oligometastatic Ovarian Cancer.

PURPOSE: Stereotactic body radiation therapy is increasingly used to treat a variety of oligometastatic histologies, but few data exist for ovarian cancer. Ablative stereotactic body radiation therapy dosing is challenging in sites like the abdomen, pelvis, and central thorax due to proximity and motion of organs at risk. A novel radiation delivery method, stereotactic magnetic-resonance-guided online-adaptive radiation therapy (SMART), may improve the therapeutic index of stereotactic body radiation therapy through enhanced soft-tissue visualization, real-time nonionizing imaging, and ability to adapt to the anatomy-of-the-day, with the goal of producing systemic-therapy-free intervals. This phase I trial assessed feasibility, safety, and dosimetric advantage of SMART to treat ovarian oligometastases. METHODS AND MATERIALS: Ten patients with recurrent oligometastatic ovarian cancer underwent SMART for oligometastasis ablation. Initial plans prescribed 35 Gy/5 fractions with goal 95% planning target volume coverage by 95% of prescription, with dose escalation permitted, subject to strict organ-at-risk dose constraints. Daily adaptive planning was used to protect organs-at-risk and/or increase target dose. Feasibility (successful delivery of >80% of fractions in the first on-table attempt) and safety of this approach was evaluated, in addition to efficacy, survival metrics, quality-of-life, prospective timing and dosimetric outcomes. RESULTS: Ten women with seventeen ovarian oligometastases were treated with SMART, and 100% of treatment fractions were successfully delivered. Online adaptive plans were selected at time of treatment for 58% of fractions, due to initial plan violation of organs-at-risk constraints (84% of adapted fractions) or observed opportunity for planning target volume dose escalation (16% of adapted fractions), with a median on-table time of 64 minutes. A single Grade ≥3 acute (within 6 months of SMART) treatment-related toxicity (duodenal ulcer) was observed. Local control at 3 months was 94%; median progression-free survival was 10.9 months. Median Kaplan-Meier estimated systemic-therapy-free survival after radiation completion was 11.5 months, with concomitant quality-of-life improvements. CONCLUSIONS: SMART is feasible and safe for high-dose radiation therapy ablation of ovarian oligometastases of the abdomen, pelvis, and central thorax with minimal toxicity, high rates of local control, and prolonged systemic-therapy-free survival translating into improved quality-of-life.

Persistent response of an ovarian cancer patient after a short-term single-agent immunotherapy: a case report.

Epithelial ovarian cancer is extremely difficult to treat due to its high recurrence rate and acquired tolerance to chemotherapy. Immune checkpoint inhibitors (ICIs) are expected to be promising solutions for treatment failure. However, the low response rate to a single ICI agent was demonstrated in approximately all published clinical trials. Surprisingly patients with complete response were also noticed as an anecdote. Proper indicators of treatment response were urgently required. Programmed death- ligand 1 expression levels in the tumor tissues provide relatively limited discrimination. Tumor mutation burden (TMB) serves as a more reliable parameter. Here we presented an ovarian cancer case with multiple gene mutations and high TMB, who benefited from a short-term treatment of pembrolizumab and experienced a long-lasting complete response of 2 years till now. The patient was irradiated in the pelvic before pembrolizumab. Our study demonstrated that ICIs might provide survival benefits for ovarian cancer with high TMB and that pelvic radiation might have synergistical effects with immunotherapy.

Abdominopelvic FLASH Irradiation Improves PD-1 Immune Checkpoint Inhibition in Preclinical Models of Ovarian Cancer.

Treatment of advanced ovarian cancer using PD-1/PD-L1 immune checkpoint blockade shows promise; however, current clinical trials are limited by modest response rates. Radiotherapy has been shown to synergize with PD-1/PD-L1 blockade in some cancers but has not been utilized in advanced ovarian cancer due to toxicity associated with conventional abdominopelvic irradiation. Ultrahigh-dose rate (FLASH) irradiation has emerged as a strategy to reduce radiation-induced toxicity, however, the immunomodulatory properties of FLASH irradiation remain unknown. Here, we demonstrate that single high-dose abdominopelvic FLASH irradiation promoted intestinal regeneration and maintained tumor control in a preclinical mouse model of ovarian cancer. Reduced tumor burden in conventional and FLASH-treated mice was associated with an early decrease in intratumoral regulatory T cells and a late increase in cytolytic CD8+ T cells. Compared with conventional irradiation, FLASH irradiation increased intratumoral T-cell infiltration at early timepoints. Moreover, FLASH irradiation maintained the ability to increase intratumoral CD8+ T-cell infiltration and enhance the efficacy of αPD-1 therapy in preclinical models of ovarian cancer. These data highlight the potential for FLASH irradiation to improve the therapeutic efficacy of checkpoint inhibition in the treatment of ovarian cancer.

Low-Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy.

Developing strategies to inflame tumors is critical for increasing response to immunotherapy. Here, we report that low-dose radiotherapy (LDRT) of murine tumors promotes T-cell infiltration and enables responsiveness to combinatorial immunotherapy in an IFN-dependent manner. Treatment efficacy relied upon mobilizing both adaptive and innate immunity and depended on both cytotoxic CD4+ and CD8+ T cells. LDRT elicited predominantly CD4+ cells with features of exhausted effector cytotoxic cells, with a subset expressing NKG2D and exhibiting proliferative capacity, as well as a unique subset of activated dendritic cells expressing the NKG2D ligand RAE1. We translated these findings to a phase I clinical trial administering LDRT, low-dose cyclophosphamide, and immune checkpoint blockade to patients with immune-desert tumors. In responsive patients, the combinatorial treatment triggered T-cell infiltration, predominantly of CD4+ cells with Th1 signatures. Our data support the rational combination of LDRT with immunotherapy for effectively treating low T cell-infiltrated tumors. SIGNIFICANCE: Low-dose radiation reprogrammed the tumor microenvironment of tumors with scarce immune infiltration and together with immunotherapy induced simultaneous mobilization of innate and adaptive immunity, predominantly CD4+ effector T cells, to achieve tumor control dependent on NKG2D. The combination induced important responses in patients with metastatic immune-cold tumors.This article is highlighted in the In This Issue feature, p. 1.

Moderate Static Magnet Fields Suppress Ovarian Cancer Metastasis via ROS-Mediated Oxidative Stress.

Metastasis is the leading cause of cancer patient death, which is closely correlated with reactive oxygen species (ROS) levels. It is well known that the effects of ROS on tumors are diverse, depending on ROS concentration and cell type. We found that ovarian cancer cells have significantly lower levels of ROS than normal ovarian cells. Moreover, increased ROS levels in ovarian cancer cells can substantially inhibit their migration and invasion ability. Furthermore, the results show that moderate static magnetic field (SMF) can inhibit ovarian cancer cell migration, invasion, and stemness in a ROS-dependent manner. RNA sequencing results confirm that SMFs increased the oxidative stress level and reduced the stemness of ovarian cancer cells. Consistently, the expressions of stemness-related genes were significantly decreased, including hyaluronan receptor (CD44), SRY-box transcription factor 2 (Sox2), and cell myc proto-oncogene protein (C-myc). Furthermore, moderate SMFs provided by a superconducting magnet and permanent magnet have good biosafety and can both inhibit ovarian cancer metastasis in mice. Therefore, our study demonstrates the effects of SMFs on oxidative stress and metastasis in the ovarian cancer cells, which reveals the potential of applying SMF as a physical method in cancer therapy in the future.

Photochemistry and in vitro anticancer activity of Pt(IV)Re(I) conjugates.

The photophysical and photochemical properties of two Pt(IV)Re(I) conjugates were studied via both experimental and computational methods. Both conjugates exhibit modest photocytotoxicity against ovarian cancer cells. X-ray fluorescence microscopy showed that Pt and Re colocalize in cells whether they had been irradiated or not. This work demonstrates the potential of photoactivated multilimetallic agents for combating cancer.

Metal stent for the ureteral stricture after surgery and/or radiation treatment for malignancy.

BACKGROUND: To assess the efficacy and safety of self-expanding metal ureteral stent for the stricture following surgery and/or radiation for malignancy. METHODS: We performed 36 metal ureteral stent insertion procedures (32 patients) between May 2019 and June 2020. The main inclusion criterion was the patients with ureteral stricture due to surgery and/or radiation treatment for malignancy. The diagnosis of stricture was ascertained by history and radiographic imaging. The etiologies underlying the strictures were: surgery and/or radiation therapy for cervical and rectal cancer, surgery for ovarian cancer. The primary outcome was the stent patency rate, and the secondary outcomes were the postoperative complications and glomerular filtration rate (GFR). Stent patency was defined as stent in situ without evident migration, unanticipated stent exchange or recurrent ureteral obstruction. Cost analysis was calculated from stent cost, anesthesia cost and operating room fee. RESULTS: The pre-metallic stent GFR was 22.53 ± 6.55 mL/min/1.73 m2. Eight patients were on double-J stents before insertion of metallic stents. The total annual cost of per patient in our study was $10,600.2 US dollars (range $9394.4-$33,527.4 US dollars). During a median follow-up time of 16 months (range 8-21 months), 27 cases (31 sides, 84%) remained stent patency. Twelve patients died from their primary malignancy carrying a patency stent. Stent migration was observed in 4 patients within 10 months after insertion. Ectopic stents were endoscopically removed and replaced successfully. Three stents were occluded, and no encrustation was seen in our study. Three and four patients had postoperative fever and gross hematuria, respectively. Infection was observed in 2 cases, mandating antibiotics therapy. In addition, postoperative volume of hydronephrosis postoperatively was significantly reduced compared with preoperation (54.18 ± 15.42 vs 23.92 ± 8.3, P = 0.019). However, no statistically significant differences regarding GFR, creatinine levels, blood urea nitrogen and hemoglobin existed between preoperation and last follow-up. CONCLUSIONS: The current study demonstrated that metal ureteral stent is effective and safe in the treatment of stricture following surgery and/or radiation therapy for malignant cancer. Patients hydronephrosis could be improved by the stent placement.