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.

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.

The role of radiotherapy in ovarian cancer.

Epithelial ovarian cancer accounts for around 1.9% of all malignancies and often presents late at an advanced stage. Prognosis is therefore poor. Currently the mainstay of treatment is radical cytoreductive surgery and chemotherapy but, in the past, the standard of care also included adjuvant whole abdominal radiotherapy. This is no longer standard practice, largely due to high toxicity rates and the effectiveness of platinum-based chemotherapy. Presently, a role is emerging for modern radiotherapy techniques in both the salvage and palliative settings. This review aims to examine the historical use of radiotherapy in ovarian cancer before looking forward to its potential future role.

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.

Brain metastasis from ovarian carcinoma: Analysis of eight cases from a single radiotherapy center.

OBJECTIVE: Brain metastasis from epithelial ovarian carcinoma (EOC) is rarely seen having rate of 1-3% with very poor prognosis. Studies on brain metastatic EOC is limited with low number of participants. An increasing trend in EOC related to brain metastasis has been reported recently confronting managing clinicians with new challenges. Therefore, more information on this issue is needed. We aimed to analyze a single radiotherapy center experience on EOC related brain metastases. MATERIALS AND METHODS: Data of all patients treated between January 1998 and December 2016 at a radiation center of a university hospital were reviewed retrospectively. Clinicopathological characteristics, treatment details and outcome were analyzed. RESULTS: We identified only ten cases with EOC related brain metastasis in our department during 18-year period. Two patients were excluded because of data unavailability and therefore our study was performed among 8 patients. The median time between EOC diagnosis and detection of brain metastasis was 19.8 months. Brain metastasis was multiple in majority (75%). Extracranial metastasis at the time of brain metastasis was 62.5%. All patients died in the follow-up. The median survival time after the diagnosis of brain metastasis was 4.5 months. The median overall survival (OS) after the diagnosis of EOC was 28.9 months. The interval between the initial diagnosis and brain metastasis was negatively correlated with survival after brain metastasis (B-OS) occurred as time interval (p = 0.047). Presence of extracranial metastasis at time of occurrence of brain metastasis and application of multimodal treatment after brain metastasis were positively correlated with B-OS time (p = 0.007, p = 0.046, respectively). CONCLUSION: Prognosis of brain metastasis from EOC remains poor. The factors associated with better B-OS were the longer time between initial diagnosis and brain metastasis, absence of extracranial disease at time of brain metastasis, and application of the multimodal treatment.

Radiotherapy in women with epithelial ovarian cancer: historical role, current advances, and indications.

Epithelial ovarian cancer (OC) is known to be a neoplasm responsive to radiotherapy (RT). Nevertheless, the role of RT in the management of this disease represent a topic of controversy, and the indications for its use are not fully established. Initial studies suggested that the addition of RT in the form of intraperitoneal (IP) radioisotopes was useful. Indications for this treatment were peritoneal cytology with tumor cells, peritoneal implants, and capsule rupture. The instillation of radioisotopes was contraindicated when macroscopic residual disease was present. Pelvic RT was used after surgery in patients with an absence of gross residual disease. Early studies established the inadequacy of this technique and the need for treating the whole abdomen. Whole abdominal irradiation (WAI) was a therapeutic tool used in the prechemotherapy era to eradicate large amounts of microscopic peritoneal disease. Ideal candidates for WAI were stage I patients with grade 2 or 3 tumors; stage II patients with grade 1 or 2 tumors and residual disease, and stage III, grade 1 patients with <2 cm residual disease. The disadvantages of WAI were the dose-limiting toxicities, which were predominantly acute hematologic and late gastrointestinal. The era of aggressive debulking and platinum agents made WAI fall out of favor as a treatment of OC. Selective approaches with highly conformal radiotherapy (CRT) have been used in case of limited recurrent or unresectable disease with the potential for long-term disease control. Currently, the role of RT in OC applies for patients with recurrent oligometastatic or oligoprogressive disease and in the palliative setting for symptom control. We performed a nonsystematic review and included data from both retrospective and prospective studies focusing on the use of RT for OC and its biological rationale. Furthermore, ongoing trials on this issue are reported.

Targeting Ku86 enhances X-ray-induced radiotherapy sensitivity in serous ovarian cancer cells.

Drug resistance and recurrence are significant contributors to the poor prognosis of serous ovarian cancer (SOC). Radiotherapy is primarily used for the treatment of cancer recurrence; however, it is rarely applied in cases of SOC. Ku86, also known as XRCC5(X-ray repair cross complementing 5), has rarely been reported in the radiotherapy of SOC. Therefore, this study aimed to investigate the role of Ku86 in the development of SOC and in radiotherapy sensitivity induced by X-ray. In vitro experiments and database analysis showed significantly elevated expression of Ku86 in SOC. Further, after down-regulating Ku86 using RNAi technology, cell proliferation was inhibited. Further, the cell cycle was blocked in the G2 phase, and G2/G1 was increased since X-ray irradiation led to an increase in γ-H2AX. Down-regulation of Ku86 in the case of X-ray irradiation will promote the above biological effects, with more γ-H2AX and higher G2/G1. Here, we further deduce that Ku86 promotes the X-ray induced effect is most likely to activate the ATR pathway to block the cell cycle while inhibiting the NHEJ pathway to inhibit DNA damage response(DDR). Together these findings suggest that the down-regulation of Ku86 can improve X-ray-induced radiotherapy by affecting ATR and NHEJ pathways, and provide a new strategy for the treatment of ovarian cancer.

Management of recurrent ovarian cancer: when platinum-based regimens are not a therapeutic option.

Ovarian cancer relapses have been traditionally classified according to the platinum-free interval, leading to an arbitrary categorization of possible scenarios and treatment options. Its relevance in assessing treatment strategies has been revised in the last several years, as the panorama is constantly changing in the era of personalized medicine and targeted therapies. Factors to be considered while defining the best management of recurrent disease, and, consequently, the available treatment alternatives are increasing. Platinum remains one of the milestones of ovarian cancer treatment, but for some patients it might not be an ideal choice for several reasons other than limited platinum sensitivity. This review aims to analyze the scenarios in which platinum is not considered suitable in the management of patients with recurrent ovarian cancer, and the currently available alternatives.

The role of radiotherapy in epithelial ovarian cancer: a literature overview.

Ovarian cancer (OC) accounts for 3% of all cancer in women and for 5% of all cancer-related deaths. Epithelial Ovarian Cancer (EOC) is a radiosensitive malignancy with a poor prognosis. In the pre-chemotherapy era, radiation therapy (RT) delivered to the abdominopelvic region (whole abdominal irradiation, WAI) has historically played a role in the adjuvant and consolidation setting. Specific cluster of patients with early-stage disease and definite histologies may take advantage of RT. Platinum-based chemotherapy (CT) has replaced RT and plays a major role in most of the clinical settings. Radiation Therapy for palliation is recommended in patients with localized symptoms. Nevertheless, modern RT represents a reliable treatment option, with a mild toxicity profile, particularly effective for oligo-recurrent or progressive disease. The present literature review aims to highlight the historical role of RT in EOC, the actual lines of evidence, and the future perspectives.

Radiotherapy for isolated recurrent epithelial ovarian cancer: A single institutional experience.

AIM: To evaluate the efficacy and toxicity of external beam radiotherapy (RT) for isolated recurrent epithelial ovarian cancer (EOC). METHODS: Twenty-four isolated recurrent EOC patients treated with RT at Osaka University Hospital between January 2000 and January 2017 were included in the current study. Data regarding the primary or recurrent diseases, follow-up findings, and efficacy or toxicities of RT were collected and retrospectively analyzed. Survival rates were calculated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: Their median age was 59 years. Most patients had International Federation of Gynecology and Obstetrics stage III-IV diseases at the initial diagnosis. Histologically, serous adenocarcinoma was predominant, followed by clear cell adenocarcinoma. All patients had received at least one regimen of platinum-based chemotherapy; 8 were platinum-sensitive relapse and the others were platinum-resistant. Lymph nodes were the most common sites of recurrence, and the median tumor size was 25.5 mm. The median total dose of RT administered was 54 Gy, with a median daily dose of 2 Gy. RT was well-tolerated, and no patients experienced Grade 3/4 toxicities. The in-field overall response rate was 58.3% (14/24), the median regression rate was -40.2% (range: -100 to 0) and the median survival period after RT was 17 months. The 1-year survival and local progression-free survival rates after RT were 66.7% and 45.8%, respectively. CONCLUSION: RT showed significant antitumor effect against isolated recurrent EOC without causing severe toxicities. Prospective studies with sufficient statistical power are warranted to further evaluate the role of RT in this patient population.

Intraperitoneal α-Emitting Radioimmunotherapy with 211At in Relapsed Ovarian Cancer: Long-Term Follow-up with Individual Absorbed Dose Estimations.

Eliminating microscopic residual disease with α-particle radiation is theoretically appealing. After extensive preclinical work with α-particle-emitting 211At, we performed a phase I trial with intraperitoneal α-particle therapy in epithelial ovarian cancer using 211At conjugated to MX35, the antigen-binding fragments-F(ab')2-of a mouse monoclonal antibody. We now present clinical outcome data and toxicity in a long-term follow-up with individual absorbed dose estimations. Methods: Twelve patients with relapsed epithelial ovarian cancer, achieving a second complete or nearly complete response with chemotherapy, received intraperitoneal treatment with escalating (20-215 MBq/L) activity concentrations of 211At-MX35 F(ab')2.Results: The activity concentration was escalated to 215 MBq/L without any dose-limiting toxicities. Most toxicities were low-grade and likely related to the treatment procedure, not clearly linked to the α-particle irradiation, with no observed hematologic toxicity. One grade 3 fatigue and 1 grade 4 intestinal perforation during catheter implantation were observed. Four patients had a survival of more than 6 y, one of whom did not relapse. At progression, chemotherapy was given without signs of reduced tolerability. Overall median survival was 35 mo, with a 1-, 2-, 5-, and 10-y survival of 100%, 83%, 50%, and 25%, respectively. Calculations of the absorbed doses showed that a lower specific activity is associated with a lower single-cell dose, whereas a high specific activity may result in a lower central dose in microtumors. Individual differences in absorbed dose to possible microtumors were due to variations in administered activity and the specific activity. Conclusion: No apparent signs of radiation-induced toxicity or decreased tolerance to relapse therapy were observed. The dosimetric calculations show that further optimization is advisable to increase the efficacy and reduce possible long-term toxicity.

Radiation Therapy in Ovarian Cancer: An Overview and Future Directions.

Clear cell cancer of the ovary is a rare and aggressive subtype. There is a general paucity of data from randomised trials to inform the most appropriate approach to adjuvant therapy. Retrospective data has highlighted an improvement in disease free survival with the addition of whole abdominal radiotherapy. This approach merits further exploration in a randomised clinical trial.

Stereotactic Body Radiation Therapy in Oligometastatic Ovarian Cancer: A Promising Therapeutic Approach.

OBJECTIVE: Stereotactic body radiation therapy (SBRT) has been successfully used to treat oligometastases of several primary tumors, but few experiences have been described in patients with gynecological oligometastatic cancer, particularly in ovarian neoplasm. The aim of this study was to evaluate the role of this new radiotherapy modality in a series of oligometastatic ovarian cancer patients. MATERIALS AND METHODS: Clinical records of patients affected by oligometastatic ovarian carcinoma treated with SBRT were reviewed. RESULTS: Twenty-six patients with 44 metastatic lesions (lymph nodes, 63.6%; liver, 31.8%; and lung, 4.5%) treated with SBRT between January 2011 and May 2017 were analyzed. After a median follow-up period of 28.5 months (range, 6-86 months), 17 patients (65.4%) were still alive at time of analysis: 6 are without evidence of disease, 11 experienced a disease progression. Eight patients died of disease, 1 died because of an heart attack while being disease free. The median local control (LC) was not reached. One-, 2-, and 5-year LCs were 92.9%. Median progression-free survival was 19 months, with 1-year progression-free survival of 69.3% and 38% at 2 years, 19% at 5 years. Median overall survival was 64.5 months, with all patients alive after 1 year, 92.7% at 2 years, and 61.7% at 5 years. Five (11.3%) cases experienced G2 toxicity; most common adverse effect was nausea and vomiting (3 cases [6.8%]) followed by abdominal pain (2 cases [4.5%]). None of the patients had grade 3 or grade 4 acute or late toxicity. CONCLUSIONS: In conclusion, SBRT is a feasible and safe approach for selected cases of oligometastatic ovarian cancer, with satisfactory results in terms of LC and disease free survival.

Long-Term Survival After Surgery and Radiotherapy for Recurrent or Persistent Ovarian and Tubal Cancer.

OBJECTIVE: This study examines the factors associated with long-term disease-specific survival (DSS) and complications after radiotherapy (RT) for recurrent or persistent ovarian and tubal cancer. METHODS/MATERIALS: Between 1980 and 2015, 65 women with ovarian (57), tubal (3), or co-existent ovarian/endometrial carcinoma (5) received RT (>45 Gy) with curative intent for recurrent (45) or persistent cancer (20) found at second-look surgery. Surgery to debulk (± restage) was integrated into the management of all but 7 cases. RESULTS: Twenty-two women had no evidence of disease at last contact after a median of 15.6 years (range = 1.0-35.8 years). Of the 53 patients treated more than 10 years ago, 18 (34%) are in this long-term no evidence of disease group. Univariate analysis showed that the following factors were significantly associated with longer DSS (P < 0.05): initial stage I, II (vs III, IV); endometrioid histology (vs serous and other); no or 1 previous chemotherapy (vs ≥2); no macroscopic tumor before RT (vs macroscopic); localized tumor encompassed by a limited-volume RT field (vs more widespread tumor), and chemotherapy and RT (vs RT only). Multivariate analysis showed that endometrioid (vs other histology HR = 4.37, P = 0.017) and localized tumor (vs more widespread tumor, HR = 2.43, P = 0.017) were significantly associated with longer DSS.After RT to the pelvis and/or abdomen, 13 (21.7%) of 60 patients developed G3 or 4 bowel complications requiring surgery. In 10, these occurred in the presence of tumor, RT changes, and adhesions, and in 3, there was no sign of cancer. Six patients (9.2%) developed a subsequent malignancy. CONCLUSIONS: We conclude that there is a role for the use of RT in selected cases of localized recurrent or persistent ovarian cancer and may confer long-term survival. Surgery is useful to debulk and define the extent of tumor to be irradiated but may confer an increased risk of severe bowel complications.