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Objectives: In our institutional experience, involved-field radiation therapy (IFRT) yields favorable outcomes in patients with recurrent epithelial ovarian cancer (EOC). This retrospective study aimed to investigate the clinical benefits of IFRT in this patient population., Methods: Among patients treated with IFRT for recurrent EOC between 2010 and 2017, 61 patients with 90 treatments were included. IFRT encompassed all treatable lesions identified via imaging studies with 10-15-mm margins. Prescribed doses were ≥45 Gy (equivalent dose in 2 Gy/fraction)., Results: Patients were followed up for a median of 19.0 (Interquartile range, 8.6-34.9) months after IFRT. The 2-year in-field control, progression-free survival, and overall survival (OS) rates were 42.7%, 24.2%, and 78.9%, respectively. Fifty-three IFRT sessions (58.9%) were followed by systemic chemotherapy, and the median chemotherapy-free interval (CFI) was 10.5 (95% confidence interval=7.3-13.7) months. A higher carbohydrate antigen-125 (CA-125) level correlated with a worse 2-year OS (69.2% vs. 91.0%; p=0.001) and shorter median CFI (4.7 vs. 11.9 months; p<0.001). Twenty-eight (31.1%) of 90 treatments yielded a long-term CFI >12 months. For patients with a normal CA-125 level and/or platinum-sensitive tumor, IFRT prolonged CFI regardless of pre-existing carcinomatosis, gross tumor volume, and number of treatment sites., Conclusion: Our early experience demonstrates the safety and feasibility of IFRT as an effective salvage therapy and enables a "chemotherapy holiday" in selected recurrent EOC settings. The CA-125 value before IFRT (within normal range) and/or platinum sensitivity could be used as selection criteria for IFRT., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2019. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.)

The use of nanobodies (Nbs) as vehicles in targeted alpha therapy (TAT) has gained great interest because of their excellent properties. They combine high in vivo affinity and specificity of binding with fast kinetics. This research investigates a novel targeted therapy that combines the α-particle emitter astatine-211 ( 211 At) and the anti-HER2 Nb 2Rs15d to selectively target HER2+ cancer cells. Two distinctive radiochemical methodologies are investigated using three different coupling reagents. The first method uses the coupling reagents, N -succinimidyl 4-(1,2-bis- tert -butoxycarbonyl)guanidinomethyl-3-(trimethylstannyl)benzoate (Boc 2 -SGMTB) and N -succinimidyl-3-(trimethylstannyl)benzoate ( m -MeATE), which are both directed to amino groups on the Nb, resulting in random conjugation. The second method aims at obtaining a homogeneous tracer population, via a site-specific conjugation of the N -[2-(maleimido)ethyl]-3-(trimethylstannyl)benzamide (MSB) reagent onto the carboxyl-terminal cysteine of the Nb. The resulting radioconjugates are evaluated in vitro and in vivo. 2Rs15d is labeled with 211 At using Boc 2 -SGMTB, m -MeATE, and MSB. After astatination and purification, the binding specificity of the radioconjugates is validated on HER2+ cells, followed by an in vivo biodistribution assessment in SKOV-3 xenografted mice. α-camera imaging is performed to determine uptake and activity distribution in kidneys/tumors. 2Rs15d astatination resulted in a high radiochemical purity >95% for all radioconjugates. The biodistribution studies of all radioconjugates revealed comparable tumor uptake (higher than 8% ID/g at 1 h). [ 211 At]SAGMB-2Rs15d showed minor uptake in normal tissues. Only in the kidneys, a higher uptake was measured after 1 h, but decreased rapidly after 3 h. Astatinated Nbs consisting of m -MeATE or MSB reagents revealed elevated uptake in lungs and stomach, indicating the presence of released 211 At. α-Camera imaging of tumors revealed a homogeneous activity distribution. The radioactivity in the kidneys was initially concentrated in the renal cortex, while after 3 h most radioactivity was measured in the medulla, confirming the fast washout into urine. Changing the reagents for Nb astatination resulted in different in vivo biodistribution profiles, while keeping the targeting moiety identical. Boc 2 -SGMTB is the preferred reagent for Nb astatination because of its high tumor uptake, its low background signals, and its fast renal excretion. We envision [ 211 At]SAGMB-2Rs15d to be a promising therapeutic agent for TAT and aim toward efficacy evaluation.

Eliminating microscopic residual disease with α-particle radiation is theoretically appealing. After extensive preclinical work with α-particle-emitting 211 At, we performed a phase I trial with intraperitoneal α-particle therapy in epithelial ovarian cancer using 211 At 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 211 At-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., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Except for its use in palliative care, radiotherapy has been largely abandoned in the management of ovarian cancer because of the recognised efficacy and lower toxicity of systemic chemotherapy compared with radiotherapy. New data have emerged that show synergy of radiotherapy with immunotherapy to control or eradicate cancer. Different doses of hypofractionated radiotherapy have been shown to induce immunogenic cell death and in-situ vaccination in several tumour models. However, doses less than 2 Gy can also reprogramme the tumour microenvironment. This Series paper discusses the past and present use of radiotherapy for ovarian cancer, and the mechanisms by which radiotherapy can mobilise anticancer immunity. We provide emerging preclinical and clinical data for combining immunotherapy with radiotherapy for ovarian cancer treatment and offer a clinical development roadmap to guide the next generation of clinical trials for this combination strategy for this disease., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The pathological characteristics, treatment strategies and prognosis of ovarian primary primitive neuroectodermal tumor (PNET) were unclear due to the rarity of PNET. All cases treated at Peking Union Medical College Hospital (PUMCH) between 1975 and 2016 and published in the English literature between 1980 to 2017 were reviewed., Results: Finally four cases from PUMCH and 15 cases in the literature were included. The median age was 25 years (range 13-79), and the median diameter of the tumors was 13.4 cm (range 5.0-30.0). The most common initial symptoms were abdominal pain, bloating and a pelvic mass. Diagnosis primarily depended on immunohistochemical and fluorescence in situ hybridization data. Treatment consisted of surgery, various chemotherapy regimens and/or radiotherapy. The 5-year overall survival (OS) and progression-free survival (PFS) rates were 15 and 52%, respectively. For patients with OS and PFS > 12 months, the median ages were 21 years (range 13-35) and 17 years (range 13-35), respectively, while for patients with OS < 12 months and PFS < 12 months, the median ages were 48 years (range 14-79) and 25 years (range 18-79), respectively., Conclusions: No standard therapy for ovarian primary PNET exists, and an individualized strategy is recommended. Young patients seem to have better prognoses.

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., (© 2019 Japan Society of Obstetrics and Gynecology.)

Background: Pelvic radiotherapy causes tissue atrophy and fibrosis, leading to urinary tract dysfunction. Tissue ischaemia poses a significant surgical challenge. This study examined the urological sequelae of radiotherapy, types of reconstructive urological surgery (RUS) required and functional outcomes. Methods: A retrospective review was performed of all radiotherapy patients who underwent RUS at a tertiary centre between 2007-2017. Details including time from radiotherapy, pre-operative assessments, type of surgery performed and functional outcome were analysed. Results: Fifty-four patients were identified. The primary malignancy was cervical (32), colorectal (9) and other urogenital/metastatic origins in the remaining cases. Mean time between radiation and RUS was 13 years. Sixty-nine reconstructive surgeries were performed. Twenty-two patients had fistulae, but only 27% were closed and 73% ended with urinary diversion. Eighteen had ureteric strictures, with 56% having associated bladder dysfunction. Twelve (67%) patients had RUS, of whom 83% required bowel interposition, and 33% primary diversion. Nine of 24 patients with contracted bladders were reconstructed and eight remain functionally continent. Renal function stabilised or improved in 87%. Nine patients (17%) had Clavien 3 or 4 complications. Conclusions: A variety of complex, major RUS were required. In 61%, urinary diversion was necessary, with radiotherapy fistulae being a particular challenge and closed in only a third. In total, 37% of patients were reconstructed achieving functional continence and restoration of upper-tract drainage with renal function preservation. This surgery was at a cost of a re-intervention rate of 28% and significant morbidity in 17%. RUS in the radiotherapy field should be performed in centres with experience.

A 67-year-old woman presented with malignant struma ovarii after radical bilateral salpingo-oophorectomy. The surgery revealed a 4.4 cm papillary thyroid carcinoma (follicular variant) within a right-sided ovarian teratoma. I sodium iodide positron emission tomography / computed tomography and cervical ultrasound showed 2 slightly hyperfunctional thyroid nodules and several metastases, including bone metastases with intense iodine uptake. Thyroidectomy was necessary in preparation for radioiodine therapy and proofed the thyroid nodules to be benign. Complete remission was achieved by single radioiodine therapy (30 months of follow-up).

Ovarian cancer has a high mortality rate among women worldwide. Radiotherapy is considered an effective method of ovarian cancer treatment, however, radioresistance presents a challenge. It is necessary to develop techniques that can increase radiosensitivity in ovarian cancer, and gene therapy is a promising option. The aim of the present study was to investigate the effects of metadherin (MTDH) silencing on the radiosensitivity of ovarian cancer. Ovarian cancer tissues (n=273) and normal ovarian tissues (n=277) were used, as were SKOV3 ovarian cancer cells and the immortalized human ovarian epidermal HOSEpiC cell line. MTT, Transwell and wound-healing assays were performed to assess the proliferation, invasion and migration abilities of the SKOV3 cells. Colony-forming assays and flow cytometry were applied to detect the radiosensitivity and apoptosis of the SKOV3 cells. Nude mouse xenograft models were established to evaluate the effect of MTDH gene silencing on tumor growth and the efficacy of radiotherapy. Ovarian cancer, in tissues and cells, was demonstrated to have a high level of MTDH. Additionally, MTDH silencing was found to significantly inhibit proliferation, migration and invasion, and induce apoptosis in SKOV3 cells, and it was suggested that MTDH depletion significantly increased the sensitivity of the SKOV3 cells to X-ray radiation. MTDH silencing enhanced radiosensitivity and delayed tumor growth in the nude mouse xenograft model. Collectively, the results obtained in the present study suggest the potential role of MTDH silencing as a technique for ameliorating radioresistance in ovarian cancer. The present study provides a promising experimental basis for the improvement of ovarian cancer radiotherapy treatment.

Objective: To evaluate the efficacy and safety of involved-field radiation therapy (IFRT) in patients with locoregionally confined recurrent or persistent epithelial ovarian cancer., Methods: This study included patients with recurrent epithelial ovarian cancer eligible for IFRT either during diagnosis of the recurrence or after salvage therapies. IFRT was performed at a dose of ≥45 Gy for all tumors with 10-15-mm margins as seen on standard imaging. The primary endpoint was progression-free survival (PFS); the secondary endpoints were safety, response rate, local control, and overall survival (OS)., Results: Thirty patients with a mean number of 5.7 metastatic lesions each were enrolled between 2014 and 2016. Seventeen were treated with 3-D conformal radiation therapy (RT) and 13 with intensity-modulated RT. IFRT was well tolerated in all patients, and acute toxicity ≥ grade 2 was not observed. One case of grade 3 abdominal pain was reported 10 months post-RT. The overall and complete response rates were 85.7% and 50%, respectively. After a median follow-up of 28 (range, 17-42) months, the median PFS was 7 months. The 2-year PFS rate was 39.3%. Six of the 16 patients who developed outfield disease progression after IFRT were successfully treated with repeat IFRT as salvage treatment. The 3-year local control and OS rates were 84.4% and 55.8%, respectively., Conclusions: Although the primary endpoint was not met, IFRT might be safe and effective for in-field tumor control in patients with persistent epithelial ovarian cancer with a limited number of metastatic foci. We plan to conduct a larger scale multi-center phase II prospective study., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: The most appropriate treatments for brain metastases from ovarian cancer have not been established mainly because of its rarity. The objective of this study was to describe clinical results of treatment and prognostic factors of patients with brain metastases from ovarian cancer treated at a single institution., Materials and Methods: We retrieved information from the electronic medical records of 56 consecutive patients (2.8%) with brain metastases, from a total of 2008 patients with ovarian cancer. Endpoints were the pattern of treatment failure, progression-free survival, and overall survival (OS)., Results: Radiation was the most common initial treatment for brain metastases (59%), followed by surgery (23%). The median progression-free survival was 9.8 months. Radiological progression was confirmed in 20 patients: 7 had leptomeningeal carcinomatosis (37%), 8 had local recurrence, and 5 had distant recurrence. Median OS was 11.25 months, and the 1-year OS rate was 48.2%. Patients received surgery for single metastasis as initial treatment showed median OS of 24.1 months, which was significantly prolonged compared with the other patients (P = 0.0002). Of the 48 patients who died, 29 (60%) died of systemic disease and 7 (15%) died of central nervous system progression. Karnofsky Performance Status greater than or equal to 70, control of systemic cancer, serous histology, and surgery for brain metastases were associated with improved OS in multivariable analysis (P < 0.05)., Conclusions: Surgical resection for single or symptomatic brain metastases from ovarian cancer prolonged OS significantly. Multimodality treatment, including control of systemic cancer, appeared to be an important factor in prolonging OS.

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.

Objective: Approximately 15-25% of high-grade serous ovarian carcinomas (HGSOC) harbor BRCA1/2 mutations. Inhibition of Poly (ADP-ribose) polymerase (PARP) is synthetically lethal to cells and tumors with BRCA1/2 mutation. Our goal was to investigate the radiosensitizing effects of PARP inhibitor olaparib in HGSOC with different BRCA1 status., Methods: The radiosensitizing effects of olaparib were tested on BRCA1-proficient and deficient HGSOC by clonogenic survival and tumor growth assays. The effects of olaparib and radiation on DNA damage, PARP activity, and apoptosis were determined., Results: BRCA1-deficient HGSOC cells were more sensitive to RT alone and exhibited significantly higher levels of olaparib-mediated radiosensitization compared to BRCA1-proficient cells. Furthermore, when combined with RT, olaparib inhibited DNA damage repair and PARP1 activity, increased apoptosis, decreased growth of HGSOC xenografts and increased overall host survival. The growth-inhibitory effects of the combined olaparib and RT treatment were more pronounced in mice bearing BRCA1-deficient tumors compared to BRCA1-proficient tumors., Conclusions: These results provide a preclinical rationale for improved treatment modalities using olaparib as an effective radiosensitizer in HGSOC, particularly in tumors with BRCA1-deficiencies., (Copyright © 2018. Published by Elsevier Inc.)

We have developed the 16F12 mouse monoclonal antibody (mAb), which targets the Müllerian-inhibiting substance receptor, type II (MISRII), expressed by ovarian tumors. Here, we assessed in preclinical models the possibility of using radiolabeled 16F12 in a theranostic approach for small-volume ovarian peritoneal carcinomatosis, such as after cytoreductive surgery. Methods: DOTA-, DTPA- or deferoxamine mesylate-conjugated 16F12 mAb was radiolabeled with β-particle ( 177 Lu) or α-particle ( 213 Bi) emitters for therapeutic use and with 89 Zr for PET imaging. On the 13th postxenograft day, mice bearing intraperitoneal MISRII-positive AN3CA endometrial carcinoma cell xenografts were treated by conventional intraperitoneal radioimmunotherapy (IP-RIT) with 10 MBq of 177 Lu-16F12 or 12.9 MBq of 213 Bi-16F12 or by brief intraperitoneal radioimmunotherapy (BIP-RIT) using 50 MBq of 177 Lu-16F12 or 37 MBq of 213 Bi-16F12. For BIP-RIT, 30 min after injection of the radiolabeled mAbs, the peritoneal cavity was washed to remove the unbound radioactivity. The biodistribution of 177 Lu- and 213 Bi-16F12 mAbs was determined and then used for dose assessment. Hematologic toxicity was also monitored. Results: The 16F12 mAb was satisfactorily radiolabeled for both therapy and imaging. IP-RIT with 177 Lu-16F12 was slightly more efficient in delaying tumor growth than IP-RIT with 213 Bi-16F12. Conversely, 213 Bi-16F12 was more efficient than 177 Lu-16F12 in BIP-RIT. The biodistribution analysis showed that the tumor-to-blood uptake ratio was significantly higher with BIP-RIT than with IP-RIT for both 213 Bi- and 177 Lu-16F12. Hematologic toxicity was more pronounced with 177 Lu-16F12 than with 213 Bi-16F12. SPECT/CT images (after BIP-RIT with 177 Lu-16F12) and PET/CT images (after injection of 89 Zr-16F12 in the tail vein) showed focal uptake at the tumor site. Conclusion: Radiolabeled 16F12 could represent a new theranostic tool for small-volume ovarian peritoneal carcinomatosis. Specifically, 213 Bi-16F12-based BIP-RIT could be proposed to selected patients as an alternative adjuvant treatment immediately after cytoreductive surgery. An anti-MISRII mAb is currently being used in a first-in-human study, thus making radiolabeled anti-MISRII mAbs a realistic theranostic option for the clinic., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

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., (Copyright © 2018. Published by Elsevier Ltd.)

Purpose: To evaluate stereotactic body radiation therapy (SBRT) for metachronous oligometastatic ovarian cancer patients in terms of local control, delay of systemic treatment, survival outcomes, and toxicity., Methods and Materials: Retrospective data collection from a single institution was performed. The inclusion criteria were as follows: (1) oligorecurrent or oligoprogressive disease in ovarian cancer patients during or after systemic therapy; (2) surgery or other local therapies not feasible; and (3) relative contraindication to systemic therapy for reasons such as unavailability of additional chemotherapy lines or refusal of the patient. Tumor response and toxicity were evaluated using the Response Evaluation Criteria in Solid Tumors and the Common Terminology Criteria for Adverse Events version 4.03, respectively. A new systemic therapy regimen was started after an SBRT treatment course in 57 of 109 cases (52.3%). Local progression-free survival, progression-free survival, and overall survival were calculated via the Kaplan-Meier method. The systemic treatment-free interval was calculated in cases without concomitant systemic therapy., Results: Between May 2012 and December 2016, 82 patients (156 lesions) underwent SBRT with a median dose of 24 Gy in 3 fractions. The median follow-up period was 17.4 months. Patients received a median of 3 systemic therapy regimens prior to SBRT. Concomitant systemic therapy was performed for 29 lesions (18.6%). Among 152 evaluable lesions, a complete radiologic response, partial response, stabilization, and progressive disease were observed in 91 (60%), 26 (17%), 24 (16%), and 11 (7%), respectively. No grade 3 or 4 acute or late toxicities were observed. The median systemic treatment-free interval after SBRT was 7.4 months, and 1 of 3 patients was disease free at 1 year after SBRT. The actuarial 2-year local progression-free survival, progression-free survival, and overall survival rates were 68%, 18%, and 71%, respectively. The pattern of failure was predominantly out of field., Conclusions: SBRT for oligometastatic ovarian cancer showed good local control and a good toxicity profile. It might be an appealing alternative to other invasive local therapies to delay systemic therapy in the case of chemorefractory disease or intolerance to systemic agents., (Copyright © 2018. Published by Elsevier Inc.)

Affibody molecules are small proteins engineered using a nonantibody scaffold. Radiolabeled Affibody molecules are excellent imaging probes, but their application to radionuclide therapy has been prevented by high renal reabsorption. The aim of this study was to test the hypothesis that Affibody-based peptide nucleic acid (PNA)-mediated pretargeted therapy of human epidermal growth factor receptor 2 (HER2)-expressing cancer extends survival without accompanying renal toxicity. Methods: A HER2-targeting Affibody molecule ligated with an AGTCGTGATGTAGTC PNA hybridization probe (Z HER2:342 -SR-HP1) was used as the primary pretargeting agent. A complementary AGTCGTGATGTAGTC PNA conjugated to the chelator DOTA and labeled with the radionuclide 177 Lu ( 177 Lu-HP2) was used as the secondary agent. The influence of different factors on pretargeting was investigated. Experimental radionuclide therapy in mice bearing SKOV-3 xenografts was performed in 6 cycles separated by 7 d. Results: Optimal tumor targeting was achieved when 16 MBq/3.5 μg (0.65 nmol) of 177 Lu-HP2 was injected 16 h after injection of 100 μg (7.7 nmol) of Z HER2:342 -SR-HP1. The calculated absorbed dose to tumors was 1,075 mGy/MBq, whereas the absorbed dose to kidneys was 206 mGy/MBq and the absorbed dose to blood (surrogate of bone marrow) was 4 mGy/MBq. Survival of mice was significantly longer ( P < 0.05) in the treatment group (66 d) than in the control groups treated with the same amount of Z HER2:342 -SR-HP1 only (37 d), the same amount and activity of 177 Lu-HP2 only (32 d), or phosphate-buffered saline (37 d). Conclusion: The studied pretargeting system can deliver an absorbed dose to tumors appreciably exceeding absorbed doses to critical organs, making Affibody-based PNA-mediated pretargeted radionuclide therapy highly attractive., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

The goal of this review is to discuss the current utility of fluorine-18-fluorodeoxyglucose (FDG)-PET for radiation oncologists who treat gynecologic malignancies. FDG-PET/computed tomography (CT) is recommended for baseline assessment in cervical cancer and for staging in vulvar and vaginal cancer. The authors use FDG-PET/CT in definitive radiation treatment planning for cervical, vulvar, and vaginal cancer. PET may be helpful for salvage radiation treatment planning for any recurrent gynecologic malignancy. There are published data to support the use of PET in posttreatment evaluation of cervical and vulvar cancer., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: This study aimed to report response rates and predictors of response to palliative radiotherapy (RT) for recurrent ovarian cancer., Methods/materials: Database review identified 64 patients with symptomatic ovarian cancer recurrence who received a total of 76 courses of RT for 103 indications from March 2003 to August 2014. Radiotherapy indications were pain (44%), bleeding (32%), obstruction (15%), and other (9%). Responses were categorized as complete, partial, or none; all response (AR) was the sum of complete and partial responses. Response rates were compared using a χ test. Multivariate analysis was performed using logistic regression. Patients were followed up for symptom recurrence and death., Results: Response rates were significantly higher for pain (AR, 87%) and bleeding (93%) than for obstruction (62%) and other (60%; P < 0.01). Patients treated for pain at nonbony sites had higher response rates (AR 96%) compared with those treated at bony sites (75%; P = 0.04). Patients with clear cell histology had the lowest response rates (AR, 60%) compared with those with serous (82%), endometrioid (95%), or other Müllerian histology (85%; P = 0.01). Platinum status at diagnosis or the time of RT was not associated with response, nor was tumor size or number of prior chemotherapy regimens. On multivariate analysis, histology, RT indication, and RT dose were independent predictors of response (all P < 0.01)., Conclusions: Palliative RT provides relief of pain and bleeding in most patients with ovarian cancer recurrence. Patients with symptomatic obstruction, bony involvement, and clear cell histology may experience lower clinical response rates.

Purpose: To assess treatment tolerance and toxicity rates of consolidative whole-abdominal radiation therapy (WART) following cytoreductive surgery and carboplatin/paclitaxel chemotherapy in high-risk patients with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage III) using intensity modulated radiation therapy., Methods and Materials: The OVAR-IMRT-02 study is a multicenter, single-arm, phase 2 trial. Twenty patients with optimally debulked ovarian cancer (International Federation of Gynecology and Obstetrics stage III) with complete remission after chemotherapy were treated with intensity modulated WART as a consolidation therapy. A total dose of 30 Gy in 20 fractions of 1.5 Gy was applied to the entire peritoneal cavity. The primary endpoint was treatment tolerability, defined as lack of any Common Terminology Criteria for Adverse Events grade 4 toxicity within 10 weeks after start of treatment; secondary objectives were acute and chronic toxicity, quality of life, rates of therapy disruption and abortion, and progression-free and overall survival., Results: Intensity modulated WART resulted in excellent coverage of the whole peritoneal cavity, with effective sparing of all organs at risk. The primary analysis included all 20 enrolled patients, of whom 19 did not experience Common Terminology Criteria for Adverse Events grade 4 toxicity. Only 1 patient experienced acute grade 4 hematologic toxicity. Thus, the tolerability rate of intensity modulated WART was significantly higher than 70%. No gastrointestinal acute toxicities higher than grade 2 have been observed. During WART, mean global health status decreased by 18.1 points (95% confidence interval 7.1, 29.0). Six weeks after WART, global health status had already increased, with a mean score difference of 4.6 (95% confidence interval -11.1, 20.4) compared with baseline. Similar characteristics were observed for all function scale scores., Conclusion: Intensity modulated WART after aggressive surgery and carboplatin/paclitaxel chemotherapy is associated with an acceptable risk of acute toxicity and a treatment tolerability rate significantly higher than 70%. Together with our knowledge about clinical feasibility, meaning excellent coverage of the planning target volume and effective sparing of organs at risk, intensity modulated WART could offer a new therapeutic option for consolidation treatment of patients with advanced ovarian cancer., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Our aim was to evaluate the population-based outcomes of stages I and II invasive ovarian mucinous carcinomas (MCs) treated with adjuvant platinum-based chemotherapy and abdominopelvic radiotherapy (XRT)., Methods: International Federation of Gynecology and Obstetrics stage I/II MC cases referred to the British Columbia Cancer Agency between 1984 and 2014 were reviewed. Chemotherapy (minimum of 3 cycles) and XRT were the institutional policy for stages IA/B (grade 2/3) and IC/II (any grade). Physician patterns of practice determined XRT use in eligible patients, allowing for the comparison of outcomes based on receipt of XRT treatment on disease-free survival (DFS) and overall survival (OS)., Results: We identified 129 patients. Univariate analyses on substages IA, IC no rupture, IC with intraoperative rupture, and IC with preoperative rupture demonstrated 10-year DFS rates of 67%, 67%, 67%, and 27% (P = 0.004), respectively, and OS rates of 72%, 72%, 67%, and 38% (P = 0.01), respectively. For all patients, adjuvant XRT demonstrated improved 10-year DFS (78% vs 36%, P = 0.05) and OS (83% vs 36%, P = 0.02). Subgroup analysis did not detect a benefit of adjuvant therapy for stage IA grade 1/2. Multivariate analysis confirmed the benefit of XRT on DFS (hazard ratio, 0.14; 95% confidence interval, 0.02-0.98; P = 0.047) and a trend to improved OS (hazard ratio, 0.12; 95% confidence interval, 0.009-1.64; P = 0.11), whereas decision tree analysis demonstrated a reduced rate of relapse (33% vs 77%) and death (20% vs 46%) with the use of XRT, exclusive of patients with preoperative rupture., Conclusions: This population-based retrospective study is the first to demonstrate that the use of adjuvant abdominopelvic XRT after chemotherapy can improve survival in patients diagnosed as having stage I/II MC. Patients with stage IA grade 1 and grade 2 MC can have adjuvant therapy omitted.

Radiotherapy in ovarian cancer frequently invokes resistance; this severely compromises its therapeutic effect and results in poor clinical prognosis. How to overcome the acquired resistance and re-sensitize tumors to radiation is the central question in this clinical setting. Cancer cell survival was evaluated using a clonogenic assay. The microRNA expression profile was analyzed using a microarray. Transcript expression was determined using real time PCR. The expression of protein was determined by immunoblotting. Transcription activation was measured using a luciferase reporter assay. Transcription factor binding was determined using ChIP-PCR. Xenograft model was established and exposed to radiation with the simultaneous administration of oleuropein. Tumor growth was monitored. We demonstrated that treatment of oleuropein-sensitized ovarian cells with radiation altered the microRNA expression profile. The endogenous expression of miR-299 was suppressed by a hypoxia inducible factor and relieved in response to oleuropein, which in turn suppressed HPSE1 expression and consequently led to increased sensitivity to radiation. Our data elucidates an unappreciated mechanism mediating radiotherapy resistance in ovarian cancer and exploits the potential synergistic effect of oleuropein with radiation, which warrants further clinical investigation.

A new series of nitro analogues of the duocarmycins was prepared and evaluated for hypoxia-selective anticancer activity. The compounds incorporate 13 different amine-containing side chains designed to bind in the minor groove of DNA while spanning a wide range of base strength from pK a 9.64 to 5.24. The most favorable in vitro properties were associated with strongly basic side chains, but the greatest in vivo antitumor activity was found for compounds containing a weakly basic morpholine. This applies to single-agent activity and for activity in combination with irradiation or chemotherapy (gemcitabine or docetaxel). In combination with a single dose of γ irradiation 50 at 42 μmol/kg eliminated detectable clonogens in some SiHa cervical carcinoma xenografts, and in combination with gemcitabine using a well-tolerated multidose schedule, the same compound caused regression of all treated A2780 ovarian tumor xenografts. In the latter experiment, three of seven animals receiving the combination treatment were completely tumor free at day 100.

Struma ovarii (SO), a rare tumor containing at least 50% of thyroid tissue, represents approximately 5% of all ovarian teratomas; its malignant transformation rate is reported to occur in up to 10% of cases and metastases occur in about 5-6% of them. We describe a 36-year old woman who underwent laparoscopic left annessectomy two years earlier because of an ovarian cyst. Follow-up imaging revealed a right adnexal mass, ascitis and peritoneal nodes that were diagnosed as comprising a malignant SO with peritoneal secondary localizations at histopathology performed after intervention. Restaging with 18F-FDG-PET/CT scan, abdominal CT and ultrasonography showed abnormalities in the perihepatic region and presacral space and left hypochondrium localizations. The patient underwent thyroidectomy, hepatic nodulectomy and cytoreductive peritonectomy: histopathological examination did not show any malignant disease in the thyroid and confirmed the presence of peritoneal localizations due to malignant SO; molecular analysis detected NRAS Q61K mutation in exon 3, whereas no mutations were identified on the BRAF gene. The patient underwent radioiodine treatment: serum Tg was decreased at first follow-up after three months of 131I-therapy. We believe that our case raises some interesting considerations. First, pathologists should be aware of this entity and should check for the presence of point mutations suggesting an aggressive disease behavior, which could be beneficial for an optimal therapeutic approach. Second, although most of the knowledge in this field comes from case reports, efforts should be made to standardize the management of patients affected by malignant SO, including use of practice guidelines.

Objective: The aim of this review was to present the current radiation therapy status in recurrent ovarian cancer (OC) and explore potential solution to improve clinical outcomes in this setting of patients., Materials and Methods: PubMed search was performed. An attempt was made to include all relevant studies. Pertinent references cited in selected articles were also considered., Results: The role of radiation therapy in recurrent OC needs to be defined. This is the largest reported analysis of published data., Conclusions: Chemotherapy is the mainstay of recurrent OC treatment but prognosis remains very poor, and novel therapies are required to be integrated into this consolidated treatment regimen. Radiation therapy represents a valid alternative approach, even if no clear guidelines are available concerning it.

Because most patients with epithelial ovarian cancer have advanced disease at the time of initial diagnosis, radiation therapy usually does not play a major role in their treatment. Although ovarian carcinomas appear to be no less sensitive to radiation therapy than Müllerian carcinomas arising in other sites, the dose of radiation required to control gross disease, typically at least 60 Gy, cannot be safely delivered to the entire abdomen or even to large partial volumes of the pelvis and abdomen. Moreover, in most cases, localized radiation is ineffective because of the high risk of disseminated recurrence in peritoneal and extraperitoneal sites. There is strong evidence that radiation therapy can be used to achieve prolonged disease-free intervals and even cure selected patients with epithelial ovarian cancer. The challenge is to determine the select few who stand to benefit from radiation therapy. In all cases, the potential benefits of treatment must be carefully weighed against the risks, particularly for patients who are referred after multiple operations and courses of chemotherapy. For patients with incurable ovarian cancer, radiation therapy can also be very effective as a tool for improving symptoms and quality of life., (Copyright © 2016. Published by Elsevier Ltd.)

Despite standard treatment, about 70% of ovarian cancer will recur. Cancer stem cells (CSCs) have been implicated in the drug-resistance mechanism. Several drug resistance mechanisms have been proposed, and among these, autophagy plays a crucial role for the maintenance and tumorigenicity of CSCs. Compared to their differentiated counterparts, CSCs have been demonstrated to display a significantly higher level of autophagy flux. Moreover, mitophagy, a specific type of autophagy that selectively degrades excessive or damaged mitochondria, is shown to contribute to cancer progression and recurrence in several types of tumors. Nanomedicine has been shown to tackle the CSCs problem by overcoming drug resistance. In this work, we developed a nanomedicine, 188 Re-liposome, which was demonstrated to target autophagy and mitophagy in the tumor microenvironment. Of note, the inhibition of autophagy and mitophagy could lead to significant tumor inhibition in two xenograft animal models. Lastly, we presented two cases of recurrent ovarian cancer, both in drug resistance status that received a level I dose from a phase I clinical trial. Both cases developing drug resistance showed drug sensitivity to 188 Re-liposome. These results suggest that inhibition of autophagy and mitophagy by a nanomedicine may be a novel strategy to overcome drug resistance in ovarian cancer.

The combination of different therapeutic modalities is a promising option to combat the recurrence of tumors. In this study, polylactic and polyglycolic acid nanoparticles were used for the simultaneous delivery of a boron-curcumin complex (RbCur) and an amphiphilic gadolinium complex into tumor cells with the aim of performing boron and gadolinium neutron capture therapy (NCT) in conjunction with the additional antiproliferative effects of curcumin. Furthermore, the use of Gd complexes allows magnetic resonance imaging (MRI) assessment of the amount of B and Gd internalized by tumor cells. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles were targeted to ovarian cancer (IGROV-1) cells through folate receptors, by including in the formulation a PEGylated phospholipid functionalized with the folate moiety. NCT was performed on IGROV-1 cells internalizing 6.4 and 78.6 μg g -1 of 10 B and 157 Gd, respectively. The synergic action of neutron treatment and curcumin cytotoxicity was shown to result in a significant therapeutic improvement., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Introduction: Novel therapies that effectively kill both differentiated cancer cells and cancer initiating cells (CICs), which are implicated in causing chemotherapy-resistance and disease recurrence, are needed to reduce the morbidity and mortality of ovarian cancer. These studies used monoclonal antibody (mAb) 376.96, which recognizes a B7-H3 epitope expressed on ovarian cancer cells and CICs, as a carrier molecule for targeted α-particle radioimmunotherapy (RIT) in preclinical models of human ovarian cancer., Methods: mAb 376.96 was conjugated to the chelate 2-(4-isothiocyanotobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamoylmethyl)-cyclododecane (TCMC) and radiolabeled with 212 Pb, a source of α-particles. In vitro Scatchard assays determined the specific binding of 212 Pb-376.96 to adherent differentiated or non-adherent CIC-enriched ES-2 and A2780cp20 ovarian cancer cells. Adherent ovarian cancer cells and non-adherent CIC-enriched tumorspheres treated in vitro with 212 Pb-376.96 or the irrelevant isotype-matched 212 Pb-F3-C25 were assessed for clonogenic survival. Mice bearing i.p. ES-2 or A2780cp20 xenografts were injected i.p. with 0.17-0.70MBq 212 Pb-376.96 or 212 Pb-F3-C25 and were used for in vivo imaging, ex vivo biodistribution, and therapeutic survival studies., Results: 212 Pb-376.96 was obtained in high yield and purity (>98%); K d values ranged from 10.6-26.6nM for ovarian cancer cells, with 10 4 -10 5 binding sites/cell. 212 Pb-376.96 inhibited the clonogenic survival of ovarian cancer cells up to 40 times more effectively than isotype-matched control 212 Pb-F3-C25; combining 212 Pb-376.96 with carboplatin significantly decreased clonogenic survival compared to either agent alone. In vivo imaging and biodistribution analysis 24h after i.p. injection of 212 Pb-376.96 showed high peritoneal retention and tumor tissue accumulation (28.7% ID/g in ES-2 ascites, 73.1% ID/g in A2780cp20 tumors); normal tissues showed lower and comparable uptake for 212 Pb-376.96 and 212 Pb-F3-C25. Tumor-bearing mice treated with 212 Pb-376.96 alone or combined with carboplatin survived 2-3 times longer than mice treated with 212 Pb-F3-C25 or non-treated controls., Conclusion: These results support additional RIT studies with 212 Pb-376.96 for future evaluation in patients with ovarian cancer., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The goal of this study was to investigate whether targeted α-therapy can be used to successfully treat macrotumors, in addition to its established role for treating micrometastatic and minimal disease. We used an intravenous fractionated regimen of α-radioimmunotherapy in a subcutaneous tumor model in mice. We aimed to evaluate the absorbed dose levels required for tumor eradication and growth monitoring, as well as to evaluate long-term survival after treatment. Methods: Mice bearing subcutaneous tumors (50 mm 3 , NIH:OVCAR-3) were injected repeatedly (1-3 intravenous injections 7-10 d apart, allowing bone marrow recovery) with 211 At-MX35-F(ab') 2 at different activities (close to acute myelotoxicity). Mean absorbed doses to tumors and organs were estimated from biodistribution data and summed for the fractions. Tumor growth was monitored for 100 d and survival for 1 y after treatment. Toxicity analysis included body weight, white blood cell count, and hematocrit. Results: Effects on tumor growth after fractionated α-radioimmunotherapy with 211 At-MX35-F(ab') 2 was strong and dose-dependent. Complete remission (tumor-free fraction, 100%) was found for tumor doses of 12.4 and 16.4 Gy. The administered activities were high, and long-term toxicity effects (≤60 wk) were clear. Above 1 MBq, the median survival decreased linearly with injected activity, from 44 to 11 wk. Toxicity was also seen by reduced body weight. White blood cell count analysis after α-radioimmunotherapy indicated bone marrow recovery for the low-activity groups, whereas for high-activity groups the reduction was close to acute myelotoxicity. A decrease in hematocrit was seen at a late interval (34-59 wk after therapy). The main external indication of poor health was dehydration. Conclusion: Having observed complete eradication of solid tumor xenografts, we conclude that targeted α-therapy regimens may stretch beyond the realm of micrometastatic disease and be eradicative also for macrotumors. Our observations indicate that at least 10 Gy are required. This agrees well with the calculated tumor control probability. Considering a relative biological effectiveness of 5, this dose level seems reasonable. However, complete remission was achieved first at activity levels close to lethal and was accompanied by biologic effects that reduced long-term survival., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: The combination of low-dose radiation therapy with PARP inhibition enhances anti-tumor efficacy through potentiating DNA damage. We combined low-dose fractionated whole abdominal radiation (LDFWAR) with ABT-888 in patients with peritoneal carcinomatosis with a dose escalation in ovarian and fallopian cancer patients (OV)., Methods: Patients were treated with veliparib, 40-400mg orally BID on days 1-21 of 3 28-day cycles on 6 dose levels. Dose levels 5 and 6 included only OV patients. LDFWAR consisted of 21.6Gy in 36 fractions, 0.6Gy twice daily on days 1 and 5 for weeks 1-3 of each cycle. Circulating tumor material and quality of life were serially assessed., Results: 32pts were treated. Median follow-up was 45months (10-50). The most common treatment-related grade 3 and 4 toxicities were lymphopenia (59%), anemia (9%), thrombocytopenia (12%), neutropenia (6%), leukopenia (6%), nausea (6%), diarrhea (6%), anorexia (6%), vomiting (6%) and fatigue (6%). The maximum tolerated dose was determined to be 250mg PO BID. Median PFS was 3.6months and median OS was 9.1months. In OV patients, OS was longer for platinum-sensitive patients (10.9mo) compared to platinum-resistant patients (5.8mo). QoL decreased for all groups during treatment. Germline BRCA status was known for 14/18 patients with OV cancers, 5 of whom were BRCA mutation carriers. One objective response (3%) was observed., Conclusion: ABT-888 plus LDFWAR is tolerable with gastrointestinal symptoms, fatigue and myelosuppression as the most common toxicities. The single observed objective response was in a germline BRCA mutated, platinum-sensitive patient., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Poly (ADP-ribose) polymerase 1 (PARP-1) is the major target of clinical PARP inhibitors and is a potential predictive biomarker for response to therapy. Due to the limited success of PARP inhibitors as monotherapy, investigators have shifted the clinical role of PARP inhibitors to the adjuvant setting. In this study, we evaluate the radiotracer [ 18 F]FluorThanatrace ([ 18 F]FTT) as a marker of PARP expression in vitro and the associated biological implications of PARP-1 expression in PARP inhibitor treatment adjuvant to radiation therapy., Materials and Methods: SNU-251 (BRCA1-mutant) and SKOV3 (BRCA1-WT) cell lines were evaluated in vitro by using the radiotracer [ 18 F]FTT. Pharmacological binding assays were performed at baseline and were correlated with PARP-1 protein expression measured by Western blot protein analysis. Cell viability and clonogenic assays were used to characterize in vitro cytotoxicity for treatments, including: PARP inhibitors alone, radiation alone, and PARP inhibitor adjuvant to radiation. Western blot protein analysis was used to assess response to treatment by using γH2AX to measure DNA damage and PAR to measure the catalytic inhibition of PARP., Results: [ 18 F]FTT was capable of measuring PARP-1 protein expression in vitro and corresponded to Western blot protein analysis at baseline. The addition of a PARP inhibitor enhanced radiation effects in both cell lines; however, a greater synergy was observed in the SNU-251 cell line that expresses a BRCA1 mutation and homologous recombination deficiency. Western blot protein analysis showed that the addition of a PARP inhibitor adjuvant to radiation increases DNA damage in both cell lines and reduces PARP enzymatic activity as measured by PAR., Conclusions: In this work, we found that PARP-1 expression positively corresponds in vitro to the response of PARP inhibitors in combination with radiation therapy in ovarian cancer.

Objective: To assess the impact of adjuvant radiotherapy (RT) on survival in patients with stage I and II ovarian clear cell carcinoma (OCCC)., Methods: Data collection and analysis of stage I and II OCCC patients treated at two tertiary centers in Toronto, between 1995 and 2014, was performed. Descriptive statistics and Kaplan-Meier survival probability estimates were completed. The log-rank test was used to compare survival curves., Results: 163 patients were eligible. 44 (27%) patients were treated with adjuvant RT: 37 of them received adjuvant chemotherapy (CT), and 7 had RT only. In the no-RT group, there were 119 patients: 83 patients received adjuvant CT and 36 had no adjuvant treatment. The 10year progression free survival (PFS) was 65% for patients treated with RT, and 59% no-RT patients. There were a total of 41 (25%) recurrences in the cohort: 12 (27.2%) patients in RT group and 29 (24.3%) in the no-RT group. On multivariable analysis, adjuvant RT was not significantly associated with an increased PFS (0.85 (0.44-1.63) p=0.63) or overall survival (OS) (0.84 (0.39-1.82) p=0.66). In the subset of 59 patients defined as high-risk: stage IC with positive cytology and/or surface involvement and stage II: RT was not found to be associated with a better PFS (HR 1.18 (95% CI: 0.55-2.54) or O S(HR 1.04 (95% CI: 0.40-2.69))., Conclusion: Adjuvant RT was not found to be associated with a survival benefit in patients with stage I and II ovarian clear cell carcinoma or in a high risk subset of patients including stage IC cytology positive/surface involvement and stage II patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Given the relative chemo-resistant nature of clear-cell gynecologic cancers, we investigated the utility of radiation therapy (RT) to treat recurrent clear-cell carcinoma (CCC) of the ovary., Methods: A retrospective chart review of patients with recurrent CCC managed from 1994-2012 was conducted at 2 academic medical centers. Demographic and clinicopathologic factors were abstracted and evaluated using Pearson χ or t tests, Kaplan-Meier and Cox regression analyses., Results: Fifty-three patients had recurrent CCC, and 24 (45.3%) of these patients received RT. There were no significant differences in age, stage, optimal cytoreduction, platinum response, or the percentage of patients that received more than 3 regimens of chemotherapy between the 2 groups. Patients who received RT for recurrent CCC were more likely to have had a focal recurrence (62.5% vs 10.3%, P ≤ 0.001) and to have undergone secondary cytoreduction (70.8% vs 10.3%, P ≤ 0.001). Of patients who received RT, 73.9% underwent surgery with or before their treatment. Five-year survival after recurrence was significantly higher in the group that received RT, 62.9% versus 18.8% (P = 0.002). In a multivariate analysis, platinum-sensitive disease and RT were associated with improved survival from recurrence, (hazard ratio, 0.26; 95% confidence interval, 0.08-0.81; P = 0.02 and hazard ratio, 0.28; 95% confidence interval, 0.09-0.90, P = 0.03, respectively)., Conclusions: In this cohort of patients with recurrent CCC, platinum-sensitive disease and RT are associated with improved survival. However, it is important to note that the majority of these patients underwent surgery along with RT, and it may be that the benefit of RT is limited to those who undergo secondary cytoreduction.

Objective: Evaluate the impact of radiotherapy on cause specific survival (CSS) and overall survival (OS) for stage (I-III) clear cell, mucinous, and endometriod ovarian cancer., Methods: We analyzed incidence, survival, and treatments from the Surveillance, Epidemiology, and End Results (SEER) Program from 2004 to 2011 for clear cell, mucinous, and endometriod histologies of the ovary for stages (I-III). We examined CSS and OS for all three histologies combined and each histology with relation to the use of adjuvant radiation therapy (RT). Survival analysis was calculated by Kaplan-Meier and log-rank analysis., Results: CSS was higher in individuals not receiving RT at 5 years (81% vs. 74%) and 10 years (74% vs. 65%, p=0.003). OS was higher in individuals not receiving RT at 5 years (76% vs. 73%) and 10 years (64% vs. 59%, p=0.039). Stage III patients receiving RT had a higher OS at 5 years (54% vs. 44%) and 10 year intervals (36% vs. 30%, p=0.037). Stage III patients with mucinous histology receiving RT had a higher OS at 5 years (50% vs. 36%) and 10 years (45% vs. 26%, p=0.052)., Conclusion: Those receiving RT had a lower CSS and OS at 5 and 10 years. However, subgroup analysis revealed a benefit of RT in terms of OS for all stage III patients and for stage III patients with mucinous histology.

Relapses of ovarian cancer have poor prognosis, overall survival (OS) after recurrence depends on patient's performance status, his- tological cell type, size and number of the relapse, and duration of the platinum-free interval. Pelvis, peritoneum, pleural effusion, liver, lung, lymph nodes, and central nervous system are the most frequent sites of relapse. The standard treatment for ovarian cancer is a com- bination of surgery and chemotherapy. This retrospective study aimed to describe incidence, characteristics, outcomes and prognostic factors of patients with ovarian cancer underwent radiotherapy., Results: In 47 with ovarian cancer underwent radiotherapy. Treatment modalities were radiotherapy 8- 56 Gy. After optimal treatment the authors observed complete remission in seven patients, and progression and/or metastases in 40 patients. The present study confirmed that patients with low advancement stage had better prognoses than patients with advanced disease, as confirmed by OS rates in groups TI vs. T3 (p = 0.066) and T3 vs. T4 (p = 0.066). What was in- teresting was that the disease-free survival (DFS) in the group of patients with T3 cancer was longer than in the group of patients with TI cancer. Time to marker progression (Ca 125) was longer in groups with FIGO Stage I vs. II and I vs. III (p = 0.01 6,p = 0.044), while the time to progression in FIGO Stage II cancer patients was shorter than in FIGO Stage III cancer patients. An interesting result was also obtained in the analysis of 36-month survival where a larger number of patients without the disease symptoms had T3 Stage cancer. New prospective studies, designed to include the aspects of target volumes, total doses and fraction doses, together with the use of state of the art planning techniques, and therapeutic instrumentation are required.

Cancer is one of the leading causes of mortality worldwide. Usually, the diagnosis of cancer at an early stage is important to facilitate proper treatment and survival. Nuclear medicine has been successfully used in the diagnosis, staging, therapy and monitoring of cancers. Single-photon emission computed tomography and PET-based companion imaging agents are in development for use as a companion diagnostic tool for patients with ovarian cancer. The present review discusses the basic and clinical studies related to the use of radiopharmaceuticals in the diagnosis and management of ovarian cancer, focusing on their utility and comparing them with other imaging techniques such as computed tomography and MRI.

Objectives: This study aimed to report on long-term effectiveness of involved field radiation therapy (IFRT) in the salvage of localized recurrent ovarian cancer (ROC)., Methods: A retrospective analysis of 27 patients with a diagnosis of epithelial ovarian cancer who received tumor volume-directed IFRT for localized extraperitoneal recurrences (either as consolidation after cytoreductive surgery (CRS) or as attempted salvage if unresectable) forms the basis of this report. All patients were heavily pretreated with multiple chemotherapy regimens. Involved field radiation therapy was primarily with external beam (median dose, 50.4 Gy). Local recurrence-free survival (LRFS) was defined as freedom from in-field recurrences and was considered as a measure of effectiveness of radiotherapy. Statistical analyses evaluated association between disease-free survival, overall survival, LRFS, and various prognostic factors. Comparison was also made with a similar but unmatched cohort with localized recurrences salvaged by additional chemotherapy instead of local therapies (NIFRT group)., Results: Of 27 patients, 17 had optimal CRS before RT. The actuarial survival at 5 and 10 years (in parenthesis) from date of radiation were LRFS (70% and 60%), overall survival (30% and 19%), and disease-free survival (33% and 20%). None of the NIFRT patients survived beyond 5 years from initiation of salvage chemotherapy., Conclusions: Long-term follow-up in this selected series confirmed the benefit of IFRT (±CRS) in localized ROC. Chemotherapy salvage in a similar NIFRT group was not equivalent, suggesting a role for locoregional therapies in selected patients with ROC.

Background and Purpose: Cancer stem cells exhibit distinctive cellular metabolism compared with the more differentiated counterparts or normal cells. We aimed to investigate the impact of a novel radionuclide anti-cancer agent (188)Re-Liposome on stemness markers' expression and cellular metabolism in an ovarian cancer model., Material and Methods: A 2×2 factorial experiment was designed in which factor 1 represented the drug treatment comparing (188)Re-BMEDA, a free form of (188)Re, with (188)Re-Liposome, a nanoparticle-encapsulated form of (188)Re. Factor 2 represented the delivery route, comparing intravenous with intraperitoneal delivery., Results: Intraperitoneal delivery of (188)Re-Liposome predominantly killed the CSCs-like cells in tumours and switched metabolism from glycolysis to oxidative phosphorylation. Further, intraperitoneal delivery of (188)Re-Liposome treatment was able to block epithelial-to-mesenchymal transition (EMT) and reactivate p53 function. Collectively, these molecular changes led to a striking tumour-killing effect., Conclusions: Radionuclides encapsulated in liposomes may represent a novel treatment for ovarian cancer when delivered intraperitoneally (a type of loco-regional delivery). In the future, this concept may be further extended for the treatment of several relevant cancers that have been proved to be suitable for loco-regional delivery of therapeutic agents, such as colon cancer, gastric cancer, and pancreatic cancer., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: To evaluate local control, survival outcomes, and toxicity after intensity modulated radiotherapy (IMRT) for recurrent chemorefractory ovarian cancer., Methods: Between 2006 and 2014, 33 patients were treated with IMRT for recurrent ovarian cancer. Patients received a median of 3 chemotherapy regimens prior to IMRT (range, 1-12) with 11 (33%) undergoing concurrent therapy. Local control (LC), recurrence free survival (RFS), and overall survival (OS) were calculated via Kaplan-Meier method. Toxicity was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) v4.03. Impact of patient characteristics on outcomes was evaluated via Cox's proportional hazard model., Results: Median follow up was 23.7 months. Forty-nine sites were treated to a median dose of 5040cGy (range, 4500-7000). Nine (18%) of the 49 sites had in-field failures. Two year actuarial LC, RFS, and OS were 82%, 11%, and 63%, respectively. Seventeen patients had both a pre and post-treatment FDG-PET/CT; 6 (35%) had a complete metabolic response while 11 (65%) had a partial metabolic response. Acute ≥ grade 3 gastrointestinal (GI) toxicities occurred in 2 (6%) patients, late ≥ grade 3 GI toxicities occurred in 12 (36%), acute ≥ grade 3 hematological toxicities occurred in 5 (15%) and late ≥ grade 3 hematological toxicities occurred in 14 (42%)., Conclusions: IMRT for recurrent chemorefractory ovarian cancer is associated with excellent local control and limited radiation related toxicity. Future studies will be required to determine which subpopulation will benefit most from IMRT and whether alternative techniques such as stereotactic body radiotherapy may be feasible., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Synchronous multiple primary malignancies in the female genital tract are infrequent. From 50 to 70% of them corresponds to synchronous cancers of the endometrium and ovary. To our knowledge, this is only the third case report in the international literature of three concurrent gynaecological cancers of epithelial origin. A case is presented, as well as a literature review due to the infrequency of its diagnosis and the lack of information on the subject., Clinical Case: A 49-year-old woman, with previous gynaecological history of ovarian endometriosis. She underwent a hysterectomy and bilateral oophorectomy, as she had been diagnosed with endometrial hyperplasia with atypia. The final histopathology reported synchronous ovarian, Fallopian tube, and endometrial cancer. An extension study and complete surgical staging was performed, both being negative. She received adjuvant treatment of chemotherapy and radiotherapy. She is currently free of disease., Conclusions: The aetiology is uncertain. There is controversy relating to increased susceptibility of synchronous neoplasms to pelvic endometriosis and inherited genetic syndromes. Its diagnosis needs to differentiate them from metastatic disease. Additionally, they are problematical from a clinical, diagnostic, therapeutic, and prognostic point of view. The presentation of more cases of triple synchronous cancers is necessary for a complete adjuvant and surgical treatment., (Copyright © 2015 Academia Mexicana de Cirugía A.C. Published by Masson Doyma México S.A. All rights reserved.)

Andrographolide (AND), a diterpenoid lactone isolated from Andrographis paniculata, has been shown to have radiosensitivity in several types of cancer. Whether AND can radiosensitize ovarian cancer remains unknown. The present study investigated the radiosensitizing effects of AND in human ovarian SKOV3 xenografts and examined the molecular mechanisms of AND-mediated radiosensitization. Nude mice bearing human ovarian SKOV3 were treated with AND to investigate the effects of drug administration on tumor growth, radiosensitivity, apoptosis, and autophagy. Subsequent Western blot analysis and monodansylcadaverine (MDC) staining (autophagy analysis) were used to determine the role of AND. Finally, the pathway of apoptosis was characterized by caspase-3 activity assay as well as TUNEL analysis. AND potently sensitized SKOV3 xenografts to radiation. Moreover, apoptosis and autophagy in radiation combined with drug-treated xenografts increased significantly compared with the simple drug or single radiation treatment. This result was associated with an increase in the Bax/Bcl-2 protein ratio and p-p53 expression after exposure to combination treatment. Meanwhile, the level of Beclin 1 and Atg5 and the conversion from LC3-I to LC3-II, three important proteins involved in autophagy, were increased. AND acts as a strong radiosensitizer in human ovarian SKOV3 xenografts in vivo by increasing the Bax/Bcl-2 protein ratio and promoting the activation of caspase-3, leading to enhanced apoptosis as well as autophagy.

Purpose: Ovarian cancer is often diagnosed at an advanced stage with dissemination in the peritoneal cavity. Most patients achieve clinical remission after surgery and chemotherapy, but approximately 70% eventually experience recurrence, usually in the peritoneal cavity. To prevent recurrence, intraperitoneal (i.p.) targeted α therapy has been proposed as an adjuvant treatment for minimal residual disease after successful primary treatment. In the present study, we calculated absorbed and relative biological effect (RBE)-weighted (equivalent) doses in relevant normal tissues and estimated the effective dose associated with i.p. administration of (211)At-MX35 F(ab')2., Methods and Materials: Patients in clinical remission after salvage chemotherapy for peritoneal recurrence of ovarian cancer underwent i.p. infusion of (211)At-MX35 F(ab')2. Potassium perchlorate was given to block unwanted accumulation of (211)At in thyroid and other NIS-containing tissues. Mean absorbed doses to normal tissues were calculated from clinical data, including blood and i.p. fluid samples, urine, γ-camera images, and single-photon emission computed tomography/computed tomography images. Extrapolation of preclinical biodistribution data combined with clinical blood activity data allowed us to estimate absorbed doses in additional tissues. The equivalent dose was calculated using an RBE of 5 and the effective dose using the recommended weight factor of 20. All doses were normalized to the initial activity concentration of the infused therapy solution., Results: The urinary bladder, thyroid, and kidneys (1.9, 1.8, and 1.7 mGy per MBq/L) received the 3 highest estimated absorbed doses. When the tissue-weighting factors were applied, the largest contributors to the effective dose were the lungs, stomach, and urinary bladder. Using 100 MBq/L, organ equivalent doses were less than 10% of the estimated tolerance dose., Conclusion: Intraperitoneal (211)At-MX35 F(ab')2 treatment is potentially a well-tolerated therapy for locally confined microscopic ovarian cancer. Absorbed doses to normal organs are low, but because the effective dose potentially corresponds to a risk of treatment-induced carcinogenesis, optimization may still be valuable., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Ovarian transposition is a highly effective surgical procedure used to preserve ovarian function in premenopausal patients with cancers requiring postoperative or primary pelvic radiotherapy. Pelvic irradiation determines severe damage of ovarian DNA and iatrogenic ovarian failure with premature menopause, necessity of long-term hormone replacement therapy and infertility., Materials and Methods: We conducted an extensive research of the literature in Medline between January 2000 and April 2015 using the key-words "ovarian transposition radiotherapy", "radiotherapy gonadal function", radiotherapy fertility sparing". The population included young women with normal ovarian function affected by cancers that required pelvic radiotherapy. We have examined 32 articles reporting on 1189 women undergoing ovarian transposition. Median age was 32.5 years, follow up was median 48 months. The procedure has been performed in patients less than 40 years of age. Surgery has been achieved by laparotomy or laparoscoy. We have analyzed effects of radiotherapy on ovarian function., Results: The proportion of women treated by ovarian transposition preserved ovarian function was 70%. About 86% of patients did not develop ovarian cysts and in 98-99% of cases did not occur any metastatic disease., Conclusions: Ovarian transposition is associated with significant preservation of ovarian function and a low frequency of complications as cysts and metastasis. In 31% of cases the procedure can fail. Further studies are needed to evaluate the efficacy of ovarian transposition and the follow up. Ovarian transposition should be discussed at the time of cancer diagnosis in every premenopausal woman requiring pelvic radiotherapy.

To evaluate the incidence of secondary primary malignancy (SPM) in patients with ovarian cancer using a nationwide retrospective population-based dataset. Patients newly diagnosed with ovarian cancer between 1997 and 2010 were identified using Taiwan's National Health Insurance database. Patients with antecedent malignancies were excluded. Standardized incidence ratios (SIRs) for SPM were calculated and compared with the cancer incidence in the general population. Risk factors for cancer development were analyzed using Cox proportional hazard models. Effects of surgery, chemotherapy, and radiotherapy after ovarian cancer diagnosis were regarded as time-dependent variables to prevent immortal time bias. During the 14-year study period (follow-up of 56,214 person-years), 707 cancers developed in 12,127 patients with ovarian cancer. The SIR for all cancers was 2.78 (95% confidence interval 2.58-3.00). SIRs for follow-up periods of >5, 1-5, and <1 year were 1.87, 2.04, and 6.40, respectively. After the exclusion of SPM occurring within 1 year of ovarian cancer diagnosis, SIRs were significantly higher for cancers of the colon, rectum, and anus (2.14); lung and mediastinum (1.58); breast (1.68); cervix (1.65); uterus (7.96); bladder (3.17), and thyroid (2.23); as well as for leukemia (3.98) and others (3.83). Multivariate analysis showed that age ≥ 50 years was a significant SPM risk factor (hazard ratio [HR] 1.60). Different treatments for ovarian cancer, including radiotherapy (HR 2.07) and chemotherapy (HR 1.27), had different impacts on SPM risk. Patients with ovarian cancer are at increased risk of SPM development. Age ≥ 50 years, radiotherapy, and chemotherapy are independent risk factors. Close surveillance of patients at high risk should be considered for the early detection of SPM.

The purpose of this study was to evaluate the effects of salvage chemotherapy on recurrent or persistent ovarian clear cell carcinoma (CCC) with the goal of identifying a more rational treatment regimen for this lethal disease.The medical records of patients with CCC were retrospectively reviewed to select patients that were subsequently treated for recurrent or persistent disease.Of the 164 women with recurrent or persistent CCC, 485 chemotherapy courses with 1766 cycles were administered. Overall, the clinical benefit rate (CBR) was 39.4%, and the mean progression-free survival (PFS) was 4.5 months. Grade 3/4 toxicities occurred in 94 courses (19.4%). The CBR for TC was 45.1%, with a PFS of 3.7 months. Compared to that of TC, the CBRs for PC and CC were significantly lower (P = 0.020 and 0.021, respectively). The CBRs and PFS for PAF-C were slightly higher (P = 0.518 and 0.077, respectively), but showed a significantly higher adverse event rate (AER, P = 0.039). The CBR for bevacizumab was 50% with an extraordinarily long PFS (49.8 months). Gemcitabine and oxaliplatin had similar values for CBRs (44.4% and 44.1%) and PFS (2.5 and 3.4 months), respectively. Docetaxel (weekly) exhibited a notably low AER of 2.7%, and topotecan was associated with a relatively long PFS (7.7 months).For cis/carboplatin-pretreated patients, the existing active agents, such as oxaliplatin, gemcitabine, topotecan, and especially bevacizumab, are promising. Docetaxel (weekly) is well tolerated and might offer a particularly viable option for heavily pretreated patients. However, additional research to identify for a continued search for the optimal combination of chemotherapeutics or novel agents is still warranted.