Advanced Gynecologic Malignancies Research Articles

Estimation of dose-volume parameters of female urethra as organ-at-risk during interstitial brachytherapy in gynecological malignancies.

Purpose: Interstitial brachytherapy (ISBT) is often used as post-external beam radiotherapy (EBRT) to treat locally advanced gynecological malignancies. Female urethra is in close proximity to the target during ISBT. However, it has not been evaluated as an organ-at-risk (OAR). Overlapping symptoms caused by radiation-induced bladder toxicity vs. urethral toxicity make it difficult to identify and report urethral toxicities separately. This was a retrospective study to estimate dose-volume parameters of female urethra during high-dose-rate ISBT.Material and methods: Data of 24 patients with gynecological malignancies treated by ISBT were selected. Urethra and periurethral regions were retrospectively contoured. Mean volume, Dmax, Dmean, D2cc, D1cc, D0.5cc, D0.2cc, and D0.1cc were documented. Unpaired t-test was used for comparison of means.Results: 20/24 Ca. cervix, 1/24 Ca. vagina, and 3/24 Ca. vaginal vault received 6-6.5 Gy in 4 ISBT fractions. Mean urethral length was 3.54 ±0.55 cm. Mean doses received by urethra per BT fraction were Dmax = 4.23 ±1.32 Gy, Dmean = 2.71 ±1.01 Gy, D0.2cc = 3.31 ±1.07, and D0.1cc = 3.54 ±1.09 Gy. Comparison of total BT 2 Gy equivalent dose (EQD2) with 4 fractions for urethra between patients with (9/24) and without anterior vaginal wall (15/24) involvement included Dmean = 18.79 ±7.49 Gy vs. 11.14 ±6.15 Gy*, D1cc = 10.90 ±10.03 Gy vs. 4.54 ±3.93 Gy*, D0.5cc = 19.50 ±8.69 Gy vs. 11.97 ±6.54 Gy*, D0.2cc = 23.78 ±8.94 Gy vs. 15.51 ±7.39 Gy*, and D0.1cc = 25.88 ±9.37 Gy vs. 17.39 ±8.03 Gy*, respectively (*p < 0.05).Conclusions: Female urethra receives significant doses during ISBT for gynecological malignancies, especially when the anterior vaginal wall is within the target volume. Reporting doses to urethra would enable to develop clinical correlation and dose-volume constraints for urethra as organ-at-risk in future.

A new development in ultrasound-compatible gynecologic brachytherapy simulators

PurposeGynecologic brachytherapy is an essential component in the curative treatment of cervical cancer. With the decline in brachytherapy utilization, gynecologic brachytherapy simulators are being used to provide a mechanism to enhance proficiency-based resident training. However, most models that have been used lack procedural fidelity as they are either repurposed from OB/GYN basic models or from physics phantoms. Therefore, we set out to develop a high-fidelity, ultrasound- and CT-compatible gynecologic brachytherapy training simulator. Methods and MaterialsBased on prior experience with gynecologic training simulators on the market, we developed a wish list for an ultrasound-compatible brachytherapy training model. A custom simulator was developed based on an existing pelvic ultrasound trainer. Features included a cervical os and endometrial canal as well as a palpable and hypoechoic cervical tumor. ResultsThe model took about 3 months from the initial meeting with the developer to completion. The properties of the material were equivalent to water for ultrasound, CT, and also MRI and the model did not show signs of degradation after multiple tandem insertions. ConclusionsA high-fidelity ultrasound-compatible simulator was effectively developed and utilized to improve resident training to perform brachytherapy implants with a derivative benefit in the long term of improving survival for women with advanced gynecologic malignancies through having access to more proficient brachytherapists. Future directions include enhancing the model to allow for repetitive needle insertion and suturing for interstitial training as well as creating variations in anatomy (e.g., retroverted uterus, bulky tumors, etc.) for more advanced technical training.

Gynecologic malignancy-associated bowel obstruction: Outcomes and prognostic implications

Objective: Malignancy-associated bowel obstruction (MBO) represents a devastating sequelae of advanced gynecologic malignancy. Admission for MBO carries poor prognostic significance, although its exact impact remains under investigation. Given the potential for high-intensity intervention in this setting, understanding patients’ end-of-life priorities becomes paramount, and MBO admissions may be an important opportunity for goals of care conversations. The present study aims to categorize the mortality associated with MBO, and to explore rates of intervention and goals-of-care discussions in this population.

Primary Pelvic Exenteration for Advanced Gynaecological Malignancies

Abstract Introduction: Indication of primary pelvic exenteration, without previous radiotherapy, is questionable in advanced stages of gynaecological malignancies. Materials and Methods: 24 patients who underwent primary pelvic exenteration for pelvic malignancies were studied retrospectively. The indications were cervical (n=17), vaginal (n=4), bladder (n=2) and endometrial cancer (n=1). Results: According to the type of exenteration, 14 were anterior and 10 total. Relying on the resection lines in relation with levator ani muscles, 14 were supralevatorial and 10 infralevatorial, of which five involved vulvectomy. Early complications occurred in 7 patients with 1 perioperative death. Conclusions: Primary pelvic exenterantion as first line therapy for advanced gynaecological malignancies can lead to long-term survival and it can even be curative in suitable selected patients. Still, postoperative complications are frequent, which can be lethal.

Outcomes of freehand interstitial brachytherapy in advanced gynecologic malignancies

PurposeThe purpose of the study is to present the first results of freehand interstitial brachytherapy (ISBT) used to treat patients with carcinoma of the cervix and the vagina. Methods and MaterialsPatients diagnosed with carcinoma of the cervix or carcinoma of the vagina who were not suitable for intracavitary brachytherapy were treated with freehand ISBT. The implant was performed transperineally using C arm or transrectal ultrasound guidance. Patients received an external beam radiotherapy dose of 50 Gy in 25 fractions. The dose delivered by high-dose-rate ISBT was 18 Gy in three fractions, 6 Gy per fraction, 6 h apart. The brachytherapy dose volume parameters were analyzed after CT-based planning using GEC ESTRO image-guided brachytherapy-based guidelines. ResultsFrom June 2018 till November 2018, 14 patients were treated with freehand ISBT. The mean dose received by 90% of the high-risk clinical target volume (D90) was 82 Gy EQD210 for patients with carcinoma of the cervix and 80 Gy EQD210 for patients with carcinoma of the vagina. The mean dose received by 2 cc volume of the bladder and rectum was 80 Gy EQD23 and 70 Gy EQD23 for patients with carcinoma of the cervix and 75 Gy EQD23 and 72 Gy EQD23 for patients with carcinoma of the vagina, respectively. The mean dose received by 2 cc of the sigmoid was 65 Gy EQD23 for cervical carcinoma and 58 Gy EQD23 for vaginal carcinoma, respectively. At a median followup of 14 months, 2 patients developed local recurrence. Two patients developed Grade 2 gastro intestinal toxicity, and 1 patient developed Grade 2 genitourinary toxicity. None of the patients developed Grade 3 or 4 toxicities. ConclusionA freehand interstitial implant is feasible in resource limited settings and provides acceptable local control with minimal acute toxicity.

The anti-DKK1 antibody DKN-01 as an immunomodulatory combination partner for the treatment of cancer

ABSTRACT Introduction The Wnt/beta-catenin pathway is a complex signaling pathway known to be dysregulated in several cancers; Dickkopf-1 (Dkk1) is an inhibitor of canonical Wnt signaling via negative feedback. Elevated Dkk1 is associated with a poor prognosis in several cancers, including gynecologic and gastroesophageal malignancies. This review focuses on the potential therapeutic benefit of targeting Dkk1 with the IgG4 monoclonal antibody, DKN-01. Areas covered We highlight current treatment approaches for advanced gynecologic and esophageal malignancies highlighting the need for more effective therapies, specifically improved immune-modulating agents and combinations. Our discussion of DKN-01 addresses the rationale for targeting Dkk1, available safety, pharmacokinetic and efficacy data. Expert opinion DKN-01 presents an interesting therapeutic consideration in advanced gynecologic and gastroesophageal malignancies. It has been especially promising in patients with high-Dkk1-expressing tumors or known Wnt mutations. We postulate that the complementary mechanisms, limited adverse effects and emerging biomarker data position DKN-01 as a promising agent for combination therapy in patients with advanced malignancies. Specifically, we believe this occurs through an immuno-modulatory effect, primarily acting through the innate arm of the immune system. This highlights the possibility for addressing innate immune resistance and expanding the portion of patients who may benefit, possibly in a biomarker-selected manner.

Combination immunotherapy with ipilimumab and nivolumab in patients with rare gynaecological malignancies.

6091 Background: Up to 50% of gynecological cancers are considered rare. The outcome of these patients (pts) is poor given a lack of scientific and clinical knowledge. Immunotherapy using single agent anti- PD-1/PD-L1 treatment (tx) has shown only modest activity in patients with common gynecological malignancies, such as high grade serous ovarian cancer (ca) and microsatellite stable endometrial ca. Combined CTLA-4/PD-1 blockade using ipilimumab (ipi) and nivolumab (nivo) has demonstrated superior efficacy compared to single agent anti-PD-1 therapy in pts with advanced melanoma and renal cell ca. To date, no trials have been undertaken with ipi/nivo in patients with rare gynecological malignancies. Methods: 41 pts with advanced rare gynecological malignancies were enrolled into the CA209-538 trial. Pts received nivo 3mg/kg and ipi 1mg/kg q 3 weekly for four doses, followed by nivo 3mg/kg q 2 weekly. Tx continued for up to 96 weeks, or until disease progression or the development of unacceptable toxicity. Response (RECIST 1.1) was assessed every 12 weeks. The primary endpoint was clinical benefit rate (CBR = CR +PR + SD). Exploratory endpoints include correlation of efficacy with biomarkers (incl PD-L1/TMB). Results: Pts with 10 rare tumor types were enrolled (Table). 39/41 pts have received prior therapy (1-7 lines). Objective responses were observed in 11 pts (27%) including pts with vaginal SCC, ovarian clear cell and low grade serous ca, ovarian and uterine carcinosarcoma, uterine clear cell, uterine serous ca and leiomyosarcoma. A further 9 pts had SD as their best radiological response resulting in a CBR of 49%. The median duration of response had not been reached (range 3.5 – 25+ months) with seven responses being ongoing. 63% of pts experienced an immune related adverse event (irAEs) with 4 pts developing Grade 3/4 irAEs. Conclusions: Ipi/Nivo tx demonstrates efficacy in a range of different rare gynecological cancers with a significant number of durable responses being observed. Tumor agnostic biomarkers are required to assist with better patient selection. Clinical trial information: NCT02923934. [Table: see text]

Molecular Guided Treatments in Gynecologic Oncology: Analysis of a Real-World Precision Cancer Medicine Platform.

IntroductionAdvanced gynecologic cancers have a poor prognosis and constitute a major challenge for adequate treatment strategies. By analyzing and targeting molecular alterations, molecular guided treatments may be a viable option for the treatment of advanced gynecologic cancers.Patients and MethodsIn this single‐center, real‐world retrospective analysis of our platform for precision cancer medicine (PCM), we describe the molecular profiling of 72 patients diagnosed with different types of advanced gynecologic malignancies. Tumor samples of the patients were examined by next‐generation sequencing panel and immunohistochemistry (IHC).ResultsIn total, we identified 209 genetic aberrations in 72 patients. The ten most frequent alterations were TP53 (n = 42, 20%), KRAS (n = 14, 6.6%), PIK3CA (n = 11, 5.2%), PIK3R1 (n = 9, 4.3%), ATR (n = 8, 3.8%), PTEN (n = 8, 3.8%), BRCA1 (n = 6, 2.8%), NF1 (n = 4, 1.9%), NOTCH1 (n = 4, 1.9%), and POLE (n = 4, 1.9%), which account for more than half of all molecular alterations (52.6%). In 21 (29.1%) patients only one mutation could be detected, and 44 (61.1%) patients had more than one mutation. No molecular alterations were detected in seven (9.7%) patients. IHC detected expression of phosphorylated mammalian target of rapamycin and epidermal growth factor receptor in 58 (80.6%) and 53 (73.6%) patients, respectively. In over two thirds (n = 49, 68.1%), a targeted therapy was suggested, based on the identified genetic aberrations. The most frequently recommended specific treatment was the combination of everolimus with exemestane (n = 18, 25 %).ConclusionBased on our observations, it seems that PCM might be a feasible approach for advanced gynecologic cancers with limited treatment options.Implications for PracticeNowadays molecular profiling of advanced gynecologic malignancies is feasible in the clinical routine. A molecular portrait should be done for every patient with an advanced therapy‐refractory gynecologic malignancy to offer molecular‐based treatment concepts.

Palliative treatment of intestinal obstruction in patients with gynecologic malignancies - single center experience.

One of the common symptoms in patients with advanced gynecologic tumors is intestinal obstruction. Palliativemanagement may include pharmacological treatment, stenting as well as surgical removal of obstruction cause.Selection of appropriate treatment should be based on careful and individual assessment of advantages, disadvantagesand possible complications. The aim of the study was to analyze the effectiveness of non-invasive treatment in patientswith gynecologic malignancies suffering from intestinal obstruction. It was a retrospective analysis of factors associated with primary non-invasive intestinal obstructiontreatment effectiveness. Data were collected from medical records of 17 patients managed and followed-up in a singlegynecologic oncology center due to endometrial cancer, fallopian tube cancer, uterine leiomyosarcoma, and ovarian canceradmitted to the ward because of symptomatic intestinal obstruction. Mean observation time lasted 40.6 months. Non-invasivetreatment included fluid therapy, dexamethasone, buscolysin, mebeverine, ranitidine, simethicone, omeprazole,magnesium sulphate, semi-liquid diet, and parenteral nutrition. Characteristics including age, BMI, comorbidities, oncologicaltreatment, histology type, stage, grade, presence of ascites, location of primary tumor and metastases were analyzed. The number of obstruction episodes varied from 1 to 5. Mean time between multiple episodes lasted 3.2 months. 5 patientsrequired surgical treatment. For the rest of the patients primary non-invasive treatment was sufficient. Most cases of bowel obstruction in patients with advanced gynecologic malignancies can be successfullymanaged without invasive treatment. Moreover, non-invasive obstruction management can be applied multiple times incase of recurrence.

MRI of surgical flaps in pelvic reconstructive surgery: a pictorial review of normal and abnormal findings.

Surgical flaps are commonly used for pelvic reconstruction in a subgroup of patients with locally advanced or recurrent anorectal and gynecologic malignancies and following complications of pelvic irradiation. Surgical scenarios where flaps may be placed include (but are not limited to) extended or radical abdominal perineal resection (APR) and total pelvic exenteration (PE). Surgical flaps in pelvic reconstruction serve several functions, including reducing dead space and providing structural support, facilitating wound closure and cosmetic appearance, enhancing the postsurgical healing process, protecting anastomosesand helping to prevent adhesions of organs and viscera to adjacent structures and the pelvic side wall. The most commonly used surgical flaps in pelvic reconstruction surgery include the VRAM (Vertical Rectus Abdominis Muscle), MRAM (Modified Rectus Abdominis Myocutaneous flap), gracilis, sartoriusand omental flaps. Surgical flaps can be mistaken for recurrent or residual tumor by radiologists who are not familiar with the appearance or surgical methods of flap placement, since flaps may have a mass-like appearance on cross sectional imaging, including CT and MRI. Recurrent neoplasm may be difficult to differentiate from postoperative changes of flap placement and associated postsurgical anatomic distortion. This review article focuses on understanding the nuances of surgically placed pelvic flaps and identifying their normal and abnormal appearances on magnetic resonance imaging (MRI) along a time continuum. Postsurgical complications, including hematoma, postoperative fluid collections, infection, ischemia, and necrosis as well as tumor recurrence on the initial and follow-up magnetic resonance imaging are illustrated and discussed.

Early results of a phase I evaluation of TAK-228 (TORC 1/2 inhibitor) in combination with TAK-117 (PI3K alpha inhibitor) and paclitaxel in advanced gynecologic malignancies and metastatic breast cancer

Early results of a phase I evaluation of TAK-228 (TORC 1/2 inhibitor) in combination with TAK-117 (PI3K alpha inhibitor) and paclitaxel in advanced gynecologic malignancies and metastatic breast cancer

Outcomes of whole genome and transcriptome sequencing (WGTS) in advanced gynecologic malignancies: Results from the personalized oncogenomics program (POG)

Objective: Advanced/recurrent gynecologic malignancies are a heterogeneous group of cancers with limited treatment options lacking predictive biomarkers. The personalized oncogenomics program (POG) is a British Columbia cancer investigational program that performs whole genome and transcriptome sequencing (WGTS) of recurrent cancers. A tumor board identifies potentially predictive and actionable biomarkers. We analyzed the discussed actionable items and their impact on treatment decisions among patients with recurrent gynecologic cancers.

Interdisciplinary surgery for advanced gynecologic malignancies: Outcome and complication rate.

e17002 Background: Advanced gynecologic malignancies are known to have a poor prognosis. Due to local invasion in adjacent organs, finding the most suitable therapeutic option is often difficult. This study aims to assess the outcome of interdisciplinary surgery for locally advanced gynecologic malignancies focusing on women treated by pelvic exenteration (PE). Methods: All women that were treated with PE at the University Hospital Marburg between 04/2011 and 06/2016, were enrolled in this retrospective study. A data sheet was prepared assessing e.g. demographic informations, tumor type and previous therapies. Furthermore, complication rate (Clavien Dindo, follow-up and outcome were evaluated. Results: From the 57 women identified, the indications for PE were malignancies of the cervix (47.2%), vagina (15.1%), vulva (13.2%), endometrium (11.3%), ovaries (5.7%) and undifferentiated (uterus) (1.9%). 51.9% were treated for recurrent cancer. 26% received no treatment prior to PE, 16%, 38%, 20% received 1, 2 or 3 previous treatments respectively (chemotherapy, radiation, surgery). 54.7% of the patients underwent anterior, 37.8% total and 7.5% posterior PE. Urinary diversion was predominantly ileum conduit (76%). Major complications (Clavien Dindo &gt; 2) were observed for 40.4%, 19.2% had no complications. No correlation with clinical parameters (e.g. BMI, age, time of surgery), previous therapy or urinary diversion could be shown. Renal function improved significantly postoperatively (p &lt; 0.05). Mean hospital stay was 25 d. Median overall survival (OS) was 15.2 months. It was not influenced by the entity of the tumor. Two years survival rate (SR) was 38.2%; 3 years SR 27.3%. After 47 months median follow-up time, 23.7% of the treated women were still alive. Conclusions: PE remains to be a meaningful treatment option for women with invasive gynecologic malignancies also after multiple previous therapies, showing acceptable complication rates and satisfactory OS in regard to the extensive nature of the malignancies and the procedure.

A phase II clinical trial of ipilimumab/nivolumab combination immunotherapy in patients with rare upper gastrointestinal, neuroendocrine, and gynecological malignancies.

2570 Background: Patients (pts) with rare cancers represent an unmet medical need and have an inferior overall survival compared to patients with more common malignancies. Due to their low frequency, no therapies, including immunotherapies, have systematically been investigated in this population. Ipilimumab (ipi)/Nivolumab (nivo) combination treatment has demonstrated significant clinical activity in pts with advanced melanoma and renal cell carcinoma and response rates with this regimen are higher compared to single agent anti-PD-1 therapy. This phase II study assessed the efficacy and safety of ipi/nivo in rare cancer pts. Methods: 60 pts with advanced rare upper gastrointestinal (GI), neuroendocrine (NE) and gynaecological (GY) malignancies were enrolled in 3 cohorts. Patients received nivo 3mg/kg and ipi 1mg/kg every 3 weeks for four doses, followed by nivo 3mg/kg every 2 weeks. Treatment continued for up to 96 weeks, or until disease progression or the development of unacceptable toxicity. Response (RECIST 1.1) was assessed every 12 weeks. The primary endpoint was clinical benefit rate (CBR), CR, PR and SD. Exploratory endpoints include correlation of efficacy with relevant biomarkers including PDL1 status and tumour mutation burden. Results: 42 pts have so far undergone restaging, 11 pts clinically progressed prior to their first restaging scan. 50 pts have received prior therapy (1-5 lines). Objective responses have been observed in a range of different malignancies. Clinical trial information: NCT02923934. Grade 3/4 immune related adverse events were detected in 31% of pts. The results of correlative biomarker studies will be presented at the meeting. Conclusions: Ipi/Nivo combination treatment has efficacy in a wide range of advanced rare malignancies. Immune related toxicity is in keeping with previously reported clinical trials using the same dosing regimen.[Table: see text]

A retrospective review on extended carboplatin infusion and incidence of hypersensitivity reaction in gynecologic malignancies in a single institution.

e17102 Background: Carboplatin has been the standard treatment for advanced gynecologic malignancies in the first line setting as well as treatment of relapsed disease. Carboplatin induced hypersensitivity reaction (HSR) is observed more frequently in a second line setting and symptoms can range from rash to life threatening symptoms such as anaphylaxis, which could preclude further treatment. A retrospective study by O’Cearbhaill showed HSR rate with extended infusion protocol to be 3.4%. However, two subsequent prospective studies by Lax and O’Cearbhaill did not find that extended infusion reduced the risk or severity of HSR. We reviewed the incidence of HSR with three hour extended-infusion carboplatin at our institution. Methods: Our practice at the Monter Cancer Center changed from standard 1 hour carboplatin retreatment infusion to extended-infusion in 2011. We reviewed charts of 162 patients from 2011 to present who received a three hour extended infusion of carboplatin. All patients received prophylactic H1 and H2 blockers along with steroids. HSR was determined in two ways: 1) Identifying patients who reported clinical symptoms of HSR. 2) Identifying which patients had received diphenhydramine, hydrocortisone and/or epinephrine as indicated for an infusion reaction. Results: 162 patients were identified: 83 with ovarian cancer, 44 with uterine cancer, and 16 with fallopian tube cancer, 10 with primary peritoneal cancer, and 9 with cervical/vulvar cancer. Most had relapsed disease and were previously treated for stage IV (35%), or stage III (47%) with platinum doublet chemotherapy at least six months prior. Only 1 out of 162 (0.6%) had a grade 1 reaction with hives and was treated with dexamethasone and diphenhydramine. She was previously treated with carboplatin 17 months prior. Her current HSR occurred during her fifth cycle of retreatment. She was not re challenged with the drug and elected not to undergo desensitization. Conclusions: Hypersensitivity reactions develop in about 12-33% of women retreated with carboplatin peaking at eight cycles (Lax et al.). The mechanism behind HSR is unclear but considered to be from repeated exposure to free platinum metal concentration. Incidence of HSR at our institution was lowest ever-reported at 0.6%, suggesting that our extended infusion protocol with the appropriate premedication is appropriate for carboplatin-retreat patients. Further prospective studies to evaluate this regimen is warranted.

A machine-learning–based prediction model of fistula formation after interstitial brachytherapy for locally advanced gynecological malignancies

PurposeExternal beam radiotherapy combined with interstitial brachytherapy is commonly used to treat patients with bulky, advanced gynecologic cancer. However, the high radiation dose needed to control the tumor may result in fistula development. There is a clinical need to identify patients at high risk for fistula formation such that treatment may be managed to prevent this toxic side effect. This work aims to develop a fistula prediction model framework using machine learning based on patient, tumor, and treatment features. Methods and MaterialsThis retrospective study included 35 patients treated at our institution using interstitial brachytherapy for various gynecological malignancies. Five patients developed rectovaginal fistula and two developed both rectovaginal and vesicovaginal fistula. For each patient, 31 clinical features of multiple data types were collected to develop a fistula prediction framework. A nonlinear support vector machine was used to build the prediction model. Sequential backward feature selection and sequential floating backward feature selection methods were used to determine optimal feature sets. To overcome data imbalance issues, the synthetic minority oversampling technique was used to generate synthetic fistula cases for model training. ResultsSeven mixed data features were selected by both sequential backward selection and sequential floating backward selection methods. Our prediction model using these features achieved a high prediction accuracy, that is, 0.904 area under the curve, 97.1% sensitivity, and 88.5% specificity. ConclusionsA machine-learning–based prediction model of fistula formation has been developed for patients with advanced gynecological malignancies treated using interstitial brachytherapy. This model may be clinically impactful pending refinement and validation in a larger series.

Current Systemic Treatment Landscape of Advanced Gynecologic Malignancies.

Developments in systemic therapies beyond traditional cytotoxic chemotherapy have resulted in an unparalleled number of US Food and Drug Administration approvals in the past 5years for ovarian, endometrial, and cervical cancer. In this review, we highlight registration trials leading to recent Food and Drug Administration approvals for targeted systemic therapies in advanced gynecologic malignancies, encompassing three classes of agents: the antiangiogenic anti-vascular endothelial growth factor antibody bevacizumab in ovarian and cervical cancer, poly (ADP-ribose) polymerase inhibitors in ovarian cancer, and the immune checkpoint inhibitor pembrolizumab in cervical and endometrial cancer. The addition of bevacizumab to chemotherapy has been approved in frontline and relapsed advanced ovarian cancer, in both platinum-resistant and platinum-sensitive settings. Three poly (ADP-ribose) polymerase inhibitors are approved for women with ovarian cancer. Olaparib and rucaparib are utilized in recurrent germline or somatic BRCA mutated ovarian cancer. Along with a third poly (ADP-ribose) polymerase inhibitor, niraparib, they are also Food and Drug Administration approved as maintenance therapy regardless of BRCA mutation status for patients with recurrent ovarian cancer in complete or partial response to platinum-based chemotherapy. More recently, olaparib was approved as maintenance therapy for BRCA mutated ovarian cancer following first-line platinum-based chemotherapy. Pembrolizumab has been approved for relapsed cervical cancer with programmed death ligand 1 positivity and relapsed solid tumors with mismatch repair deficiency, which applies to 30% of endometrial cancers. Together, these therapies represent the advent of personalized medicine in gynecologic malignancies. Additional information is required to determine cost-effective strategies for incorporating these therapies and rational means of sequencing these agents.

Pelvic exenteration as ultimate ratio for gynecologic cancers: single-center analyses of 37 cases.

Pelvic exenterations are a last resort procedure for advanced gynecologic malignancies with elevated risks in terms of patients' morbidity. This single-center analysis reports surgical details, outcome and survival of all patients treated with exenteration for non-ovarian gynecologic malignancies at our university hospital during a 13-year time period. We collected data regarding patients and tumor characteristics, surgical procedures, peri- and postoperative management, transfusions, complications, and analyzed the impact on survival outcomes. We identified 37 patients between 2005 and 2013 with primary or relapsed cervical cancer (59.5%), vulvar cancer (24.3%) or endometrial cancer (16.2%). Median age was 60years and most patients (73%) had squamous cell carcinomas. Median progression-free survival was 26.2months and median overall survival was 49.9months. The 5-year survival rates were 34.4% for progression-free survival and 46.4% for overall survival. There were no significant differences in progression-free survival and overall survival with regard to disease entity. Patients with tumor at the resection margins (R1) had a nearly significantly worse progression-free survival (median: 28.5 vs. 7.3months, HR 2.59, 95% CI 0.98-6.88, p = 0.056) and a significantly worse overall survival (median: not reached vs. 10.9months, HR 4.04, 95% CI 1.40-11.64, p = 0.010) compared to patients with complete tumor resection (R0). In addition, patients without lymphovascular space invasion had a significantly better progression-free survival (p = 0.017) and overall survival (p = 0.034) then patients with lymphovascular space invasion. We observed complications in 14 patients (37.8%), 10 of those were classified as Clavien-Dindo 3 or 4. There was a trend to worse progression-free survival in patients that suffered complications (p = 0.052). Median total amount of transfused blood products was 4 (range 0-20). Pelvic exenteration is a procedure that provides substantial progression-free survival and overall survival improvement and-in selected patients-can even achieve cure in otherwise hopeless clinical situations. Patients need to be offered earnest counseling for sufficient informed consent with realistic expectations what to expect.

The impact of inter-fraction changes for perineal template-based interstitial gynecologic brachytherapy implants.

PurposePerineal template-based interstitial gynecologic brachytherapy (ISBT) treatments are evaluated to determine whether adaptive inter-fraction re-planning is beneficial and necessary to meet the treatment aims of the American Brachytherapy Society (ABS) consensus guidelines for interstitial brachytherapy. Adherence to the EMBRACE II protocol is also assessed.Material and methodsTen patients receiving radical intent treatment for locally advanced or recurrent gynecologic malignancies underwent a three-fraction ISBT treatment with an ABS-recommended prescription regimen of 21 to 24 Gy. Clinical treatment plans were created according to a computed tomography (CT) acquired immediately post-implant. The first fraction was delivered on the same day as the implant (Day 1). The remaining two fractions were delivered on the next day (Day 2), at least six hours apart. Prior to treating on Day 2, a verification CT was acquired, permitting assessment of over-night changes. The Day 2 CT was used to evaluate deviations in 2-Gy-per-fraction equivalent dose (EQD2) from the clinically intended dosimetry for clinical target volume (CTV), bladder, rectum, and sigmoid.ResultsFor all patients, the median (range) difference between the intended and the delivered dosimetry for the CTV D90% was 1.4 Gy10 (0.3-4.4 Gy10). For all normal tissues, the median (range) difference from the intended normal tissue dose was 2.6 Gy3 (0.1-15.5 Gy3). In all cases, the deviation from clinically intended dosimetry did not lead to a violation of recommended normal tissue dose guidelines. For two of 10 patients with large normal tissue differences (> 10 Gy3 from the intended dose), inter-fraction adaptive planning did improve the plan quality, but was not strictly required to meet the normal tissue dose planning aims.ConclusionsThe implementation of perineal template-based ISBT treatment without inter-fraction adaptive planning can be delivered to comply with the ABS normal tissue dose guidelines and EMBRACE II limits for prescribed dose.

Dedicated MRI simulation for cervical cancer radiation treatment planning: Assessing the impact on clinical target volume delineation.

Magnetic Resonance Imaging (MRI) provides excellent soft tissue definition of pelvic tumours and organs. The aim of this study was to quantify differences in delineated clinical target volumes (CTVs) between computed tomography (CT) and MRI. Twenty patients with locally advanced gynaecological malignancies were recruited. Patients underwent dedicated MRI simulation following CT simulation. Four clinicians independently contoured each CT and MRI. CTV structures were contoured using the Radiation Therapy Oncology Group (RTOG) guidelines and lymph node CTV (LN-CTV) according to published guidelines. Interobserver variability was analysed using the dice similarity coefficient (DSC) and mean absolute surface distance (MASD). Gross tumour volume delineation was more consistent on MRI compared to CT, the DSC improved from 0.77 on CT to 0.81 on MRI, P<0.01. GTV volumes were significantly smaller on MRI compared to CT (MRI 92cc vs. CT 117cc, P<0.01). The LN-CTV and combined CTV volumes were both significantly smaller on MRI compared to CT (LN-CTV: MRI 324cc vs CT 354cc, P<0.01 and combined CTV: MRI 560cc vs CT 600cc, P<0.01). The LN-CTV DSC was 0.75 for both MRI and CT, and the combined CTV DSC was 0.81 for MRI and 0.80 for CT, P=0.27. Vagina and parametria volumes exhibited more variability compared to other structures. Magnetic Resonance Imaging contouring resulted in smaller and more consistently delineated volumes when compared to CT for most CTV structures. An MRI contouring atlas is provided to complement the existing RTOG contouring guidelines.