PErsonalized TReatment for Endometrial Carcinoma (PETREC): study design and methods of a prospective Finnish multicenter trial.

BACKGROUND: Endometrial carcinomas can be classified into four molecular subgroups - mismatch repair deficient (MMRd), p53 abnormal (p53abn), polymerase-ϵ (POLE) ultramutated, and 'no specific molecular profile' (NSMP). Retrospective data imply that the response to adjuvant therapies may depend on the molecular subgroup. These findings emphasize the need for adjuvant therapy trials where patients are randomized to treatment arms separately within each molecular subgroup. PRIMARY OBJECTIVE: The PErsonalized TReatment for Endometrial Carcinoma (PETREC) trial clarifies the value of molecular classification in the determination of adjuvant therapies of high-intermediate risk and early-stage high-risk endometrial carcinoma. STUDY HYPOTHESIS: Compared with vaginal brachytherapy, the utilization of whole pelvic radiotherapy may result in improved outcomes for either MMRd or NSMP high-intermediate risk carcinomas. Early-stage high-risk p53abn and nonendometrioid carcinomas are postulated to gain benefits from chemoradiotherapy, as opposed to chemotherapy alone. POLE ultramutated carcinomas harboring high-intermediate or high-risk clinicopathologic features are speculated to have favorable prognosis without any adjuvant therapy. TRIAL DESIGN: This prospective, multicenter, phase 3 trial compares the efficacy of vaginal brachytherapy vs whole pelvic radiotherapy in high-intermediate risk MMRd and NSMP molecular subgroups, and chemotherapy vs chemoradiotherapy in early-stage high-risk p53abn subtype and nonendometrioid carcinomas. Eligible women who consent to participation in the trial are randomly allocated (1:1) to treatment arms. MAJOR INCLUSION/EXCLUSION CRITERIA: Women with stages I-II molecular integrated high-intermediate risk or high-risk endometrial carcinoma will be included. PRIMARY ENDPOINT: The primary endpoint is the 5 year cumulative incidence of disease recurrence. SAMPLE SIZE: A total sample size of 294 patients (49 subjects in each treatment arm of the three subgroups intended for randomization) was estimated to be sufficient. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Patient recruitment will be completed in 2025, and follow-up will be completed in 2030. TRIAL REGISTRATION: NCT05655260.

Dynamic contrast-enhanced MRI to characterize angiogenesis in primary epithelial ovarian cancer: An exploratory study.

PURPOSE: Angiogenesis is essential for tumor growth. Currently, there are no established imaging biomarkers to show angiogenesis in tumor tissue. The aim of this prospective study was to evaluate whether semiquantitative and pharmacokinetic DCE-MRI perfusion parameters could be used to assess angiogenesis in epithelial ovarian cancer (EOC). METHOD: We enrolled 38 patients with primary EOC treated in 2011-2014. DCE-MRI was performed with a 3.0 T imaging system before the surgical treatment. Two different sizes of ROI were used to evaluate semiquantitative and pharmacokinetic DCE perfusion parameters: a large ROI (L-ROI) covering the whole primary lesion on one plane and a small ROI (S-ROI) covering a small solid, highly enhancing focus. Tissue samples from tumors were collected during the surgery. Immunohistochemistry was used to measure the expression of vascular endothelial growth factor (VEGF), its receptors (VEGFRs) and to analyse microvascular density (MVD) and the number of microvessels. RESULTS: VEGF expression correlated inversely with Ktrans (L-ROI, r = -0.395 (p = 0.009), S-ROI, r = -0.390, (p = 0.010)), Ve (L-ROI, r = -0.395 (p = 0.009), S-ROI, r = -0.412 (p = 0.006)) and Vp (L-ROI, r = -0.388 (p = 0.011), S-ROI, r = -0.339 (p = 0.028)) values in EOC. Higher VEGFR-2 correlated with lower DCE parameters Ktrans (L-ROI, r = -0.311 (p = 0.040), S-ROI, r = -0.337 (p = 0.025)) and Ve (L-ROI, r = -0.305 (p = 0.044), S-ROI, r = -0.355 (p = 0.018)). We also found that MVD and the number of microvessels correlated positively with AUC, Peak and WashIn values. CONCLUSIONS: We observed that several DCE-MRI parameters correlated with VEGF and VEGFR-2 expression and MVD. Thus, both semiquantitative and pharmacokinetic perfusion parameters of DCE-MRI represent promising tools for the assessment of angiogenesis in EOC.

Greater increases in intratumoral apparent diffusion coefficients after chemoradiotherapy predict better overall survival of patients with cervical cancer.

PURPOSE: To evaluate whether 1) the intratumoral apparent diffusion coefficients (ADCs) change during cervical cancer treatment and 2) the pretreatment ADC values or their change after treatment predict the treatment outcome or overall survival of patients with cervical cancer. METHODS: We retrospectively enrolled 52 patients with inoperable cervical cancer treated with chemoradiotherapy, who had undergone diffusion weighted MRI before treatment and post external beam radiotherapy (EBRT) and concurrent chemotherapy. A subgroup of patients (n = 28) underwent altogether six consecutive diffusion weighted MRIs; 1) pretreatment, 2) post-EBRT and concurrent chemotherapy; 3-5) during image-guided brachytherapy (IGBT) and 6) after completing the whole treatment course. To assess interobserver and intertechnique reproducibility two observers independently measured the ADCs by drawing freehand a large region of interest (L-ROI) covering the whole tumor and three small ROIs (S-ROIs) in areas with most restricted diffusion. RESULTS: Reproducibility was equally good for L-ROIs and S-ROIs. The pretreatment ADCs were higher in L-ROIs (883 mm2/s) than in S-ROIs (687 mm2/s, P < 0.001). The ADCs increased significantly between the pretreatment and post-EBRT scans (L-ROI: P < 0.001; S-ROI: P = 0.001). The ADCs remained significantly higher than pretreatment values during the whole IGBT. Using S-ROIs, greater increases in ADCs between pretreatment and post-EBRT MRI predicted better overall survival (P = 0.018). CONCLUSION: ADC values significantly increase during cervical cancer treatment. Greater increases in ADC values between pretreatment and post-EBRT predicted better overall survival using S-ROIs. Standardized methods for timing and delineation of ADC measurements are advocated in future studies.

Neoadjuvant chemotherapy induces an elevation of tumour apparent diffusion coefficient values in patients with ovarian cancer.

OBJECTIVES: Multiparametric magnetic resonance imaging (mMRI) is the modality of choice in the imaging of ovarian cancer (OC). We aimed to investigate the feasibility of different types of regions of interest (ROIs) in the measurement of apparent diffusion coefficient (ADC) values of diffusion-weighted imaging in OC patients treated with neoadjuvant chemotherapy (NACT). METHODS: We retrospectively enrolled 23 consecutive patients with advanced OC who had undergone NACT and mMRI. Seventeen of them had been imaged before and after NACT. Two observers independently measured the ADC values in both ovaries and in the metastatic mass by drawing on a single slice of (1) freehand large ROIs (L-ROIs) covering the solid parts of the whole tumour and (2) three small round ROIs (S-ROIs). The side of the primary ovarian tumour was defined. We evaluated the interobserver reproducibility and statistical significance of the change in tumoural pre- and post-NACT ADC values. Each patient's disease was defined as platinum-sensitive, semi-sensitive, or resistant. The patients were deemed either responders or non-responders. RESULTS: The interobserver reproducibility of the L-ROI and S-ROI measurements ranged from good to excellent (ICC range: 0.71-0.99). The mean ADC values were significantly higher after NACT in the primary tumour (L-ROI p < 0.001, S-ROIs p < 0.01), and the increase after NACT was associated with sensitivity to platinum-based chemotherapy. The changes in the ADC values of the omental mass were associated with a response to NACT. CONCLUSION: The mean ADC values of the primary tumour increased significantly after NACT in the OC patients, and the amount of increase in omental mass was associated with the response to platinum-based NACT. Our study indicates that quantitative analysis of ADC values with a single slice and a whole tumour ROI placement is a reproducible method that has a potential role in the evaluation of NACT response in patients with OC. TRIAL REGISTRATION: Retrospectively registered (institutional permission code: 5302501; date of the permission: 31.7.2020).

The impact of different treatment protocols on achieved radiation doses of high-dose-rate brachytherapy for locally advanced cervical cancer: a comparison between 2 fractions in 1 application and separate applications for each fraction.

Purpose: To compare radiation doses achieved by image-guided brachytherapy for locally advanced cervical carcinoma implemented with two different protocols. Material and methods: Medical records of 117 patients with locally advanced cervical carcinoma treated with brachytherapy from 2009 to 2018 at our institution were retrospectively reviewed. All patients had received previous external beam radio/chemotherapy. We performed magnetic resonance image-guided adaptive high-dose-rate brachytherapy delivered by intra-cavitary/interstitial applicators. Dose prescription was 7 Gy for four fractions within two weeks. Original schedule of brachytherapy was two fractions delivered on consecutive days with one applicator insertion; this process was repeated one week later (group 1, 54 patients). From 2015 onwards, another protocol of brachytherapy was mainly used, separately performing applicator insertions for each of the four administered fractions (group 2, 63 patients). Results: The high-risk clinical target volume (HR-CTV) D90 planning aim (PA) of ≥ 85 Gy (hard constraint) was not achieved in 9 cases out of 54 (17%) in group 1 compared with only 2 out of 63 cases (3%) in group 2 (p = 0.022). A difference between the two groups was also found in the fulfillment of PA 90 Gy (soft constraint) (p = 0.027). We conducted a sub-group analysis of target volume groups and observed that the differences were most pronounced with very large tumors (> 50 cm3). In these patients, PA 85 Gy was only fulfilled in 67% cases when treatment involved two applications, but in all cases with four separate applicator insertions (p = 0.010). Conclusions: In our experience, by performing an applicator insertion for each of the fractions, it is possible to correct the non-optimal position of the applicator immediately, and to deliver better doses for consecutive fractions. As a result, the planning aim is more often achieved, especially for large tumors.

AAV8-mediated sVEGFR2 and sVEGFR3 gene therapy combined with chemotherapy reduces the growth and microvasculature of human ovarian cancer and prolongs the survival in mice.

Background: Vascular endothelial growth factors (VEGFs) are major regulators of intratumoral angiogenesis in ovarian cancer (OVCA). Overexpression of VEGFs is associated with increased tumor growth and metastatic tendency and VEGF-targeting therapies are thus considered as potential treatments for OVCA. Here, we examined the antiangiogenic and antitumoral effects on OVCA of adeno-associated virus 8 (AAV8)-mediated expression of soluble VEGF receptors (sVEGFRs) sVEGFR2 and sVEGFR3 together with paclitaxel and carboplatin chemotherapy. Materials and methods: Immunodeficient mice were inoculated with human OVCA cell line SKOV-3m. Development of tumors was confirmed with magnetic resonance imaging (MRI) and mice were treated with gene therapy and paclitaxel and carboplatin chemotherapy. The study groups included (I) non-treated control group, (II) blank control vector AAV8-CMV, (III) AAV8-CMV with chemotherapy, (IV) AAV8-sVEGFR2, (V) AAV8-sVEGFR3, (VI) AAV8-sVEGFR2 and AAV8-sVEGFR3, and (VII) AAV8-sVEGFR2 and AAV8-sVEGFR3 with chemotherapy. Antiangiogenic and antitumoral effects were evaluated with immunohistochemical stainings and serial MRI. Results: Reduced intratumoral angiogenesis was observed in all antiangiogenic gene therapy groups. The combined use of AAV8-sVEGFR2 and AAV8-sVEGFR3 with chemotherapy suppressed ascites fluid formation and tumor growth, thus improving the overall survival of mice. Antitumoral effect was mainly caused by AAV8-sVEGFR2 while the benefits of AAV8-sVEGFR3 and chemotherapy were less prominent. Conclusion: Combined use of the AAV8-sVEGFR2 and AAV8-sVEGFR3 with chemotherapy reduces intratumoral angiogenesis and tumor growth in OVCA mouse model. Results provide preclinical proof-of-concept for the use of soluble decoy VEGFRs and especially the AAV8-sVEGFR2 in the treatment of OVCA.

Postoperative pain in a prospectively assessed surgical short-stay cohort: A subgroup analysis.

BACKGROUND: There is sparse information about postoperative pain after short stay surgery. We explored the incidence of immediate postoperative pain and its relationship with persistent pain or opioid use 2 weeks after surgery. METHODS: This was a subgroup analysis of prospective and controlled data from adult patients (n = 931) who underwent short-stay surgery in a tertiary care hospital. Data comprised patient demographics, surgical category, pain scores and analgesic management during the recovery unit stay, before discharge on the postoperative morning after surgery and again 2 weeks after surgery. RESULTS: Half of the patients had severe dynamic pain in the recovery unit. It was commonest after orthopaedic (70% of patients), followed by gynaecological (54%), gastrointestinal (51%) and spine surgery (49%). Multimodal pain management was used for most patients (n = 811, 87%) with opioid use predominant. The median oxycodone dose during short-stay was the highest after orthopaedic surgery (39 mg). The first individual dynamic pain score after surgery was associated with follow-up pain score at rest (OR = 1.37), dynamic pain (OR = 1.35) and pain interference (OR = 1.34) at 2 weeks after surgery. Maximum dynamic pain reported in the recovery unit was associated with pain at rest (OR = 1.56), dynamic pain (OR = 1.65) and pain interference (OR = 1.45) at 2 weeks after surgery. Pain scores at 2 weeks were highest and analgesic use greatest in those patients who underwent spinal surgery. CONCLUSIONS: Intense postoperative pain remains common after short-stay surgery in some surgical categories including orthopaedic surgery and is associated with a greater likelihood of pain at 2 weeks.

Resilience, pain, and health-related quality of life in gynecological patients undergoing surgery for benign and malignant conditions: a 12-month follow-up study.

BACKGROUND: Gynecological surgery has many impacts on women's physical and mental health, and efforts to improve recovery from surgery are constantly under evaluation. Resilience is an ability to overcome stressors and adversities, such as traumas and surgeries. This study aimed to explore patients' resilience and psychological symptoms in relation to recovery, health-related quality of life (HRQoL), and pain one year after gynecological surgery. METHODS: In a prospective cohort study, we enrolled consecutive elective gynecologic surgery patients who completed questionnaires before and at one year after surgery: the Resilience Scale-25, the 15D instrument of HRQoL (15D), the Life Satisfaction Scale-4, and the Hospital Anxiety and Depression Scale. Their mean 15D scores were compared to those of an age-matched sample of women from the general Finnish population (n = 2743). RESULTS: We enrolled 271 women who underwent gynecological surgery due to benign (n = 190) and malignant (n = 81) diagnoses. Resilience was equally high in women with benign and malignant diagnoses at both time points. Higher resilience associated with less pain, analgesic use, and better pain relief from the use of pain medication at 12 months after surgery. Pain intensity was similar in the two groups, but patients with benign diseases had less pain at 12 months than before surgery. Before surgery, patients' HRQoL was worse than that of the general population, but at 12 months the mean HRQoL of patients with benign diseases had improved to the same level as that in the general population but had decreased further in patients with malignant diseases. Anxiety was higher and life satisfaction was lower in patients with malignant diseases before surgery. At 12 months, anxiety had decreased in both groups, and life satisfaction had increased in patients with malignant diseases. Depression was similarly low in both groups and time points. CONCLUSIONS: Resilience correlated with less pain one year after surgery. After surgery, HRQoL improved in patients with benign diseases but deteriorated in patients with malignant diseases. Patients with low resilience should be identified during preoperative evaluation, and health care professionals should give these patients psychological support to enhance their resilience. Trial Registration ClinicalTrials.gov; registered October 29, 2019; identifier: NCT04142203; retrospectively registered.

Patient functional recovery after a 23-h surgery - a prospective, follow-up study.

PURPOSE: We evaluated patients' functional outcomes 2 weeks after a 23-h surgery model in a tertiary care hospital. METHODS: This prospective study comprised data on 993 consecutive adult patients who underwent a 23-h surgery. Patients were interviewed before surgery and at 14 days after surgery by telephone with a multidimensional structural survey including closed- and open-ended questions. Regarding functional outcomes, the patients were asked to assess their general wellbeing, energy levels and activities of daily living on a 5-point numeric rating scale (1 = poor to 5 = excellent). Data on patient characteristics, medical history, alcohol use, smoking status and pre-, peri- and postoperative pain and satisfaction with the care received were collected and analysed to determine whether these factors contributed to their recovery. The primary outcome measure was patient functional recovery at 14 days after surgery. RESULTS: Most patients reported moderate to excellent functional outcomes: 93.6% (95% CI, 92.1--95.1) of the patients showed a score ≥ 3 on the 5-point numeric scale. One out of four patients (23%) scored all three domains as excellent. A weak inverse correlation was noted between functional recovery and most pain in the 23-h postanaesthesia care unit as well as pain at 2 weeks after surgery. A weak positive correlation was noted between functional recovery and patient satisfaction with the instructions at discharge. CONCLUSIONS: Most patients showed ample functional recovery at 14 days after the 23-h surgery. Higher pain scores in the postanaesthesia care unit and 2 weeks after surgery predicted poor functional outcomes, and satisfaction with postoperative counselling predicted better outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT04142203.

Robotic-assisted laparoscopy is a feasible method for resection of deep infiltrating endometriosis, especially in the rectosigmoid area.

OBJECTIVE: This study aimed to compare outcomes of mini-invasive surgical treatment of endometriosis, especially conventional laparoscopy with robotic-assisted laparoscopy, and to evaluate the quality of life. METHODS: One hundred three consecutive patients with endometriosis who had surgery from 2014 to 2017 owing to an indication of pain were enrolled in this retrospective study. The majority (n = 77, 75%) of patients underwent conventional laparoscopy and 18 (17%) had robotic-assisted laparoscopy. The quality of life was postoperatively assessed with a questionnaire. RESULTS: The rates of parametrectomy (76% vs. 45%,) and rectovaginal resection (28% vs. 4%) were significantly higher in robotic-assisted laparoscopy than in laparoscopy. Additionally, the rate of bowel operations (50% vs. 17%), especially the shaving technique, was higher in robotic-assisted laparoscopy surgery than in laparoscopy (39% vs. 8%). There was no difference in the rate of postoperative complications between laparoscopy and robotic-assisted laparoscopy. Most (91%) of the patients who answered the questionnaire felt that surgical treatment had relieved their pain. In the laparoscopic and robotic-assisted groups, 88% of respondents felt that their quality of life had improved after surgery. CONCLUSIONS: This study suggests that robotic-assisted laparoscopy is a feasible method to resect deep infiltrating endometriosis, especially in the rectosigmoid area.

MRI-guided brachytherapy for locally advanced cervical cancer: Program initiation, learning curve and dose delivery results in Kuopio University Hospital.

BACKGROUND AND PURPOSE: Image guided adaptive brachytherapy, the standard treatment for locally advanced cervical cancer (LACC), is a complex medical procedure that requires an experienced multidisciplinary team. The aims of this analysis were to assess (1) the learning curve of brachytherapy team, (2) dose-volume parameters, (3) the use of an interstitial component, and (4) the overall treatment time (OTT). MATERIALS AND METHODS: Our study cohort comprised 117 LACC patients treated in Kuopio University Hospital with magnetic resonance imaging guided intracavitary (IC) or combined intracavitary/interstitial (IC/IS) high dose rate brachytherapy during 2009-2018. Target volumes and organs at risk (OAR) were contoured according to ICRU/GEC-ESTRO recommendations. Treatment plans were optimized individually without using standard loading patterns. RESULTS: Mean dose to 90% of the high-risk clinical target volume (HR-CTV D90) improved after the first 15 patients, however the team's learning curve to reliably fulfill the main planning aim (PA) of 85 Gy required a total 43 patients and more than 10 patients annually. Significant difference was detected between IC and IC/IS brachytherapy in achieving the PA of HR-CTV D90. Especially, HR-CTV volumes >30 cm3 benefitted from IS needles. Needle insertion did not cause serious complications. With the brachytherapy program, the OTT of patients from outside institutions was reduced to the same level as our own patients. CONCLUSION: Brachytherapy requires good experience of multidisciplinary team and the continuous development of the program to fulfill PA and to avoid OTT prolongation. The use of IS needles is safe and improves the fulfillment of PA to target volume.

Is adaptive treatment planning for single-channel vaginal brachytherapy necessary?

PURPOSE: In vaginal cuff brachytherapy, only limited information is available about the need for individualized treatment planning or imaging. Treatment planning is still performed mostly with no contouring target volume or organs at risk and with standard plan approach. Dose prescription, fractionation, and treatment planning practices vary from site to site. Without imaging, dose must be prescribed in terms of fixed distances from a known reference, such as the applicator surface. Because of different anatomies of patients, this might lead to under-dosing of target and unnecessarily high-doses delivered to adjacent organs. Also, reliable recording of dose delivered is difficult. These various uncertainties related to standard planning and lack of imaging indicate a clear need for finding an optimal method of dose planning for vaginal cuff brachytherapy. MATERIAL AND METHODS: A study was conducted, in which 100 vaginal cuff brachytherapy patients' computed tomography (CT) images with applicator in situ were retrospectively analyzed to investigate target-area coverage and critical-organ doses. In addition, 28 patients' plans were re-planned with different planning approaches, to evaluate an optimal dose-planning strategy. From treatment plans, target coverage and organs-at-risk doses were assessed. RESULTS AND CONCLUSIONS: The analysis showed that, in order to cover distal part of the vaginal cuff, dose prescription should be a 10 mm from the tip of the applicator. Individualized image-based planning is recommended at least for first fraction. This would yield lower doses to the bladder. Rectum and sigmoid doses are not significantly affected by planning approach.

Microvessels in Epithelial Ovarian Tumors: High Microvessel Density Is a Significant Feature of Malignant Ovarian Tumors.

BACKGROUND/AIM: Examine features of blood and lymphatic vessels in ovarian tumors and their significance to prognosis of ovarian cancer. PATIENTS AND METHODS: A total of 139 women with epithelial ovarian tumors were included: 86 malignant, 17 borderline and 36 benign. Density, percentage, mean size and number of blood microvessels in tumors were measured by immunohistochemistry with antibodies against CD34 and CD105. Lymphatic vessel density was assayed using the D2-40 antibody against podoplanin. RESULTS: Angiogenesis was most profuse in malignant tumors. Small size of lymph vessels predicted 26% shorter 5-year survival of ovarian cancer patients. Further, high percentage of lymphatic vessels in tumors was associated with lymph node metastasis, and high density with cancer recurrence. Lower number of microvessels, as assessed by CD34 staining, predicted shorter progression-free survival. Additionally, the large size of microvessels assessed by CD34 and the high number of vessels assessed by CD105 were related to residual tumor >1 cm at primary surgery and also, large vessel size was associated with stage III, as assessed by CD105 staining. CONCLUSION: CD34 and CD105 define different characteristics of microvessels. Parameters of lymph vessels may predict the prognosis of ovarian cancer.

High expression of Tie-2 predicts poor prognosis in primary high grade serous ovarian cancer.

BACKGROUND: Antiangiogenic therapy, although part of standard treatment in ovarian cancer, has variable efficacy. Furthermore, little is known about the prognostic biomarkers and factors influencing angiogenesis in cancer tissue. We evaluated the expression of angiopoietin-2 and two endothelial tyrosine kinase receptors, Tie-1 and Tie-2, and assessed their value in the prediction of survival in patients with malignant epithelial ovarian cancer. We also compared the expression of these factors between primary high grade serous tumors and their distant metastasis. MATERIALS AND METHODS: We evaluated 86 women with primary epithelial ovarian cancer. Matched distal omental metastasis were investigated in 18.6% cases (N = 16). The expression levels of angiogenic factors were evaluated by immunohistochemistry in 306 specimens and by qRT-PCR in 111 samples. RESULTS: A high epithelial expression level of Tie-2 is a significant prognostic factor in primary high grade serous ovarian cancer. It predicted significantly shorter overall survival both in univariate (p<0.001) and multivariate survival analyses (p = 0.022). Low angiopoietin-2 expression levels in primary ovarian tumors were significantly associated with shorter overall survival (p = 0.015) in the univariate survival analysis. A low expression of angiopoietin-2 was also significantly related to high grade tumors, size of residual tumor after primary surgery and the recurrence of cancer (p = 0.008; p = 0.012; p = 0.018) in the whole study population. The expression of angiopoietin-2 and Tie-2 was stronger in distal omental metastasis than in primary high grade serous tumors in matched-pair analysis (p = 0.001; p = 0.002). CONCLUSIONS: The angiogenic factor, angiopoietin-2, and its receptor Tie-2 seem to be significant prognostic factors in primary epithelial ovarian cancer. Their expression levels are also increased in metastatic lesions in comparison with primary tumors.

Niraparib plus bevacizumab versus niraparib alone for platinum-sensitive recurrent ovarian cancer (NSGO-AVANOVA2/ENGOT-ov24): a randomised, phase 2, superiority trial.

BACKGROUND: Platinum-based chemotherapy is the foundation of treatment for platinum-sensitive recurrent ovarian cancer, but has substantial toxicity. Bevacizumab and maintenance poly(ADP-ribose) polymerase (PARP) inhibitors both significantly improve efficacy versus standard therapy, primarily in terms of progression-free survival, and offer the potential for chemotherapy-free treatment. AVANOVA2 compared niraparib and bevacizumab versus niraparib alone as definitive treatment for platinum-sensitive recurrent ovarian cancer. METHODS: This open-label, randomised, phase 2, superiority trial in 15 university hospitals in Denmark, Sweden, Finland, Norway, and the USA enrolled women aged 18 years or older with measurable or evaluable high-grade serous or endometrioid platinum-sensitive recurrent ovarian cancer. Patients had to have an Eastern Cooperative Oncology Group performance status of 0-2, and had to have previously received platinum-containing therapy for primary disease but ≤1 prior non-platinum-containing regimen for recurrent disease. Previous treatment with bevacizumab or first-line maintenance PARP inhibitors was permitted. Eligible patients were randomly assigned 1:1 (by random permuted blocks with block sizes of two and four, no masking), stratified by homologous recombination deficiency status and chemotherapy-free interval, to receive once-daily oral niraparib 300 mg alone or with intravenous bevacizumab 15 mg/kg once every 3 weeks until disease progression. The primary endpoint was progression-free survival, assessed by the investigators in the intention-to-treat population after events in at least 62 patients. Safety was analysed in all patients who received at least one dose of study drug. This ongoing trial is registered with ClinicalTrials.gov, number NCT02354131. FINDINGS: Between May 23, 2016, and March 6, 2017, 97 patients were enrolled and randomly assigned: 48 to niraparib plus bevacizumab and 49 to single-agent niraparib. Median follow-up was 16·9 months (IQR 15·4-20·9). Niraparib plus bevacizumab significantly improved progression-free survival compared with niraparib alone (median progression-free survival 11·9 months [95% CI 8·5-16·7] vs 5·5 months [3·8-6·3], respectively; adjusted hazard ratio [HR] 0·35 [95% CI 0·21-0·57], p<0·0001). Grade 3 or worse adverse events occurred in 31 (65%) of 48 patients who received niraparib plus bevacizumab and 22 (45%) of 49 who received single-agent niraparib. The most common grade 3 or worse adverse events in both groups were anaemia (7 [15%] of 48 vs 9 [18%] of 49) and thrombocytopenia (5 [10%] vs 6 [12%]), and hypertension in the combination group (10 [21%] vs 0). Niraparib plus bevacizumab was associated with increased incidences of any-grade proteinuria (10 [21%] of 48 patients vs 0) and hypertension (27 [56%] of 48 vs 11 [22%] of 49) compared with niraparib alone. No treatment-related deaths occurred. INTERPRETATION: The efficacy observed with this chemotherapy-free combination of approved agents in women with platinum-sensitive recurrent ovarian cancer warrants further evaluation. A randomised phase 3 trial investigating niraparib plus bevacizumab versus chemotherapy plus bevacizumab in platinum-sensitive recurrent ovarian cancer is planned. FUNDING: Nordic Society of Gynaecological Oncology and Tesaro.

Dynamic contrast-enhanced perfusion parameters in ovarian cancer: Good accuracy in identifying high HIF-1α expression.

BACKGROUND: Hypoxia significantly influences treatment response and clinical outcome in solid tumors. A noninvasive marker for hypoxia will help physicians in treatment planning and encourage the efficient use of hypoxia targeted therapies. The purpose of this study was to investigate whether pharmacokinetic dynamic contrast-enhanced (DCE) perfusion parameters are associated with a specific marker of hypoxia, hypoxia-inducible factor 1 alpha (HIF-1α) in ovarian cancer (OC). MATERIALS AND METHODS: Thirty-eight patients with primary OC were enrolled in this prospective study approved by the local ethical committee. Patients underwent dynamic gadolinium-enhanced 3.0 T MRI as part of their staging investigations. Pharmacokinetic perfusion parameters, including a rate constant for transfer of contrast agent from plasma to extravascular extracellular space (EES) (Ktrans) and a rate constant from EES to plasma (Kep), were measured by drawing two types of regions of interest (ROIs): a large solid lesion (L-ROI) and a solid, most enhancing small area (S-ROI) (NordicICE platform). Tissue samples for immunohistochemical analysis were collected during surgery. Kruskal-Wallis, Mann-Whitney U and Chi-square tests were used in statistical analyses. Receiver Operating Characteristic curve analyzes were done for DCE parameters to discriminate high HIF-1α expression. RESULTS: Pharmacokinetic perfusion parameters Ktrans and Kep were inversely associated with HIF-1α expression (Ktrans L-ROI P = 0.021; Ktrans S-ROI P = 0.018 and Kep L-ROI P = 0.032; Kep S-ROI P = 0.033). Ktrans and Kep showed good accuracy in identifying high HIF-1α expression (AUC = 0.832 Ktrans L-ROI; 0.840 Ktrans S-ROI; 0.808 Kep L-ROI and 0.808 Kep L-ROI). CONCLUSION: This preliminary study demonstrated that pharmacokinetic DCE-MRI perfusion parameters are associated with the hypoxia specific marker, HIF-1α in OC. DCE-MRI may be a useful supplementary tool in the characterization of OC tumors in a staging investigation.

Expression profiles of VEGF-A, VEGF-D and VEGFR1 are higher in distant metastases than in matched primary high grade epithelial ovarian cancer.

BACKGROUND: In many malignancies including ovarian cancer, different angiogenic factors have been related to poor prognosis. However, data on their relations to each other or importance as a prognostic factor in ovarian cancer is missing. Therefore, we investigated the expressions of VEGF-A, VEGF-C, and VEGF-D, and the receptors VEGFR1, VEGFR2, and VEGFR3 in patients with malignant epithelial ovarian neoplasms. We further compared expression levels between primary tumors and related distant omental metastases. METHODS: This study included 86 patients with malignant ovarian epithelial tumors and 16 related distant metastases. Angiogenic factor expression was evaluated using immunohistochemistry (n = 102) and qRT-PCR (n = 29). RESULTS: Compared to primary high grade serous ovarian tumors, the related omental metastases showed higher expressions of VEGF-A (p = 0.022), VEGF-D (p = 0.010), and VEGFR1 (p = 0.046). In univariate survival analysis, low epithelial expression of VEGF-A in primary tumors was associated with poor prognosis (p = 0.024), and short progression-free survival was associated with high VEGF-C (p = 0.034) and low VEGFR3 (p = 0.002). The relative expressions of VEGF-D, VEGFR1, VEGFR2, and VEGFR3 mRNA determined by qRT-PCR analyses were significantly correlated with the immunohistochemically detected levels of these proteins in primary high grade serous ovarian cancer and metastases (p = 0.004, p = 0.009, p = 0.015, and p = 0.018, respectively). CONCLUSIONS: The expressions of VEGF receptors and their ligands significantly differed between malignant ovarian tumors and paired distant metastases. VEGF-A, VEGF-D, and VEGFR1 protein expressions seem to be higher in distant metastases than in the primary high grade serous ovarian cancer lesions.

Prognostic value of preoperative dynamic contrast-enhanced magnetic resonance imaging in epithelial ovarian cancer.

OBJECTIVES: To investigate whether semi-quantitative and pharmacokinetic perfusion dynamic contrast-enhanced (DCE) parameters are associated with traditional prognostic factors and can predict clinical outcome in ovarian cancer (OC). METHODS: This prospective study, approved by local ethical committee, enrolled 38 patients with primary OC, 2011-2014. After preoperative DCE-MRI (3.0 T), two observers measured perfusion (Ktrans, Kep, Ve, Vp) and semi-quantitative parameters (area under the curve, peak, time-to-peak) by drawing regions of interest (ROIs) covering the large solid lesion (L-ROI) and the most enhancing small area (S-ROI) (NordicICE platform). Kruskal-Wallis was used to analyze associations between MRI parameters and classified prognostic factors. RESULTS: Mean Ktrans values were higher in high-grade serous OC than in other types (L-ROI, P = 0.041; S-ROI, P = 0.018), and lower mean Ktrans values predicted residual tumor (L-ROI P = 0.030; S-ROI, P = 0.012). Higher minimum Vp values were associated with higher International Federation of Gynecology and Obstetrics (FIGO) stage (S-ROI, P = 0.023).Shorter recurrence-free survival was predicted by higher Ve (minimum L-ROI, P = 0.035; maximum S-ROI, P = 0.046), Vp (maximum S-ROI, P = 0.033), and lower time-to-peak (maximum S-ROI, P = 0.047) in Kaplan-Meier analysis. Multiparametric MRI variables combining DCE and diffusion weighted data were also predictive for survival. CONCLUSION: DCE-MRI parameters may represent imaging biomarkers for predicting tumor aggressiveness and prognosis in OC. Higher Ktrans levels were associated with better results in cytoreductive surgery but with earlier recurrence.

Cervical cancer staging, pretreatment planning, and surgical treatment in the Nordic countries-Survey from the Surgical Subcommittee of the Nordic Society of Gynecological Oncology.

INTRODUCTION: Women with cervical cancer in the Nordic countries are increasingly undergoing pretreatment imaging by ultrasound, magnetic resonance imaging (MRI), positron emission tomography-computed tomography (PET-CT) or computed tomography, or sentinel lymph node procedure. The present survey reports the influence of pretreatment imaging findings on the recorded clinical International Federation of Gynecology and Obstetrics (FIGO) stage in Nordic countries and its impact on treatment planning and preferred surgical approach in cervical cancer. MATERIAL AND METHODS: The Nordic Society of Gynecological Oncology Surgical Subcommittee developed a questionnaire-based survey that was conducted from 1 January to 31 March 2017. All the 22 Nordic Gynecological Oncology Centers (Denmark 5, Finland 5, Iceland 1, Norway 4, and Sweden 7) were invited to participate. RESULTS: The questionnaires were returned by 19 of 22 (86.3%) centers. The median number (range) of women with cervical cancer treated at each center annually was 32 (15-120). In 58% (11/19) of the centers, imaging findings were reported to influence the clinical staging. MRI in combination with PET-CT was the preferred imaging method and the results influenced treatment planning. Robotic-assisted radical hysterectomy was the preferred surgical method in 72% (13/18) of the centers. Sentinel lymph node procedure was not routinely implemented in the majority of the Nordic centers. CONCLUSION: More than half of the Nordic Gynecological Oncology Centers already report a clinical FIGO stage influenced by pretreatment imaging findings. The trend in preferred treatment is robotic-assisted radical hysterectomy and the sentinel lymph node procedure is gradually being introduced.

A prospective, randomized, open label, controlled study investigating the efficiency and safety of 3 different methods of rectus sheath block analgesia following midline laparotomy.

BACKGROUND: There is a controversy regarding the efficacy of rectus sheath block (RSB). The aim of the present study was to evaluate analgesic efficacy and safety of three different methods of RSB in postoperative pain management after midline laparotomy. METHODS: A prospective, randomized, controlled, open-label clinical trial with 4 parallel groups was conducted in a tertiary care hospital in Finland. A total of 57 patients undergoing midline laparotomy were randomized to the control group (n = 12) or to 1 of the 3 active RSB analgesia groups: single-dose (n = 16), repeated-doses (n = 12), or continuous infusion (n = 17). Opioid consumption with iv-patient-controlled analgesia pump was recorded, and pain scores and patients' satisfaction were surveyed on an 11-point numeric rating scale for the first 48 postoperative h. Plasma concentrations of oxycodone and levobupivacaine were analyzed. All adverse events during the hospital stay were recorded. RESULTS: Oxycodone consumption was less during the first 12 h in the repeated-doses and in the continuous infusion groups (P = .07) and in numerical values up to 48 h in the repeated-doses group. Plasma oxycodone concentrations were similar in all 4 groups. Pain scores were lower in the repeated-doses group when coughing during the first 4 h (P = .048 vs. control group), and at rest on the first postoperative morning (P = .034 vs. the other 3 groups) and at 24 h (P = .006 vs. the single-dose group). All plasma concentrations of levobupivacaine were safe. The patients' satisfaction was better in the repeated-doses group compared with the control group (P = .025). No serious or unexpected adverse events were reported. CONCLUSIONS: RSB analgesia with repeated-doses seems to have opioid sparing efficacy, and it may enhance pain relief and patients' satisfaction after midline laparotomy.