Novel predictors of response and outcome in advanced epithelial ovarian cancer

Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) is an alternative treatment approach to primary surgery for primarily inoperable advanced epithelial ovarian cancer (EOC) patients with a poor diagnosis. A clinical challenge has been a lack of reliable noninvasive NACT response assessment methods. Evaluation of the total tumor burden changes with the serum tumor marker HE4 and metabolic 18F-FDG-PET/CT imaging provide novel opportunities for studying NACT response. A total of 54 advanced EOC patients were recruited in the study; 32 patients treated with NACT followed by IDS and 22 patients referred to primary surgery. Serum HE4 and CA125 were determined at baseline and before each NACT and postoperative chemotherapy cycles. The HE4 and CA125 percentual changes during NACT were determined. In addition to CT imaging, 18F-FDG-PET/CT was performed before and after NACT. The metabolical response to NACT was estimated by using omentum as a reference lesion and by calculating the total metabolic tumor volume (MTV). The HE4 and CA125 profiles during NACT did not correspond with the anatomical CT response. An HE4 decrease of >80% during NACT associated with longer survival. The postoperative serum HE4 levels corresponded with the residual tumor in surgery, whereas the same observation was not noted for CA125. In 18F-FDG-PET/CT, the omental SUVmax change during NACT associated with omental histopathological response. The total MTV decrease during NACT corresponded with the primary therapy outcome. The changes in serum HE4 and in 18F-FDG-PET/CT during NACT could be used to identify the patients not responding to NACT.Uudet ennusteelliset tekijät edenneen munasarjasyövän hoitovasteen ja ennusteen arvioinnissa Leikkausta edeltävää solunsalpaajahoitoa (neoadjuvanttihoito) annetaan huonoennusteisessa edenneessä munasarjasyövässä niille potilaille, jotka diagnoosivaiheessa eivät sovellu leikkaukseen. Kliinisessä työssä haasteena on ollut luotettavien noninvasiivisten menetelmien puuttuminen neoadjuvanttihoidon vastearvioinnissa. Kokonaistuumorimassan muutoksien arviointi seerumin HE4-merkkiaineella ja 18F-FDG-PET/TT-kuvantamisella ovat uusia mahdollisuuksia neoadjuvanttihoitovasteen tutkimiseen. Tutkimukseen rekrytoitiin 54 edennyttä munasarjasyöpää sairastavaa potilasta, joista 32 sai leikkausta edeltävän neoadjuvanttihoidon ja 22 leikattiin primaaristi. Seerumin HE4- ja CA125-määritykset tehtiin diagnoosivaiheessa sekä ennen jo¬kaist¬a neoadjuvantti- ja leikkauksen jälkeistä solunsalpaajakuuria. Seeru¬mista määritettiin HE4- ja CA125-pitoisuuksien neoadjuvanttihoidon aikainen muutos. Varjoainetehosteisen TT-tutkimuksen lisäksi potilaille tehtiin 18F-FDG-PET/TT-kuvaus ennen ja jälkeen neoadjuvanttihoidoa. 18F-FDG-PET/TT-kuvista määritettiin vatsapaidan kasvaimen metabolisen ak¬tiivisuuden (maximum standardized uptake value, SUVmax) sekä metabolisesti aktiivin kokonaistuumoritilavuuden muutos neoadjuvanttihoidon aikana. Neoadjuvanttihoidon aikaiset HE4 ja CA125 profiilit eivät olleet yhteydessä anatomiseen TT-vasteeseen. Yli 80%:n muutos HE4:ssä neoadjuvanttihoidon aikana ennusti pidempää elossaoloa. Leikkauksen jälkeen määritetty HE4 kuvasti jäännöskasvaimen määrää, mutta samaa havaintoa ei voitu osoittaa CA125:llä. 18F-FDG-PET/TT:ssä vatsapaidan kasvaimen SUVmax muutos oli yhteydessä kasvaimen histopatologiseen vasteeseen ja kokonaistuumoritilavuuden vähentyminen neoadjuvanttihoidon aikana ennusti primaarihoidon vastetta. Seerumin HE4-pitoisuudessa ja 18F-FDG-PET/TT:ssä nähtävillä neoadjuvanttihoidon aikaisilla muutoksilla voitiin tunnistaa ne potilaat, jotka eivät hyötyneet neoadjuvanttihoidosta

Advanced epithelial ovarian cancer – studies on preoperative [18F] FDG PET/CT and HE4 profile during primary chemotherapy

Epithelial ovarian cancer (EOC) is usually diagnosed in an advanced stage. The prognosis depends highly on the amount of the residual tumor in surgery. In patients with extensive disease, neoadjuvant chemotherapy (NACT) is used to diminish the tumor load before debulking surgery. New non-invasive methods are needed to preoperatively evaluate the disease dissemination and operability. [18F] FDG PET/CT (Positron emission tomography/computed tomography) is a promising method for cancer diagnostics and staging. The biomarker profiles during treatment can predict patient’s outcome. This prospective study included 41 EOC patients, 21 treated with primary surgery and 20 with NACT and interval surgery. The performances of preoperative contrast enhanced PET/CT (PET/ceCT) and diagnostic CT (ceCT) were compared. Perioperative visual estimation of tumor spread was studied in primary and interval surgery. The profile of the serum marker HE4 (Human epididymis 4) during primary chemotherapy was evaluated. In primary surgery, surgical findings were found to form an adequate reference standard for imaging studies. After NACT, the sensitivity for visual estimation of cancer dissemination was significantly worse. Preoperative PET/ceCT was more effective than ceCT alone in detecting extra-abdominal disease spread. The high number of supradiaphragmatic lymph node metastases detected by PET/ceCT at the time of diagnosis brings new insight in EOC spread patterns. The sensitivity of both PET/CT and ceCT remained modest in intra-abdominal areas important to operability. The HE4 profile was in concordance with the CA125 profile during primary chemotherapy. Its role in the evaluation of EOC chemotherapy response will be clarified in further studies.Siirretty Doriast

Cytoreductive surgery for Ovarian cancer:Improvement of surgical outcome with the PlasmaJet Surgical device

IntroductionIn 2021, 1238 Dutch women were diagnosed with ovarian cancer. More than 75% of these women were diagnosed with an advanced stage disease: metastases were found throughout the whole abdominal cavity (FIGO stage III) or even outside the abdominal cavity (FIGO stage IV). The survival gain for women with advanced stage ovarian cancer (≥FIGO stage IIB) is mainly found in women in whom complete cytoreductive surgery (CRS) can be achieved. This means that all visible tumor in the abdomen is removed. In recent years, it became increasingly clear that there are large differences in overall survival between those women in whom all disease could be removed and those in whom minimal disease (less than 1 cm) remained after surgery. Therefore, surgical teams are committed to removing all disease in every woman, even from difficult sites and precarious surfaces such as the bowel, the small bowel and the diaphragm. MethodsA multicenter randomized trial was designed, the PlaComOv study. 'PlaComOv' is an acronym for 'Will the use of the PLAsmaJet® device improve the rate of COMplete cytoreductive surgery for advanced-stage OVarian cancer?' The primary objective of the PlaComOv study was to assess the efficacy and safety of the PlasmaJet. Secondary outcomes were the impact on tissue damage, cost and quality-of-life.Results327 women with advanced stage epithelial ovarian cancer were included for the PlaComOv study between February 2018 and September 2020. Of these women, 157 were randomized into the intervention group and 170 into the control group. Randomization involved stratification for suspected ovarian cancer versus proven ovarian cancer, primary versus interval CRS, presence versus absence of peritoneal carcinomatosis on CT scan, and whether or not hyperthermic intraperitoneal chemotherapy (HIPEC) was administered. For patients in the intervention group, the surgeon could decide whether or not to use the PlasmaJet during surgery. The intention-to-treat analysis showed that 75.8% of the patients in the intervention group underwent complete CRS compared to 67.6% of the patients in the control group (p=0.131). The per-protocol analysis showed the surgical outcome of the patients who actually underwent CRS. In addition to excluding 27 patients who did not undergo CRS, 3 patients were excluded because of protocol violation: those patients underwent surgery in which the PlasmaJet was used while they were included in the control group. In the per-protocol analysis, complete cytoreductive surgery was achieved in 85.6% of the intervention group compared to 71.5% in the control group (p=0.005).A sub-analysis for patients with peritoneal carcinomatosis (≥50 lesions on the diaphragm, peritoneum and/or mesentery) showed that the use of the PlasmaJet improved the surgical outcome: complete CRS was achieved in 72.2% in the intervention group versus 51.5% in the control group (p=0.034).No differences were found between the two groups in terms of operative time or blood loss. Postoperatively, the number of complications, re-laparotomies or readmissions did not appear to be significantly different between the two groups. In a series of 106 histological samples from 17 patients who underwent interval CRS, the mean depth of tissue damage was found to be smaller in tissue treated with the PlasmaJet (0.15 mm) than in tissue treated with electrocoagulation (0.33 mm) (p&lt;0.001). All healthcare costs for the patients included in the PlaComOv study were analyzed. These costs comprised the healthcare costs of patients with advanced stage ovarian cancer from diagnosis and treatment until six weeks after the last chemotherapy. The mean total health care costs for patients treated with the PlasmaJet were significantly higher than those for patients treated with conventional CRS (€19,414 versus €18,165, p=0.017). 285 patients (87%) completed the questionnaires about Quality-of-Life (QoL), and two years postoperatively, 172 patients (77%) out of 224 living patients completed the questionnaires. QoL decreased postoperatively but increased after six months to the same QoL level as before surgery. Higher QoL was reported in several domains by patients treated in the intervention group. Twelve months after surgery, patients in the intervention group rated their QoL higher than patients in the control group (p=0.005). Two years after surgery, this difference in QoL was no longer significant.ConclusionsThe use of the PlasmaJet increased the probability of complete CRS, especially in patients with a large number of peritoneal lesions without a higher complication rate.Long term results as a cost-effectiveness analysis, the progression free survival and overall survival have to be waited.<br/

Cytoreductive surgery for Ovarian cancer:Improvement of surgical outcome with the PlasmaJet Surgical device

IntroductionIn 2021, 1238 Dutch women were diagnosed with ovarian cancer. More than 75% of these women were diagnosed with an advanced stage disease: metastases were found throughout the whole abdominal cavity (FIGO stage III) or even outside the abdominal cavity (FIGO stage IV). The survival gain for women with advanced stage ovarian cancer (≥FIGO stage IIB) is mainly found in women in whom complete cytoreductive surgery (CRS) can be achieved. This means that all visible tumor in the abdomen is removed. In recent years, it became increasingly clear that there are large differences in overall survival between those women in whom all disease could be removed and those in whom minimal disease (less than 1 cm) remained after surgery. Therefore, surgical teams are committed to removing all disease in every woman, even from difficult sites and precarious surfaces such as the bowel, the small bowel and the diaphragm. MethodsA multicenter randomized trial was designed, the PlaComOv study. 'PlaComOv' is an acronym for 'Will the use of the PLAsmaJet® device improve the rate of COMplete cytoreductive surgery for advanced-stage OVarian cancer?' The primary objective of the PlaComOv study was to assess the efficacy and safety of the PlasmaJet. Secondary outcomes were the impact on tissue damage, cost and quality-of-life.Results327 women with advanced stage epithelial ovarian cancer were included for the PlaComOv study between February 2018 and September 2020. Of these women, 157 were randomized into the intervention group and 170 into the control group. Randomization involved stratification for suspected ovarian cancer versus proven ovarian cancer, primary versus interval CRS, presence versus absence of peritoneal carcinomatosis on CT scan, and whether or not hyperthermic intraperitoneal chemotherapy (HIPEC) was administered. For patients in the intervention group, the surgeon could decide whether or not to use the PlasmaJet during surgery. The intention-to-treat analysis showed that 75.8% of the patients in the intervention group underwent complete CRS compared to 67.6% of the patients in the control group (p=0.131). The per-protocol analysis showed the surgical outcome of the patients who actually underwent CRS. In addition to excluding 27 patients who did not undergo CRS, 3 patients were excluded because of protocol violation: those patients underwent surgery in which the PlasmaJet was used while they were included in the control group. In the per-protocol analysis, complete cytoreductive surgery was achieved in 85.6% of the intervention group compared to 71.5% in the control group (p=0.005).A sub-analysis for patients with peritoneal carcinomatosis (≥50 lesions on the diaphragm, peritoneum and/or mesentery) showed that the use of the PlasmaJet improved the surgical outcome: complete CRS was achieved in 72.2% in the intervention group versus 51.5% in the control group (p=0.034).No differences were found between the two groups in terms of operative time or blood loss. Postoperatively, the number of complications, re-laparotomies or readmissions did not appear to be significantly different between the two groups. In a series of 106 histological samples from 17 patients who underwent interval CRS, the mean depth of tissue damage was found to be smaller in tissue treated with the PlasmaJet (0.15 mm) than in tissue treated with electrocoagulation (0.33 mm) (p&lt;0.001). All healthcare costs for the patients included in the PlaComOv study were analyzed. These costs comprised the healthcare costs of patients with advanced stage ovarian cancer from diagnosis and treatment until six weeks after the last chemotherapy. The mean total health care costs for patients treated with the PlasmaJet were significantly higher than those for patients treated with conventional CRS (€19,414 versus €18,165, p=0.017). 285 patients (87%) completed the questionnaires about Quality-of-Life (QoL), and two years postoperatively, 172 patients (77%) out of 224 living patients completed the questionnaires. QoL decreased postoperatively but increased after six months to the same QoL level as before surgery. Higher QoL was reported in several domains by patients treated in the intervention group. Twelve months after surgery, patients in the intervention group rated their QoL higher than patients in the control group (p=0.005). Two years after surgery, this difference in QoL was no longer significant.ConclusionsThe use of the PlasmaJet increased the probability of complete CRS, especially in patients with a large number of peritoneal lesions without a higher complication rate.Long term results as a cost-effectiveness analysis, the progression free survival and overall survival have to be waited.<br/

ESMO-ESGO consensus conference recommendations on ovarian cancer: Pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease

The development of guidelines is one of the core activities of the European Society for Medical Oncology (ESMO) and European Society of Gynaecologial Oncology (ESGO), as part of the mission of both societies to improve the quality of care for patients with cancer across Europe. ESMO and ESGO jointly developed clinically-relevant and evidence-based guidelines in several selected areas in order to improve the quality of care for women with ovarian cancer. The ESMO-ESGO consensus conference on ovarian cancer was held on 12-14 April 2018 in Milan, Italy, and comprised a multidisciplinary panel of 40 leading experts in the management of ovarian cancer. Before the conference, the expert panel worked on five clinically relevant questions regarding ovarian cancer relating to each of the following four areas: pathology and molecular biology, early-stage and borderline tumours, advanced stage disease and recurrent disease. Relevant scientific literature, as identified using a systematic search, was reviewed in advance. During the consensus conference, the panel developed recommendations for each specific question and a consensus was reached. The recommendations presented here are thus based on the best available evidence and expert agreement. This article presents the recommendations of this ESMO-ESGO consensus conference, together with a summary of evidence supporting each recommendation

Primary and metastatic peritoneal surface malignancies

Peritoneal surface malignancies comprise a heterogeneous group of primary tumours, including peritoneal mesothelioma, and peritoneal metastases of other tumours, including ovarian, gastric, colorectal, appendicular or pancreatic cancers. The pathophysiology of peritoneal malignancy is complex and not fully understood. The two main hypotheses are the transformation of mesothelial cells (peritoneal primary tumour) and shedding of cells from a primary tumour with implantation of cells in the peritoneal cavity (peritoneal metastasis). Diagnosis is challenging and often requires modern imaging and interventional techniques, including surgical exploration. In the past decade, new treatments and multimodal strategies helped to improve patient survival and quality of life and the premise that peritoneal malignancies are fatal diseases has been dismissed as management strategies, including complete cytoreductive surgery embedded in perioperative systemic chemotherapy, can provide cure in selected patients. Furthermore, intraperitoneal chemotherapy has become an important part of combination treatments. Improving locoregional treatment delivery to enhance penetration to tumour nodules and reduce systemic uptake is one of the most active research areas. The current main challenges involve not only offering the best treatment option and developing intraperitoneal therapies that are equivalent to current systemic therapies but also defining the optimal treatment sequence according to primary tumour, disease extent and patient preferences. New imaging modalities, less invasive surgery, nanomedicines and targeted therapies are the basis for a new era of intraperitoneal therapy and are beginning to show encouraging outcomes

The ESSO core curriculum committee update on surgical oncology

Cancer care; Curriculum; Surgical oncologyCuidado del cancer; Plan de estudios; Oncología quirúrgicaCura del càncer; Pla d'estudis; Oncologia quirúrgicaIntroduction Surgical oncology is a defined specialty within the European Board of Surgery within the European Union of Medical Specialists (UEMS). Variation in training and specialization still occurs across Europe. There is a need to align the core knowledge needed to fulfil the criteria across subspecialities in surgical oncology. Material and methods The core curriculum, established in 2013, was developed with contributions from expert advisors from within the European Society of Surgical Oncology (ESSO), European Society for Radiotherapy and Oncology (ESTRO) and European Society of Medical Oncology (ESMO) and related subspeciality experts. Results The current version reiterates and updates the core curriculum structure needed for current and future candidates who plans to train for and eventually sit the European fellowship exam for the European Board of Surgery in Surgical Oncology. The content included is not intended to be exhaustive but, rather to give the candidate an idea of expectations and areas for in depth study, in addition to the practical requirements. The five elements included are: Basic principles of oncology; Disease site specific oncology; Generic clinical skills; Training recommendations, and, lastly; Eligibility for the EBSQ exam in Surgical Oncology. Conclusions As evidence-based care for cancer patients evolves through research into basic science, translational research and clinical trials, the core curriculum will evolve, mature and adapt to deliver continual improvements in cancer outcomes for patients

Ovarian cancer. Biomarkers, surgical outcome and survival.

Ovarian cancer is the eighth most common female cancer worldwide and the most lethal of the gynaecologic malignancies. Around 700 women are diagnosed in Sweden per year. Due to vague symptoms most of the patients are diagnosed with late-stage epithelial ovarian cancer (EOC) and prognosis is poor, with a five-year survival of 49%. However, for early-stage EOC the prognosis is excellent. Biomarkers for screening and early diagnosis have been sought for decades. To date, CA125 and HE4 are the only biomarkers in clinical use. Both lack sensitivity and specificity for early-stage EOC. The standard treatment for EOC is primary surgery with adjuvant chemotherapy. Centralisation of ovarian cancer care to high-volume hospitals with subspecialist surgeons and improved chemotherapy regimens have improved outcome and survival. Ovarian cancer surgery was centralised in Sweden in 2012.The aims of my thesis were to assess new biomarkers for their potential to improve the diagnostic performance of CA125 and HE4 in women with ovarian tumours (studies I and II), to evaluate ovarian cancer surgery after centralisation (study III) and to assess the incidence and survival in EOC in Sweden since the 1960s (study IV). Study I: CA125, HE4, B7-H4 and cleaved and intact suPAR were analysed in preoperative plasma samples from 350 women with ovarian tumours. Plasma levels of CA125, HE4 and suPAR(II-III) were found to increase from benign tumours to borderline, EOC type I and EOC type II while B7-H4 was only elevated in EOC II. Logistic regression models were fitted and a model combining CA125, HE4, suPAR(II-III) and age performed better (AUC=0.933) than the established ROMA algorithm (CA125, HE4 and menopause status) for discrimination of benign tumours from EOC in premenopausal women. The ROMA performed best in postmenopausal women (AUC=0.914). Furthermore, we correlated preoperative biomarker levels with survival after EOC diagnosis. High HE4, CA125 and suPAR(I) were prognostic for poor survival. At 12 months suPAR(I) was the only independent biomarker prognostic for poor short-term survival. In women above 75 years, high suPAR(I) indicated very poor prognosis in the first year after diagnosis (HR=8.9, p=0.01).Study II: 177 inflammation- and cancer-associated biomarkers were analysed in preoperative plasma samples from 180 women with ovarian tumour, using the proximity extension assay. HE4 was the best performing single biomarker for discrimination between benign tumours and EOC. Three-biomarker combinations of HE4, CA125 and one additional biomarker were compared to a reference model of HE4 and CA125. No biomarker significantly improved the diagnostic performance of HE4 and CA125. Study III: We analysed data from the GynOp Registry 2013-15. Out of 1108 cases of ovarian cancer surgery with curative intent, 30% were performed in regional hospitals with fewer than 20 cases per year. Four tertiary centres performed more than 25 surgeries per year. Compared with regional hospitals, tertiary centres perform more extensive surgery without an increased frequency of major complications. Large differences exist in patient selection for primary surgery and complete resection rates between the tertiary centres. Study IV: We identified all women with a diagnosis of epithelial ovarian, fallopian tube, and peritoneal cancers or undesignated abdominal/pelvic cancer from 1960 to 2014 in the Swedish Cancer Registry. Analyses of age-standardised incidence and relative survival (RS) were carried out and time trend graphs were modelled according to age, tumour site, and morphology. Since 1980 the age-standardised incidence of EOC has declined in Sweden. The age-standardised RS in EOC up to five years from diagnosis improved from 1960 to 2014. The 10-year RS has remained unchanged since 1960. In conclusion, CA125 plus HE4 continues to stand out as the best biomarker combination for assessment of cancer risk in a woman with ovarian tumours. CA125, HE4 and suPAR(I) are potential prognostic markers. Adding biomarkers to the preoperative assessment, especially in elderly women, could aid in the treatment decision on extensive primary surgery or neoadjuvant treatment. After centralisation of ovarian cancer surgery in Sweden, many women still have surgery at low-volume regional hospitals. The treatment for advanced EOC seems to differ considerably between the tertiary centres. Further centralisation as well as increased collaboration and exchange of knowledge between tertiary centres are needed to ensure equal access to care, regardless of region of living. Improved surgical and oncological treatment has prolonged life after EOC diagnosis. However, long-term survival remains poor. Most patients will die of their cancer. In order to cure EOC we need to find the patients at early stages. Better diagnostic tools are urgently needed