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PURPOSE Tissue factor is highly expressed in cervical carcinoma and can be targeted by tisotumab vedotin (TV), an antibody-drug conjugate. This phase Ib/II study evaluated TV in combination with bevacizumab, pembrolizumab, or carboplatin for recurrent or metastatic cervical cancer (r/mCC). METHODS This open-label, multicenter study (ClinicalTrials.gov identifier: NCT03786081) included dose-escalation arms that assessed dose-limiting toxicities (DLTs) and identified the recommended phase II dose (RP2D) of TV in combination with bevacizumab (arm A), pembrolizumab (arm B), or carboplatin (arm C). The dose-expansion arms evaluated TV antitumor activity and safety at RP2D in combination with carboplatin as first-line (1L) treatment (arm D) or with pembrolizumab as 1L (arm E) or second-/third-line (2L/3L) treatment (arm F). The primary end point of dose expansion was objective response rate (ORR). RESULTS A total of 142 patients were enrolled. In dose escalation (n = 41), no DLTs were observed; the RP2D was TV 2 mg/kg plus bevacizumab 15 mg/kg on day 1 once every 3 weeks, pembrolizumab 200 mg on day 1 once every 3 weeks, or carboplatin AUC 5 on day 1 once every 3 weeks. In dose expansion (n = 101), the ORR was 54.5% (n/N, 18/33; 95% CI, 36.4 to 71.9) with 1L TV + carboplatin (arm D), 40.6% (n/N, 13/32; 95% CI, 23.7 to 59.4) with 1L TV + pembrolizumab (arm E), and 35.3% (12/34; 19.7 to 53.5) with 2L/3L TV + pembrolizumab (arm F). The median duration of response was 8.6 months, not reached, and 14.1 months, in arms D, E, and F, respectively. Grade ≥3 adverse events (≥15%) were anemia, diarrhea, nausea, and thrombocytopenia in arm D and anemia in arm F (none ≥15%, arm E).CONCLUSION TV in combination with bevacizumab, carboplatin, or pembrolizumab demonstrated manageable safety and encouraging antitumor activity in treatment-naive and previously treated r/mCC.

Endometrial carcinosarcoma is a rare and aggressive high-grade endometrial carcinoma with secondary sarcomatous trans-differentiation (conversion theory). The clinical presentation and diagnostic work-up roughly align with those of the more common endometrioid counterpart, although endometrial carcinosarcoma is more frequently diagnosed at an advanced stage. Endometrial carcinosarcoma is not a single entity but encompasses different histological subtypes, depending on the type of carcinomatous and sarcomatous elements. The majority of endometrial carcinosarcomas are characterized by p53 abnormalities. The proportion of POLE and microsatellite instablity-high (MSI-H) is directly related to the epithelial component, being approximately 25% and 3% in endometrioid and non-endometrioid components.The management of non-metastatic disease is based on a multimodal approach with optimal surgery followed by (concomitant or sequential) chemotherapy and radiotherapy, even for early stages. Palliative chemotherapy is recommended in the metastatic or recurrent setting, with carboplatin/paclitaxel doublet being the first-line regimen. Although the introduction of immunotherapy plus/minus a tyrosine kinase inhibitor shifted the paradigm of treatment of patients with recurrent endometrial cancer, patients with endometrial carcinosarcoma were excluded from most studies evaluating single-agent immunotherapy or the combination. However, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved the use of pembrolizumab and lenvatinib in endometrial cancer (all histotypes) after progression on chemotherapy and single-agent immunotherapy in MSI-H cancers. In the era of precision medicine, emerging knowledge on molecular endometrial carcinosarcoma is opening new promising therapeutic options for more personalized treatment. The present review outlines state-of-the-art knowledge and future directions for patients with endometrial carcinosarcoma.

Endometrial carcinosarcoma is a rare and aggressive high-grade endometrial carcinoma with secondary sarcomatous trans-differentiation (conversion theory). The clinical presentation and diagnostic work-up roughly align with those of the more common endometrioid counterpart, although endometrial carcinosarcoma is more frequently diagnosed at an advanced stage. Endometrial carcinosarcoma is not a single entity but encompasses different histological subtypes, depending on the type of carcinomatous and sarcomatous elements. The majority of endometrial carcinosarcomas are characterized by p53 abnormalities. The proportion of POLE and microsatellite instablity-high (MSI-H) is directly related to the epithelial component, being approximately 25% and 3% in endometrioid and non-endometrioid components.The management of non-metastatic disease is based on a multimodal approach with optimal surgery followed by (concomitant or sequential) chemotherapy and radiotherapy, even for early stages. Palliative chemotherapy is recommended in the metastatic or recurrent setting, with carboplatin/paclitaxel doublet being the first-line regimen. Although the introduction of immunotherapy plus/minus a tyrosine kinase inhibitor shifted the paradigm of treatment of patients with recurrent endometrial cancer, patients with endometrial carcinosarcoma were excluded from most studies evaluating single-agent immunotherapy or the combination. However, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved the use of pembrolizumab and lenvatinib in endometrial cancer (all histotypes) after progression on chemotherapy and single-agent immunotherapy in MSI-H cancers. In the era of precision medicine, emerging knowledge on molecular endometrial carcinosarcoma is opening new promising therapeutic options for more personalized treatment. The present review outlines state-of-the-art knowledge and future directions for patients with endometrial carcinosarcoma.

Invasive lobular carcinoma (ILC) is the most common histologic subtype of breast cancer after invasive ductal carcinoma (i.e., no special type [NST]). ILC differs from NST in clinical presentation, site-specific metastases and response to conventional therapies. Loss of E-cadherin protein expression, due to alterations in its encoding gene is the most frequent oncogenic event in ILC. Synthetic lethality approaches have shown promising antitumor effects of ROS1 inhibitors in models of E-cadherin-defective breast cancer in studies and provide the rationale for testing their clinical activity in patients with ILC. Entrectinib is a tyrosine kinase inhibitor targeting TRK, ROS1 and ALK tyrosine kinases. Here, the authors present ROSALINE (NCT04551495), a phase II study testing neoadjuvant entrectinib and endocrine therapy in women with estrogen receptor-positive, HER2-negative early ILC.

Clear cell endometrial carcinoma represents an uncommon and poorly understood entity. Data from molecular/genomic profiling highlighted the importance of various signatures in assessing the prognosis of endometrial cancer according to four classes of risk (POLE mutated, MMRd, NSMP, and p53 abnormal). Unfortunately, data specific to clear cell histological subtype endometrial cancer are lacking. More recently, data has emerged to suggest that most of the patients (more than 80%) with clear cell endometrial carcinoma are characterized by p53 abnormality or NSMP type. This classification has important therapeutic implications. Although it is an uncommon entity, clear cell endometrial cancer patients with POLE mutation seem characterized by a good prognosis. Chemotherapy is effective in patients with NSMP (especially in stage III and IV) and patients with p53 abnormal disease (all stages). While, preliminary data suggested that patients with MMRd are less likely to benefit from chemotherapy. The latter group appears to benefit much more from immune checkpoint inhibitors: recent data from clinical trials on pembrolizumab plus lenvatinib and nivolumab plus cabozantinib supported that immunotherapy plus tyrosine kinase inhibitors (TKI) would be the most appropriate treatment for recurrent non-endometrioid endometrial cancer (including clear cell carcinoma) after the failure of platinum-based chemotherapy. Moreover, ongoing clinical trials testing the anti-tumor activity of innovative products will clarify the better strategies for advanced/recurrent clear cell endometrial carcinoma. Further prospective evidence is urgently needed to better characterize clear cell endometrial carcinoma. (C) 2022 Elsevier Inc. All rights reserved.

357 p., ill., SCIENTIFIC REPORT 23 -- 1 INTRODUCTION 23 -- 1.1 OVARIAN CANCER 24 -- 1.1.1 Background 24 -- 1.1.2 Epidemiology of ovarian cancer in Belgium 24 -- 1.2 DISPERSION OF CARE FOR OVARIAN CANCER IN BELGIUM 25 -- 1.3 MEASURING QUALITY 26 -- 2 OBJECTIVES AND SCOPE 27 -- 2.1 AIM OF THE STUDY 27 -- 2.2 SCOPE 27 -- 2.3 TARGET AUDIENCE 27 -- 3 METHODOLOGY 28 -- 3.1 STEP 1: IDENTIFICATION OF THE TARGET POPULATION: DATA SELECTION AND LINKAGE OF DATABASES 28 -- 3.1.1 Selection of the study population in the Belgian Cancer Registry database 28 -- 3.1.2 Linkage with health insurance data 30 -- 3.1.3 Vital status 31 -- 3.1.4 Pathology reports 31 -- 3.1.5 Data unavailable for assessment of quality indicators 31 -- 3.2 STEP 2: IDENTIFICATION AND SELECTION OF POSSIBLE QUALITY INDICATORS 31 -- 3.2.1 Identification of possible quality indicators 31 -- 3.2.2 Selection process and results 31 -- 3.2.3 Measurability of selected quality indicators 32 -- 3.2.4 Final selection of quality indicators to be fully elaborated 32 -- 3.3 STEP 3: OPERATIONALIZATION OF INDICATORS 34 -- 3.3.1 Technical fiches 35 -- 3.3.2 Defining diagnostic and therapeutic procedures 35 -- 3.3.3 Defining the treatment scheme of the patient 41 -- 3.3.4 Case-mix adjustment 41 -- 3.3.5 Statistical analysis 44 -- 3.4 STEP 4: ASSIGNMENT OF EACH PATIENT TO ONE CENTRE 47 -- 3.5 STEP 5: VALIDATION OF DIAGNOSTIC AND THERAPEUTIC DATA 50 -- 3.5.1 Introduction and methodology 50 -- 3.5.2 Results of the validation of the algorithm to assign each patient to one centre of first diagnosis and one centre of main treatment 51 -- 3.5.3 Validation of the patient and tumour characteristics and of diagnostic and therapeutic procedures 52 -- 3.5.4 Validation of the quality indicator results 56 -- 3.5.5 Conclusion 56 -- 4 CHARACTERISTICS OF THE STUDY COHORT 56 -- 4.1 BASELINE DEMOGRAPHICS AND TUMOUR CHARACTERISTICS 57 -- 4.2 MAIN DIAGNOSTIC PROCEDURES 57 -- 4.3 MAIN THERAPEUTIC PROCEDURES 58 -- 4.3.1 Surgical procedures 58 -- 4.3.2 Chemotherapy

29 p., ill., Le Centre fédéral d’Expertise des Soins de santé (KCE) publie un ensemble de 15 indicateurs de qualité pour la prise en charge du cancer de l’ovaire. Cette démarche s’inscrit dans un processus continu d’amélioration de la qualité des soins en oncologie en Belgique et a déjà été appliquée avec fruit pour d’autres types de cancers. Les résultats des 15 indicateurs ont été calculés au niveau national, et tous les hôpitaux recevront ensuite un rapport d'évaluation individuel envoyé par la Fondation Registre du Cancer. Cela leur permettra d'identifier leurs points forts et leurs points faibles et d'améliorer leurs pratiques si nécessaire. Dans une seconde partie, l’étude a démontré que les chances de survie sont nettement plus élevées dans les hôpitaux qui traitent un grand nombre de patientes chaque année. Le KCE plaide donc pour une concentration de la prise en charge du cancer de l’ovaire dans un nombre limité de centres de référence. La reconnaissance de ces centres de référence ne doit cependant pas se baser sur le seul nombre de patientes traitées., PRÉFACE 1 -- MESSAGES CLÉS 2 -- 1. CONTEXTE ET OBJECTIFS 6 -- 1.1. LE SYSTÈME BELGE D’AMÉLIORATION DE LA QUALITÉ DES SOINS EN ONCOLOGIE 6 -- 1.2. LE CANCER DE L’OVAIRE 7 -- 1.3. OBJECTIFS DE CETTE ÉTUDE 7 -- 2. DONNÉES ET MÉTHODES 8 -- 2.1. IDENTIFICATION ET SÉLECTION DES INDICATEURS DE QUALITÉ 8 -- 2.2. POPULATION CIBLE DE CETTE ÉTUDE 8 -- 2.2.1. Sources de données 8 -- 2.2.2. Plus de 5 000 patientes incluses entre 2014 et 2018 9 -- 2.2.3. Traitements administrés 10 -- 2.2.4. Autres caractéristiques prises en compte 10 -- 2.2.5. Assignation de chaque patiente à un hôpital 10 -- 2.3. ÉTUDE DE VALIDATION 10 -- 3. RÉSULTATS DES INDICATEURS DE QUALITÉ 11 -- 3.1. DIAGNOSTIC ET STADIFICATION 13 -- 3.2. CHIMIOTHÉRAPIE 14 -- 3.3. COMPLICATIONS, MORTALITÉ ET SURVIE 15 -- 4. IMPACT DU VOLUME HOSPITALIER SUR LES RÉSULTATS 16 -- 4.1. GRANDE DISPERSION DES SOINS EN BELGIQUE 16 -- 4.2. RELATION ENTRE LE VOLUME HOSPITALIER DE PRISE EN CHARGE THÉRAPEUTIQUE ET LA SURVIE EN BELGIQUE 17 -- 4.3. RELATION ENTRE LE VOLUME CHIRURGICAL HOSPITALIER ET LA SURVIE EN BELGIQUE 18 -- 4.4. REVUE DE LITTÉRATURE INTERNATIONALE 18 -- 5. CONCLUSION 19 -- RECOMMANDATIONS 22 -- RÉFÉRENCES 26

29 p., ill., Het Federaal Kenniscentrum voor de Gezondheidszorg (KCE) publiceert een set van 15 kwaliteitsindicatoren voor de behandeling van eierstokkanker. Dit maakt deel uit van een continu proces om de kwaliteit van de kankerzorg in België te verbeteren en is reeds met succes toegepast bij andere types kanker. De 15 indicatoren werden berekend voor alle ziekenhuizen, die een individueel feedbackrapport van de Stichting Kankerregister zullen ontvangen, zodat zij hun sterke en zwakke punten kunnen identificeren en waar nodig de zorg verbeteren. In een tweede deel toont de studie aan dat de kans van patiënten op overleven duidelijk hoger is in ziekenhuizen die elk jaar een groot aantal patiënten behandelen. Het KCE pleit er dan ook voor de behandeling van eierstokkanker in een beperkt aantal referentiecentra te concentreren. Bij de erkenning van deze referentiecentra mag het aantal behandelde patiënten zeker niet het enige criterium zijn., VOORWOORD 1 --  KERN-BOODSCHAPPEN 2 -- 1. CONTEXT EN DOELSTELLINGEN 7 -- 1.1. HET BELGISCH SYSTEEM TER VERBETERING VAN DE KWALITEIT VAN ZORG IN DE -- ONCOLOGIE 7 -- 1.2. EIERSTOKKANKER 8 -- 1.3. DOELSTELLINGEN VAN DEZE STUDIE 8 -- 2. GEGEVENS EN METHODEN 9 -- 2.1. IDENTIFICATIE EN SELECTIE VAN DE KWALITEITSINDICATOREN 9 -- 2.2. DOELPOPULATIE VAN DE STUDIE 9 -- 2.2.1. Gegevensbronnen 9 -- 2.2.2. Meer dan 5.000 patiënten in de studie opgenomen tussen 2014 en 2018 10 -- 2.2.3. Toegepaste behandelingen 11 -- 2.2.4. Andere kenmerken die in aanmerking werden genomen in de analyses 11 -- 2.2.5. Toewijzing van elke patiënte aan een ziekenhuis 11 -- 2.3. VALIDATIESTUDIE 12 -- 3. RESULTATEN VAN DE KWALITEITSINDICATOREN 12 -- 3.1. DIAGNOSE EN STADIËRING 14 -- 3.2. CHEMOTHERAPIE 16 -- 3.3. COMPLICATIES, STERFTE EN OVERLEVING 17 -- 4. INVLOED VAN HET ZIEKENHUISVOLUME OP DE RESULTATEN 18 -- 4.1. GROTE VERSNIPPERING VAN DE ZORG 18 -- 4.2. VERBAND TUSSEN HET ZIEKENHUISVOLUME VAN BEHANDELING EN DE OVERLEVING IN BELGIË 19 -- 4.3. VERBAND TUSSEN HET CHIRURGISCH VOLUME VAN HET ZIEKENHUIS EN DE OVERLEVING IN BELGIË 19 -- 4.4. LITERATUURSTUDIE 20 -- 5. CONCLUSIE 21 -- AANBEVELINGEN 24 -- REFERENTIES 28

37 p., ill., KEY MESSAGES 1 -- SHORT REPORT 3 -- 1. BACKGROUND 6 -- 1.1. QUALITY IMPROVEMENT INITIATIVES IN ONCOLOGY 6 -- 1.2. EPIDEMIOLOGY OF OVARIAN CANCER 6 -- 1.3. SCOPE 6 -- 1.4. AIM OF THE STUDY 7 -- 2. DATA AND METHODS 7 -- 2.1. IDENTIFICATION AND SELECTION OF QUALITY INDICATORS 7 -- 2.2. DATA SELECTION AND LINKAGE OF DATABASES 7 -- 2.3. DEFINITION OF SURGERY BASED ON PATHOLOGY REPORTS 8 -- 2.4. CASE-MIX ADJUSTMENT 8 -- 2.5. STATISTICAL ANALYSES 8 -- 2.6. ASSIGNMENT OF PATIENTS TO A CENTRE 9 -- 2.7. VALIDATION STUDY AND SUBSEQUENT DATA CHECKS 9 -- 3. QUALITY OF CARE FOR PATIENTS WITH EPITHELIAL OVARIAN CANCER 10 -- 3.1. BASELINE DEMOGRAPHICS AND TUMOUR CHARACTERISTICS 10 -- 3.2. MAIN THERAPEUTIC PROCEDURES 11 -- 3.3. RESULTS FOR 15 QUALITY INDICATORS 12 -- 3.3.1. Diagnosis and staging 14 -- 3.3.2. Treatment 16 -- 3.3.3. Safety of care – 30-day complicated recovery and mortality after surgery 18 -- 3.3.4. Survival after the diagnosis of epithelial ovarian cancer 19 -- 3.4. ASSOCIATION BETWEEN HOSPITAL VOLUME AND OUTCOMES 21 -- 3.4.1. Dispersion of care 21 -- 3.4.2. Hospital main treatment volume 22 -- 3.4.3. Hospital surgical volume 23 -- 3.4.4. Discussion 24 -- 4. STRENGTHS AND LIMITATIONS 25 -- 5. CONCLUSIONS AND PERSPECTIVES FOR THE FUTURE 27 -- RECOMMENDATIONS 30 -- REFERENCES 33

A phase II study (PRIMMO) of patients with pretreated persistent/recurrent/metastatic cervical or endometrial cancer is presented. Patients received an immunomodulatory five-drug cocktail (IDC) consisting of low-dose cyclophosphamide, aspirin, lansoprazole, vitamin D, and curcumin starting 2 weeks before radioimmunotherapy. Pembrolizumab was administered three-weekly from day 15 onwards; one of the tumor lesions was irradiated (8Gyx3) on days 15, 17, and 19. The primary endpoint was the objective response rate per immune-related response criteria (irORR) at week 26 (a lower bound of the 90% confidence interval [CI] of > 10% was considered efficacious). The prespecified 43 patients (cervical, n = 18; endometrial, n = 25) were enrolled. The irORR was 11.1% (90% CI 2.0–31.0) in cervical cancer and 12.0% (90% CI 3.4–28.2) in endometrial cancer. Median duration of response was not reached in both cohorts. Median interval-censored progression-free survival was 4.1 weeks (95% CI 4.1–25.7) in cervical cancer and 3.6 weeks (95% CI 3.6–15.4) in endometrial cancer; median overall survival was 39.6 weeks (95% CI 15.0–67.0) and 37.4 weeks (95% CI 19.0–50.3), respectively. Grade ≥ 3 treatment-related adverse events were reported in 10 (55.6%) cervical cancer patients and 9 (36.0%) endometrial cancer patients. Health-related quality of life was generally stable over time. Responders had a significantly higher proportion of peripheral T cells when compared to nonresponders (p = 0.013). In conclusion, PRIMMO did not meet its primary objective in both cohorts; pembrolizumab, radiotherapy, and an IDC had modest but durable antitumor activity with acceptable but not negligible toxicity. Trial registration ClinicalTrials.gov (identifier NCT03192059) and EudraCT Registry (number 2016-001569-97)., SCOPUS: ar.j, info:eu-repo/semantics/published