Overall Survival in Patients with Endometrial Cancer Treated with Dostarlimab plus Carboplatin-Paclitaxel in the Randomized ENGOT-EN6/GOG-3031/RUBY Trial.

BACKGROUND: Part 1 of the RUBY trial (NCT03981796) evaluated dostarlimab plus carboplatin-paclitaxel compared with placebo plus carboplatin-paclitaxel in patients with primary advanced or recurrent endometrial cancer. At the first interim analysis, the trial met one of its dual-primary endpoints with statistically significant progression-free survival benefits in the mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) and overall populations. Overall survival (OS) results are reported from the second interim analysis. PATIENTS AND METHODS: RUBY is a phase 3, global, double-blind, randomized, placebo-controlled trial. Part 1 of RUBY enrolled eligible patients with primary advanced stage III or IV or first recurrent endometrial cancer who were randomly assigned (1:1) to receive either dostarlimab (500 mg) or placebo, plus carboplatin-paclitaxel every 3 weeks for 6 cycles followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. OS was a dual-primary endpoint. RESULTS: A total of 494 patients were randomized (245 in dostarlimab arm; 249 in placebo arm). In the overall population, with 51% maturity, RUBY met the dual-primary endpoint for OS at this second interim analysis, with a statistically significant reduction in the risk of death (HR = 0.69; 95% CI, 0.54-0.89; P = 0.0020) in patients treated with dostarlimab plus carboplatin-paclitaxel versus carboplatin-paclitaxel alone. The risk of death was lower in the dMMR/MSI-H population (HR = 0.32; 95% CI, 0.17-0.63; nominal P = 0.0002) and a trend in favor of dostarlimab was seen in the mismatch repair proficient/microsatellite stable (MMRp/MSS) population (HR = 0.79; 95% CI, 0.60-1.04; nominal P = 0.0493). The safety profile for dostarlimab plus carboplatin-paclitaxel was consistent with the first interim analysis. CONCLUSIONS: Dostarlimab in combination with carboplatin-paclitaxel demonstrated a statistically significant and clinically meaningful overall survival benefit in the overall population of patients with primary advanced or recurrent endometrial cancer while demonstrating an acceptable safety profile.

Randomized phase II BGOG/ENGOT-cx1 study of paclitaxel-carboplatin with or without nintedanib in first-line recurrent or advanced cervical cancer.

OBJECTIVE: Nintedanib is an oral tyrosine kinase inhibitor targeting, among others, vascular endothelial growth factor receptor. The aim was to establish the role of nintedanib in addition to paclitaxel and carboplatin in first-line recurrent/metastatic cervical cancer. METHODS: Double-blind phase II randomized study in patients with first-line recurrent or primary advanced (FIGO stage IVB) cervical cancer. Patients received carboplatin-paclitaxel with oral nintedanib 200 mg BID/placebo. The primary endpoint was progression-free survival (PFS) at 1.5 years and α = 0.15, ß = 80%, one sided. RESULTS: 120 patients (62 N, 58C) were randomized. Median follow-up was 35 months. Baseline characteristics were similar in both groups (total population: squamous cell carcinoma 62%, prior radiotherapy 64%, primary advanced 25%, recurrent 75%). The primary endpoint was met with a PFS at 1.5 years of 15.1% versus 12.8% in favor of the nintedanib arm (p = 0.057). Median overall survival (OS) was 21.7 and 16.4 months for N and C, respectively. Confirmed RECIST response rate was 48% for N and 39% for C. No new adverse events were noted for N. However, N was associated with numerically more serious adverse events for anemia and febrile neutropenia. Global health status during and at the end of the study was similar in both arms. CONCLUSION: The study met its primary endpoint with a prolonged PFS in the N arm. No new safety signals were observed.

Recurrent or primary metastatic cervical cancer: current and future treatments.

Despite screening programs for early detection and the approval of human papillomavirus vaccines, around 6% of women with cervical cancer (CC) are discovered with primary metastatic disease. Moreover, one-third of the patients receiving chemoradiation followed by brachytherapy for locally advanced disease will have a recurrence. At the end, the vast majority of recurrent or metastatic CC not amenable to locoregional treatments are considered incurable disease with very poor prognosis. Historically, cisplatin monotherapy, then a combination of cisplatin and paclitaxel were considered the standard of care. Ten years ago, the addition of bevacizumab to chemotherapy demonstrated favorable data in terms of response rate and overall survival. Even with this improvement, novel therapies are needed for the treatment of recurrent CC in first as well as later lines. In the last decades, a better understanding of the interactions between human papillomavirus infection and the host immune system response has focused interest on the use of immunotherapeutic drugs in CC patients. Indeed, immune checkpoint inhibitors (pembrolizumab, cemiplimab, and others) have recently emerged as novel therapeutic pillars that could provide durable responses with impact on overall survival in patients in the primary (in addition to chemotherapy) or recurrent (monotherapy) settings. Tisotumab vedotin, an antibody-drug conjugate targeting the tissue factor, is another emerging drug. Several trials in monotherapy or in combination with immunotherapy, chemotherapy, or bevacizumab showed very promising results. There is a high need for more potent biomarkers to better accurately determine which patients would receive the greatest benefit from all these aforementioned drugs, but also to identify patients with specific molecular characteristics that could benefit from other targeted therapies. The Cancer Genome Atlas Research Network identified several genes significantly mutated, potentially targetable. These molecular data have highlighted the molecular heterogeneity of CC.

Homologous recombination repair deficiency (HRD) testing in newly diagnosed advanced-stage epithelial ovarian cancer: A Belgian expert opinion.

Ovarian cancer (OC) has a poor prognosis as most patients present with non-specific symptoms and the disease is mostly diagnosed at advanced stages. Approximately 90% of cases are classified as epithelial OC (EOC), a category comprising histologically and molecularly distinct tumours. Identifying reliable biomarkers and employing personalised therapies in OC subgroups is crucial for battling the disease. EOCs are often characterised by homologous recombination repair deficiency (HRD), frequently caused by inactivation of the breast cancer susceptibility (BRCA) genes. These findings have led to the development of poly- (adenosine diphosphate [ADP])- ribose polymerase inhibitors (PARPi), which are synthetically lethal to HRD tumour cells. Both patients with HRD and non-HRD tumours can benefit from PARPi therapy in the recurrent setting. Moreover, recent phase III trials in patients with newly diagnosed advanced-stage OC have demonstrated greater clinical benefit from PARPi in treating HRD than non-HRD tumours. These findings offer new opportunities for the use of PARPi as maintenance therapy after first-line chemotherapy based on the presence of HRD. In the current article, we provide recommendations for HRD testing and treatment of patients with newly diagnosed advanced-stage EOC.

[Aseptic loosening after knee mega-prostheses]. / L'image du mois. Descellement aseptique d'une méga-prothèse de genou.

The use of mega-joint prostheses has become common practice in the field of reconstructive orthopedic surgery. These new implants are considered as the gold standard for reconstruction after joint and periarticular tumor and bone resections. The placement of these prostheses makes it possible, compared to an amputation, to preserve the pathological limb, but also to be able to ensure a solid assembly allowing immediate support and a quick functional recovery. However, the incidence of various complications following the placement of these implants remains higher compared to conventional joint replacement surgery. The most frequent can be classified into two distinct categories: mechanical and non-mechanical complications.

Le recours aux méga-prothèses de remplacement de cortex osseux articulaires est devenu pratique courante dans le domaine de la chirurgie orthopédique de reconstruction. Ces implants sont d'usage courant dans le domaine des opérations de résection tumorale et osseuse articulaire et péri-articulaire. La mise en place de ces prothèses permet, par rapport à une amputation, de conserver le membre atteint, mais aussi de pouvoir assurer un montage solide autorisant un appui immédiat et une récupération fonctionnelle rapide et efficace. Cependant, l'incidence de diverses complications après la mise en place de ces implants demeure plus élevée en comparaison aux opérations d'arthroplastie classique. Les principales complications peuvent être classées en deux catégories distinctes : les complications mécaniques et non mécaniques.

[Locally-advanced cervix cancer : multidisciplinary management]. / Cancer du col utérin localement avancé : approche multidisciplinaire.

Cervical cancer is the fourth most common cancer in women and is linked in over 95 % of cases to papillomavirus infection, the incidence of which has fallen in recent years due to screening and vaccination. Almost half of these cancers are diagnosed at a locally advanced stage with an overall 5-year survival of around 65 %. In recent decades, the management strategy of these locally advanced cancers has changed considerably and has allowed the improvement of survival but above all of local control as well as the reduction of toxicity, due to the implementation of imaging. Standard treatment consists of external beam radiation therapy combined with concomitant chemotherapy followed by intrauterine brachytherapy. The role of neo-adjuvant and adjuvant chemotherapy is still being evaluated. New therapeutic approaches (particularly immunotherapy) in addition to standard treatment are also being studied.

Le cancer du col de l'utérus est le quatrième cancer le plus fréquent chez la femme et est lié, dans sup�rieur a 95 % des cas, à une infection par le papillomavirus, dont l'incidence a chuté ces dernières années grâce au dépistage et à la vaccination. Près de la moitié de ces cancers sont diagnostiqués à un stade localement avancé avec une survie globale à 5 ans de l'ordre de 65 %. Ces dernières décennies, la stratégie de prise en charge de ces cancers localement avancés a considérablement changé. Elle a permis l'amélioration de la survie, mais surtout du contrôle local, ainsi que la réduction de la toxicité, grâce notamment à l'implémentation de l'imagerie. Le traitement standard consiste en une radiothérapie externe associée à une chimiothérapie concomitante, suivie d'une curiethérapie intra-utérine. La place de la chimiothérapie néo-adjuvante et adjuvante est toujours en cours d'évaluation. De nouvelles approches thérapeutiques (immunothérapie), en complément du traitement standard, sont aussi à l'étude.

Treatment algorithm in patients with ovarian cancer.

Most ovarian cancer patients are diagnosed only at advanced stages when survival outcomes are worse, andwhen therapeutic decisions might prove challenging. The fundamental treatment for women with ovarian cancerincludes debulking surgery whenever possible and appropriate systemic therapy (chemotherapy, targeted andantiangiogenic agents). In the last few years, knowledge about histological and molecular characteristics of ovariancancer subtypes and stages has increased considerably. This has enabled the development and improvement ofseveral options for the diagnosis and treatment of ovarian cancer in a patient-tailored approach. Accordingly,therapeutic decisions are guided by the characteristics of the patient and the tumour, especially the molecularfeatures of the cancer subtype and disease stage. Particularly relevant are the advances in early genetic testing ofgermline and somatic mutations involved in DNA repair, and the clinical development of targeted agents. In orderto implement the best individual medical strategies, in this article, we present an algorithm of treatment options,including recently developed targeted agents, for primary and recurrent ovarian cancer patients in Belgium.

[Carcinoma of unknown primary : a not so rare entity]. / Le carcinome de site primitif inconnu, une entité pas si rare .

Carcinomas of unknown primary (CUP) form a whole group of heterogeneous neoplasias. CUP are defined as metastatic epithelial tumors in which the initial work up has failed to detect the primary site. Their frequency is 3-5 % of the adult solid neoplasias. The prognosis is poor with a life expectancy of a few months (inferior to 1 year). The treatment depends on the histology and, particularly, on the metastatic localiza¬tion. Surgery with or without radiotherapy is the preferred treatment option for isolated lesions. Systemic chemotherapy (with platinum compound) will be recommended for multiple lesions. The genetic expression profile of tumor cells could be useful in the future to determine the site of the primary tumor and/or to offer the best therapy for each patient.

Les carcinomes de site primitif inconnu ou CaPI, forment un groupe d'entités pathologiques très hétérogènes de par leurs modes de révélation et leurs présentations cliniques. Le CaPI se définit par une tumeur épithéliale maligne, d'emblée métastatique, dont le site initial reste occulte au terme du bilan pré-thérapeutique exhaustif. Il représente 3 à 5 % des tumeurs solides malignes de l'adulte. Son pronostic est sombre avec une médiane de survie allant de 6 à 10 mois. La thérapeutique sera fonction de l'histologie tumorale, de la localisation métastatique et de la suspicion d'origine du primitif. En présence d'une néoplasie localisée, une prise en charge chirurgicale accompagnée ou non d'une radiothérapie sera proposée; en cas de dissémination métastatique multiple, une chimiothérapie systémique à base de sels de platine est recommandée. L'espoir réside dans l'analyse du profil moléculaire, afin de définir avec précision l'origine tumorale primitive et d'offrir la thérapeutique la mieux adaptée possible.

[Management of febrile neutropenia in cancer patients]. / Prise en charge de la neutropénie fébrile chez le patient cancéreux.

The incidence of cancer is raising and the treatments are increasingly aggressive. Consequently, general practitioners, emergency departments, hematologists and oncologists are regularly facing a severe side-effect of cytotoxic therapy, febrile neutropenia (FN). FN is a serious complication of chemotherapy because it can be quickly fatal and causes a temporary or definitive cessation of treatment. In this article, we summarize the latest recommendations for the management of patients with FN under anti-cancer treatments.

[Multidisciplinary treatment of glioblastoma]. / Le traitement multidisciplinaire du glioblastome.

Glioblastoma is a primary brain tumor that occurs most often in elderly patients. Despite improved management, the prognosis of this cancer remains poor. This review describes the multidisciplinary management of the patient with glioblastoma. It includes surgery, radiation therapy and chemotherapy.

[New treatments for castration-resistant prostate cancer]. / Actualités thérapeutiques dans le traitement médical du cancer de la prostate résistant à la castration.

Docetaxel chemotherapy is a standard treatment for fit men with symptomatic castration-resistant prostate cancer. Unfortunately docetaxel resistant disease will systematically develop and second-line treatment may be appropriate. Until recently no standard treatment was approved in this setting and mitoxantrone was commonly used. Three new drugs have shown benefit in randomised phase 3 multicenter clinical trials published since 2010. Cabazitaxel, abiraterone and enzalutamide were shown to prolong overall survival of men with metastatic castration-resistant prostate cancer previously treated with chemotherapy. Although still modest these results were deemed clinically significant and led to the reimbursement of Jevtana (cabazitaxel) and Zytiga (abiraterone) in Belgium in 2012.

[Clinical case of the month. Ovarian cancer metastasis to the pectoral muscle]. / Le cas clinique du mois. Métastase musculaire en présence d'un cancer de l'ovaire.

We report the case of a patient with a sero-papillary ovarian cancer and a pectoral muscle metastasis. Muscular metastases are more common than previously suspected; any physician could encounter this type of case in his daily practice. This paper summarizes the literature on the subject.

[Pazopanib (Votrient) in the management of renal cell cancer and soft tissue sarcomas]. / Pazopanib (Votrient) dans le traitement du cancer du rein et des sarcomes des tissus mous.

Renal cell carcinoma accounts for 3% of all malignant tumors. Until a few years ago, immunotherapy (Interferon and/or Interleukin-2) was the only approved systemic treatment in the metastatic setting. Better knowledge of renal cell cancer biology drew attention on the fundamental role of angiogenesis. Several strategies targeting angiogenesis have been developed including VEGF and VEGFR inhibitors. They are now the standard treatment in first and second line. Pazopanib, a VEGFR tyrosine kinase inhibitor, is one of the treatment options recommended for patients with metastatic renal cell carcinoma, in first line and after cytokines failure. Since more recently, pazopanib is also approved in the treatment of metastatic soft tissue sarcoma, after failure of at least one line of chemoterapy. In this paper, we will review the mechanism of action and the clinical results of pazopanib in renal cell carcinoma and sarcoma.

[Does Radiotherapy have a role in end-of-life care?]. / Y a-t-il une place pour la radiothérapie en fin de vie?

Up to 50% of cancer patients will receive radiation therapy as a part of their treatment. Radiation may be delivered with curative or palliative intent, according to the extent of disease, the patient's performance status and his wishes. The aim of palliative radiotherapy is to locally control primary tumor or metastasis and, thus, to slow down the disease. Another purpose is to decrease symptoms as part of the supportive care in the end of life. The total dose, the dose per fraction and the technique of irradiation used vary with the treatment aim. Indications of radiotherapy in the end of life are reviewed in this paper

[Peritoneal carcinomatosis of unknown origin]. / Carcinomatose péritonéale d'origine indéterminée.

Peritoneal carcinomatosis is defined as a secondary neoplastic invasion of the peritoneum. This entity may represent a significant challenge in terms of its diagnosis, its exploration and research of its origin and its treatment. This clinical history illustrates the difficulties generated by a case of peritoneal carcinomatosis and describes the importance of a multidisciplinary approach. When the primary origin is unknown before the initiation of treatment, the peritoneal carcinomatosis is a form of carcinoma of unknown primary (CUP). When this condition affects a woman, it becomes a particular entity with a better outcome, for which a specific first-line treatment should be initiated.

[Trabectedin (ET-743/Yondelis) for treating soft tissue sarcomas and ovarian cancer]. / Trabectédine (ET-743/Yondelis) dans le traitement des sarcomes des tissus mous et du cancer de l'ovaire.

Soft tissue sarcomas account for 1% of all malignant tumours. Until a few years ago, doxorubicine and ifosfamide were the only active chemotherapy drugs in the metastatic setting. Recently, a new drug has proven its efficacy after failure of standard treatments: the trabectedin; its activity is based on interference with ADN repair mechanisms. Trabectedin has just been also validated and reimbursed in patients with ovarian cancer, in partially sensitive recurrence. In this paper, we will review the mechanism of action and the clinical results of trabectedin.

[Everolimus (RAD001/Afinitor) in the treatment of metastatic cell carcinoma]. / Le médicament du mois. Evérolimus (RAD001/Afinitor) dans le traitement du cancer du rein métastatique.

Renal cell carcinoma accounts for 3% of all malignant tumours. Until a few years ago, immunotherapy (interferon and/or interleukin-2) was the only approved option in the metastatic setting. Better knowledge of renal cell cancer biology drew attention on the fundamental role of angiogenesis. Several strategies targeting angiogenesis have been developed including VEGF ("Vascular Endothelial Growth Factor") and VEGFR inhibitors. They are now the usual treatment in first line. Until recently, no standard treatment was available after failure under or after these inhibitors. Everolimus (Afinitor), a mTOR ("mammalian Target Of Rapamycin") inhibitor, has just been validated and reimbursed in this setting. In this paper, we will review the mechanism of action and the clinical results of everolimus.

["Triple negative" breast cancer]. / Le cancer du sein "triple négatif".

In western countries, every woman out of eight will develop breast cancer. Over the last two decades, the incidence has considerably increased, but mortality has remained stable and begins to decrease in Europe and the United-States, probably because of new therapy, changes in the use of hormone replacement therapy in postmenopausal women and early diagnosis. Breast cancer is still the first cause of death by cancer in woman under 65. "Triple negative" a breast cancer, a subtype representing 10% of all breast cancers, is characterised by the absence of receptors to oestrogen, progesterone and no histochemical expression of HER-2 growth factor. This subtype carries a poor prognosis and a high incidence of early metastatic recurrence. Furthermore, no target therapy can be defined up to now in this subtype. Thus, identification of new target therapy and prediction of tumoral response to various treatments could help in the global understanding of patients affected by this particularly aggressive type of breast cancer.

Assessment of Response to Therapy for Bone Metastases: Is it Still a Challenge in Oncology?

Bone is one of the most common sites of metastases from cancer. Most anticancer treatments are highly toxic but only a fraction of all patients respond to them. Guidelines are needed to evaluate the response in the routine practice of oncology as well as in clinical trials in which new treatment options are evaluated. All current imaging procedures have major limitations. This article reviews old and new criteria for response evaluation. The major problem of accurate response evaluation in bone disease is discussed in detail. Some examples from our daily practice illustrate the difficulties. The indications for bone biopsy are also reviewed.