[Apalutamide, Erleada®]. / Le Médicament du mois. Apalutamide, Erleada®.

Androgen-deprivation therapy (ADT), either bilateral orchiectomy or treatment with a gonadotropin-releasing hormone analogue agonist or antagonist, is the mainstay of treatment for advanced prostate cancer. In the metastatic setting, although ADT is initially effective, castration-resistant disease eventually develops in almost all men with prostate cancer. Since 2015, the addition of docetaxel, abiraterone, enzalutamide, apalutamide or darolutamide with docetaxel to ADT has been shown to improve overall survival (OS) of patients starting ADT for metastatic disease. Castration resistance occurs when disease progresses despite testosterone in the castrate range most commonly with or, more rarely, without detectable metastases. The addition of next-generation antiandrogens to ADT has been shown to improve OS in patients with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC) identified by a PSA doubling time (DT) ? 10 months. Apalutamide is a nonsteroidal antiandrogen agent that binds directly to the ligand-binding domain of the androgen receptor without agonist activity. When added to ADT apalutamide has been shown to improve OS by 35 % in patients starting ADT for metastatic prostate cancer both in patients with upfront metastatic disease or after previous treatment with curative intent. Similarly apalutamide has been shown to provide a 14-month OS improvement in patients with nmCRPC and short PSA DT. These OS benefits were obtained at no cost in terms of quality of life. Apalutamide is given orally once a day and is well tolerated. The most common side effects are fatigue, rash, hypertension and hot flushes. Potential interactions with concomitant medication should be taken into account.

La privation androgénique, chimique au moyen d'agonistes ou d'antagonistes de la LHRH, ou chirurgicale par orchidectomie, est un élément essentiel du traitement du cancer de la prostate avancé. Chez les patients métastatiques, son efficacité est cependant transitoire et une progression survient invariablement. Depuis 2015, une amélioration de la survie des patients métastatiques devant débuter une privation androgénique a été démontrée par l'instauration précoce soit d'une chimiothérapie par docétaxel, soit d'une hormonothérapie de nouvelle génération telle que l'abiratérone, l'enzalutamide, l'apalutamide, voire un traitement combinant docétaxel et darolutamide. Lorsque les patients progressent en dépit de la privation androgénique, on les dit résistants à la castration, le plus souvent en présence de métastases mais parfois en l'absence de lésion secondaire identifiable. Dans le cas des patients non métastatiques résistant à la castration à risque élevé d'évolution défavorable en raison d'un temps de doublement du PSA ? 10 mois, on a également démontré que l'ajout d'un anti-androgène de nouvelle génération améliorait la survie globale des patients. L'apalutamide, ou Erleada®, est un inhibiteur sélectif du récepteur aux androgènes, sans activité agoniste, administré par voie orale. Son instauration, en même temps que la privation androgénique, permet de réduire de 35 % la mortalité des patients métastatiques d'emblée ou secondairement après un traitement initial à visée curative. De même, l'apalutamide permet d'augmenter de 14 mois la survie des patients non métastatiques résistant à la castration à risque élevé d'évolution défavorable. Ces améliorations de la survie globale ont été obtenues sans détérioration de la qualité de vie. L'Erleada® est globalement bien toléré, et facile à administrer, s'agissant d'une prise orale unique quotidienne. La fatigue, la toxicité cutanée souvent modérée, l'hypertension artérielle et les bouffées de chaleur sont les effets secondaires les plus fréquents. Il convient également d'être attentif aux interactions médicamenteuses potentielles.

Treatment of patients with newly diagnosed metastatic hormone sensitive prostate cancer (mHSPC) in Belgium: a real world data analysis.

INTRODUCTION: Abiraterone acetate + prednisone (AAP) and docetaxel have proven their efficacy in the treatment of patients with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) in clinical trials. However, real-world data are scarce. The goal of this study is to evaluate real-world data on the efficacy and safety of these therapies in mHSPC patients. PATIENTS AND METHODS: Records of 93 patients from 21 different centres were retrospectively reviewed. Primary and secondary endpoints were radiographic and PSA progression-free survival (RPFS - PSA-PFS) and cancer specific and overall survival (CSS - OS), respectively. Adverse events (AEs) were evaluated according to the Common Terminology Criteria for Adverse Events version 5.0. Differences in oncological outcome and AEs were evaluated between three treatment groups: ADT only (N=26) - ADT + AAP (N=48) - ADT + docetaxel (N=19). Survival analysis was performed using Kaplan-Meier statistics. RESULTS: Median RPFS was 13 months (95% confidence interval [CI]: 9-17) for ADT only, 21 months (95% CI: 19-23) for ADT + AAP and 12 months (95% CI: 11-14) for ADT + docetaxel (p = 0.004). The 1-year PSA-PFS, CSS and OS were 73.5%, 90.7% and 88.7%, respectively, with no significant differences between the three groups. Adverse events of grade 3 or higher were not observed more frequently. CONCLUSION: Retrospective real-world data show a significantly longer RPFS for mHSPC patients treated with ADT + AAP compared to ADT only or ADT + docetaxel at short-term follow-up. This can aid in counselling of mHSPC patients in daily clinical practice.

[Immunotherapy for head and neck squamous cell carcinoma]. / Place de l'immunothérapie dans le traitement des carcinomes épidermoïdes de la tête et du cou.

Current recommendations for systemic treatments of head and neck squamous cell carcinoma have been significantly modified with the advent of immunotherapy for a majority of these cancers. Indeed, immune checkpoint inhibitors are now recommended in metastatic disease and in locoregional recurrence not amenable to a local treatment. PD-L1 positive tumours are eligible for immunotherapy in first line and immunotherapy is also available in second line, after failure of platinum based chemotherapy, regardless of PD-L1 expression. Ongoing clinical trials are exploring the role of immune checkpoint inhibitors in the adjuvant setting as well as with radiotherapy as definitive treatment. Immunotherapy has changed the treatment landscape and has improved the prognosis of patients with head and neck squamous cell carcinoma.

Les recommandations actuelles concernant les traitements systémiques des carcinomes épidermoïdes de la tête et du cou ont été largement modifiées avec l'avènement de l'immunothérapie pour une majorité de ces cancers. En effet, les inhibiteurs de points de contrôle immunitaire sont maintenant recommandés en situation métastatique ou en cas de récidive locorégionale inaccessible à un traitement local et ce, dès la première ligne pour les tumeurs exprimant le PD-L1. L'immunothérapie est également accessible en deuxième ligne, après échec d'une chimiothérapie par sels de platine, quelle que soit l'expression du PD-L1. Des études cliniques étudiant leur place en situation adjuvante ou concomitante à la radiothérapie sont également en cours. Ces traitements d'immunothérapie ont élargi les possibilités thérapeutiques et amélioré le pronostic des patients présentant un carcinome épidermoïde de la tête et du cou.

[Management of metastatic hormone-naive prostate cancer at diagnosis]. / Prise en charge d'un cancer de la prostate métastatique au diagnostic.

In Belgium, 12 % of patients present with upfront metastatic hormone-naive prostate cancer. Surgical or medical castration has been the only approved treatment for decades. Since 2014, several randomized trials have demonstrated that survival could be significantly improved in patients who are deemed fit enough to cope with the potential added side-effects. Docetaxel chemotherapy and androgen receptor axis-targeted next generation hormonal agents such as abiraterone, enzalutamide and apalutamide have been shown to improve overall survival when given within 12 weeks after castration initiation. Similarly, prostate radiotherapy, in the absence of urological contraindications, might also improve overall survival in patients presenting with less than 5 bone metastases. How these strategies can be combined remains a matter of debate and is currently under investigation.

En Belgique, le cancer de la prostate se présente sous une forme métastatique d'emblée chez 12 % des patients. Depuis des décennies, le traitement repose sur la castration, chirurgicale ou médicamenteuse. Depuis 2014, plusieurs études randomisées ont démontré le bénéfice de compléter cette castration chez les patients aptes à tolérer les effets secondaires éventuels des traitements complémentaires proposés. La chimiothérapie par docétaxel et les hormonothérapies de nouvelle génération visant l'axe androgènes/récepteurs aux androgènes, telles que l'abiratérone, l'enzalutamide et l'apalutamide, permettent d'augmenter significativement la survie des patients lorsqu'elles sont instaurées dans les 3 mois qui suivent la mise en oeuvre de la castration. De même, l'irradiation de la prostate, lorsque la situation urologique le permet, pourrait augmenter la survie des patients ayant moins de 5 métastases osseuses. Le bénéfice éventuel de combiner ces stratégies reste débattu et en cours d'investigation.

[What is the standard treatment approach for a cervical lymph node metastasis from a squamous cell carcinoma of unknown origin?]. / Exploration et traitement d'un carcinome épidermoïde ganglionnaire cervical sans primitif décelé.

The diagnostic work-up of cervical lymph node metastases from an occult primary tumour in the head and neck region is well established. PET-scan, which was controversial, is nowadays an integral part of it. Common therapeutic strategies include neck dissection followed by extensive irradiation of pharyngeal mucosa and bilateral lymph node areas. Chemotherapy is often added to these treatment modalities, especially if negative prognostic factors are present on the pathological specimen. However, its therapeutic benefit is not yet proven. There are numerous phase II studies available in the literature, sometimes with controversial conclusions. Therefore, as long as there are no data issued from randomized controlled trials, the treatment decisions are copied from the ones which are used when the primary tumour is well identified in the head and neck area.

[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.

Phase II study of everolimus in patients with locally advanced or metastatic transitional cell carcinoma of the urothelial tract: clinical activity, molecular response, and biomarkers.

BACKGROUND: This phase II study assessed the safety and efficacy of everolimus, an oral mammalian target of rapamycin inhibitor in advanced transitional carcinoma cell (TCC) after failure of platinum-based therapy. PATIENTS AND METHODS: Thirty-seven patients with advanced TCC received everolimus 10 mg/day until progressive disease (PD) or unacceptable toxicity. The primary end point was the disease control rate (DCR), defined as either stable disease (SD), partial response (PR), or complete response at 8 weeks. Angiogenesis-related proteins were detected in plasma and changes during everolimus treatment were analyzed. PTEN expression and PIK3CA mutations were correlated to disease control. RESULTS: Two confirmed PR and eight SD were observed, resulting in a DCR of 27% at 8 weeks. Everolimus was well tolerated. Compared with patients with noncontrolled disease, we observed in patients with controlled disease a significant higher baseline level of angiopoietin-1 and a significant early plasma decrease in angiopoietin-1, endoglin, and platelet-derived growth factor-AB. PTEN loss was observed only in patients with PD. CONCLUSIONS: Everolimus showed clinical activity in advanced TCC. The profile of the plasma angiogenesis-related proteins suggested a role of the everolimus antiangiogenic properties in disease control. PTEN loss might be associated with everolimus resistance.

[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.

[Neoadjuvant chemotherapy in head and neck cancer]. / Chimiothérapie néoadjuvante dans les cancers "tête et cou".

Head and neck cancer represent 5% of all cancer and is often diagnosed at advanced stage. Treatment requires a multidisciplinary approach and relies on surgery, radiotherapy and/or chemotherapy. In locally advanced disease, chemotherapy has been shown to improve survival, particularly when delivered concomitantly with radiotherapy (6.5% absolute benefit in overall survival. Although induction or neoadjuvant chemotherapy has been much studied, no clear benefit has been identified but for larynx preservation. New chemotherapy regimens with adjonction of taxanes have drawn attention again on induction chemotherapy. Several randomised controlled trials have demonstrated improved response rate, disease free survival, or overall survival when docetaxel is added to cisplatin and 5 FU as induction chemotherapy. A definitive proof of the benefit of the induction approach is still lacking. To date, induction chemotherapy can only be recommended with the aim of preserving laryngeal function. Ongoing trials are expected to validate or rule out the induction strategy as a standard approach in locally advanced head and neck cancer.

[Therapeutic monoclonal antibodies in hemato-oncology]. / Anticorps monoclonaux à usage thérapeutique en hémato-oncologie. Généralités.

For many years, chemotherapy, hormonotherapy and immunotherapy were the mainstay of cancer treatment. Recent advances in our knowledge of cell biology and particularly of cancer cell transformation, growth and metastasis have led to the identification of specific pathways playing a role in the pathophysiology of cancer. New drugs specifically developed to control these targets are collectively named "targeted therapies". Two types of targeted therapies are available: kinase (mainly tyrosine kinase) inhibitors (suffix -nib) are small molecules binding directly to the intracellular kinase domain and acting as competitive inhibitor of ATP binding and monoclonal antibodies (suffix -mab) directed towards specific cell surface receptors or their ligands to prevent receptor activation. This paper will only review monoclonal antibodies (mabs). Thirty years after their discovery mAbs have become efficient therapeutic tools. Progress in molecular engineering as well as improved knowledge of cell signalling pathways together with a better selection of the targets turned them into valuable treatments. Several mAbs are currently licensed for the treatment of hematological or solid malignancies and many others are expected in the near future.

[Monoclonal antibodies for the treatment of head and neck cancer]. / Place des anticorps monoclonaux dans le traitement des tumeurs de la tête et du cou.

Monoclonal antibodies are now part of the armamentarium available for the treatment of head and neck cancer. Cétuximab, a monoclonal antibody targeting EGFR, improves overall survival as compared with radiotherapy alone as radical treatment of locally advanced head and neck cancer. It is now reimbursed in Belgium after multidisciplinary discussion if cisplatin is contra-indicated. In the metastatic setting adding cétuximab to platinum based chemotherapy improves overall survival as compared with chemotherapy alone, a first-time event over a 30-year period, unfortunately not yet accessible to the Belgian patients. Other monoclonal antibodies targeting EGFR or VEGF are also currently under investigation while cétuximab is being explored in the induction, the maintenance or the post-operative radiotherapy settings.

[Radiation recall dermatitis after oral cyclophosphamide]. / Le cas clinique du mois. Réaction de rappel d'irradiation induite par l'administration de cyclophosphamide.

Radiation recall dermatitis is an inflammatory skin reaction occurring in a previously irradiated field following the delivery of a promoting agent. It has been described after a number of antineoplastic agents such as gemcitabine, taxanes, anthracyclines. We report the case of a 50-year-old man with metastatic prostate cancer who developed two consecutive radiation recall dermatitis episodes triggered by oral cyclophosphamide. They occurred 4 to 5 weeks after palliative radiotherapy on bone metastasis. Spontaneous resolution was observed within 6 weeks after discontinuation of cyclophosphamide and with local supportive care. To our knowledge this is the first reported case of radiation recall dermatitis after oral cyclophosphamide.

[Head and neck tumors: standards of care and new approaches]. / Les tumeurs de la sphère ORL: standards de traitement et nouvelles approches en radiothérapie.

We intend to review the general value of radiotherapy in the management of head and neck cancer. Our aim is to define a treatment protocol which is evidence-based and therefore of use in daily clinical practice. There is general agreement on the efficacy of the concomitant schedules combining radiotherapy and chemotherapy, both in the adjuvant setting as well as in the exclusive non-surgical approach. This however does not preclude further research aiming at optimizing the therapeutic index. As far as neoadjuvant chemotherapy is concerned, applied prior to radical local treatment, there are no conclusive data available which allows us to implement this treatment option in routine clinical practice. This approach deserves further investigations and patients should be entered in well designed prospective randomized trials.

[Chemotherapy of ovarian cancer: state of the art]. / Traitement chimiotérapique actuel du cancer de l'ovaire.

Epithelial ovarian cancer is frequently diagnosed at advanced-stage disease and chemotherapy is nearly always required. Optimally debulked patients may need adjuvant chemotherapy while, most of the time this chemotherapy will be given to those with advanced-stage disease. Also relapses will be treated differently whether they occur early or late in the course of the disease. This paper reviews medical treatment modalities according to stage based on published data. Maintenance and consolidation treatments are also discussed. Finally a brief insight into new therapeutic tools is also given.

[Current therapeutic progress in oncology: the development of targeted therapies]. / Actualités thérapeutiques en oncologie: l'essor des thérapeutiques ciblées.

Over the last decades, significant advances were make in basic research as concerns the malignant transformation of normal cells. As a result, new targets for treatment were identified. "Targeted therapies" indicates that treatments are directed against specific molecular targets that play a major role in the activation of cell division and in the growth and dissemination of tumors. In particular, targeted therapies were developed against epithelial growth factor receptors and angiogenesis. We can expect specifise therapies against many other targets in the near future. Several drugs have obtained a marketing license. Predictive factors for tumor response and long term outcome should be developed for a better selection of the patient population who will benefit from these treatments. New imaging techniques are under development in order to assess the molecular response to these new approaches.

[Targeted therapies in breast cancer: current status and perspectives]. / Actualités thérapeutiques en oncologie sénologique: place actuelle et perspectives des traitements ciblés.

The introduction of targeted therapies has largely modified the treatment strategies in oncology. Two targets are currently used for defining the systemic treatment of breast cancer: hormone receptors and HER2 overexpression. Trastuzumab, a monoclonal antibody, is the only registered antiHER2 treatment in Belgium. The association of trastuzumab with chemotherapy is now the recommended adjuvant treatment for early breast cancer overexpressing HER2. Other antiHER2 medications are available and some will probably be registered soon. Angiogenesis is another potential target for improving the treatment results. The CHU Liège, as a reference center for the systemic treatment of solid tumors, participates in many international trials in order to validate these new approaches. The highest quality of care is required to be in compliance with the conduct of these clinical trials. Another benefit for the patient is the easy access to last generation medical treatments, generally not accessible in our health care system in Belgium outside of clinical trials.

Computation of the phase response curve: a direct numerical approach.

Neurons are often modeled by dynamical systems--parameterized systems of differential equations. A typical behavioral pattern of neurons is periodic spiking; this corresponds to the presence of stable limit cycles in the dynamical systems model. The phase resetting and phase response curves (PRCs) describe the reaction of the spiking neuron to an input pulse at each point of the cycle. We develop a new method for computing these curves as a by-product of the solution of the boundary value problem for the stable limit cycle. The method is mathematically equivalent to the adjoint method, but our implementation is computationally much faster and more robust than any existing method. In fact, it can compute PRCs even where the limit cycle can hardly be found by time integration, for example, because it is close to another stable limit cycle. In addition, we obtain the discretized phase response curve in a form that is ideally suited for most applications. We present several examples and provide the implementation in a freely available Matlab code.

[Relapse of testicular mixed germ cell tumor 15 years after initial treatment]. / Le cas clinique du mois. Récidive d'une tumeur testiculaire mixte 15 ans après le traitement initial.

We report the case of a patient with a symptomatic retroperitoneal tumor. The patient had undergone, 15 years earlier, an orchiectomy and three cycles of chemotherapy for a testicular mixed germ cell tumor. Histology after radical surgical excision revealed a metastasis of mature teratoma. The 183 month interval between initial treatment and relapse is one of the longest ever reported.

The onset and extinction of neural spiking: a numerical bifurcation approach.

We study the onset of neural spiking when the equilibrium rest state loses stability by the change of a critical parameter, the applied current. In the case of the well-known Morris-Lecar model, we start from a complete numerical study of the bifurcation diagram in the most relevant two-parameter range. This diagram includes all equilibrium and limit cycle bifurcations, thus correcting and completing earlier studies. We discuss and classify the behavior of the spiking orbits, when increasing or decreasing the applied current. A complete classification can be extracted from the complete bifurcation diagram. It is based on three components: bifurcation type of the equilibrium at the loss of stability, subcritical behavior in the limit of decreasing the applied current and supercritical behavior in the limit of increasing the applied current.