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19 active trials for Laryngeal Cancer

Olaparib and Radiotherapy in Head and Neck Cancer

Accelerated, normofractionated radiotherapy is the treatment of choice in stage II-III laryngeal and oropharyngeal squamous cell carcinoma (SCC). However, twenty to thirty percent of patients with stage II-III laryngeal and HPV negative oropharyngeal SCC develop disease progression, mainly due to lack of locoregional control. Radiosensitizers such as cisplatin and cetuximab are added to radiotherapy in more advanced stage of head and neck (H&N) cancer. These radiosensitizers improve loco-regional control and overall survival. Unfortunately, as these radiosensitizers, notably cisplatin, also dose intensify the radiation dose in normal tissues, they also significantly increase toxicity. Adding a more tumor-specific radiosensitizing agent could improve loco-regional control and overall survival without significantly increasing toxicity. Radiotherapy kills tumor cells by inducing DNA damage. The efficacy of radiotherapy is limited by the ability of tumor cells to repair this DNA damage. Poly(ADP-ribose)polymerase (PARP) is an essential enzyme in base excision repair and single strand break DNA repair, DNA lesions arising from radiation treatment. PARP inhibition and consequently the inhibition of PARP-facilitated DNA repair enhances the anti-tumor activity of radiotherapy, as shown in preclinical studies including head and neck xenograft studies. This radiosensitization is thought to be proliferation dependent and is more pronounced in homologous recombination (HR) deficient cells, providing an opportunity for tumor specific targeting. Genetic analyses suggest that HR deficiency is commonly found in H&N SCC: ATM loss has been reported in 60% of human H&N SCC biopsies and FANC-F defects were reported in 15-21% of human H&N SCC biopsies and cell lines. The efficacy of radiotherapy is also limited by tumor hypoxia, as tumor hypoxia results in radioresistance. Some PARP inhibiting compounds increase tumor perfusion in xenograft models, thereby reducing hypoxia and specifically sensitizing tumor cells to radiotherapy. Hypoxia is commonly found in H&N SCC and a high pre-treatment hypoxic fraction in H&N SCC tumors is associated with worse outcome. The high prevalence of both hypoxia and HR deficiencies in H&N SCC support the concept of tumor-specific radiosensitization by PARP inhibition in head and neck cancer patients. Olaparib is a potent PARP inhibitor developed as an anti-cancer drug for HR defected tumors and as a dose intensifier for chemo- and radiotherapy. In humans, olaparib has a low toxicity profile as a single agent, with increasing bone marrow toxicity when combined with chemotherapy. The combination of olaparib and radiotherapy for H&N SCC is expected to improve locoregional control and thereby overall survival. However, this combination treatment has never been tested in humans before. The purpose of this study is to determine the safety and tolerability of radiotherapy for stage II-III laryngeal and stage II-III HPV-negative oropharyngeal SCC with concurrent olaparib.

AmsterdamStart: September 2014
Aortic Laryngeal Rehabilitation Graft

The larynx is a cartilaginous organ of the respiratory system located in the throat, which plays an essential role in respiratory function, swallowing and sound production. In the case of advanced tumours, the surgical option most often remains total laryngectomy, with the corollary of a major impact on quality of life, not so much because of the loss of voice, but because of the presence of a definitive tracheostoma with particularly deleterious consequences. The majority of the work of the different teams around the world has focused on restoring phonatory function, but no technique - apart from the artificial larynx developed in the ENT department of the Hautepierre Hospital - has yet succeeded in removing the tracheotomy orifice, requiring the restoration of a common passage between the respiratory and swallowing passages. If nutrition and phonatory function can still be supplemented after such an operation (oesophageal rehabilitation, implant placed between the trachea and oesophagus), natural breathing is no longer possible. Patients are forced to wear a permanent tracheotomy opening. There are currently only 2 ways to try to restore all the functions of the larynx after total laryngectomy: i) laryngeal transplantation, but this procedure requires maintaining immunosuppressive treatment, which is not possible in patients suffering from cancer of the larynx, which is not a vital organ, ii) artificial larynx made of biomaterials (titanium), the first cases of which were performed worldwide in the ENT department of the Strasbourg University Hospital in 2012, results published in the NEJM (API 2008-2009 HUS No. 4493- IDRCB No.: 2011-A00032-39. However, difficulties were encountered with the use of the titanium prosthesis due to the bulk and rigidity of the removable and non-removable part, which caused residual swallowing difficulties (false routes). It is now possible, due to the development of new allograft techniques in humans for tracheal replacement (studies published on a large number of cases with several years of hindsight, cf. references), to switch to the "all biological" using an aortic graft stented with a silicone stent. We wish to use these grafts in laryngeal restoration after total laryngectomy by our team, while exploiting all the data and experience acquired (unique in the world) within the ENT department of Hautepierre Hospital. This new conceptual leap should make it possible to significantly improve the patient's quality of life and the performance previously acquired in clinical trials on the artificial larynx in its entirety (breathing, phonation) or partially (swallowing). The investigators thus propose to evaluate this new artificial larynx in aortic allograft, the objective of which is to supplement the respiratory, swallowing and phonation functions in patients laryngectomized for carcinological causes.

StrasbourgStart: March 2021