Pembrolizumab versus cetuximab concurrent with radiotherapy in patients with locally advanced squamous cell carcinoma of head and neck unfit for cisplatin (GORTEC 2015-01 PembroRad): a multicenter, randomized, phase II trial.

BACKGROUND: To evaluate potential synergistic effect of pembrolizumab with radiotherapy (RT) compared with a standard-of-care (SOC) cetuximab-RT in patients with locally advanced-squamous cell carcinoma of head and neck (LA-SCCHN). PATIENTS AND METHODS: Patients with nonoperated stage III-IV SCC of oral cavity, oropharynx, hypopharynx, and larynx and unfit for receiving high-dose cisplatin were enrolled. Patients received once-daily RT up to 69.96 Gy in 33 fractions with weekly cetuximab (cetuximab-RT arm) or 200 mg Q3W pembrolizumab during RT (pembrolizumab-RT arm). The primary endpoint was locoregional control (LRC) rate 15 months after RT. To detect a difference between arms of 60%-80% in 15-month LRC, inclusion of 66 patients per arm was required to achieve a power of at least 0.85 at two-sided significance level of 0.20. RESULTS: Between May 2016 and October 2017, 133 patients were randomized to cetuximab-RT (n = 66) and pembrolizumab-RT (n = 67). Two patients (one in each arm) were not included in the analysis (a consent withdrawal and a progression before treatment start). The median age was 65 years (interquartile range 60-70 years), 92% were smokers, 60% were oropharynx (46% of oropharynx with p16+) and 75% were stage IV. Median follow-up was 25 months in both arms. The 15-month LRC rate was 59% with cetuximab-RT and 60% with pembrolizumab-RT ]odds ratio 1.05, 95% confidence interval (CI) 0.43-2.59; P = 0.91]. There was no significant difference between arms for progression-free survival (hazard ratio 0.85, 95% CI 0.55-1.32; P = 0.47) and for overall survival (hazard ratio 0.83, 95% CI 0.49-1.40; P = 0.49). Toxicity was lower in the pembrolizumab-RT arm than in the cetuximab-RT arm: 74% versus 92% patients with at least one grade ≥3 adverse events (P = 0.006), mainly due to mucositis, radiodermatitis, and rash. CONCLUSION: Compared with the SOC cetuximab-RT, pembrolizumab concomitant with RT did not improve the tumor control and survival but appeared less toxic in unfit patients with LA-SCCHN.

Impact of the method chosen for the analysis of recurrences after radiotherapy for head and neck cancers: volume-based, point-based and combined methods.

Intensity modulated radiation therapy for head and neck is a complex technique. Inappropriate delineation and/or dose distribution can lead to recurrences. Analysis of these recurrences should lead to improve clinical practice. For several years, different methods of analysis have been described. The purpose of this review is to describe these different methods and to discuss their advantages and limitations. The first published methods used a volume-based approach studying the entire volume of recurrence according to initial target volumes, or dose distribution. The main limitation of these methods was that the volume of recurrence studied was dependent on the delay in diagnosis of that recurrence. Subsequently, other methods used point-based approaches, conceptualizing recurrence either as a spherical expansion from a core of radioresistant cells (center of mass of recurrence volume) or using a more clinical approach, taking into account tumor expansion pathways. More recently, more precise combined methods have been described, combining the different approaches. The choice of method is decisive for conclusions on the origin of recurrence.

[Proposal for the delineation of postoperative primary clinical target volumes in ethmoid cancers]. / Proposition de délinéation des volumes cibles anatomocliniques postopératoires de la tumeur primitive des cancers de l'ethmoïde.

It is proposed to delineate the anatomo-clinical target volumes of primary tumor (CTV-P) in ethmoid cancers treated with post-operative radiotherapy. This concept is based on the use of radioanatomy and the natural history of cancer. It is supported by the repositioning of the planning scanner with preoperative imaging for the replacement of the initial GTV and the creation of margins around it extended to the microscopic risk zones according to the anatomical concept. This article does not discuss the indications of external radiotherapy but specifies the volumes to be delineated if radiotherapy is considered.

[Concurrent chemoradiotherapy for head neck cancers. Should organs at risk dose constraints be revisited ?] / Chimioradiothérapie concomitante des cancers des voies aérodigestives supérieures. Faut-il revoir les contraintes de dose dans les organes à risque ?

Concurrent chemoradiotherapy improves the outcome of locally advanced head and neck cancers and the current reference chemotherapy is cisplatin. These results are obtained at the cost of increased toxicities. To limit the risk of toxicity, organ at riskdose constraints have been established starting with 2D radiotherapy, then 3D radiotherapy and intensity-modulated radiotherapy. Regarding grade ≥3 acute toxicities, the scientific literature attests that concurrent chemoradiotherapy significantly increases risks of mucositis and dysphagia. Constraints applied to the oral mucosa volume excluding the planning target volume, the pharyngeal constrictor muscles and the larynx limit this adverse impact. Regarding late toxicity, concurrent chemoradiotherapy increases significantly the risk of postoperative neck fibrosis and hearing loss. However, for some organs at risk, concurrent chemotherapy appears to increase late radiation induced effect, even though the results are less marked (brachial plexus, mandible, pharyngeal constrictor muscles, parotid gland). This additional adverse impact of concomitant chemotherapy may be notable only when organs at risk receive less than their usual dose thresholds and this would be vanished when those thresholds are exceeded as seems to be the situation for the parotid glands. Until the availability of more robust data, it seems appropriate to apply the principle of delivering dose to organs at risk as low as reasonably achievable.

[Reirradiation for head and neck squamous cell carcinoma: Indications and results]. / Réirradiations des carcinomes épidermoïdes des voies aérodigestives supérieures : indications et résultats.

Despite progress in the management of head and neck squamous cell carcinoma (HNSCC), a significant proportion of patients previously irradiated for head-and-neck cancer will develop locoregional recurrence or a second primary. Because of the heterogeneity of this population with respect to disease-related factors (localization, volume, recurrence or second primary, time interval from previous irradiation…) and patient-related factors (comorbidities, sequelae of previous irradiation…), the optimal reirradiation treatment remains to be defined. Salvage therapy using reirradiation, despite some encouraging results, has historically been avoided because of concerns regarding toxicity. The results of more recent studies using contemporary treatment techniques and conformal delivery methods such as intensity modulated radiation therapy (IMRT) or stereotactic radiotherapy (SBRT) have been somewhat more promising. The aim of this review is to discuss the reirradiation of HNSCC in terms of patient selection and modern radiotherapy techniques.

[Proposal for the selection and delineation of clinical target volumes for the radiotherapy of submandibular gland tumours]. / Proposition de sélection et délinéation des volumes cibles anatomocliniques tumoraux et ganglionnaire pour la radiothérapie des cancers de la glande sous-mandibulaire.

This article provides a proposal for the selection and delineation of clinical target volumes for the treatment with radiation of submandibular glands tumours. This article does not deal with external radiotherapy indications but specifies the volumes to be treated if radiotherapy is chosen. High-risk and low-risk peritumoral clinical target volumes are described based on the probability of local tumoral spread. High-risk and low-risk clinical target volumes are illustrated on CT-scan slices. A proposal for the selection of nodal clinical target volumeis also proposed.

[Delineation of the primary tumour clinical target volumes and neck node levels selection of parotid cancers]. / Proposition de délinéation des volumes cibles tumoraux et sélection des aires ganglionnaires des cancers de la glande parotide.

Salivary glands tumours are uncommon tumours showing a large diversity of histological types. This article presents a synthesis of patterns and paths of invasion of parotid glands tumours in order to propose an approach of the delineation of primary tumour clinical target volumes and of the selection of lymph nodes target volumes. This article does not discuss treatment indications but defines clinical target volumes to treat if radiotherapy is indicated. Postoperative situation being the most frequent, the delineation of primary tumour clinical target volume is based on an anatomical approach.

[Toxicity of docetaxel, platine, 5-fluorouracil-based induction chemotherapy for locally advanced head and neck cancer: The importance of nutritional status]. / Toxicité de la chimiothérapie d'induction par docétaxel, platine, 5-fluorouracile (TPF) pour les cancers des voies aérodigestives supérieures localement évolués en routine clinique : importance du statut nutritionnel.

PURPOSE: The objective of this study was to identify predictive factors of toxicity of docetaxel, platin, 5-fluorouracil (TPF) induction chemotherapy for locally advanced head and neck cancers. PATIENTS AND METHODS: From July 2009 to March 2015, 57 patients treated consecutively with TPF were included retrospectively. There were 47 males (83%), the median age was 56 years [40-71 years]. Thirty-eight patients (67%) were treated for inoperable cancer (highly symptomatic and/or high tumor burden) and 19 (33%) were treated for laryngeal preservation. There were 47% stage IVa, 32% stage III and 21% stage IVb. At diagnosis, there were 53% stable weight, 28% grade 1 weight loss, 17% grade 2 weight loss and 2% grade 3 weight loss. RESULTS: Forty-seven percent of patients were in partial response after TPF, 28% in complete response, 7% stable, 2% progressing and 2% discordant response. The possibility of oral feeding without a feeding tube was predictive of a better response (P=0.02). Thirty-nine percent of patients increased weight during TPF, 35% were stable, 18% in grade 1 weight loss, 6% in grade 2 and 2% in grade 3. Six of the patients (10.5%) died during chemotherapy: four from febrile neutropenia, one from pneumopathy and one of unknown cause. Age 57years and older was associated with a higher risk of grade≥3 anemia and thrombocytopenia. There was a higher risk of grade≥3 infection for weight loss at diagnosis (P=0.04) and feeding tube (P=0.05). There was a higher risk of grade≥3 neutropenia for weight loss during TPF (P=0.03). CONCLUSION: Induction chemotherapy by TPF has an strong anti-tumor efficacy (75.5% objective response) but an important morbidity with 10% toxic deaths in our very symptomatic population with a very important tumor burden. Age and nutritional status are important factors to consider.

[Description of the GORTEC 2017-03 study: Postoperative stereotactic radiotherapy for early stage oropharyngeal and oral cavity cancer with high risk margin (PHRC-K-16-164)]. / Présentation de l'étude Gortec 2017-03 : radiothérapie en conditions stéréotaxiques postopératoire des cancers localisés de l'oropharynx et de la cavité buccale avec marges à risque (PHRC-K-16-164).

The GORTEC 2017-03-Stereo-postop study is a phase 2, multicentric, nationwide study, funded by the hospital clinical research program (PHRC). The sponsor is Centre Jean-Perrin in Clermont-Ferrand, in partnership with the GORTEC. The principal investigators are Dr J Biau and Dr M Lapeyre. The main objective is to study severe late toxicity of postoperative stereotactic radiotherapy (6×6Gy) for early stage oropharyngeal and oral cavity cancer with high risk margins. The secondary objectives include acute toxicity, efficacy, nutritional impact and quality of life. The population is adult patients, with pT1 or pT2 squamous cell carcinoma of the oropharynx or oral cavity (except lips), without indication of neck irradiation or concomitant chemotherapy, with at risk margin (R1, less than 5mm or uncertain). Ninety patients will be included over a 2-year period; this was calculated to limit the rate of 2-year severe toxicity at 5 to 15%, with a 2-year local control of at least 80 to 90%. If this study is considered as positive, stereotactic radiotherapy (6×6Gy) could become the third therapeutic option, with brachytherapy and normofractionated intensity-modulated radiotherapy (IMRT), for postoperative irradiation of oropharyngeal and oral cavity cancer with high risk margins.

[Radioresistance parameters in head and neck cancers and methods to radiosensitize]. / Paramètres de radiorésistance des cancers des voies aérodigestives supérieures et stratégies de radiosensibilisation.

Head and neck cancers have been widely studied concerning their sensitivity to radiation therapy. Several parameters affect tumour response to radiation therapy. Some parameters are linked to the tumour. Large or invasive tumours, localization, such as oral cavity or adenopathy, are factors of radioresistance. Others parameters are linked to the patients themselves. Tobacco intoxication during radiotherapy and a low hemoglobin level contribute to radioresistance. More recently, a positive human papilloma virus (HPV) status has been reported to positively affect radiosensitivity. Finally, other parameters are related to tumour biology. Hypoxia, intrinsic radiosensitivity of tumour cells, tumour differentiation and repopulation (provided by Ki-67 index or EGFR level) are components of radiosensitivity. Currently, concurrent chemoradiotherapy is one of the gold standard treatments to overcome clinical outcome of locally advanced head and neck cancer. This combination increases locoregional control and survival. Taxane-based induction chemotherapy can also be an alternative. Another validated approach is the association of radiotherapy with cetuximab (EGFR targeting) but only one randomized study has been published. Fractionation modifications, especially hyperfractionation, have given positive results on both tumour control and survival. Strategies targeting hypoxia improve locoregional control but have less clinical impact.

[Delineation of the lymph nodes for head neck cancers]. / Délinéation des adénopathies et aires ganglionnaires pour les cancers de la sphère ORL.

The aim of this article is to present the determination and delineation of nodal target volumes for head and neck cancers treated with intensity-modulated radiotherapy. The delineation on computerized tomography scanner (CT scan) requires a precise methodology. Different elements are necessary: clinical examination, diagram of the initially involved lymph nodes, surgical and pathological reports and medical imagings (CT scan, magnetic resonance imaging and fluorodeoxyglucose positron emission tomography). The different clinical target volumes are approached and the concept of selectivity of neck nodal targets is specified according to current literature.

[Intensity-modulated radiotherapy in head and neck cancer: ethics and methodology]. / Radiothérapie conformationnelle avec modulation d'intensité des cancers des voies aérodigestives supérieures : enjeux éthiques et méthodologiques.

Numerous studies have shown that intensity-modulated radiation therapy is the standard technique for the radiation treatment of head and neck cancers. Intensity-modulated radiation therapy reduces side effects (xerostomia, dysphagia, fibrosis, etc.) and improves the results for cancer localizations with highly complex shapes such as the cavum or nasal cavity. Intensity-modulated radiation therapy is also a costly technique that necessitates a numerous staff, highly trained, with regular practice. If this technique cannot be available (understaffing, overwork, etc.) the choice between entrusting the patient to a colleague and treating the patient with a less sophisticated technique such as 3-dimensional conformal radiation therapy depends on different objective and ethical criteria.

[Image-guided radiotherapy and partial delegation to radiotherapy technicians: Clermont-Ferrand experience]. / Radiothérapie guidée par l'image et partage des tâches avec les manipulateurs en électroradiologie : expérience de Clermont-Ferrand.

The various image-guided radiotherapy techniques raise the question of how to achieve the control of patient positioning before irradiation session and sharing of tasks between radiation oncologists and radiotherapy technicians. We have put in place procedures and operating methods to make a partial delegation of tasks to radiotherapy technicians and secure the process in three situations: control by orthogonal kV imaging (kV-kV) of bony landmarks, control by kV-kV imaging of intraprostatic fiducial goldmarkers and control by cone beam CT (CBCT) imaging for prostate cancer. Significant medical overtime is required to control these three IGRT techniques. Because of their competence in imaging, these daily controls can be delegated to radiotherapy technicians. However, to secure the process, initial training and regular evaluation are essential. The analysis of the comparison of the use of kV/kV on bone structures allowed us to achieve a partial delegation of control to radiotherapy technicians. Controlling the positioning of the prostate through the use and automatic registration of fiducial goldmarkers allows better tracking of the prostate and can be easily delegated to radiotherapy technicians. The analysis of the use of daily cone beam CT for patients treated with intensity modulated irradiation is underway, and a comparison of practices between radiotherapy technicians and radiation oncologists is ongoing to know if a partial delegation of this control is possible.