Background: Failure of locoregional control is the main cause of recurrence in advanced head and neck cancer. This multi-center trial aims to improve outcome in two ways. Firstly, by redistribution of the radiation dose to the metabolically most FDG-PET avid part of the tumour. Hereby, a biologically more effective dose distribution might be achieved while simultaneously sparing normal tissues. Secondly, by improving patient selection. Both cisplatin and Epidermal Growth Factor Receptor (EGFR) antibodies like Cetuximab in combination with Radiotherapy (RT) are effective in enhancing tumour response. However, it is unknown which patients will benefit from either agent in combination with irradiation. We will analyze the predictive value of biological markers and ⁸⁹Zr-Cetuximab uptake for treatment outcome of chemoradiation with Cetuximab or cisplatin to improve patient selection. Methods: ARTFORCE is a randomized phase II trial for 268 patients with a factorial 2 by 2 design: cisplatin versus Cetuximab and standard RT versus redistributed RT. Cisplatin is dosed weekly 40 mg/m² for 6 weeks. Cetuximab is dosed 250mg/m² weekly (loading dose 400 mg/m²) for 6 weeks. The standard RT regimen consists of elective RT up to 54.25 Gy with a simultaneous integrated boost (SIB) to 70 Gy in 35 fractions in 6 weeks. Redistributed adaptive RT consists of elective RT up to 54.25 Gy with a SIB between 64-80 Gy in 35 fractions in 6 weeks with redistributed dose to the gross tumour volume (GTV) and clinical target volume (CTV), and adaptation of treatment for anatomical changes in the third week of treatment. Patients with locally advanced, biopsy confirmed squamous cell carcinoma of the oropharynx, oral cavity or hypopharynx are eligible. Primary endpoints are: locoregional recurrence free survival at 2 years, correlation of the median ⁸⁹Zr-cetuximab uptake and biological markers with treatment specific outcome, and toxicity. Secondary endpoints are quality of life, swallowing function preservation, progression free and overall survival. Discussion: The objective of the ARTFORCE Head and Neck trial is to determine the predictive value of biological markers and ⁸⁹Zr-Cetuximab uptake, as it is unknown how to select patients for the appropriate concurrent agent. Also we will determine if adaptive RT and dose redistribution improve locoregional control without increasing toxicity. ClinicalTrials.gov Identifier: NCT01504815

Tumor hypoxia increases resistance to radiotherapy and systemic therapy. Our aim was to develop and validate a disease-agnostic and disease-specific CT (+FDG-PET) based radiomics hypoxia classification signature. A total of 808 patients with imaging data were included: N=100 training/ N=183 external validation cases for a disease-agnostic CT hypoxia classification signature, N=76 training/ N=39 validation cases for the H&N CT signature and N=62 training /N=36 validation cases for the Lung CT signature. The primary gross tumor volumes (GTV) were manually defined by experts on CT. In order to dichotomize between hypoxic/well-oxygenated tumors a threshold of 20% was used for the [18F]-HX4-derived hypoxic fractions (HF). A random forest (RF)-based machine-learning classifier/ regressor was trained to classify patients as hypoxia-positive/ negative based on radiomic features. A 11 feature "disease-agnostic CT model" reached AUC's of respectively 0.78 (95% confidence interval [CI], 0.62 to 0.94), 0.82 (95% CI, 0.67 to 0.96) and 0.78 (95% CI, 0.67 to 0.89) in three external validation datasets. A "disease-agnostic FDG-PET model" reached an AUC of 0.73 (0.95% CI, 0.49 to 0.97) in validation by combining 5 features. The highest "lung-specific CT model" reached an AUC of 0.80 (0.95% CI, 0.65 to 0.95) in validation with 4 CT features, while the "H&N-specific CT model" reached an AUC of 0.84 (0.95% CI, 0.64 to 1.00) in validation with 15 CT features. A significant survival split (P=0.037) was found between CT-classified hypoxia strata in an external H&N cohort (n=517), while 117 significant hypoxia gene-CT signature feature associations were found in an external lung cohort (n=80). The disease-specific radiomics signatures perform better than the disease agnostic ones. By identifying hypoxic patients our signatures have the potential to enrich interventional hypoxia-targeting trials.

During a course of radiotherapy for head-and-neck-cancer (HNC), non-rigid anatomical changes can be observed on daily Cone Beam CT (CBCT). To objectify responses to these changes, we use a decision support system (traffic light protocol). Action levels orange and red may lead to re-planning. The purpose of this study was to evaluate how often re-planning was done for non-rigid anatomical changes, which anatomical changes led to re-planning and in which subgroups of patients treatment adaptation was deemed necessary. A consecutive series of 388 HNC patients were retrospectively selected using the digital log of CBCT scans. The logs were analyzed for the number of new plans on an original planning CT scan (O-pCT) or a new pCT scan (N-pCT). Reasons for re-planning were categorized into: target volume increase/decrease, body contour decrease/increase and local shift of target volume. Subgroup analysis was performed to investigate relative differences of re-planning between treatment modalities. For 33 patients the treatment plan was adapted due to anatomical changes, resulting in 37 new plans in total. Re-planning on a N-pCT with complete re-delineation was done 22 times. In fifteen cases a new plan was created after adjustment of contours on the O-pCT. Main reasons for re-planning were target volume increase, body contour decrease and local shifts of target volume. Most re-planning (23%) was seen in patients treated with chemoradiotherapy. Visual detection of anatomical changes on CBCT during treatment of HNC, results in re-planning in 1 out of 10 patients.