Adaptive and innovative Radiation Treatment FOR improving Cancer treatment outcomE (ARTFORCE); a randomized controlled phase II trial for individualized treatment of head and neck cancer

Abstract

BackgroundFailure 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.MethodsARTFORCE 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.DiscussionThe 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

Patterns-of-failure guided biological target volume definition for head and neck cancer patients: FDG-PET and dosimetric analysis of dose escalation candidate subregions

“…The authors of the ARTFORCE phase II study designed their dose escalation sub-volumes based on 50% of the maximum uptake in the primary tumor plus a 3 mm margin to create a final PTV-FDG-PET. [14] Investigators from Ghent University Hospital implemented different strategies in two phase I dose escalation studies, using focal dose painting by contours based on the source-to-background ratio in one study[15] and dose painting by number in the second study. [16]…”

PET Scan in Hodgkin Lymphoma

“…The higher acute disease control, with a 3-7 % superior PFS, as shown in four published randomized clinical comparing CMT vs. chemotherapy alone in early-stage HL [ 61 -64 ], did not translate to an improvement in OS of CMT. On the contrary, the fi nal analysis of the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) and Eastern Cooperative Oncology Group (ECOG) HD.6 study showed superior OS for chemotherapy alone at 12 years, due to increased late events/ toxicity in the CMT arm [ 65 ]. Similarly, the GHSG in the HD10/11 trials while showing an improved long-term disease control (8-y time to treatment failure) was unable to show an advantage in OS for patients treated with CMT as compared to chemotherapy alone [ 66 ].…”

“…These new methods increased the effectiveness of this treatment modality which delivered much smaller doses to critical organs such as the lung, heart, and breast [61]. So far only a few clinical trials have been conducted in which dose escalation was prescribed on an FDG avid area within the GTV [64][65][66][67]. In the modern era of conformal radiotherapy, TNI and the EFRT are no longer in practice and supplanted by limited-field radiation therapy: IFRT, if the RT field encompasses all of the clinically involved nodal regions, and INRT, with an assumption to deliver the dose only to the initially involved nodes, rather than including the entire region of the involved nodal chain.…”

Validation of functional imaging as a biomarker for radiation treatment response

“…The multicentre randomized Phase II PET Boost trial in NSCLC (PET Boost, NCT01024829) thus far has reported no increase in toxicity. 72 Moreover, a Phase III randomized study in HNSCC is investigating the redistribution of the radiation dose to the metabolically most 18 F-FDG-PETavid part of the tumour (ARTFORCE, ClinicalTrials.gov identifier: NCT01504815 73 ).…”