Validation of dose escalation through FDG-PET dose painting (DP) for oropharyngeal squamous cell carcinoma (SCC) requires randomized clinical trials with large sample size, potentially involving different treatment planning and delivery systems. As a first step of a joint clinical study of DP, a planning comparison was performed between Tomotherapy HiArt® (HT) and Varian RapidArc® (RA).

Objective. To develop a methodology for using FDG PET/CT in adaptive dose painting by numbers (DPBN) in head and neck squamous cell carcinoma (HNSCC) patients. Issues related to noise in PET and treatment robustness against geometric errors are addressed.Methods. Five patients with locally advanced HNSCC scheduled for chemo-radiotherapy were imaged with FDG-PET/CT at baseline and 2-3 times during radiotherapy (RT). The GTV(PET) was segmented with a gradient-based method. A double median filter reduces the impact of noise in the PET uptake-to-dose conversion. Filtered FDG uptake values were linearly converted into a voxel-by-voxel prescription from 70 (median uptake) to 86 Gy (highest uptake). A PTVPET was obtained by applying a dilation of 2.5 mm to the entire prescription. Seven iso-uptake thresholds led to seven sub-levels compatible with the Tomotherapy HiArt((R)) Treatment Planning System. Planning aimed to deliver a median dose of 56 Gy and 70 Gy in 35 fractions on the elective and therapeutic PTVs, respectively. Plan quality was assessed with quality volume histogram (QVH). At each time point, plans were generated with a total of 3-4 plans for each patient. Deformable image registration was used for automatic contour propagation and dose summation of the 3 or 4 treatment plans (MIMvista((R))).Results. GTV(PET) segmentations were performed successfully until week 2 of RT but failed in two patients at week 3. QVH analysis showed high conformity for all plans (mean V-Q = 0.95 93%; mean V-Q = 1.05 3.9%; mean QF 2.2%). Good OAR sparing was achieved while keeping high plan quality.Conclusion. Our results show that adaptive FDG-PET-based escalated dose painting in patients with locally advanced HNSCC is feasible while respecting strict dose constraints to organs at risk. Clinical studies must be conducted to evaluate toxicities and tumor response of such a strategy.

Abstract Objective. To evaluate from a planning point of view the dose distribution of adaptive radiation dose escalation in head and neck squamous cell carcinoma (HNSCC) using 18F-Fluoroazomycin arabinoside (FAZA) positron emission tomography/computed tomography (PET-CT). Material/methods. Twelve patients with locally advanced HNSCC underwent three FAZA PET-CT before treatment, after 7 fractions and after 17 fractions of a carboplatin-5FU chemo-radiotherapy regimen (70 Gy in 2 Gy per fraction over 7 weeks). The dose constraints were that every hypoxic voxel delineated before and during treatment (newborn hypoxic voxels) should receive a total dose of 86 Gy. A median dose of 2.47 Gy per fraction was prescribed on the hypoxic PTV defined on the pre-treatment FAZA PET-CT; a median dose of 2.57 Gy per fraction was prescribed on the newborn voxels identified on the first per-treatment FAZA PET-CT; a median dose of 2.89 Gy per fraction was prescribed on the newborn voxels identified on the second per-treatment FAZA PET-CT. Results. Ten of 12 patients had hypoxic volumes. Six of 10 patients completed all the FAZA PET-CT during radiotherapy. For the hypoxic PTVs, the average D50% matched the prescribed dose within 2% and the homogeneity indices reached 0.10 and 0.12 for the nodal PTV 86 Gy and the primary PTV 86 Gy, respectively. Compared to a homogeneous 70 Gy mean dose to the PTVs, the dose escalation up to 86 Gy to the hypoxic volumes did not typically modify the dose metrics on the surrounding normal tissues. Conclusion. From a planning point of view, FAZA-PET-guided dose adaptive escalation is feasible without substantial dose increase to normal tissues above tolerance limits. Clinical prospective studies, however, need to be performed to validate hypoxia-guided adaptive radiation dose escalation in head and neck carcinoma.

In locally advanced head and neck squamous cell carcinoma (HNSCC), the role of imaging becomes more and more critical in the management process. In this framework, molecular imaging techniques such as PET allow noninvasive assessment of a range of tumour biomarkers such as metabolism, hypoxia and proliferation, which can serve different purposes. First, in a pretreatment setting they can influence therapy selection strategies and target delineation for radiation therapy. Second, their predictive and/or prognostic value could help enhance the therapeutic ratio in the management of HNSCC. Third, treatment modification can be performed through the generation of a molecular-based heterogeneous dose distribution with dose escalation to the most resistant parts of the tumour, a concept known as dose painting. Fourth, they are increasingly becoming a tool for monitoring response to therapy. In this review, PET imaging biomarkers used in the routine management of HNSCC or under investigation are discussed.

Purpose Hypoxia in head and neck squamous cell carcinoma (HNSCC) is associated with poor prognosis and outcome. (18) F-Fluoroazomycin arabinoside (FAZA) is a positron emission tomography (PET) tracer developed to enable identification of hypoxic regions within tumor. The aim of this study was to evaluate the use of (18) F-FAZA-PET for assessment of hypoxia before and during radiation therapy.Methods Twelve patients with locally advanced HNSCC underwent (18) F-FAZA-PET scans before and at fraction 7 and 17 of concomitant chemo-radiotherapy. A hypoxic voxel was defined as a voxel expressing a standardized uptake value (SUV) equal or above the SUVmean of the posterior contralateral neck muscles plus three standard deviations. The fractional hypoxic volume fraction (FHV) and the spatial move of hypoxic volumes during treatment were analyzed.Results A hypoxic volume could be identified in ten patients before treatment. FAZA-PET FHV varied from 0 to 54.3 % and from 0 to 41.4 % in the primary tumor and in the involved node, respectively. Six out of these ten patients completed all the FAZA-PET-computed tomography (CT) during the radiotherapy. In all patients, FHV and SUVmax values decreased. All patient presented a spatial move of hypoxic volume, but only three patients had newborn hypoxic voxels after 17 fractions.Conclusion This study indicated that (18) F-FAZA-PET could be used to identify and quantify tumor hypoxia before and during concomitant radio-chemotherapy in patients with locally advanced HNSCC. In addition to the information on prognostic value, the use of (18) F-FAZA-PET allowed the delineation of hypoxic volumes for dose escalation protocols. However, due to fluctuation of hypoxia during treatment, repeated scan will have to be performed (i.e. adaptive radiotherapy).

BACKGROUND:In the context of dose painting by numbers delivered with intensity-modulated radiotherapy, the robustness of dose distributions against geometric uncertainties can be ensured by robust optimization. As robust optimization is seldom available in treatment planning systems (TPS), we propose an alternative method that reaches the same goal by modifying the heterogeneous dose prescription (based on (18)FDG-PET) and guarantees coverage in spite of systematic and random errors with known standard deviations Σ and σ, respectively.MATERIAL AND METHODS:The objective was that 95% of all voxels in the GTVPET received at least 95% of the prescribed dose despite geometric errors. The prescription was modified by a geometric dilation of αΣ for systematic errors and a deconvolution by a Gaussian function of width σ for random errors. For a 90% confidence interval, α = 2.5. Planning was performed on a TomoTherapy system, such that 95% of the voxels received at least 95% of the modified prescription and less than 5% of the voxels received more than 105% of the modified prescription. The applicability of the method was illustrated for two head-and-neck tumors.RESULTS:Systematic and random displacements larger than αΣ and σ degraded coverage. Down to 62.8% of the points received at least 95% of prescribed dose for the largest considered displacements (5 mm systematic translation and 3 mm standard deviation for random errors). When systematic and random displacements were smaller than αΣ and σ, no degradation of target coverage was observed.CONCLUSIONS:The method led to treatment plans with target coverage robust against geometric uncertainties without the need to incorporate these in the optimizer of the TPS. The methodology was illustrated for head-and-neck cancer but can be potentially extended to all treatment sites.