Molecular imaging-based dose painting: a novel paradigm for radiation therapy prescription

Abstract

Dose painting is the prescription of a nonuniform radiation dose distribution to the target volume based on functional or molecular images shown to indicate the local risk of relapse. Two prototypical strategies for implementing this novel paradigm in radiation oncology are reviewed: subvolume boosting and dose painting by numbers. Subvolume boosting involves the selection of a "target within the target," defined by image segmentation on the basis of the quantitative information in the image or morphologically, and this is related to image-based target volume selection and delineation. Dose painting by numbers is a voxel-level prescription of dose based on a mathematical transformation of the image intensity of individual pixels. The quantitative use of images to decide both where and how to delivery radiation therapy in an individual case is also called theragnostic imaging. Dose painting targets are imaging surrogates for cellular or microenvironmental phenotypes associated with poor radioresponsiveness. In this review, the focus is on the following positron emission tomography tracers: FDG and choline as surrogates for tumor burden, fluorothymidine as a surrogate for proliferation (or cellular growth fraction) and hypoxia-sensitive tracers, including [(18)F] fluoromisonidazole, EF3, EF5, and (64)Cu-labeled copper(II) diacetyl-di(N(4)-methylthiosemicarbazone) as surrogates of cellular hypoxia. Research advances supporting the clinicobiological rationale for dose painting are reviewed as are studies of the technical feasibility of optimizing and delivering realistic dose painted radiation therapy plans. Challenges and research priorities in this exciting research field are defined and a possible design for a randomized clinical trial of dose painting is presented.

Figure 1

Established clinical causes of local treatment failure after fractionated radiation therapy and selected PET tracers of interest as surrogates for these phenotypes.

Figure 2

Patient with a right-sided T4-N1-M0 hypopharyngeal squamous cell carcinoma receiving concomitant chemo-radiotherapy and imaged with intravenous contrast CT, MRI (T2 weighted sequence) and FDG PET before treatment and at the end of week 3 (30 Gy) and 5 (50 Gy). Primary tumor shrinkage is observed with all imaging modalities, but is more pronounced with FDG-PET.

Figure 3

Patient with a T3-N0-M0 posterior pharyngeal wall squamous cell carcinoma treated with simultaneous integrated boost IMRT. A total dose of 69 Gy (30 fractions of 2.3 Gy in 6 weeks) was prescribed to the primary tumor planning target volume (PTV), and 55.5 Gy (30 fractions of 1.85 Gy in 6 weeks) to the prophylactic nodal PTV. Intravenous-contrast CT and FDG-PET were performed before the start of radiotherapy and weekly during treatment. Target volumes and organs at risk were delineated on each CT study. On FDG PET scans, the GTVs were automatically segmented using a gradient-based algorithm. FDG-PET images were registered on the CT images with a rigid registration algorithm. Dose optimizations were performed at each time points on CT-based and PET-based images. Doses were then added to get the composite dose distribution. Compared with non-adaptive CT planning (classic CT-based), non-adaptive FDG-PET planning (classic PET-based) allows a significant reduction of the high dose volumes (V₉₀–V₁₀₀). While an adaptive CT-based plan allowed for a greater reduction in V₉₀–V₁₀₀ isodose volumes, the largest effect was observed with the adaptive PET-based plan. In all scenarios, the lower isodose volumes were not reduced due to the non-adapted prophylactic irradiation of the nodal PTV.

Figure 4

Comparison between FDG and EF3 for the detection of hypoxia in C3Hf/Kam mouse FSA (fibrosarcoma) and SCCVII (squamous cell carcinoma) under air-breathing or 10% oxygen breathing. ¹⁴C-EF3 (9.7 MBq) was injected in the tail vein followed 1h later by ¹⁸F-FDG (17.6 MBq). One hour after the second injection, the mice were killed and processed for autoradiography. The ¹⁸F-FDG images were obtained after a 45-min exposure. After a 48-h rest time allowing for ¹⁸F decay, the sections were exposed for 56h to obtain the ¹⁴C-EF3 distribution.

Figure 5

Schematic representation of a proposed phase III trial of dose painting. See text for discussion.