Biological 18[F]-FDG-PET image-guided dose painting by numbers for painful uncomplicated bone metastases: A 3-arm randomized phase II trial.

BACKGROUND: Antalgic radiotherapy for bone metastases might be improved by implementing biological information in the radiotherapy planning using (18)F-FDG-PET-CT based dose painting by numbers (DPBN). MATERIALS AND METHODS: Patients with uncomplicated painful bone metastases were randomized (1:1:1) and blinded to receive either 8Gy in a single fraction with conventionally planned radiotherapy (arm A) or 8Gy in a single fraction with DPBN (dose range between 610Gy and 10Gy) (arm B) or 16Gy in a single fraction with DPBN (dose range between 1410Gy and 18Gy) (arm C). The primary endpoint was overall pain response at 1month. The phase II trial was designed to select the experimental arm with sufficient promise of efficacy to continue to a phase III trial. RESULTS: Forty-five patients were randomized. Eight (53%), 12 (80%) and 9 patients (60%) had an overall response to treatment in arm A, B and C, respectively. The estimated odds ratio of overall response for arm B vs. A is 3.5 (95% CI: 0.44-17.71, p=0.12). The estimated odds ratio of arm C vs. A is 1.31 (95% CI: 0.31-5.58, p=0.71). CONCLUSION: A single fraction of 8Gy with DPBN will be further evaluated in a phase III-trial.

Comparative dosimetry of three-phase adaptive and non-adaptive dose-painting IMRT for head-and-neck cancer.

PURPOSE: The anatomical changes, which occur during the radiotherapy treatment for head-and-neck cancer, may compromise the effectiveness of the treatment. This study compares dosimetrical effects of adaptive (ART) and non-adaptive (RT) dose-painted radiotherapy. MATERIALS AND METHODS: For 10 patients, three treatment phases were preceded by a planning PET/CT scan. In ART, phases II and III were planned using PET/CT2 and PET/CT3, respectively. In RT, phases II and III were planned on PET/CT1 and recalculated on PET/CT2 and PET/CT3. Deformable image co-registration was used to sum the dose distributions and to propagate regions-of-interest (ROIs) drawn on PET/CT1 to PET/CT2, PET/CT3 and a last-treatment-day CT-scan. RESULTS: Re-adjusted dose-painting ART provided higher minimum and lower maximum doses in target ROIs in comparison to RT. On average, ART reduced the parotids' median dose and swallowing structures mean dose by 4.6-7.1% (p>0.05) and 3% (p=0.06), respectively. Dose differences for targets were from -1.6% to 6.6% and for organs-at-risk from -7.1% to 7.1%. Analysis of individual patient data showed large improvements of ROI dose/volume metrics by ART, reaching a 24.4% minimum-dose increase in the elective neck planning target volume and 21.1% median-dose decrease in swallowing structures. CONCLUSION: Compared to RT, ART readjusts dose-painting, increases minimum and decreases maximum doses in target volumes and improves dose/volume metrics of organs-at-risk. The results favored the adaptive strategy, but also revealed considerable heterogeneity in patient-specific benefit. Reporting population-average effects underestimates the patient-specific benefits of ART.

Deformation field validation and inversion applied to adaptive radiation therapy.

Development and implementation of chronological and anti-chronological adaptive dose accumulation strategies in adaptive intensity-modulated radiation therapy (IMRT) for head-and-neck cancer. An algorithm based on Newton iterations was implemented to efficiently compute inverse deformation fields (DFs). Four verification steps were performed to ensure a valid dose propagation: intra-cell folding detection finds zero or negative Jacobian determinants in the input DF; inter-cell folding detection is implemented on the resolution of the output DF; a region growing algorithm detects undefined values in the output DF; DF domains can be composed and displayed on the CT data. In 2011, one patient with nonmetastatic head and neck cancer selected from a three phase adaptive DPBN study was used to illustrate the algorithms implemented for adaptive chronological and anti-chronological dose accumulation. The patient received three (18)F-FDG-PET/CTs prior to each treatment phase and one CT after finalizing treatment. Contour propagation and DF generation between two consecutive CTs was performed in Atlas-based autosegmentation (ABAS). Deformable image registration based dose accumulations were performed on CT1 and CT4. Dose propagation was done using combinations of DFs or their inversions. We have implemented a chronological and anti-chronological dose accumulation algorithm based on DF inversion. Algorithms were designed and implemented to detect cell folding.

Three-phase adaptive dose-painting-by-numbers for head-and-neck cancer: initial results of the phase I clinical trial.

PURPOSE: To evaluate feasibility of using deformable image co-registration in three-phase adaptive dose-painting-by-numbers (DPBN) for head-and-neck cancer and to report dosimetrical data and preliminary clinical results. MATERIAL AND METHODS: Between November 2010 and October 2011, 10 patients with non-metastatic head-and-neck cancer enrolled in this phase I clinical trial where treatment was adapted every ten fractions. Each patient was treated with three DPBN plans based on: a pretreatment 18[F]-FDG-PET scan (phase I: fractions 1-10), a per-treatment 18[F]-FDG-PET/CT scan acquired after 8 fractions (phase II: fractions 11-20) and a per-treatment 18[F]-FDG-PET/CT scan acquired after 18 fractions (phase III: fractions 21-30). A median prescription dose to the dose-painted target was 70.2 Gy (fractions 1-30) and to elective neck was 40 Gy (fractions 1-20). Deformable image co-registration was used for automatic region-of-interest propagation and dose summation of the three treatment plans. RESULTS: All patients (all men, median age 68, range 48-74 years) completed treatment without any break or acute G≥4 toxicity. Target volume reductions (mean (range)) between pre-treatment CT and CT on the last day of treatment were 72.3% (57.9-98.4) and 46.3% (11.0-73.1) for GTV and PTV(high_dose), respectively. Acute G3 toxicity was limited to dysphagia in 3/10 patients and mucositis in 2/10 patients; none of the patients lost ≥20% weight. At median follow-up of 13, range 7-22 months, 9 patients did not have evidence of disease. CONCLUSIONS: Three-phase adaptive 18[F]-FDG-PET-guided dose painting by numbers using currently available tools is feasible. Irradiation of smaller target volumes might have contributed to mild acute toxicity with no measurable decrease in tumor response.

Evaluation of deformable image coregistration in adaptive dose painting by numbers for head-and-neck cancer.

PURPOSE: To assess the accuracy of contour deformation and feasibility of dose summation applying deformable image coregistration in adaptive dose painting by numbers (DPBN) for head and neck cancer. METHODS AND MATERIALS: Data of 12 head-and-neck-cancer patients treated within a Phase I trial on adaptive (18)F-FDG positron emission tomography (PET)-guided DPBN were used. Each patient had two DPBN treatment plans: the initial plan was based on a pretreatment PET/CT scan; the second adapted plan was based on a PET/CT scan acquired after 8 fractions. The median prescription dose to the dose-painted volume was 30 Gy for both DPBN plans. To obtain deformed contours and dose distributions, pretreatment CT was deformed to per-treatment CT using deformable image coregistration. Deformed contours of regions of interest (ROI(def)) were visually inspected and, if necessary, adjusted (ROI(def_ad)) and both compared with manually redrawn ROIs (ROI(m)) using Jaccard (JI) and overlap indices (OI). Dose summation was done on the ROI(m), ROI(def_ad), or their unions with the ROI(def). RESULTS: Almost all deformed ROIs were adjusted. The largest adjustment was made in patients with substantially regressing tumors: ROI(def) = 11.8 ± 10.9 cm(3) vs. ROI(def_ad) = 5.9 ± 7.8 cm(3) vs. ROI(m) = 7.7 ± 7.2 cm(3) (p = 0.57). The swallowing structures were the most frequently adjusted ROIs with the lowest indices for the upper esophageal sphincter: JI = 0.3 (ROI(def)) and 0.4 (ROI(def_ad)); OI = 0.5 (both ROIs). The mandible needed the least adjustment with the highest indices: JI = 0.8 (both ROIs), OI = 0.9 (ROI(def)), and 1.0 (ROI(def_ad)). Summed doses differed non-significantly. There was a trend of higher doses in the targets and lower doses in the spinal cord when doses were summed on unions. CONCLUSION: Visual inspection and adjustment were necessary for most ROIs. Fast automatic ROI propagation followed by user-driven adjustment appears to be more efficient than labor-intensive de novo drawing. Dose summation using deformable image coregistration was feasible. Biological uncertainties of dose summation strategies warrant further investigation.