Disease Control and Late Toxicity in Adaptive Dose Painting by Numbers Versus Nonadaptive Radiation Therapy for Head and Neck Cancer: A Randomized Controlled Phase 2 Trial.

PURPOSE: Local recurrence remains the main cause of death in stage III-IV nonmetastatic head and neck cancer (HNC), with relapse-prone regions within high 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET)-signal gross tumor volume. We investigated if dose escalation within this subvolume combined with a 3-phase treatment adaptation could increase local (LC) and regional (RC) control at equal or minimized radiation-induced toxicity, by comparing adaptive 18F-FDG-PET voxel intensity-based dose painting by numbers (A-DPBN) with nonadaptive standard intensity modulated radiation therapy (S-IMRT). METHODS AND MATERIALS: This 2-center randomized controlled phase 2 trial assigned (1:1) patients to receive A-DPBN or S-IMRT (+/-chemotherapy). Eligibility: nonmetastatic HNC of oral cavity, oro-/hypopharynx, or larynx, needing radio(chemo)therapy; T1-4N0-3 (exception: T1-2N0 glottic); KPS ≥ 70; ≥18 years; and informed consent. PRIMARY OUTCOMES: 1-year LC and RC. The dose prescription for A-DPBN was intercurrently adapted in 2 steps to an absolute dose-volume limit (≤1.75 cm3 can receive >84 Gy and normalized isoeffective dose >96 Gy) as a safety measure during the study course after 4/7 A-DPBN patients developed ≥G3 mucosal ulcers. RESULTS: Ninety-five patients were randomized (A-DPBN, 47; S-IMRT, 48). Median follow-up was 31 months (IQR, 14-48 months); 29 patients died (17 of cancer progression). A-DPBN resulted in superior LC compared with S-IMRT, with 1- and 2-year LC of 91% and 88% versus 78% and 75%, respectively (hazard ratio, 3.13; 95% CI, 1.13-8.71; P = .021). RC and overall survival were comparable between arms, as was overall grade (G) ≥3 late toxicity (36% vs 20%; P = .1). More ≥G3 late mucosal ulcers were observed in active smokers (29% vs 3%; P = .005) and alcohol users (33% vs 13%; P = .02), independent of treatment arm. Similarly, in the A-DPBN arm, significantly more patients who smoked at diagnosis developed ≥G3 (46% vs 12%; P = .005) and ≥G4 (29% vs 8%; P = .048) mucosal ulcers. One arterial blowout occurred after a G5 mucosal toxicity. CONCLUSIONS: A-DPBN resulted in superior 1- and 2-year LC for HNC compared with S-IMRT. This supports further exploration in multicenter phase 3 trials. It will, however, be challenging to recruit a substantial patient sample for such trials, as concerns have arisen regarding the association of late mucosal ulcers when escalating the dose in continuing smokers.

External partial breast irradiation in prone position: how to improve accuracy?

INTRODUCTION: In view of the limited incremental benefit between whole breast irradiation (WBI), accelerated partial breast irradiation (APBI) and omission of radiotherapy in favorable early-stage breast cancer (ESBC), APBI can only be justified if it combines adequate target coverage with the lowest achievable toxicity. Interobserver exercises demonstrated the difficulty of precise target delineation, especially in prone position; information on accuracy is even scarcer. We tested the impact of inserting an additional indicator clip, marking the depth of the tumor in the breast, and the added value of a preoperative CT in treatment position on precision and accuracy. MATERIAL AND METHODS: In 12 patients, tumor bed delineation was performed by four radiation oncologists, with CTVstandard (clinical target volume) based on standard delineation guidelines, CTVclip resulting from a 1-2-cm symmetrical expansion with the indicator clip as center and CTVclip_CT expanding from the midpoint between the indicator clip and preoperative gross tumor volume (GTV) as center. Precision was measured as the mean pairwise Jaccard index (JIpairs) between observers, accuracy as the mean overlap between GTV and respective CTVs. RESULTS: JIpairs was 0.38 for CTVstandard, 0.75 for CTVclip and 0.59 for CTVclip_CT. Overlap rate of GTV with CTVs was respectively 0.48, 0.67 and improved further to 0.88 for CTVclip_CT. High-dose coverage of GTV (D95 and D90) improved with an indicator clip, but the most optimal result was reached when preoperative CT was added. CONCLUSIONS: If EB-APBI in prone position is aimed for, an indicator clip intended to mark the depth of the tumor increases the probability of accurate target coverage, but cannot entirely replace the added value of a preoperative CT in treatment position. Avoiding the cost and effort of such CT implies a risk of missing the target, especially when small volumes are aimed for. Increasing target volumes to reduces this risk, questions the concept of APBI.

Late mucosal ulcers in dose-escalated adaptive dose-painting treatments for head-and-neck cancer.

BACKGROUND: To identify predictive factors for the development of late grade 4 mucosal ulcers in adaptive dose-escalated treatments for head-and-neck cancer. MATERIAL AND METHODS: Patient data of four dose-escalated three-phase adaptive dose-painting by numbers (DPBN) clinical trials were analyzed in this study. Correlations between the development of late grade 4 ulcers and factors related with the treatment, disease characteristics and the patient were investigated. Dosimetrical thresholds were searched among the highest doses received by 1.75 cm3 (D1.75cc) of the primary gross tumor volume (GTVT) and the corresponding normalized isoeffective dose (NID21.75cc, with a reference dose of 2Gy/fraction and α/ß of 3 Gy). RESULTS: From 39 studied patients, nine developed late grade 4 mucosal ulcers. The continuation to either smoke or drink alcohol after therapy was the factor that showed a strong (eight out of nine patients) association with the occurrence of grade 4 ulcers. Six of the patients who continued to smoke or/and drink had D1.75cc and NID21.75cc above 84 Gy and 95.5 Gy, respectively. Seven of the patients with grade 4 had the dose levels above these thresholds, but even if the D1.75cc threshold was significant in the prediction of late grade 4 ulcers, it could not be considered as the only contributing factor. CONCLUSIONS: The search for patterns provided strong reasons to apply a dosimetrical threshold for the peak-dose volume of 1.75 cm3 as a preventive measure for late grade 4 mucosal ulcers. Also, patients that continue to smoke or drink alcohol after therapy have increased risk to develop late mucosal ulcers.

Highly Accelerated Irradiation in 5 Fractions (HAI-5): Feasibility in Elderly Women With Early or Locally Advanced Breast Cancer.

PURPOSE: To investigate, in a prospective phase 1 to 2 trial, the safety and feasibility of delivering external beam radiation therapy in 5 fractions to the breast or thoracic wall, including boost and/or lymph nodes if needed, to women aged ≥65 years with breast cancer. METHODS AND MATERIALS: Ninety-five patients aged ≥65 years, referred for adjuvant radiation therapy, were treated in 5 fractions over 12 days with a total dose of 28.5 Gy/5.7 Gy to the breast or thoracic wall and, if indicated, 27 Gy/5.4 Gy to the lymph node regions and 32.5 Gy/6.5 Gy to 34.5 Gy/6.9 Gy to the tumor bed. The primary endpoint was clinically relevant dermatitis (grade ≥2). RESULTS: Mean follow-up time was 5.6 months, and mean age was 73.6 years. Clinically relevant dermatitis was observed in 11.6% of patients and only occurred in breast irradiation with boost (17.5% grade 2-3 vs 0% in the no-boost group). Although doses were high, treatment delivery with intensity modulated radiation therapy was swift, except for complex treatments, including lymph nodes for which single-arc volumetric modulated arc therapy was needed to reduce beam-on time. CONCLUSION: Accelerated radiation therapy in 5 fractions was technically feasible and resulted in low acute toxicity. Clinically relevant erythema was only observed in patients receiving a boost, but still at an acceptable rate. Although the follow-up is still short, the results on acute toxicity after accelerated radiation therapy were encouraging. A 5-fraction schedule is well tolerated in the elderly and may lower the threshold for radiation therapy in this population.

Variations in target volume definition and dose to normal tissue using anatomic versus biological imaging (18 F-FDG-PET) in the treatment of bone metastases: results from a 3-arm randomized phase II trial.

INTRODUCTION: To report the impact on target volume delineation and dose to normal tissue using anatomic versus biological imaging (18 F-FDG-PET) for bone metastases. METHODS: Patients with uncomplicated painful bone metastases were randomized (1:1:1) and blinded to receive either 8 Gy in a single fraction with conventionally planned radiotherapy (ConvRT-8 Gy) or 8 Gy in a single fraction with dose-painting-by-numbers (DPBN) dose range between 6 and 10 Gy) (DPBN-8 Gy) or 16 Gy in a single fraction with DPBN (dose range between 14 and 18 Gy) (DPBN-16 Gy). The primary endpoint was overall pain response at 1 month. Volumes of the gross tumour volume (GTV) - both biological (GTVPET ) and anatomical (GTVCT ) -, planning target volume (PTV), dose to the normal tissue and maximum standardized-uptake values (SUVMAX ) were analysed (secondary endpoint). RESULTS: Sixty-three percent of the GTVCT volume did not show 18 F-FDG-uptake. On average, 20% of the GTVPET volume was outside GTVCT . The volume of normal tissue receiving 4 Gy, 6 Gy and 8 Gy was at least 3×, 6× and 13× smaller in DPBN-8 Gy compared to ConvRT-8 Gy and DPBN-16 Gy (P < 0.05). CONCLUSION: Positron emitting tomography-information potentially changes the target volume for bone metastases. DPBN between 6 and 10 Gy significantly decreases dose to the normal tissue compared to conventional radiotherapy.

Intensity modulated arc therapy implementation in a three phase adaptive (18)F-FDG-PET voxel intensity-based planning strategy for head-and-neck cancer.

BACKGROUND: This study investigates the implementation of a new intensity modulated arc therapy (IMAT) class solution in comparison to a 6-static beam step-and-shoot intensity modulated radiotherapy (s-IMRT) for three-phase adaptive (18)F-FDG-PET-voxel-based dose-painting-by-numbers (DPBN) for head-and-neck cancer. METHODS: We developed (18)F-FDG-PET-voxel intensity-based IMAT employing multiple arcs and compared it to clinically used s-IMRT DPBN. Three IMAT plans using (18)F-FDG-PET/CT acquired before treatment (phase I), after 8 fractions (phase II) and CT acquired after 18 fractions (phase III) were generated for each of 10 patients treated with 3 s-IMRT plans based on the same image sets. Based on deformable image registration (ABAS, version 0.41, Elekta CMS Software, Maryland Heights, MO), doses of the 3 plans were summed on the pretreatment CT using validated in-house developed software. Dosimetric indices in targets and organs-at-risk (OARs), biologic conformity of treatment plans set at ≤5 %, treatment quality and efficiency were compared between IMAT and s-IMRT for the whole group and for individual patients. RESULTS: Doses to most organs-at-risk (OARs) were significantly better in IMAT plans, while target levels were similar for both types of plans. On average, IMAT ipsilateral and contralateral parotid mean doses were 14.0 % (p = 0.001) and 12.7 % (p < 0.001) lower, respectively. Pharyngeal constrictors D50% levels were similar or reduced with up to 54.9 % for IMAT compared to s-IMRT for individual patient cases. IMAT significantly improved biologic conformity by 2.1 % for treatment phases I and II. 3D phantom measurements reported an agreement of ≥95 % for 3 % and 3 mm criteria for both treatment modalities. IMAT delivery time was significantly shortened on average by 41.1 %. CONCLUSIONS: IMAT implementation significantly improved the biologic conformity as compared to s-IMRT in adaptive dose-escalated DPBN treatments. The better OAR sparing and faster delivery highly improved the treatment efficiency.

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.