D. Berwouts

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.

Hypofractionated whole breast irradiation for patients with large breasts: A randomized trial comparing prone and supine positions

BACKGROUND AND PURPOSE Comparison of acute toxicity of whole-breast irradiation (WBI) in prone and supine positions. MATERIALS AND METHODS This non-blinded, randomized, prospective, mono-centric trial was undertaken between December 29, 2010, and December 12, 2012. One hundred patients with large breasts were randomized between supine multi beam (MB) and prone tangential field (TF) intensity modulated radiotherapy (IMRT). Dose-volume parameters were assessed for the breast, heart, left anterior descending coronary artery (LAD), ipsilateral lung and contralateral breast. The primary endpoint was acute moist skin desquamation. Secondary endpoints were dermatitis, edema, pruritus and pain. RESULTS Prone treatment resulted in: improved dose coverage (p<0.001); better homogeneity (p<0.001); less volumes of over-dosage (p=0.001); reduced acute skin desquamation (p<0.001); a 3-fold decrease of moist desquamation p=0.04 (chi-square), p=0.07 (Fishers exact test)); lower incidence of dermatitis (p<0.001), edema (p=0.005), pruritus (p=0.06) and pain (p=0.06); 2- to 4-fold reduction of grades 2-3 toxicity; lower ipsilateral lung (p<0.001) and mean LAD (p=0.007) dose; lower, though statistically non-significant heart and maximum LAD. CONCLUSIONS This study provides level I evidence for replacing the supine standard treatment by prone IMRT for whole-breast irradiation in patients with large breasts. A confirmatory trial in a multi-institutional setting is warranted.

Heart dose reduction by prone deep inspiration breath hold in left-sided breast irradiation

BACKGROUND AND PURPOSE Cardiac disease has been related to heart dose after left-sided breast radiotherapy. This trial evaluates the heart sparing ability and feasibility of deep inspiration breath hold (DIBH) in the prone position for left-sided whole breast irradiation (WBI). MATERIALS AND METHODS Twelve patients underwent CT-simulation in supine shallow breathing (SB), supine DIBH, prone SB and prone DIBH. A validation cohort of 38 patients received prone SB and prone DIBH CT-scans; the last 30 patients were accepted for prone DIBH treatment. WBI was planned with a prescription dose of 40.05 Gy. RESULTS DIBH was able to reduce (p<0.001) heart dose in both positions, with results for prone DIBH at least as favorable as for supine DIBH. Mean heart dose was lowered from 2.2 Gy for prone SB to 1.3 Gy for prone DIBH (p<0.001), while preserving the lung sparing ability of prone positioning. Moreover prone DIBH nearly consistently reduced mean heart dose to less then 2 Gy, regardless of breast volume. All patients were able to perform the simulation procedure, 28/30 patients were treated with prone DIBH. CONCLUSIONS This trial demonstrates the ability and feasibility of prone DIBH to acquire optimal heart and lung sparing for left-sided WBI.

High-dose reirradiation with intensity-modulated radiotherapy for recurrent head-and-neck cancer: Disease control, survival and toxicity

PURPOSE To evaluate disease control, survival and severe late toxicity after high-dose fractionated reirradiation using intensity-modulated radiotherapy (IMRT) for recurrent head-and-neck cancer. MATERIALS AND METHODS Sixty consecutive patients were reirradiated with IMRT between 1997 and 2011. The median prescribed dose was 70 Gy in 35 daily fractions until 2004 and 69.12 Gy in 32 daily fractions thereafter. The median cumulative dose was 132 Gy. Sixty-seven percent of patients had non-metastatic stage IV disease. Surgery prior to reirradiation and concomitant systemic therapy was performed in 13 (22%) and 20 (33%) patients, respectively. RESULTS Median follow-up in living patients was 18.5 months. Actuarial 1-, 2- and 5-year locoregional control was 64%, 48% and 32%, respectively. Median overall (OS) and disease-free survival was 9.6 and 6.7 months, respectively. Actuarial 1-, 2- and 5-year OS was 44%, 32% and 22%, respectively. Seventeen (27%) and 2 (3%) patients had grade 3 and 4 acute toxicity, respectively. Cumulative incidence of late grade≥3 toxicity was 23%, 27% and 66% at 1, 2 and 5 years, respectively. In 4 patients, death was attributed to toxicity: fatal bleeding (n=2), aspiration pneumonia (n=1) and skin necrosis (n=1). CONCLUSIONS High-dose fractionated reirradiation with IMRT offers 5-year disease control and OS in recurrent head-and-neck cancer for 1/3 and 1/4 patients, respectively. Severe late toxicity after 1-2 and 5 years occurs in 1/4 and 2/3 patients, respectively.

Intensity‐modulated radiotherapy for early‐stage glottic cancer

The purpose of this study was to report on treatment outcome of intensity‐modulated radiotherapy (IMRT) for early‐stage (cT1–2 cN0 M0) squamous cell carcinoma of the glottis, as compared with patients treated with conventional radiotherapy.

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.

Distant metastases in head and neck cancer

Most trials in head and neck cancer emphasize locoregional control, as this is the main pattern of therapy failure. However, up to 15% of patients develop distant metastases. The purpose of this study was to present the investigated factors associated with distant metastasis in a single‐center patient cohort.

Deep inspiration breath hold in the prone position retracts the heart from the breast and internal mammary lymph node region

Deep inspiration breath hold in the prone position causes a caudal shift of the heart away from the nearly unmodified breast and internal mammary lymph node region, suggesting better heart protection for left-sided whole breast irradiation with or without regional nodal radiotherapy.

Long‐term outcome of 18F‐fluorodeoxyglucose‐positron emission tomography‐guided dose painting for head and neck cancer: Matched case‐control study

The purpose of this study was to report the long‐term outcome of 18F‐fluorodeoxyglucose‐positron emission tomography (18F‐FDG‐PET)‐guided dose painting for head and neck cancer in comparison to conventional intensity‐modulated radiotherapy (IMRT) in a matched case‐control study.

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

Abstract 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/β 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.