The extent of unnecessary tooth loss due to extractions prior to radiotherapy based on radiation field and dose in patients with head and neck cancer.

BACKGROUND AND PURPOSE: Prior to radiotherapy (RT), teeth with poor prognosis that pose a risk for post-RT osteoradionecrosis (ORN) are removed. To allow enough time for adequate wound healing prior to RT, decisions are made based on the estimated radiation dose. This study aimed to gain insight into (1) the overall number of teeth extracted and (2) the patient and tumor characteristics associated with the number of redundantly extracted teeth. MATERIALS AND METHODS: Patients with head and neck cancer (HNC), treated with RT between 2015 and 2019, were included in this cross-sectional study. For each extracted tooth the radiation dose was calculated retrospectively. The cut-off point for valid extraction was set at ≥ 40 Gy in accordance with the national protocol. Potential factors for doses ≥ 40 Gy were identified, including age, sex, tumor location, tumor (T) and nodal stage (N), overall tumor stage and number of teeth extracted. RESULTS: A total of 1759 teeth were removed from 358 patients. Of these 1759 teeth, 1274 (74%) appeared to have been removed redundantly, based on the mean dose (Dmean) of < 40 Gy. Using the maximum dose (Dmax) of < 40 Gy, 1080 teeth (61%) appeared to have been removed redundantly. Tumor location and N-classification emerged as the most important associative variables in the multivariable regression analysis. CONCLUSION: To our knowledge this is the first study to provide insight into the amount of teeth redundantly extracted prior to RT and represents a step forward in de-escalating the damage to the masticatory system prior to RT.

Intensity-modulated proton therapy decreases dose to organs at risk in low-grade glioma patients: results of a multicentric in silico ROCOCO trial.

BACKGROUND AND PURPOSE: Patients with low-grade glioma (LGG) have a prolonged survival expectancy due to better discriminative tumor classification and multimodal treatment. Consequently, long-term treatment toxicity gains importance. Contemporary radiotherapy techniques such as intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), tomotherapy (TOMO) and intensity-modulated proton therapy (IMPT) enable high-dose irradiation of the target but they differ regarding delivered dose to organs at risk (OARs). The aim of this comparative in silico study was to determine these dosimetric differences in delivered doses. MATERIAL AND METHODS: Imaging datasets of 25 LGG patients having undergone postoperative radiotherapy were included. For each of these patients, in silico treatment plans to a total dose of 50.4 Gy to the target volume were generated for the four treatment modalities investigated (i.e., IMRT, VMAT, TOMO, IMPT). Resulting treatment plans were analyzed regarding dose to target and surrounding OARs comparing IMRT, TOMO and IMPT to VMAT. RESULTS: In total, 100 treatment plans (four per patient) were analyzed. Compared to VMAT, the IMPT mean dose (Dmean) for nine out of 10 (90%) OARs was statistically significantly (p < .02) reduced, for TOMO this was true in 3/10 (30%) patients and for 1/10 (10%) patients for IMRT. IMPT was the prime modality reducing dose to the OARs followed by TOMO. DISCUSSION: The low dose volume to the majority of OARs was significantly reduced when using IMPT compared to VMAT. Whether this will lead to a significant reduction in neurocognitive decline and improved quality of life is to be determined in carefully designed future clinical trials.

A novel concept for tumour targeting with radiation: Inverse dose-painting or targeting the "Low Drug Uptake Volume".

BACKGROUND AND PURPOSE: We tested a novel treatment approach combining (1) targeting radioresistant hypoxic tumour cells with the hypoxia-activated prodrug TH-302 and (2) inverse radiation dose-painting to boost selectively non-hypoxic tumour sub-volumes having no/low drug uptake. MATERIAL AND METHODS: 18F-HX4 hypoxia tracer uptake measured with a clinical PET/CT scanner was used as a surrogate of TH-302 activity in rhabdomyosarcomas growing in immunocompetent rats. Low or high drug uptake volume (LDUV/HDUV) was defined as 40% of the GTV with the lowest or highest 18F-HX4 uptake, respectively. Two hours post TH-302/saline administration, animals received either single dose radiotherapy (RT) uniformly (15 or 18.5Gy) or a dose-painted non-uniform radiation (15Gy) with 50% higher dose to LDUV or HDUV (18.5Gy). Treatment plans were created using Eclipse treatment planning system and radiation was delivered using VMAT. Tumour response was quantified as time to reach 3 times starting tumour volume. RESULTS: Non-uniform RT boosting tumour sub-volume with low TH-302 uptake (LDUV) was superior to the same dose escalation to HDUV (p<0.0001) and uniform RT with the same mean dose 15Gy (p=0.0077). Noteworthy, dose escalation to LDUV required on average 3.5Gy lower dose to the GTV to achieve similar tumour response as uniform dose escalation. CONCLUSIONS: The results support targeted dose escalation to non-hypoxic tumour sub-volume with no/low activity of hypoxia-activated prodrugs. This strategy applies on average a lower radiation dose and is as effective as uniform dose escalation to the entire tumour. It could be applied to other type of drugs provided that their distribution can be imaged.

Benefit of particle therapy in re-irradiation of head and neck patients. Results of a multicentric in silico ROCOCO trial.

BACKGROUND AND PURPOSE: In this multicentric in silico trial we compared photon, proton, and carbon-ion radiotherapy plans for re-irradiation of patients with squamous cell carcinoma of the head and neck (HNSCC) regarding dose to tumour and doses to surrounding organs at risk (OARs). MATERIAL AND METHODS: Twenty-five HNSCC patients with a second new or recurrent cancer after previous irradiation (70Gy) were included. Intensity-modulated proton therapy (IMPT) and ion therapy (IMIT) re-irradiation plans to a second subsequent dose of 70Gy were compared to photon therapy delivered with volumetric modulated arc therapy (VMAT). RESULTS: When comparing IMIT and IMPT to VMAT, the mean dose to all investigated 22 OARs was significantly reduced for IMIT and to 15 out of 22 OARs (68%) using IMPT. The maximum dose to 2% volume (D2) of the brainstem and spinal cord were significantly reduced using IMPT and IMIT compared to VMAT. The data are available on www.cancerdata.org. CONCLUSIONS: In this ROCOCO in silico trial, a reduction in mean dose to OARs was achieved using particle therapy compared to photons in the re-irradiation of HNSCC. There was a dosimetric benefit favouring carbon-ions above proton therapy. These dose reductions may potentially translate into lower severe complication rates related to the re-irradiation.

Preclinical Assessment of Efficacy of Radiation Dose Painting Based on Intratumoral FDG-PET Uptake.

PURPOSE: We tested therapeutic efficacy of two dose painting strategies of applying higher radiation dose to tumor subvolumes with high FDG uptake (biologic target volume, BTV): dose escalation and dose redistribution. We also investigated whether tumor response was determined by the highest dose in BTV or the lowest dose in gross tumor volume (GTV). EXPERIMENTAL DESIGN: FDG uptake was evaluated in rat rhabdomyosarcomas prior to irradiation. BTV was defined as 30% of GTV with the highest (BTVhot) or lowest (BTVcold) uptake. To test efficacy of dose escalation, tumor response (time to reach two times starting tumor volume, TGTV2) to Hot Boost irradiation (40% higher dose to BTVhot) was compared with Cold Boost (40% higher dose to BTVcold), while mean dose to GTV remained 12 Gy. To test efficacy of dose redistribution, TGTV2 after Hot Boost was compared with uniform irradiation with the same mean dose (8 or 12 Gy). RESULTS: TGTV2 after 12 Gy delivered heterogeneously (Hot and Cold Boost) or uniformly were not significantly different: 20.2, 19.5, and 20.6 days, respectively. Dose redistribution (Hot Boost) with 8 Gy resulted in faster tumor regrowth as compared with uniform irradiation (13.3 vs. 17.1 days; P = 0.026). Further increase in dose gradient to 60% led to a more pronounced decrease in TGTV2 (10.9 days; P < 0.0001). CONCLUSIONS: Dose escalation effect was independent of FDG uptake in target tumor volume, while dose redistribution was detrimental in this tumor model for dose levels applied here. Our data are consistent with the hypothesis that tumor response depends on the minimum intratumoral dose.

What level of accuracy is achievable for preclinical dose painting studies on a clinical irradiation platform?

Advancements made over the past decades in both molecular imaging and radiotherapy planning and delivery have enabled studies that explore the efficacy of heterogeneous radiation treatment ("dose painting") of solid cancers based on biological information provided by different imaging modalities. In addition to clinical trials, preclinical studies may help contribute to identifying promising dose painting strategies. The goal of this current study was twofold: to develop a reproducible positioning and set-up verification protocol for a rat tumor model to be imaged and treated on a clinical platform, and to assess the dosimetric accuracy of dose planning and delivery for both uniform and positron emission tomography-computed tomography (PET-CT) based heterogeneous dose distributions. We employed a syngeneic rat rhabdomyosarcoma model, which was irradiated by volumetric modulated arc therapy (VMAT) with uniform or heterogeneous 6 MV photon dose distributions. Mean dose to the gross tumor volume (GTV) as a whole was kept at 12 Gy for all treatment arms. For the nonuniform plans, the dose was redistributed to treat the 30% of the GTV representing the biological target volume (BTV) with a dose 40% higher than the rest of the GTV (GTV - BTV) (~15 Gy was delivered to the BTV vs. ~10.7 Gy was delivered to the GTV - BTV). Cone beam computed tomography (CBCT) images acquired for each rat prior to irradiation were used to correctly reposition the tumor and calculate the delivered 3D dose. Film quality assurance was performed using a water-equivalent rat phantom. A comparison between CT or CBCT doses and film measurements resulted in passing rates >98% with a gamma criterion of 3%/2 mm using 2D dose images. Moreover, between the CT and CBCT calculated doses for both uniform and heterogeneous plans, we observed maximum differences of <2% for mean dose to the tumor and mean dose to the biological target volumes. In conclusion, we have developed a robust method for dose painting in a rat tumor model on a clinical platform, with a high accuracy achieved in the delivery of complex dose distributions. Our work demonstrates the technical feasibility of this approach and enables future investigations on the therapeutic effect of preclinical dose painting strategies using a state-of-the-art clinical platform.

Assessment of local blood flow with laser Doppler flowmetry in irradiated mandibular and frontal bone, an experiment in Göttingen minipigs.

PURPOSE: The aim of this study was to investigate local blood flow changes in the mandibular bone compared to the os frontale after irradiation in various doses. MATERIALS AND METHODS: This study used an animal experiment with 16 female Göttingen minipigs. Three groups of four animals were irradiated with equivalent doses of 25, 50 or 70 Gray on the mandible and os frontale and four animals served as control. Three months after irradiation laser Doppler flowmetry (LDF) was used to record local blood flow on the left mandible and in the irradiated area on the os frontale. At 6 months measurements were repeated. Descriptive and univariate analyses were conducted and p-values lower than 0.05 were considered statistically significant. RESULTS: Local blood flow measurements in the mandible were significantly higher compared to the os frontale. In the os frontale and mandible there was no significant change in the measurements with increasing irradiation dose. CONCLUSION: We found a non-significant decrease in LDF values with an increase in radiation dose in the mandible and non-significant changes in the os frontale at 3 and 6 months. We consider this to represent the process of on-going fibrosis affecting the local blood flow in the mandible.

Intensity-modulated radiation therapy for oropharyngeal cancer: radiation dosage constraint at the anterior mandible.

Because the survival of endosseous implants in irradiated bone is lower than in non-irradiated bone, particularly if the irradiation dose exceeds 50Gy, a study was carried out to assess the irradiation dose in the anterior mandible, when intensity modulated radiation therapy (IMRT) is used. The hypothesis was that adequate IMRT planning in oropharyngeal cancer patients is allowing sufficiently low anterior mandibular bone radiation dosages to safely insert endosseous implants. Ten randomly selected patients with oropharyngeal cancer, primarily treated by intensity-modulated radiotherapy (IMRT), were included in this study. First, at five determined positions distributed over the anterior mandible, the appropriate radiation dosages were calculated according to the originally arranged fractionated radiation schedule. Second, for each patient an adjusted fractionated radiation schedule was established with an extra dose constraint which allowed a lower dose in the mandible taking into account that the anterior mandible needs protection against radiation-induced osteoradionecrosis. The goal for the adjusted fractionated radiation schedule was similar as that of the original fractionated radiation schedule, including a desired tumour target dosage of 70Gy and maximum mean local dosages for organs at risk. The data revealed a considerable and statistically significant, irradiation dose reduction in the anterior mandible without compromising the other constraints. As a result of this study it is strongly advised to maximize dose constraint to the anterior mandible when planning irradiation for oropharyngeal cancer patients, using IMRT. This would greatly facilitate successful implant treatment for this group of patients. The fractionated radiation schedules used, should also be used for the planning of the best implant positions by integrating them in the implant planning software.