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Each year, 500,000 patients are treated with radiotherapy for head and neck cancer, resulting in relatively high survival rates. However, in 40% of patients, quality of life is severely compromised because of radiation-induced impairment of salivary gland function and consequent xerostomia (dry mouth). New radiation treatment technologies enable sparing of parts of the salivary glands. We have determined the parts of the major salivary gland, the parotid gland, that need to be spared to ensure that the gland continues to produce saliva after irradiation treatment. In mice, rats, and humans, we showed that stem and progenitor cells reside in the region of the parotid gland containing the major ducts. We demonstrated in rats that inclusion of the ducts in the radiation field led to loss of regenerative capacity, resulting in long-term gland dysfunction with reduced saliva production. Then we showed in a cohort of patients with head and neck cancer that the radiation dose to the region of the salivary gland containing the stem/progenitor cells predicted the function of the salivary glands one year after radiotherapy. Finally, we showed that this region of the salivary gland could be spared during radiotherapy, thus reducing the risk of post-radiotherapy xerostomia., (Copyright © 2015, American Association for the Advancement of Science.)

An increasing number of proton therapy facilities are being planned and built at hospital based centers. Most facilities are employing traditional dose delivery methods. A second generation of dose application techniques, based on pencil beam scanning, is slowly being introduced into the commercially available proton therapy systems. New developments in accelerator physics are needed to accommodate and fully exploit these new techniques. At the same time new developments such as the development of small cyclotrons, Dielectric Wall Accelerator (DWA) and laser driven systems, aim for smaller, single room treatment units. In general the benefits of proton therapy could be exploited optimally when achieving a higher level in accuracy, beam energy, beam intensity, safety and system reliability. In this review an overview of the current developments will be given followed by a discussion of upcoming new technologies and needs, like increase of energy, on-line MRI and proton beam splitting for independent uses of treatment rooms. [ABSTRACT FROM AUTHOR]

Purpose: To assess in a rat model whether adding a subtolerance dose in a region adjacent to a high-dose irradiated subvolume of the parotid gland influences its response (bath-and-shower effect). Methods and Materials: Irradiation of the whole, cranial 50%, and/or the caudal 50% of the parotid glands of Wistar rats was performed using 150-MeV protons. To determine suitable (i.e., subtolerance) dose levels for a bath-dose, both whole parotid glands were irradiated with 5 to 25 Gy. Subsequently groups of Wistar rats received 30 Gy to the caudal 50% (shower) and 0 to 10 Gy to the cranial 50% (bath) of both parotid glands. Stimulated saliva flow rate (function) was measured before and up to 240 days after irradiation. Results: Irradiation of both glands up to a dose of 10 Gy did not result in late loss of function and is thus regarded subtolerance. Addition of a dose bath of 1 to 10 Gy to a high-dose in the caudal 50% of the glands resulted in enhanced function loss. Conclusion: Similar to the spinal cord, the parotid gland demonstrates a bath and shower effect, which may explain the less-than-expected sparing of function after IMRT. [Copyright &y& Elsevier]

Purpose: Optimal implementation of new radiotherapy techniques requires accurate predictive models for normal tissue complications. Since clinically used dose distributions are nonuniform, local tissue damage needs to be measured and related to local tissue dose. In lung, radiation-induced damage results in density changes that have been measured by computed tomography (CT) imaging noninvasively, but not yet on a localized scale. Therefore, the aim of the present study was to develop a method for quantification of local radiation-induced lung tissue damage using CT. Methods and Materials: CT images of the thorax were made 8 and 26 weeks after irradiation of 100%, 75%, 50%, and 25% lung volume of rats. Local lung tissue structure (SL) was quantified from local mean and local standard deviation of the CT density in Hounsfield units in 1-mm3 subvolumes. The relation of changes in SL (ΔSL) to histologic changes and breathing rate was investigated. Feasibility for clinical application was tested by applying the method to CT images of a patient with non–small-cell lung carcinoma and investigating the local dose–effect relationship of ΔSL. Results: In rats, a clear dose–response relationship of ΔSL was observed at different time points after radiation. Furthermore, ΔSL correlated strongly to histologic endpoints (infiltrates and inflammatory cells) and breathing rate. In the patient, progressive local dose-dependent increases in ΔSL were observed. Conclusion: We developed a method to quantify local radiation-induced tissue damage in the lung using CT. This method can be used in the development of more accurate predictive models for normal tissue complications. [Copyright &y& Elsevier]

Purpose: To test the hypothesis that heart irradiation increases the risk of a symptomatic radiation-induced loss of lung function (SRILF) and that this can be well-described as a modulation of the functional reserve of the lung. Methods and Materials: Rats were irradiated with 150-MeV protons. Dose–response curves were obtained for a significant increase in breathing frequency after irradiation of 100%, 75%, 50%, or 25% of the total lung volume, either including or excluding the heart from the irradiation field. A significant increase in the mean respiratory rate after 6–12 weeks compared with 0–4 weeks was defined as SRILF, based on biweekly measurements of the respiratory rate. The critical volume (CV) model was used to describe the risk of SRILF. Fits were done using a maximum likelihood method. Consistency between model and data was tested using a previously developed goodness-of-fit test. Results: The CV model could be fitted consistently to the data for lung irradiation only. However, this fitted model failed to predict the data that also included heart irradiation. Even refitting the model to all data resulted in a significant difference between model and data. These results imply that, although the CV model describes the risk of SRILF when the heart is spared, the model needs to be modified to account for the impact of dose to the heart on the risk of SRILF. Finally, a modified CV model is described that is consistent to all data. Conclusions: The detrimental effect of dose to the heart on the incidence of SRILF can be described by a dose dependent decrease in functional reserve of the lung. [Copyright &y& Elsevier]

: PurposeThe effects of dose distribution on dose–effect relationships have been evaluated and, from this, iso-effective doses (ED50) established.: Methods and materialsWistar rats were irradiated on the cervical spinal cord with single doses of unmodulated protons (150 MeV) to obtain sharp lateral penumbras, using the shoot-through technique, which employs the plateau of the depth-dose profile rather than the Bragg peak. Two types of inhomogeneous dose distributions have been administered: (1) 2 4-mm fields with 8- or 12-mm spacing between the center of the fields (referred to as split-field) were irradiated with variable single doses and (2) cervical spinal cord was irradiated with various combinations of relatively low doses to a large volume (20 mm) combined with high doses to a small volume (4 mm) (referred to as bath and shower). The endpoint for estimating the dose–response relationships was paralysis of the fore or hind limbs.: ResultsThe split-field experiments (2 × 4 mm) showed a shift in the dose–response curves, giving significant higher ED50 values of 45.4 Gy and 41.6 Gy for 8- and 12-mm spacing, respectively, compared with the ED50 of 24.9 Gy for the single 8 mm (same total tissue volume irradiated). These values were closer to the ED50 for a single 4-mm field of 53.7 Gy. The bath and shower experiments showed a large decrease of the ED50 values from 15–22 Gy when compared with the 4-mm single field, even with a bath dose as low as 4 Gy. There were no histologic changes found in the low dose bath regions of the spinal cord at postmortem.: ConclusionsNot only the integral irradiated volume is a determining factor for the ED50 of rat cervical spinal cord, but also the shape of the dose distribution is of great importance. The high ED50 values of a small region or shower (4 mm) decreases significantly when the adjacent tissue is irradiated with a subthreshold dose (bath), even as low as 4 Gy. The significant shift to lower ED50 values for induction of paralysis of the limbs by adding a low-dose bath was not accompanied by changes in histologic lesions. These observations may have implications for the interpretation of complex treatment plans and normal tissue complication probability in intensity-modulated radiotherapy. [Copyright &y& Elsevier]