Jacobus M. Schippers

Unexpected changes of rat cervical spinal cord tolerance caused by inhomogeneous dose distributions.

PURPOSE The effects of dose distribution on dose-effect relationships have been evaluated and, from this, iso-effective doses (ED(50)) established. METHODS AND MATERIALS Wistar 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. RESULTS The split-field experiments (2 x 4 mm) showed a shift in the dose-response curves, giving significant higher ED(50) values of 45.4 Gy and 41.6 Gy for 8- and 12-mm spacing, respectively, compared with the ED(50) of 24.9 Gy for the single 8 mm (same total tissue volume irradiated). These values were closer to the ED(50) for a single 4-mm field of 53.7 Gy. The bath and shower experiments showed a large decrease of the ED(50) 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. CONCLUSIONS Not only the integral irradiated volume is a determining factor for the ED(50) of rat cervical spinal cord, but also the shape of the dose distribution is of great importance. The high ED(50) 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 ED(50) 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.

Dose-volume effects in the rat cervical spinal cord after proton irradiation

PURPOSE To estimate dose-volume effects in the rat cervical spinal cord with protons. METHODS AND MATERIALS Wistar rats were irradiated on the cervical spinal cord with a single fraction of unmodulated protons (150-190 MeV) using the shoot through method, which employs the plateau of the depth-dose profile rather than the Bragg peak. Four different lengths of the spinal cord (2, 4, 8, and 20 mm) were irradiated with variable doses. The endpoint for estimating dose-volume effects was paralysis of fore or hind limbs. RESULTS The results obtained with a high-precision proton beam showed a marginal increase of ED50 when decreasing the irradiated cord length from 20 mm (ED50 = 20.4 Gy) to 8 mm (ED50 = 24.9 Gy), but a steep increase in ED50 when further decreasing the length to 4 mm (ED50 = 53.7 Gy) and 2 mm (ED50 = 87.8 Gy). These results generally confirm data obtained previously in a limited series with 4-6-MV photons, and for the first time it was possible to construct complete dose-response curves down to lengths of 2 mm. At higher ED50 values and shorter lengths irradiated, the latent period to paralysis decreased from 125 to 60 days. CONCLUSIONS Irradiation of variable lengths of rat cervical spinal cord with protons showed steeply increasing ED50 values for lengths of less than 8 mm. These results suggest the presence of a critical migration distance of 2-3 mm for cells involved in regeneration processes.

Fast 2D phantom dosimetry for scanning proton beams

A quality control system especially designed for dosimetry in scanning proton beams has been designed and tested. The system consists of a scintillating screen (Gd2O2S:Tb), mounted at the beam-exit side of a phantom, and observed by a low noise CCD camera with a long integration time. The purpose of the instrument is to make a fast and accurate two-dimensional image of the dose distribution at the screen position in the phantom. The linearity of the signal with the dose, the noise in the signal, the influence of the ionization density on the signal, and the influence of the field size on the signal have been investigated. The spatial resolution is 1.3 mm (1 s.d.), which is sufficiently smaller than typical penumbras in dose distributions. The measured yield depends linearly on the dose and agrees within 5% with the calculations. In the images a signal to noise ration (signal/1 s.d.) of 10(2) has been found, which is in the same order of magnitude as expected from the calculations. At locations in the dose distribution possessing a strong contribution of high ionization densities (i.e., in the Bragg peak), we found some quenching of the light output, which can be described well by existing models if the beam characteristics are known. For clinically used beam characteristics such as a Spread Out Bragg peak, there is at most 8% deviation from the NACP ionization chamber measurements. The conclusion is that this instrument is a useful tool for quick and reliable quality control of proton beams. The long integration-time capabilities of the system make it worthwhile to investigate its applicability in scanning proton beams and other dynamic treatment modalities.

Performance of a fluorescent screen and CCD camera as a two-dimensional dosimetry system for dynamic treatment techniques

A two-dimensionally position sensitive dosimetry system has been tested for different dosimetric applications in a radiation therapy facility with a scanning proton beam. The system consists of a scintillating (fluorescent) screen, mounted at the beam-exit side of a phantom and it is observed by a charge coupled device (CCD) camera. The observed light distribution at the screen is equivalent to the two-dimensional (2D)-dose distribution at the screen position. It has been found that the dosimetric properties of the system, measured in a scanning proton beam, are equal to those measured in a proton beam broadened by a scattering system. Measurements of the transversal dose distribution of a single pencil beam are consistent with dose measurements as well as with dose calculations in clinically relevant fields made with multiple pencil beams. Measurements of inhomogeneous dose distributions have shown to be of sufficient accuracy to be suitable for the verification of dose calculation algorithms. The good sensitivity and sub-mm spatial resolution of the system allows for the detection of deviations of a few percent in dose from the expected (intended or calculated) dose distribution. Its dosimetric properties and the immediate availability of the data make this device a useful tool in the quality control of scanning proton beams.

Sparing the region of the salivary gland containing stem cells preserves saliva production after radiotherapy for head and neck cancer

Avoiding irradiation of the region of the parotid gland containing stem cells reduces the risk of xerostomia (dry mouth). Preserving saliva flow after radiotherapy Radiotherapy for head and neck cancer may damage the salivary glands, resulting in reduced salivation with consequent xerostomia (dry mouth). Xerostomia affects the quality of life of patients with head and neck cancer. van Luijk and co-workers reported the location of salivary (parotid) gland stem cells in the mouse, rat, and human. Next, they showed in rat and human that irradiation of the salivary gland region containing the highest number of stem cells resulted in the greatest loss of saliva production after treatment. Finally, the authors showed that it is possible to avoid irradiation of this specific area during therapy, which may reduce the patient’s risk of developing post-radiotherapy xerostomia. 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.

Radiation damage to the heart enhances early radiation-induced lung function loss

In many thoracic cancers, the radiation dose that can safely be delivered to the target volume is limited by the tolerance dose of the surrounding lung tissue. It has been hypothesized that irradiation of the heart may be an additional risk factor for the development of early radiation-induced lung morbidity. In the current study, the dependence of lung tolerance dose on heart irradiation is determined. Fifty percent of the rat lungs were irradiated either including or excluding the heart. Proton beams were used to allow very accurate and conformal dose delivery. Lung function toxicity was scored using a breathing rate assay. We confirmed that the tolerance dose for early lung function damage depends not only on the lung region that is irradiated but also that concomitant irradiation of the heart severely reduces the tolerance of the lung. This study for the first time shows that the response of an organ to irradiation does not necessarily depend on the dose distribution in that organ alone.

Collimator scatter and 2D dosimetry in small proton beams

Monte Carlo simulations have been performed to determine the influence of collimator-scattered protons from a 150 MeV proton beam on the dose distribution behind a collimator. Slit-shaped collimators with apertures between 2 and 20 mm have been simulated. The Monte Carlo code GEANT 3.21 has been validated against one-dimensional dose measurements with a scintillating screen, observed by a CCD camera. In order to account for the effects of the spatial response of the CCD/scintillator system, the line-spread function was determined by comparison with measurements made with a diamond detector. The line-spread function of the CCD/scintillator system is described by a Gaussian distribution with a standard deviation of 0.22 mm. The Monte Carlo simulations show that protons that hit the collimator on the entrance face and leave it through the wall of the aperture make the largest scatter contribution. Scatter on air is the major contribution to the extent of the penumbra. From the energy spectra it is derived that protons with a relative biological effectiveness greater than 1 cause at most 1% more damage in tissue than what would be expected from the physical dose.

Bath and Shower Effects in the Rat Parotid Gland Explain Increased Relative Risk of Parotid Gland Dysfunction After Intensity-Modulated Radiotherapy

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.

QUANTIFYING LOCAL RADIATION-INDUCED LUNG DAMAGE FROM COMPUTED TOMOGRAPHY

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 (S(L)) was quantified from local mean and local standard deviation of the CT density in Hounsfield units in 1-mm(3) subvolumes. The relation of changes in S(L) (DeltaS(L)) 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 DeltaS(L). RESULTS In rats, a clear dose-response relationship of DeltaS(L) was observed at different time points after radiation. Furthermore, DeltaS(L) correlated strongly to histologic endpoints (infiltrates and inflammatory cells) and breathing rate. In the patient, progressive local dose-dependent increases in DeltaS(L) 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.

Techniques for precision irradiation of the lateral half of the rat cervical spinal cord using 150 MeV protons

Techniques for high precision irradiation experiments with protons, to investigate the volume dependence of the tolerance dose of the rat cervical spinal cord are described. In the present study, 50% of the lateral cross section of the spinal cord was irradiated. The diameter of the cross section of this part of the rat spinal cord is at maximum 3.5 mm. Therefore, a dedicated procedure was developed to comply with the needs for a very high positioning accuracy and high spatial resolution dosimetry. By using 150 MeV protons a steep dose gradient (20-80% = 1 mm) in the centre of the spinal cord was achieved. This yields a good dose contrast between the left and right halves of the cord. A home-made digital x-ray imager with a pixel resolution of 0.18 mm/pixel was used for position verification of the spinal cord. A positioning accuracy of 0.09 mm was obtained by using information of multiple pixels. The average position stability during the irradiation was found to be 0.08 mm (1 SD) without significant systematic deviations. Profiles of the dose distribution were measured with a 2D dosimetry system consisting of a scintillating screen and a CCD camera. Dose volume histograms of the whole spinal cord as well as separately of the white and grey matters were calculated using MRI imaging of the cross section of the rat cervical spinal cord. From the irradiation of 20 animals a dose-response curve has been established. MRI showed radiation-induced damage at the high dose side of the spinal cord. Analysis of the preliminary dose-response data shows a significant dose-volume effect. With the described procedure and equipment it is possible to perform high precision irradiations on selected parts of the spinal cord.