The mean lung dose (MLD) : predictive criterion for lung damage?

AIM: The purpose of this work was to prove the validity of the mean lung dose (MLD), widely used in clinical practice to estimate the lung toxicity of a treatment plan, by reevaluating experimental data from mini pigs. MATERIALS AND METHODS: A total of 43 mini pigs were irradiated in one of four dose groups (25, 29, 33, and 37 Gy). Two regimens were applied: homogeneous irradiation of the right lung or partial irradiation of both lungs-including parts with lower dose-but with similar mean lung doses. The animals were treated with five fractions with a linear accelerator applying a CT-based treatment plan. The clinical lung reaction (breathing frequency) and morphological changes in CT scans were examined frequently during the 48 weeks after irradiation. RESULTS: A clear dose-effect relationship was found for both regimens of the trial. However, a straightforward relationship between the MLD and the relative number of responders with respect to different grades of increased breathing frequency for both regimens was not found. A morphologically based parameter NTCPlung was found to be more suitable for this purpose. The dependence of this parameter on the MLD is markedly different for the two regimens. CONCLUSION: In clinical practice, the MLD can be used to predict lung toxicity of a treatment plan, except for dose values that could lead to severe side effects. In the latter mentioned case, limitations to the predictive value of the MLD are possible. Such severe developments of a radiation-induced pneumopathy are better predicted by the NTCPlung formalism. The predictive advantage of this parameter compared to the MLD seems to remain in the evaluation and comparison of widely differing dose distributions, like in the investigated trial.

Down-regulation of heat shock protein HSP90ab1 in radiation-damaged lung cells other than mast cells.

Ionizing radiation (IR) leads to fibrosing alveolitis (FA) after a lag period of several weeks to months. In a rat model, FA starts at 8 weeks after IR. Before that, at 5.5 weeks after IR, the transcription factors Sp1 (stimulating protein 1) and AP-1 (activator protein 1) are inactivated. To find genes/proteins that were down-regulated at that time, differentially expressed genes were identified in a subtractive cDNA library and verified by quantitative RT-PCR (reverse transcriptase polymerase chain reaction), western blotting and immunohistochemistry (IH). The mRNA of the molecular chaperone HSP90AB1 (heat shock protein 90 kDa alpha, class B member 1) was down-regulated 5.5 weeks after IR. Later, when FA manifested, HSP90ab1 protein was down-regulated by more than 90% in lung cells with the exception of mast cells. In most mast cells of the normal lung, both HSP90ab1 and HSP70, another major HSP, show a very low level of expression. HSP70 was massively up-regulated in all mast cells three months after irradiation whereas HSP90AB1 was up-regulated only in a portion of mast cells. The strong changes in the expression of central molecular chaperones may contribute to the well-known disturbance of cellular functions in radiation-damaged lung tissue.

Triple angiokinase inhibition, tumour hypoxia and radiation response of FaDu human squamous cell carcinomas.

BACKGROUND AND PURPOSE: To test the effect of BIBF 1120, a novel small molecule inhibitor of multiple angiogenic receptor tyrosine kinases, on the hypoxia and radiation response of tumours. MATERIALS AND METHODS: Poorly differentiated human squamous cell carcinoma FaDu growing in nude mice was treated with BIBF 1120 and investigated by functional histology. To test the effect of BIBF 1120 on the radiobiological hypoxic fraction (rHF), the number and intrinsic radiation sensitivity of tumour stem cells and the outcome after fractionated irradiation, a series of local tumour control assays were performed. RESULTS: BIBF 1120 significantly reduced the vessel area, vessel area with a perfusion signal and tumour growth rate but did not affect tumour hypoxia or the number and intrinsic radiation sensitivity of tumour stem cells. Concurrent BIBF 1120 had no effect on local tumour control after fractionated irradiation. CONCLUSION: Triple angiokinase inhibition resulted in a clear-cut decrease of angiogenesis, vessel area with a perfusion signal and tumour growth but did not change tumour hypoxia or radiation response of tumour stem cells. Further experiments into mechanisms of interaction between anti-angiogenic strategies and irradiation appear to be necessary to better define and exploit the potential of this strategy to improve local tumour control after fractionated radiotherapy.

Inactivation of AP1 proteins by a nuclear serine protease precedes the onset of radiation-induced fibrosing alveolitis.

Radiation-induced lung damage comprises inflammation (alveolitis) as well as disturbed regulation of cell differentiation and proliferation (fibrosis). The transcriptional regulation of this process is poorly understood. One key transcription factor involved in the regulation of proliferation and differentiation is AP1 (activator protein 1). The present study examined changes in the DNA-binding activity of AP1 after irradiation and defined the underlying molecular mechanisms in an animal model. The right lungs of Fischer rats received a single radiation dose of 20 Gy. Lung tissue was tested for AP1 DNA-binding activity, AP1 mRNA, and levels of AP1 proteins as well as for c-Jun specific proteolytic activity. After an initial increase, the AP1 DNA-binding activity was completely lost starting at 5.5 weeks after irradiation, which is 2.5 weeks before the onset of fibrosing alveolitis. This was not caused by reduction of mRNA levels or size. Instead, a selective nuclear cleavage of c-Jun by a serine protease caused the loss of AP1 activity. Considering the central role of AP1 in cell proliferation and differentiation and the strict timely correlation to the onset of the disease, the complete loss of AP1 function is likely to play a critical role in radiation-induced fibrosing alveolitis.

Expression of the immunomodulator IL-10 in type I pneumocytes of the rat: alterations of IL-10 expression in radiation-induced lung damage.

Fibrosing alveolitis is a disease with inflammatory, proliferative, and fibrotic components. In different models, it has been shown that the cytokine interleukin-10 (IL-10) plays a conflicting role in inflammation-associated fibrotic processes, inasmuch as it is an anti-inflammatory cytokine but also a TH2 cytokine with inherent pro-fibrotic effects. IL-10 is produced primarily by inflammatory cells. In this report, we show in a rat model of radiation-induced fibrosing alveolitis that IL-10 is also produced by type I alveolar epithelial cells in both normal and fibrotic lungs. The total amount of IL-10 in the lung is increased after irradiation, but type I pneumoyctes contain less IL-10. The R3/1 permanent type I pneumocyte cell line also contains IL-10, which is reduced after irradiation. Whereas in the normal lung, the entire alveolar surface is covered by IL-10-producing pneumocytes, this continuity is interrupted in fibrotic lungs, because type I pneumocytes lack full differentiation and thus full spreading over the alveolar surface. The exposure of the IL-10-negative epithelial basal membrane may allow for an easier attachment of inflammatory cells such as alveolar macrophages. These cells have the potential to act in a pro-inflammatory way by tumor necrosis factor alpha and also in a pro-fibrotic way by activating TH2 cytokines.

Filmless evaluation of the mechanical accuracy of the isocenter in stereotactic radiotherapy.

BACKGROUND AND PURPOSE: The Winston-Lutz test verifies the mechanical accuracy of the isocenter in stereotactic radiotherapy. A lead ball inside a small beam is exposed to film applying different combinations of the gantry angle and the table angle. The increasing replacement of films by digital images requires alternative imaging methods. The suitability of two different electronic portal imaging systems and of a system based on digital luminescence radiography was investigated. MATERIAL AND METHODS: The imaging systems included the portal imaging devices BEAMVIEW PLUS and OPTIVUE1000 (both Siemens Medical Solutions, Erlangen, Germany) and the luminescence system KODAK ACR 2000 RT (Eastman Kodak Comp., Rochester, NY, USA). 6-MV photons from the linear accelerators PRIMUS and ONCOR (both Siemens Medical Solutions) were applied. First, only the small beam covering the lead ball was exposed. Second, an additional bigger open beam part in a certain distance to the small beam was applied. RESULTS: For all three investigated imaging systems, which are using preprocessing imaging software, only for the beam arrangement with additional open beam parts, the lead ball could be detected inside the small beam. Only for the application of a dosimetric software tool to the luminescence system, the metal ball inside the small beam became visible without an additional open beam part. CONCLUSION: Applying the proposed beam arrangements, the Winston-Lutz test can be done by digital and filmless imaging systems, thereby saving time as well.

Portal verification using the KODAK ACR 2000 RT storage phosphor plate system and EC films. A semiquantitative comparison.

BACKGROUND AND PURPOSE: The suitability of the storage phosphor plate system ACR 2000 RT (Eastman Kodak Corp., Rochester, MN, USA), that is destined for portal verification as well as for portal simulation imaging in radiotherapy, had to be proven by the comparison with a highly sensitive verification film. MATERIAL AND METHODS: The comparison included portal verification images of different regions (head and neck, thorax, abdomen, and pelvis) irradiated with 6- and 15-MV photons and electrons. Each portal verification image was done at the storage screen and the EC film as well, using the EC-L cassettes (both: Eastman Kodak Corp., Rochester, MN, USA) for both systems. The soft-tissue and bony contrast and the brightness were evaluated and compared in a ranking of the two compared images. Different phantoms were irradiated to investigate the high- and low-contrast resolution. To account for quality assurance application, the short-time exposure of the unpacked and irradiated storage screen by green and red room lasers was also investigated. RESULTS: In general, the quality of the processed ACR images was slightly higher than that of the films, mostly due to cases of an insufficient exposure to the film. The storage screen was able to verify electron portals even for low electron energies with only minor photon contamination. The laser lines were sharply and clearly visible on the ACR images. CONCLUSION: The ACR system may replace the film without any noticeable decrease in image quality thereby reducing processing time and saving the costs of films and avoiding incorrect exposures.

Portal verification of high-energy electron beams using their photon contamination by film-cassette systems.

BACKGROUND AND PURPOSE: Though electron beams are widely used in radiotherapy, their verification is not well established in clinical practice. The present study compares the suitability of several sensitive film-cassette systems for electron-portal verification by contaminating photons. MATERIAL AND METHODS: The characteristics of the optical density curves of film-cassette combinations were determined by exposing them to the bremsstrahlung contamination of a variety of electron beams. Using a Las-Vegas Phantom the spatial low-contrast resolution of the combinations was investigated. The absorbed dose rates due to the contaminant photons were measured for different geometric conditions. RESULTS: Suitable film-cassette combinations were found for portal verification of all usual electron energies. The best image quality was obtained using the EC film and the EC-L cassettes. For electron energies higher than 6 MeV some film-cassette combinations are suitable to verify abutted electron and photon portals using the same film sheet. CONCLUSION: The verification of electron portals and of abutted electron-photon portals can be performed by sensitive film-cassette systems with an image quality comparable to photon-beam verification.

Enhanced susceptibility of irradiated tumor vessels to vascular endothelial growth factor receptor tyrosine kinase inhibition.

Previous experiments with PTK787/ZK222584, a specific inhibitor of vascular endothelial growth factor receptor (VEGFR) tyrosine kinases, using irradiated human FaDu squamous cell carcinoma in nude mice, suggested that radiation-damaged tumor vessels are more sensitive to VEGFR inhibition. To test this hypothesis, the tumor transplantation site (i.e., the right hind leg of nude mice) was irradiated 10 days before transplantation of FaDu to induce radiation damage in the host tissue. FaDu tumors vascularized by radiation-damaged blood vessels appeared later, grew at a slower rate, and showed more necrosis and a smaller vessel area per central tumor section than controls. PTK787/ZK222584 at a daily dose of 50 mg/kg body weight had no impact on growth of control tumors. In contrast, tumors vascularized by radiation-damaged vessels responded to PTK787/ZK222584 with longer latency and slower growth rate than controls, and a trend toward further increase in necrosis, indicating that irradiated tumor vessels are more susceptible to VEGFR inhibition than unirradiated vessels. Although not proving causality, expression analysis of VEGF and VEGFR2 shows that enhanced sensitivity of irradiated vessels to a specific inhibitor of VEGFR tyrosine kinases correlates with increased expression of the molecular target.

In vivo verification of electron beam energy by patient exit dose and optical density of portal films.

BACKGROUND AND PURPOSE: The depth-dose curve of electron beams is mainly determined by their energy. For accelerators with scatter foils, the electron energy can, in principle, be verified by measuring the amount of the contaminating photons. This paper investigates whether exit dose measurements and evaluations of the optical density of portal films can be used to verify the energy of the electron beam in a clinically relevant setting. MATERIAL AND METHODS: During irradiation of the head and neck region of an Alderson-Rando phantom with 6- to 21-MeV electron beams, the exit dose rates behind the phantom and the dose rates at the position of a film cassette were measured. The optical density of films (EC film/EC-L Regular and EC-L Fast cassettes, Eastman Kodak Comp., Rochester, NY, USA) exposed to beams of different energies was evaluated. RESULTS: The exit and the cassette dose rates showed a steep increase with increasing electron energy. Due to its density behavior, the film with both types of cassettes failed to generate images for lower electron energies (6 and 9 MeV) but presented a strong ascent of the optical density-until reaching the saturation-with increasing electron energy. CONCLUSION: Measurements of the exit dose and evaluations of the optical density of portal films can be used to verify and document the energy of electron beams during radiotherapy.