Impact of tumor size and location on lung dose difference between stereotactic body radiation therapy techniques for non-small cell lung cancer.

BACKGROUND: To evaluate the lung dose differences between three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiation therapy (IMRT) techniques for lung stereotactic body radiation therapy (SBRT) and the correlations with tumor characteristics, such as size and location. METHODS: Dosimetric comparisons between the two SBRT techniques in high- and low- to intermediate-dose regions were retrospectively performed using four planning indices and lung-dose parameters in 31 lung tumors. The magnitude of differences in these parameters was analyzed with relation to the planning target volume (PTV) and location-related parameters. RESULTS: The absolute differences between the two techniques in lung-dose parameters were small in both ipsilateral and bilateral lungs. The dosimetric differences were mainly correlated with the PTV rather than location-related parameters, with positive and negative correlations with the high-dose and intermediate-dose parameters, respectively. The distances from the ipsilateral lung centroid to the PTV center were not correlated with the differences in any of the lung-dose parameters. Additionally, the negative correlations with the MLD and V20 differences disappeared after applying a more rapid dose fall-off in the IMRT plans for tumors with small PTVs of ≤15 cc. CONCLUSIONS: Lung dose differences between the 3D-CRT and IMRT techniques for lung SBRT were mainly correlated with the PTV rather than location-related parameters. Together with the dosimetric benefit in high-dose lung regions of IMRT for larger tumors, the relative increases in the MLD and V20 for small-sized tumors could be reduced by applying a more rapid dose fall-off outside the PTV.

Influence of tumor characteristics on correction differences between cone-beam computed tomography-guided patient setup strategies in stereotactic body radiation therapy for lung cancer.

BACKGROUND: To evaluate the correction differences between vertebra and tumor matching as cone-beam computed tomography (CBCT)-guided setup strategies in lung stereotactic body radiation therapy (SBRT), and the correlations with tumor characteristics such as size, mobility, and location. METHODS: The manual registrations for 33 lung tumors treated with SBRT were retrospectively performed by matching thoracic vertebrae for vertebra matching and then by matching CBCT-visualized tumors within the internal target volume obtained from a four-dimensional CT dataset for tumor matching. RESULTS: The mean correction difference between the two matching methods during the SBRT fractions was larger in the anterior-posterior direction (2.7 mm) than in the superior-inferior (2.1 mm) and left-right (1.4 mm) directions, with differences of less than 5 mm in 90% of the total 134 CBCT fractions. The X-axis and direct distances from the central axis to the tumor had significant correlations with the correction differences in all three directions, while the mobility-related parameters were correlated only in the superior-inferior direction. The absolute differences in lung-dose parameters after applying the margins (3.4-6.5 mm) required for the setup errors from vertebra matching relative to tumor matching were mild, with values of 1.95 Gy for the mean lung dose and 3.9% for V20. CONCLUSION: The setup differences between vertebra and tumor matching in the CBCT-guided setup without rotation correction were increased in tumors located long distances from the central axis. The additional safety margins of 3.4-6.5 mm were required for the setup errors from vertebra matching. KEY POINTS: Significant findings of the study The correction difference between the vertebra and tumor matching as CBCT-guided setup strategies was the largest in the anterior-posterior direction and significantly correlated with the X-axis and direct distances from the central axis to the tumor. What this study adds Setup differences between vertebra and tumor matching in the CBCT-guided setup were increased in tumors located long distances from the central axis. The additional safety margins of 3.4-6.5 mm were required for the setup errors from vertebra matching.

Usefulness of target delineation based on the two extreme phases of a four-dimensional computed tomography scan in stereotactic body radiation therapy for lung cancer.

BACKGROUND: An evaluation of the usefulness of target delineation based only on the two extreme phases of a four-dimensional computed tomography (4D CT) scan in lung stereotactic body radiation therapy (SBRT). METHODS: Seventeen patients treated with SBRT via 4D CT scans for lung cancer were retrospectively enrolled. Volumetric and geometric analyses were performed for the internal target volumes (ITVs) and planning target volumes (PTVs) generated using different respiratory phases (all phases and 2 extreme phases) and setup margins (3 mm and 5 mm). RESULTS: As the setup margins were added to the ITVs, the overlap percentage between the PTVs based on all phases and the two extreme phases increased (85.1% for ITVs, 89.8% for PTVs_3 mm, and 91.3% for PTVs_5 mm), and there were no differences according to the tumor parameters, such as the gross tumor volume and 3D mobility. The missing-volume differences for ITVs derived from cone-beam CT images also decreased, with values of 5.3% between ITVs, 0.5% between PTVs_3 mm, and 0.2% between PTVs_5 mm. Compared with the plan based on all phases and a 3 mm margin, the average lung-dose differences found for the PTV based on the two extreme phases and a 5 mm margin were 0.41 Gy for the mean lung dose and 0.93% for V20. CONCLUSIONS: Regardless of tumor characteristics, PTV construction based only on the two extreme phases and a 5 mm setup margin may be a useful tool for reducing the clinical workload involved in target delineation in SBRT for lung cancer.

Modulation of radiation-induced alterations in oxidative stress and cytokine expression in lung tissue by Panax ginseng extract.

We investigated the modulating effect of Panax ginseng extract (PGE) on radiation-induced lung injury (RILI) by measuring early changes in oxidative stress levels, cytokine expression, and the histopathology of mouse lung tissue treated with high dose of X-ray radiation. The mice were pretreated with 25, 50, and 100-mg/kg doses of PGE orally for four consecutive days, and their thoraces were then exposed to 15-Gy X-ray radiation 1 h after the last administration of PGE on day 4. The pretreatments with 50 and 100 mg/kg PGE led to significant reductions in the elevation of lipid peroxidation levels at 2 and 10 days, respectively, after irradiation. The mice pretreated with PGE exhibited dose-dependent reductions in the irradiation-induced production of tumor necrosis factor α and transforming growth factor ß1 cytokines 10 days after irradiation, with these reductions nearly reaching the control levels after the 100-mg/kg dose. Furthermore, together with providing significant protection against reductions in catalase activity and glutathione content, pretreatment with 100 mg/kg PGE resulted in a marked attenuation of the severity of inflammatory changes in lung tissue 10 days after irradiation. A high pretreatment dose of PGE may be a useful pharmacological approach for protection against RILI.

Reconstitution of internal target volumes by combining four-dimensional computed tomography and a modified slow computed tomography scan in stereotactic body radiotherapy planning for lung cancer.

BACKGROUND: To evaluate the volumetric and geometric differences in the ITVs generated by four-dimensional (4D) computed tomography (CT), a modified slow CT scan, and a combination of these CT methods in lung cancer patients treated with stereotactic body radiotherapy (SBRT). METHODS: Both 4D CT and modified slow CT using a multi-slice CT scanner were performed for SBRT planning in 14 patients with 15 pulmonary targets. Volumetric and geometric analyses were performed for (1) ITVall, generated by combining the gross tumor volumes (GTVs) from all 8 phases of the 4D CT; (2) ITV2, generated by combining the GTVs from 2 extreme phases of the 4D CT; (3) ITVslow, derived from the GTV on the modified slow CT scan; (4) ITVall+slow, generated by combining ITVall and ITVslow; and (5) ITV2+slow, generated by combining ITV2 and ITVslow. Three SBRT plans were performed using 3 ITVs to assess the dosimetric effects on normal lung caused by the various target volumes. RESULTS: ITVall (11.8 ± 8.3 cm3) was significantly smaller than ITVall+slow (12.5 ± 8.9 cm3), with mean values of 5.8% for the percentage volume difference, and a mean of 7.5% of ITVslow was not encompassed in ITVall. The geometric coverages of ITV2 and ITVslow for ITVall were 84.7 ± 6.6% and 76.2 ± 9.3%, respectively, but the coverage for ITVall increased to 90.9 ± 5.9% by using the composite of these two ITVs. There were statistically significant increases in the lung-dose parameters of the plans based on ITVall+slow compared to the plans based on ITVall or ITV2+slow. However, the magnitudes of these differences were relatively small, with a value of less than 3% in all dosimetric parameters. CONCLUSIONS: Due to its ability to provides additional motion information, the combination of 4D CT and a modified slow CT scan in SBRT planning for lung cancer can be used to reduce possible errors in true target delineation caused by breathing pattern variations.

The impact of respiratory gating on lung dosimetry in stereotactic body radiotherapy for lung cancer.

The purpose of this study was to evaluate the impacts of respiratory gating and different gating windows (GWs) on lung dosimetry in stereotactic body radiotherapy (SBRT) for lung cancer. Gated SBRT plans were developed using the four-dimensional computed tomography data from 17 lung cancer patients treated with SBRT. Using amplitude-based end-exhalation gating, we established 2 fixed GWs with approximate duty cycles of 50% (50% GW) and 25% (25% GW), respectively, for this study. For highly mobile tumors (3D mobility > 10 mm), additional benefits in lung-dose reductions were achieved with the 25% GW, as a result of inadequate mobility and planning target volume reductions obtained with the 50% GW. In these tumors, the absolute differences compared to the non-gated and 50% gated plans, were 0.5 Gy and 0.33 Gy for the mean lung dose and 1.11% and 0.71% for the V20, respectively. Dosimetric benefits were achieved with the 50% GW, compared with the non-gated plan, for tumors with both low mobility and small volume (gross tumor volume ≤ 10 cc). Among the identified predictive factors of dosimetric benefits, the lateral distance from midspinal canal and the motion range in anterior-posterior direction might be stronger factors because of their correlations with many of the lung-dose parameters and greater predictive capacity. The results of the present study might facilitate the selection of appropriate patients and the optimal GW according to the tumor characteristics for gated lung SBRT.

Three-dimensional conformal reirradiation for locoregionally recurrent lung cancer previously treated with radiation therapy.

BACKGROUND: To evaluate the efficacy and toxicity of reirradiation using three-dimensional conformal radiotherapy (3D-CRT) in symptomatic patients with locoregionally recurrent lung cancer. METHODS: Between 2005 and 2012, 15 patients with locoregionally recurrent lung cancer were retreated with 3D-CRT after previously receiving thoracic radiotherapy. The median interval between the initial irradiation and reirradiation was 12 months (range, five to 41 months). The median initial radiotherapy dose was 63 Gy (range, 45-70 Gy), and reirradiation doses ranged from 25.2 to 45.2 Gy (median, 36 Gy), with daily fractions of 1.8-4 Gy (median, 2 Gy). RESULTS: After reirradiation, 80% of the patients experienced resolved or diminished symptoms for one or more of their symptoms, with an 83% improvement in a total of 24 symptoms. The overall tumor response rate to reirradiation was 46.7%, with progressive disease occurring in only one patient. The median overall survival (OS) time was 11 months (range, one to 27 months), and the one-year OS rate was 47%. The progression-free survival time ranged from one to 10 months (median, five months). In univariate analysis, the use of combined chemotherapy and a higher reirradiation dose showed a trend toward improved survival after reirradiation. Treatment-induced toxicity included grade 2 radiation pneumonitis in only one patient, and there were no other complications, such as radiation esophagitis or myelopathy. CONCLUSIONS: Reirradiation using 3D-CRT with moderate doses for locoregionally recurrent lung cancer can provide palliative benefits without severe complications to the majority of selected patients with symptoms as a result of a regrowing tumor.

Melatonin reduces X-ray radiation-induced lung injury in mice by modulating oxidative stress and cytokine expression.

PURPOSE: The modification of radiation-induced lung injuries by melatonin was studied by measuring changes in oxidative stress, cytokine expression and histopathology in the lung tissue of mice following irradiation. MATERIALS AND METHODS: The thoraces of C57BL/6 mice were exposed to a single X-ray radiation dose of 12 Gy with or without 200 mg/kg of melatonin pretreatment. The level and localization of transforming growth factor (TGF)-ß1 protein were measured using an enzyme-linked immunosorbent assay (ELISA) method and immunohistochemical staining, respectively. Real-time quantitative polymerase chain reaction (PCR) was established to evaluate the relative mRNA expression levels of TGF-ß1, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and IL-6. RESULTS: Malondialdehyde (MDA) levels increased after irradiation and then significantly reduced (1.9-fold) under melatonin treatment. Changes in superoxide dismutase (SOD) and catalase activities, as well as glutathione (GSH) levels, after irradiation were significantly reduced by melatonin, including a notable 5.4-fold difference in catalase activity. We observed increased expression of TGF-ß1 and TNF-α after irradiation and a significant reduction in the elevation of their expression by melatonin treatment. Furthermore, irradiation-induced histopathologic alterations were obviously abated in the melatonin-pretreated mice. CONCLUSIONS: The present results suggest that melatonin reduces radiation-induced lung injury via a significant reduction of oxidative stress and of the production of cytokines, such as TGF-ß1 and TNF-α, the production of which increased following lung irradiation.

Prognostic significance of human apurinic/apyrimidinic endonuclease (APE/Ref-1) expression in rectal cancer treated with preoperative radiochemotherapy.

PURPOSE: Human apurinic endonuclease/redox factor 1 (APE/Ref-1) mediates repair of radiation-induced DNA lesions and regulates transcription via redox-based activation. We investigated the predictive and prognostic significance of APE/Ref-1 expression in pretreatment biopsy specimens in locally advanced rectal cancer (LARC) (cT3-T4 or N+). METHODS AND MATERIALS: APE/Ref-1 expression was analyzed by immunohistochemistry in pretreatment biopsy specimens obtained from 83 patients with LARC. Patients received preoperative radiotherapy of 50.4 Gy in 28 fractions, combined with oral capecitabine and leucovorin chemotherapy, followed by curative surgery. The prognostic significance of various clinicopathologic characteristics, including APE/Ref-1 protein expression, was evaluated. RESULTS: APE/Ref-1 was expressed in 97% of patient samples. Exclusive APE/Ref-1 nuclear staining was observed in 49 of 83 samples (59%), and mixed nuclear and cytoplasmic staining was observed in 31 samples (37%). APE/Ref-1 nuclear expression levels were low in 49 patients (59%) and high in 34 patients (41%). The level of APE/Ref-1 nuclear expression was not a prognostic factor for overall and disease-free survival. Cytoplasmic expression of APE/Ref-1 was a borderline-significant predictive factor for pathologic tumor response (p = 0.08) and a significant prognostic factor for disease-free survival, as shown by univariate analysis (p = 0.037). Multivariate analysis confirmed that cytoplasmic localization of APE/Ref-1 is a significant predictor of disease-free survival (hazard ratio, 0.45; p = 0.046). CONCLUSIONS: APE/Ref-1 was expressed in a majority of pretreatment biopsy specimens from patients with LARC. The level of APE/Ref-1 nuclear expression was not a significant predictive and prognostic factor; however, cytoplasmic localization of the protein was negatively associated with disease-free survival. These results indicate that cytoplasmic expression of APE/Ref-1 represents an adverse prognostic factor for LARC patients who receive preoperative radiochemotherapy.