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.

Panax ginseng Meyer prevents radiation-induced liver injury via modulation of oxidative stress and apoptosis.

BACKGROUND: Radiotherapy is one of the most important modalities in cancer treatment; however, normal tissue damage is a serious concern. Drug development for the protection or reduction of normal tissue damage is therefore a clinical issue. Herein, we evaluated the protective properties of Panax ginseng Meyer and its corresponding mechanisms. METHODS: C56BL/6 mice were orally pretreated with P. ginseng water extract (PGE; 25 mg/kg, 50 mg/kg, or 100 mg/kg) or intraperitoneally injected melatonin (20 mg/kg) for 4 d consecutively, then exposed to 15-Gy X-ray radiation 1 h after the last administration. After 10 d of irradiation, the biological properties of hematoxicity, fat accumulation, histopathology, oxidative stress, antioxidant activity, pro-inflammatory cytokines, and apoptosis signals were examined in the hepatic tissue. RESULTS: The irradiation markedly induced myelosuppression as determined by hematological analysis of the peripheral blood. Steatohepatitis was induced by X-ray irradiations, whereas pretreatment with PGE significantly attenuated it. Oxidative stress was drastically increased, whereas antioxidant components were depleted by irradiation. Irradiation also notably increased serum liver enzymes and hepatic protein levels of pro-inflammatory cytokines. Those alterations were markedly normalized by pretreatment with PGE. The degree of irradiation-induced hepatic tissue apoptosis was also attenuated by pretreatment with PGE, which was evidenced by a terminal deoxynucleotidyl transferase 2'-deoxyuridine 5'-triphosphate nick-end labeling assay, western blotting, and gene expressions analysis, particularly of apoptotic molecules. CONCLUSION: We suggest that PGE could be applicable for use against radiation-induced liver injury, and its corresponding mechanisms involve the modulation of oxidative stress, inflammatory reactions, and apoptosis.

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.

Fenofibrate decreases radiation sensitivity via peroxisome proliferator-activated receptor α-mediated superoxide dismutase induction in HeLa cells.

PURPOSE: The fibrates are ligands for peroxisome proliferator-activated receptor (PPAR) α and used clinically as hypolipidemic drugs. The fibrates are known to cause peroxisome proliferation, enhance superoxide dismutase (SOD) expression and catalase activity. The antioxidant actions of the fibrates may modify radiation sensitivity. Here, we investigated the change of the radiation sensitivity in two cervix cancer cell lines in combination with fenofibrate (FF). MATERIALS AND METHODS: Activity and protein expression of SOD were measured according to the concentration of FF. The mRNA expressions were measured by using real time reverse-transcription polymerase chain reaction. Combined cytotoxic effect of FF and radiation was measured by using clonogenic assay. RESULTS: In HeLa cells total SOD activity was increased with increasing FF doses up to 30 µM. In the other hand, the catalase activity was increased a little. As with activity the protein expression of SOD1 and SOD2 was increased with increasing doses of FF. The mRNAs of SOD1, SOD2, PPARα and PPARγ were increased with increasing doses of FF. The reactive oxygen species (ROS) produced by radiation was decreased by preincubation with FF. The surviving fractions (SF) by combining FF and radiation was higher than those of radiation alone. In Me180 cells SOD and catalase activity were not increased with FF. Also, the mRNAs of SOD1, SOD2, and PPARα were not increased with FF. However, the mRNA of PPARγ was increased with FF. CONCLUSION: FF can reduce radiation sensitivity by ROS scavenging via SOD induction in HeLa. SOD induction by FF is related with PPARα.

Ginsenoside rich fraction of Panax ginseng C.A. Meyer improve feeding behavior following radiation-induced pica in rats.

Panax ginseng is an indigenous medicinal herb and has traditionally been used among Asian population for relief of many human ailments. We investigated the prophylactic role of Korean P. ginseng extract (KG) against X-ray irradiation-induced emesis in an acute rat pica model. Rats were treated with KG (12.5, 25, 50 mg/kg orally at -48, -24 and 0 h) prior to X-ray irradiation (6 Gy), and intake of kaolin and normal food and body weight changes examined as an index of the acute emetic stimulus. Levels of serotonin in small intestine tissue were assessed and histopathology of gastric tissue, small intestine and colon examined specific staining. Pre-treatment with KG (12.5 and 25 mg/kg) reduced X-ray irradiation-induced kaolin intake at 24h. Normal food intake was improved in rats treated with 25 mg/kg KG. The anti-emetic effect of KG was further confirmed on the basis of serotonin release, histopathological findings. Our findings collectively indicate that KG protects against X-ray irradiation-induced acute pica to a moderate extent, leading to improved feeding behavior in rats.

High-dose ionizing radiation-induced hematotoxicity and metastasis in mice model.

Radiotherapy induces untargeted effects on normal tissues such as bone marrow. So alteration of microenvironment by ionizing irradiation is supposed to influence dynamic host-cancer ecosystem affecting cancer behavior including metastasis. Herein, the incidence of lung metastasis after high-dose irradiation has been investigated using mice model having real-time condition of leucopenia. C57BL/6 mice were pre-exposed to a X-irradiation dose of 6 Gy on previous days 2, 5, 7, 10. Complete hematological parameters including lymphocyte subpopulation in blood and lung tissues were analyzed. Additionally, a group of mice including a non-irradiated group were inoculated with B16F10 cells (3 × 10(5)/200 µl) via tail vein at the same day, and lung metastasized colonies were compared among groups at day 14 of post-inoculation. We observed that (i) total leucocytes and platelet were gradually depleted by day 10; (ii) lung tissue showed gradual infiltration of leucocytes including neutrophils and lymphocytes; (iii) pulmonary colonies were maximum and minimum on day 5 and 10 respectively; (iv) lymphocyte subpopulation analysis showed most number of natural killer (NK) cells in lung tissues on day 10; (v) gene expression of platelet/endothelial cell adhesion molecule (PECAM) in lung tissues peaked on day 5. To sum-up the study, severity of leucopenia did not influence the incidence of metastasis but blood platelets and microenvironment alteration of targeting tissue may be responsible factors for lung metastasis in our experimental model.

Melatonin exerts differential actions on X-ray radiation-induced apoptosis in normal mice splenocytes and Jurkat leukemia cells.

The ability of melatonin as a potent antioxidant was used as a rationale for testing its antiapoptotic ability in normal cells. Recently, melatonin was shown to possess proapoptotic action by increasing reactive oxygen species in certain cancer cells. The modification of radiation-induced apoptosis by melatonin and the expression of apoptosis-associated upstream regulators were studied in normal mice splenocytes and Jurkat T leukemia cells. C57BL/6 mice were exposed to a single whole body X-ray radiation dose of 2 Gy with or without 250 mg/kg melatonin pretreatment. The Jurkat cells were divided into four groups of control, 1 mm melatonin alone, 4 Gy irradiation-only and melatonin pretreatment before irradiation. The highest level of apoptosis in the normal splenic white pulp was detected by TUNEL assay at 8 hr after irradiation. At this time, the apoptotic index of irradiation-only and melatonin pretreatment groups were 35.6% and 20.7%, respectively. This reduced apoptosis by melatonin was associated with the increase of Bcl-2 expression and a reduction of Bax/Bcl-2 ratio through a relative decrease of p53 mRNA and protein. In the Jurkat cells treated with a combination of melatonin and radiation, both Annexin V-FITC(+)/PI(-) and Annexin V-FITC(+) cells were increased at 48 hr after irradiation when compared with irradiation-only or melatonin alone. The expressions of p53 between groups were well correlated with the results of Annexin V binding. The irradiation or melatonin did not influence the JNK1 expression in Jurkat cells. The present results suggest that melatonin enhances radiation-induced apoptosis in Jurkat leukemia cells, while reducing radiation-induced apoptosis in normal mice splenocytes. These differential effects on radiation-induced apoptosis by melatonin might involve the regulation of p53 expression.

The Combined Effects of Amifostine and Interleukin 1 Beta (IL-1beta) on Radiation-induced Gastrointestinal and Hematopoietic Injury.

PURPOSE: The pattern of radioprotection by the combined use of low dose amifostine plus IL-1beta was investigated in mice exposed to an acute whole-body radiation dose of 10 Gy. MATERIALS AND METHODS: Male ICR mice were divided into the control group, the irradiation-only group, the high dose amifostine (400 mg/kg i.p. 30 min before irradiation) group, and the low dose amifostine (200 mg/kg i.p. 30 min before irradiation) plus IL-1beta (5 microgram/kg i.p. 20 h before irradiation) group. The radioprotective effects were evaluated using TUNEL assay and microcolony survival assay at jejunal crypt, bone marrow cell count and CBC in peripheral blood, and survival analysis up to 30 days following irradiation. RESULTS: The apoptotic index (p=0.987), surviving crypt number (p=0.484), and the number of WBCs (p=0.226), RBCs (p=0.544), and platelets (p=0.157) were not significantly different between the high dose amifostine group and the low dose amifostine plus IL-1beta group, although the bone marrow cell count was higher in the combination group. The irradiation-only group was dead within 15 days. However, the survival rate at 30 days in the high dose amifostine and the low dose amifostine plus IL-1beta pretreatments were 61% and 66%, respectively. Moreover, the differences between the two groups were insignificant for both 10 days (p=0.9461) and 30 days (p=0.8030). CONCLUSION: These results indicate that the low dose amifostine plus IL-1beta may be applied as a non-toxic radioprotector, while the high dose amifostine, known as the strongest radioprotector, however, had toxic side effects.