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Background: With increasing recognition of growing cancer incidence globally, efficient means of expanding radiotherapy capacity is imperative, and understanding the factors impacting human and financial needs is valuable., Materials and Methods: A time-driven activity-based costing analysis was performed, using a base case of 2-machine departments, with defined cost inputs and operating parameters. Four income groups were analysed, ranging from low to high income. Scenario analyses included department size, operating hours, fractionation, treatment complexity, efficiency, and centralised versus decentralised care., Results: The base case cost/course is US$5,368 in HICs, US$2,028 in LICs; the annual operating cost is US$4,595,000 and US$1,736,000, respectively. Economies of scale show cost/course decreasing with increasing department size, mainly related to the equipment cost and most prominent up to 3 linacs. The cost in HICs is two or three times as high as in U-MICs or LICs, respectively. Decreasing operating hours below 8h/day has a dramatic impact on the cost/course. IMRT increases the cost/course by 22%. Centralising preparatory activities has a moderate impact on the costs., Conclusions: The results indicate trends that are useful for optimising local and regional circumstances. This methodology can provide input into a uniform and accepted approach to evaluating the cost of radiotherapy., (Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Radiation Pneumonitis (RP) limits radiotherapy. Detection of early metabolic changes in the lungs associated with RP may provide an opportunity to adjust treatment before substantial toxicities occur. In this work, regional lactate-to-pyruvate signal ratio (lac/pyr) was quantified in rat lungs and heart following administration of hyperpolarized (13)C-pyruvate magnetic resonance imaging (MRI) at day 5, 10, 15 and 25-post conformal radiotherapy. These results were also compared to histology and blood analyses., Methods: The lower right lungs of 12 Sprague Dawley rats were irradiated in 2 fractions with a total dose of 18.5 Gy using a modified micro-CT system. Regional lactate and pyruvate data were acquired from three irradiated and three age-matched healthy rats at each time point on days 5, 10, 15 and 25-post radiotherapy. Arterial blood was collected from each animal prior to the (13)C-pyruvate injection and was analyzed for blood lactate concentration and arterial oxygen concentration (paO₂). Macrophage count was computed from the histology of all rat lungs., Results: A significant increase in lac/pyr was observed in both right and left lungs of the irradiated cohort compared to the healthy cohort for all time points. No increase in lac/pyr was observed in the hearts of the irradiated cohort compared to the hearts of the healthy cohorts. Blood lactate concentration and paO2 did not show a significant change between the irradiated and the healthy cohorts. Macrophage count in both right and left lungs was elevated for the irradiated cohort compared to the healthy cohort., Conclusions: Metabolic changes associated with RP may be mapped as early as five days post conformal radiotherapy. Over the small sample size in each cohort, elevated macrophage count, consistent with early phase of inflammation was highly correlated to increases in lac/pyr in both the irradiated and unirradiated lungs. Further experiments with larger sample size may improve the confidence of this finding., (Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Background and Purpose: This study investigated protection of lung injury by genistein following fractionated doses of radiation and its effect on tumor response., Material and Methods: C3H/HeJ mice were irradiated (100 kVp X-rays) with 9 fractions of 3.1 Gy over 30 days (approximately equivalent to 10 Gy single dose) and were maintained on a genistein diet ( approximately 10mg/kg). Damage was assessed over 28 weeks in lung cells by a cytokinesis block micronucleus (MN) assay and by changes in breathing rate and histology. Tumor protection was assessed using a colony assay to determine cell survival following in situ irradiation of small lung nodules (KHT fibrosarcoma)., Results: Genistein caused about a 50% reduction in the MN damage observed during the fractionated radiation treatment and this damage continued to decrease at later times to background levels by 16 weeks. In mice not receiving Genistein MN levels remained well above background out to 28 weeks after irradiation. Genistein reduced macrophage accumulation by 22% and reduced collagen deposition by 28%. There was minimal protection against increases in breathing rate or severe morbidity during pneumonitis. No tumor protection by genistein treatment was observed., Conclusions: Genistein at the dose levels used in this study partially reduced the extent of fibrosis developing in mouse lung caused by irradiation but gave minimal protection against pneumonitis. There was no evidence that genistein caused protection of small tumors growing in the lung.

Purpose and Background: Conventional early breast cancer treatment consists of a lumpectomy followed by whole breast radiation therapy. Accelerated partial breast irradiation (APBI) is an investigational approach to post-lumpectomy radiation for early breast cancer. The purpose of this study is to compare four external beam APBI techniques, including tomotherapy, with conventional whole breast irradiation for their radiation conformity index, dose homogeneity index, and dose to organs at risk., Methods and Materials: Small-field tangents, three-dimensional conformal radiation therapy, intensity-modulated radiation therapy and helical tomotherapy were compared for each of 15 patients (7 right, 8 left). One radiation conformity and two dose homogeneity indices were used to evaluate the dose to the target. The mean dose to organs at risk was also evaluated., Results: All proposed APBI techniques improved the conformity index significantly over whole breast tangents while maintaining dose homogeneity and without a significant increase in dose to organs at risk., Conclusion: The four-field IMRT plan produced the best dosimetric results; however this technique would require appropriate respiratory motion management. An alternative would be to use a four-field conformal technique that is less sensitive to the effects of respiratory motion.

Background and Purpose: The purpose of the current study was to elucidate the protective/mitigating effects of a SOD-catalase mimetic, Eukarion-189 (EUK-189), on DNA damage in rat lung following irradiation. The particular focus of these studies was the efficacy of EUK-189 when given after irradiation (mitigation)., Patients and Methods: We exposed whole or lower lungs of female Sprague-Dawley rats to doses ranging from 10 to 20.5 Gray (Gy) of (60)Co gamma rays. Animals in the EUK-189 treated groups received 2 or 30 mg/kg intraperitoneally (i.p.) at various times postirradiation (PI). A micronucleus assay was used to examine DNA damage at various times up to 16 weeks PI., Results: Our results indicated that EUK-189 administration after irradiation is effective at reducing micronucleus formation in lung fibroblasts at various times following radiation exposure. Treatment with EUK-189 in the first 3 days after thoracic irradiation did not, however, modify the dose required to cause severe morbidity at 2-3 months after irradiation., Conclusions: The protection produced when Eukarion-189 was given shortly after irradiation suggests that DNA damage observed in the lung may be caused by chronic production of ROS induced by a chronic inflammatory response initiated by the radiation treatment. We speculate that our failure to observe protection against severe morbidity at 2-3 months may be because our treatment regime only blocked the initial wave of ROS production and that treatment needs to be more prolonged to suppress the effects of a chronic inflammatory response.

Background and Purpose: To perform a systematic review of the predictive ability of various dose-volume histogram (DVH) parameters (V(dose), mean lung dose (MLD), and normal tissue complication probability (NTCP)) in the incidence of radiation pneumonitis (RP) caused by external-beam radiation therapy., Methods and Materials: Studies assessing the relationship between CT-based DVH reduction parameters and RP rate in radically treated lung cancer were eligible for the review. Synonyms for RP, lung cancer, DVH and its associated parameters (NTCP, V(20), V(30), MLD) were combined in a search strategy involving electronic databases, secondary reference searching, and consultation with experts. Individual or group data were abstracted from the various reports to calculate operating characteristics and odds ratios for the different DVH metrics., Results: A total of 12 published studies and two abstracts were identified. Eleven studies assessed V(dose), seven assessed MLD, and eight assessed NTCP. Nine studies exclusively analyzed the association between various DVH metrics and RP risk. Five studies also analyzed other patient, tumor, and treatment variables in conjunction with standard DVH metrics. A direct comparison between studies and the generation of summary statistics (i.e. meta-analysis) could not be achieved due to significant predictive and outcome variable heterogeneity. Most studies did show an association between DVH parameters and RP risk. However, overall accuracy, sensitivity, specificity, and positive predictive value were generally poor to fair for all three classes of DVH metrics., Conclusions: An association between DVH parameters and RP risk has been demonstrated in the literature. However, the ideal DVH metric with excellent operating characteristics, either alone or in a model with other predictive variables, for RP risk prediction has not yet been identified. Several recommendations for reporting and conduct of future research into the association between DVH metrics and RP risk are provided.

Background and Purpose: To assess the patterns of practice among Canadian radiation oncologists who treat lung cancers., Patients and Methods: A questionnaire detailing different aspects of radiation treatment of lung cancer was mailed to all radiation oncologists treating lung cancer in Canada. Seventy-two percent (74/103) of radiation oncologists who treat lung cancer from all 34 Canadian cancer centres replied to the questionnaire., Results: (a) Radiotherapy regimens in Canadian cancer centres are in accordance with several major randomised studies. There is still some variation in treatment practice that may be due to unresolved controversies or limited resources. The most frequently used prescription dose was 40Gy/15f/3w (where f stands for fractions and w stands for weeks) for small cell lung cancer (SCLC) and 60Gy/30f/6w for non-small cell lung cancer (NSCLC). If there were no resource constraints, 30% (22/74) and 20% (15/74) would prefer to use a different dose-fractionation scheme for SCLC and NSCLC, respectively; 95% (70/74) would prefer to use 3D-conformal or intensity-modulated radiotherapy. (b) Among the various modern technologies assessed by respondents, CT (computed tomography) simulator, multi-leaf collimator, on-line electronic portal imaging and PET (positron-emission tomography) scanning were rated the highest in terms of potential patient benefit. Discrepancy between demand and availability of technology was greatest for PET scanning., Conclusions: Canadian practice in the treatment of lung cancers shows some variations although it is consistent with the trends in the literature. The lack of some modern technologies and human resources is an ongoing concern, especially the lack of PET imaging equipment.

Background and Purpose: Radiation pneumonitis and fibrosis are limiting factors in radiation treatment (RT) of thoracic tumors. The objectives of this study were to quantify the influence of irradiated lung volume and dose on lung response, and to evaluate the influence of other prognostic factors., Material and Methods: Treatment histories of 55 thymoma patients were evaluated retrospectively for radiation pneumonitis and fibrosis. Complications were scored as pneumonitis if observed within 6 months of completion of RT, and as fibrosis if observed after 6 months. Complications were classified as 'all pneumonitis' and 'all fibrosis' if a patient either showed symptoms (such as chronic cough and dyspnea) or radiographic changes in lung. The second group scored as 'symptomatic pneumonitis' and 'symptomatic fibrosis' consisted of patients that exhibited clinical symptoms. Dose-volume data were estimated using representative anatomies combined with available individual dose data. The Lyman NTCP model was used to assess the dependence of lung complication incidence on dose and volume., Results: The derived values of the parameters governing dose-volume dependence for symptomatic complications agreed with currently accepted and recently published values within the margins of error. Dose-response curves for complications that included radiographic changes were less steep than for symptomatic complications. The volume dependence for symptomatic fibrosis was more pronounced compared to all fibrosis. A strong correlation was observed between developing pneumonitis and developing fibrosis., Conclusions: The long survival allowed the assessment of lung complication data in thymoma patients for both acute and late response. Mean dose in lung strongly correlated with lung complications that manifest clinically. The determination of the dose-volume dependence is affected by the choice of endpoints (i.e. whether complications are scored based on clinical symptoms or radiographic changes not accompanied by clinical symptoms).

Purpose: These studies were designed to examine radiation-induced in-field and out-of-field DNA damage in rat lung as a function of dose and various volumes of irradiation. They also determined whether superoxide dismutase (SOD) and nitro-L-arginine methyl ester (L-NAME) protected against this damage., Methods and Materials: The whole lung, or various volumes of the lower or upper lungs of Sprague-Dawley rats were exposed to doses up to 20 Gy of 60Co gamma rays. Radiation-induced DNA damage was quantified in fibroblasts obtained at 18 h after irradiation from both irradiated and shielded lung regions using a micronucleus assay. The radioprotective role of SOD (CuZnSOD: 10 mg/kg body weight; MnSOD: 50-100mg/kg body weight) and L-NAME (0.2 mg/kg body weight.) in vivo was determined by injecting them into rats 30 min before or immediately after a dose of 10 Gy., Results: Micronucleus formation was approximately linear with dose up to 15 Gy. When 70% of the lung volume was irradiated with 10 Gy, irradiated lower lung gave similar numbers of micronuclei (MN)/binucleate cell (BN) to that observed following whole lung irradiation (0.91 MN/BN), whereas the irradiated upper lung gave only 0.66 MN/BN. Following lower lung irradiation, the shielded upper lung (30% of lung volume) showed substantial (out-of-field) damage (0.43 MN/BN). When 30% of the lung was given 10 Gy, irradiated upper or lower lung showed similar amounts of in-field damage (0.43 MN/BN) but this was smaller than that seen following irradiation of 70% of the lung volume. For 30% lower lung irradiation, the shielded upper lung showed only a small out-of-field effect (0.1 MN/BN). For both volumes of irradiation there was a similar or smaller effect in the shielded lower lung after upper lung irradiation. Injection of SOD before or L-NAME after 10 Gy to the lower 70% lung volume resulted in a reduction in DNA damage both in-field and out-of-field but the percentage was much greater for out-of-field damage (50-60%) than for in-field damage (10-30%). Following whole lung irradiation (10 Gy) significantly greater DNA damage was observed in fibroblasts from the left lung than from the right lung (0.93 MN/BN vs. 0.82 MN/BN). Following whole lung irradiation there was no significant difference in DNA damage observed in fibroblasts from the lower lung and the upper lung., Conclusions: With partial lung irradiation the lower lung sustains more in-field DNA damage following irradiation than the upper lung, whereas out-of-field effects are observed primarily in the upper lung (i.e. following lower lung irradiation). Following whole lung irradiation the left lung sustains more damage than the right lung but there is no difference between the upper and lower lung. The protective effects of SOD and L-NAME suggest that inflammatory cytokines induced by the irradiation may be involved in the initiation of a reaction resulting in the production of reactive oxyradicals and nitric oxide that cause indirect DNA damage both in and out of the radiation field.

An experiment has been performed in which fractionated irradiation was given to the whole thorax of Sprague-Dawley rats with schedules chosen so that doses per fraction and overall treatment time were changed independently. Damage was monitored by lethality. The data have been analyzed to yield dose per fraction and time parameters using multiple non-linear regression analysis. The results show that a linear-quadratic cell survival formula, extended to include an exponential time component to account for proliferation or slow repair during the treatment, can predict isoeffective doses to within 7% accuracy over a wide range of times (3.5-49 days) and doses per fraction (1.8-10.2 Gy). Other isoeffect formulae based on the linear-quadratic and empirical power law functions were also evaluated. A linear-quadratic formula with a time dependent alpha parameter fitted the data particularly well. This result suggests an alternative underlying mechanism and requires further investigation.

From 1975 to 1982, 32 patients with a diagnosis of anaplastic carcinoma of the thyroid were entered into a protocol of hyperfractionated accelerated radiotherapy. The tumor dose was 30-45 Gy at 1 Gy per fraction given 4 times a day at 3-h intervals. The results were disappointing with a median survival of less than 6 months. Two patients developed radiation myelopathy at 8 and 13 months, total spinal cord dose being 39.9 and 48.3 Gy, respectively. The risk of spinal cord damage was much higher than expected. The possible radiobiological causes and clinical implications are discussed.

Total body irradiation (TBI) is becoming increasingly prominent as a major component of therapy for patients with hematological diseases requiring bone marrow transplantation. This review considers some of the special dosimetric problems associated with TBI. Basic beam dosimetry and factors affecting dose variation within the patient are discussed and compared to conventional radiotherapy. The delivery of an accurate dose to the patient requires phantom measurements to be related to the dose at the prescription point. The use of treatment planning dose calculation procedures, including inhomogeneity corrections, is described specifically for large field treatments. Finally, some questions for future research are considered.

The comparison of different dose-time-fractionation schedules requires the use of an isoeffect formula. In recent years, the NSD isoeffect formula has been heavily criticized. In this report, we consider an isoeffect formula which is specifically developed for radiation-induced lung damage. The formula is based on the linear-quadratic model and includes a factor for overall treatment time. The proposed procedures allow for the simultaneous derivation of an alpha/beta ratio and a gamma/beta time factor. From animal data in the literature, the derived alpha/beta and gamma/beta ratios for acute lung damage are 5.0 +/- 1.0 Gy and 2.7 +/- 1.4 Gy2/day respectively, while for late damage the suggested values are 2.0 Gy and 0.0 Gy2/day. Data from two clinical studies, one prospective and the other retrospective, were also analysed and corresponding alpha/beta and gamma/beta ratios were determined. For the prospective clinical study, with a limited range of doses per fraction, the resultant alpha/beta and gamma/beta ratios were 0.9 +/- 2.6 Gy and 2.6 +/- 2.5 Gy2/day. The combination of the retrospective and prospective data yielded alpha/beta and gamma/beta ratios of 3.3 +/- 1.5 Gy and 2.4 +/- 1.5 Gy2/day, respectively. One potential advantage of this isoeffect formalism is that it might possibly be applied to both acute and late lung damage. The results of this formulation for acute lung damage indicate that time-dependent effects such as slow repair or proliferation might be more important in determining isoeffect doses than previously predicted by the estimated single dose (ED) formula. Although we present this as an alternative approach, we would caution against its clinical use until its applicability has been confirmed by additional clinical data.

In a recent clinical study, we have shown that computed tomography (CT) can provide a good qualitative endpoint for the presence of radiation-induced pulmonary damage. However, CT data are also potentially useful as a quantitative measure of lung damage. Changes in lung density were quantified by comparing CT images taken before and after radiotherapy for 54 patients. Lung densities were assessed separately in the irradiated and nonirradiated regions using both the average regional densities and density distributions. For the 36 patients demonstrating visible post-irradiation lung damage on CT, the mean relative increase in average lung density was 0.20 +/- 0.10 in the irradiated regions. The mean change in the nonirradiated regions was 0.02 +/- 0.09 for the same group. For 18 patients without visible damage, the mean relative changes were 0.00 +/- 0.09 and -0.05 +/- 0.07 for the irradiated and nonirradiated regions, respectively. The results suggest that an increase in average lung density of 5% or greater is associated with the visible detection of pulmonary damage. The dose-response relationship based on this quantitative criterion was comparable to that derived using the qualitative endpoint.