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Highlights • Changes in PET/CT tumor volume at mid-treatment correlate with lung cancer survival. • There is an inverse relationship between PET-volume reduction and overall survival. • Mid-treatment PET/CT-adapted therapy may improve overall survival for lung cancer. Abstract Background and purpose This study tested the hypotheses that 1) changes in mid-treatment fluorodeoxyglucose (FDG)-positron emission tomography (PET) parameters are predictive of overall survival (OS) and 2) mid-treatment FDG-PET–adapted treatment has the potential to improve survival in patients with non-small cell lung cancer (NSCLC). Material and methods Patients with stage I-III NSCLC requiring daily fractionated radiation were eligible. FDG-PET-CT scans were obtained prior to and mid-treatment with radiotherapy at 40–50 Gy. The normalized maximum standardized uptake value (NSUVmax), normalized mean SUV (NSUVmean), PET-metabolic tumor volume (MTV), total lesion glycolysis (TLG), and computed tomography-based gross tumor volume (CT-GTV) were consistently measured for all patients. The primary study endpoint was OS. Results The study is comprised of 102 patients who received 3-dimensional conformal radiotherapy, among whom 30 patients who received mid-treatment PET-adapted dose escalation radiotherapy. All PET-CT parameters decreased significantly (P < 0.001) mid-treatment, with greater reductions in FDG-volumetric parameters compared to FDG-activity factors. Mid-treatment changes in MTV (P = 0.053) and TLG (P = 0.021) were associated with OS, while changes in NSUVmax, NSUVmean, and CT-GTV were not (all Ps>0.1). Patients receiving conventional radiation (60-70 Gy) with MTV reductions greater than the mean had a median survival of 14 months, compared to those with MTV reductions less than the mean who had a median survival of 22 months. By contrast, patients receiving mid-treatment PET-adapted radiation with MTV reductions greater than the mean had a median survival of 33 months, compared to those with MTV reductions less than the mean who had a median survival of 19 months. Overall, PET-adapted treatment resulted in a 19% better 5-year survival than conventional radiation. Conclusion Changes in mid-treatment PET-volumetric parameters were significantly associated with survival in NSCLC. A greater reduction in the mid-treatment MTV was associated with worse survival in patients treated with standard radiation, but with better survival in patients who received mid-treatment PET-adapted treatment. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To evaluate the ability of a well-known normal tissue complication probability (NTCP) model to predict radiation esophagitis by determining updated model parameters and then comparing these results with the predictive value of other dosimetric parameters. Material and methods: Clinical and dosimetric data regarding esophagitis were analyzed in 101 inoperable/unresectable non-small-cell lung cancer patients treated by external beam irradiation. Grade 2 or higher esophagitis counted as events. Parameters (TD 50 , n, and m) of the Lyman normal tissue complication probability (NTCP) model were determined using maximum likelihood analysis, and compared to other dose/volume threshold values including: percentage of esophagus receiving >40Gy (V40) to >75Gy (V75), and maximum esophageal doses. Results: Sixteen patients developed grade 2–3 acute esophagitis (no G4 or 5). The maximum likelihood analysis produced new Lyman model parameters of: TD 50 =51Gy, n=0.44 and m=0.32. The mean NTCP value is significantly lower (P<0.001) in the group of patients without esophagitis (13.5%) than with esophagitis (27.2%). The rates of esophagitis are 2.5, 7, 9 and 13.4%, respectively, when the NTCP values are <10%, <15%, <20% and <25%. A significant association is found between esophagitis and dose/volume parameters V40 (P=0.001) to V70 (P=0.024). Conclusions: New values of TD 50 , n and m offer a good description of the esophagitis distribution in our population. Compared to the use of this model with previously published parameters (associated with late toxicity) predictions of the model for acute esophagitis using the new parameters would indicate that, for a population of patients, the distribution of events as a function of uniform dose would occur with a lower mean uniform dose value (smaller TD 50 ), over a wider range of uniform doses (larger m), while also exhibiting a bigger volume effect (larger n). These new parameter values are supported in essence by the correlations found for the dose/volume threshold parameters. [Copyright &y& Elsevier]

Abstract: Irradiation of the axillary nodes is often indicated in the clinical radiotherapy of patients with lymphoma and breast cancer. The relative location of the axillary nodes and the humeral head has historically been estimated based on lymphangiographic data. Since CT offers more precise definition, the axillary nodal region in relation to the humeral head was systematically studied in 61 patients undergoing CT simulation for breast conservation therapy. Differences in arm position (degree of abduction) significantly affected the location of the axillary nodal region in relation to the humeral head. With the arm abducted beyond 55 degrees, humeral head blocking would result in blocking of some of the axillary nodes. [Copyright &y& Elsevier]

• Lymphopenia is associated with poor survivals in breast cancer patients. • AI model with full DVH dosimetry was established to predict lymphopenia after RT in breast cancer. • This model achieved a well predictive accuracy and externally validated. • Low-dose volumes of V1 in OARs were strong predictors for lymphopenia after RT, especially V1 of ipsilateral lung. • Low-dose volumes of V1 deserve special attention in RT plan. Lymphopenia is known for its significance on poor survivals in breast cancer patients. Considering full dosimetric data, this study aimed to develop and validate predictive models for lymphopenia after radiotherapy (RT) in breast cancer. Patients with breast cancer treated with adjuvant RT were eligible in this multicenter study. The study endpoint was lympopenia, defined as the reduction in absolute lymphocytes and graded lymphopenia after RT. The dose-volume histogram (DVH) data of related critical structures and clinical factors were taken into account for the development of dense neural network (DNN) predictive models. The developed DNN models were validated using external patient cohorts. A total of 918 consecutive patients with invasive breast cancer enrolled. The training, testing, and external validating datasets consisted of 589, 203, and 126 patients, respectively. Treatment volumes at nearly all dose levels of the DVH were significant predictors for lymphopenia following RT, including volumes at very low-dose 1 Gy (V1) of organs at risk (OARs) including lung, heart and body, especially ipsilateral-lung V1. A final DNN model, combining full DVH dosimetric parameters of OARs and three key clinical factors, achieved a predictive accuracy of 75 % or higher. This study demonstrated and externally validated the significance of full dosimetric data, particularly the volume of low dose at as low as 1 Gy of critical structures on lymphopenia after radiation in patients with breast cancer. The significance of V1 deserves special attention, as modern VMAT RT technology often has a relatively high value of this parameter. Further study is warranted for RT plan optimization. [ABSTRACT FROM AUTHOR]

• IMRT with replanning significantly improved 8-year local–regional recurrence-free survival rate. • IMRT with replanning did not improve 8-year distant metastasis-free survival and overall survival rate. • Replanning during IMRT had a favorable impact on the late toxicities and long-term quality of life. Recent studies show that adaptive replanning for patients with nasopharyngeal carcinoma (NPC) during intensity-modulated radiation therapy (IMRT) improve the short-term local–regional recurrence-free survival (LRFS), and quality of life (QoL). We aimed to assess the long-term survival outcomes and QoL in patients with non-metastatic NPC who received IMRT with replanning compared to those who received IMRT without replanning. We conducted an updated and expanded retrospective analysis from an existing prospective cohort for non-metastatic NPC patients undergoing IMRT in our institution. Non-metastatic NPC patients receiving IMRT from June 2007 to December 2015 were consecutively enrolled based on electronic medical record. Patients who were still alive were eligible for the QoL study. The survival outcomes and QoL were compared between patients with and without replanning. Among 290 patients, 147 (50.7%) received IMRT without replanning and 143 (49.3%) received IMRT with replanning. Replanning group had a higher 8-year LRFS rate (87.4% vs. 75.6%, P = 0.025). However, 8-year overall survival rate was not statistically significant. Patients with replanning compared to those who without replanning had significant improvements in social functioning (P = 0.016), insomnia (P = 0.048), dry mouth (P = 0.004), and sticky saliva (P = 0.005). Additionally, the score of the role functioning was marginally higher in patients treated with IMRT replanning (P = 0.063). This extended follow-up study demonstrates the long-term security and validity for adaptive radiotherapy in IMRT for non-metastatic NPC patients. We highly recommend that adaptive replanning should be routinely implemented for non-metastatic NPC patients. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To use probability density function (PDF) to model motion effects and incorporate this information into treatment planning for lung cancers. Material and methods: PDFs were calculated from the respiratory motion traces of 10 patients. Motion effects were evaluated by convolving static dose distributions with various PDFs. Based on a differential dose prescription with relatively lower dose to the clinical target volume (CTV) than to the gross tumor volume (GTV), two approaches were proposed to incorporate PDFs into treatment planning. The first approach uses the GTV-based internal target volume (ITV) as the planning target volume (PTV) to ensure full dose to the GTV, and utilizes the motion-induced dose gradient to cover the CTV. The second approach employs an inhomogeneous static dose distribution within a minimized PTV to best match the prescription dose gradient. Results: Motion effects on dose distributions were minimal in the anterior–posterior (AP) and lateral directions: a 10-mm motion only induced about 3% of dose reduction in the peripheral target region. The motion effect was remarkable in the cranial–caudal direction. It varied with the motion amplitude, but tended to be similar for various respiratory patterns. For the first approach, a 10–15mm motion would adequately cover the CTV (presumed to be 60–70% of the GTV dose) without employing the CTV in planning. For motions <10-mm, an additional PTV with a margin inversely related to the motion was needed to cover the CTV. The second approach was used for motions >15-mm. An example of inhomogeneous static dose distribution in a reduced PTV was given, and it showed significant dose reduction in the normal tissue without compromising target coverage. Conclusions: Respiratory motion-induced dose gradient can be utilized to cover the CTV and minimize the lung dose without the need for more sophisticated technologies. [Copyright &y& Elsevier]

• EDIC significantly correlated with lymphocyte nadir during thoracic radiotherapy. • Lymphocyte nadir and EDIC were independent factors for survival outcome in LS-SCLC. EDIC appear to have a better survival prediction accuracy than lymphocyte nadir. • More attention should be paid to EDIC to avoid circulating lymphocyte toxicity. Effective dose to immune cell (EDIC), an estimated radiation dose to the circulating lymphocytes, is of significance for overall survival (OS) in non-small cell lung cancer. This study aimed to validate the EDIC's OS effect on limited-stage small cell lung cancer (LS-SCLC). This study included LS-SCLC patients received definitive chemo-radiation in one single center from 2012 to 2017. All patients had multiple complete-blood-count tests including lymphocyte count at pre-, during- and end- radiotherapy. EDIC, computed according to doses of the lung, heart, and the total body, was assessed for its correlation with lymphocyte nadir, OS and progression free survival (PFS). Of 503 eligible patients, the mean EDIC was 7.34 Gy. The mean lymphocyte nadir was 0.48 × 109 cells/L, significantly lower than 1.65 × 109 cells/L at pre-radiotherapy (p < 0.001). EDIC was significantly correlated with lymphocyte nadir under both univariate (p < 0.001) and multivariable linear regression (p < 0.001). Multivariable analysis showed EDIC (HR = 0.1072, p = 0.005) and lymphocyte nadir (HR = 0.345, p = 0.003) were both significant for OS. EDIC was also significant for PFS (HR = 1.046, p = 0.026). The C-indexes of OS prediction were 0.593, 0.617, 0.676, and 0.684, for lymphocyte nadir alone, EDIC alone, combined lymphocyte nadir model, and combined EDIC model, respectively. This study demonstrated that EDIC is an independent predictor for lymphocyte nadir, PFS and OS. EDIC may serve as a predictor for lymphocyte nadir and a surrogate marker for OS in LS-SCLC. More attention should be paid to EDIC to decease the lymphocyte toxicity and improve survival. [ABSTRACT FROM AUTHOR]

• Contouring subclavian-axillary veins underestimates grade ≥ 2 RIBP risk in dosimetry. • Significant underestimation of BP doses was observed in patients with PTV-B. • Maximum and 0.3 cc biologically effective doses to BP may be predictors of RIBP. Examine the significance of contouring the brachial plexus (BP) for toxicity estimation and select metrics for predicting radiation-induced brachial plexopathy (RIBP) after stereotactic body radiotherapy. Patients with planning target volume (PTV) ≤ 2 cm from the BP were eligible. The BP was contoured primarily according to the RTOG 1106 atlas, while subclavian-axillary veins (SAV) were contoured according to RTOG 0236. Apical PTVs were classified as anterior (PTV-A) or posterior (PTV-B) PTVs. Variables predicting grade 2 or higher RIBP (RIBP2) were selected through least absolute shrinkage and selection operator regression and logistic regression. Among 137 patients with 140 BPs (median follow-up, 32.1 months), 11 experienced RIBP2. For patients with RIBP2, the maximum physical dose to the BP (BP-D max) was 46.5 Gy (median; range, 35.7 to 60.7 Gy). Of these patients, 54.5 % (6/11) satisfied the RTOG limits when using SAV delineation; among them, 83.3 % (5/6) had PTV-B. For patients with PTV-B, the maximum physical dose to SAV (SAV-D max) was 11.2 Gy (median) lower than BP-D max. Maximum and 0.3 cc biologically effective doses to the BP based on the linear-quadratic-linear model (BP-BED max LQL and BP-BED 0.3cc LQL , α/β = 3) were selected as predictive variables with thresholds of 118 and 73 Gy, respectively. Contouring SAV may significantly underestimate the RIBP2 risk in dosimetry, especially for patients with PTV-B. BP contouring indicated BP-BED 0.3cc LQL and BP-BED max LQL as potential predictors of RIBP2. [ABSTRACT FROM AUTHOR]

• Clinical and dosimetric risk factors for symptomatic RP after SBRT were analyzed in a large series of patients. • Respiratory comorbidity, previous lung radiation, right lung location, BED10 of the prescription dose, MLD and V20 of total lungs, and MLD of ipsilateral lung were significant factors for higher risk of symptomatic RP. • Should the risk of RP2 be limited less than 10%, the mean doses of total lung and ipsilateral lung be constrained to less than 6 Gy and 20 Gy, respectively. Radiation pneumonitis (RP) can be a potential fatal toxicity of stereotactic body radiation therapy (SBRT) for medically inoperable non-small cell lung cancer (NSCLC). This study aimed to examine the risk factors that predict RP and explore dosimetric tolerance for safe practice in a large institutional series of NSCLC patients. Patients with early-stage and locally recurrent NSCLC who received lung SBRT between 2002 and 2015 formed the study population. The primary endpoint was grade 2 or above radiation pneumonitis (RP2). Lungs were re-contoured consistently by one radiation oncologist according to the RTOG atlas for organs at risk. Dosimetric factors were computed consistently with exclusion of gross tumor volume of either ipsilateral, contralateral, or total lungs. A total of 339 patients were eligible. With a median follow-up of 47 months, RP2 was recorded in 10% patients. History of respiratory comorbidity, previous thoracic radiation, right lung location, mean lung doses of total or ipsilateral lung, and total lung volume receiving 20 Gy were all significantly associated with the risk of RP2. The dosimetric parameters of contralateral lung, including mean dose and volume receiving more than 5, 10, and 20 Gy, were not significantly associated with RP2 (ps > 0.05). A model of combining significant clinical and dosimetric factors had a predictive accuracy AUC of 0.76. According to this model, RP2 can be limited to <10% should the patient have no previous lung radiation and the mean dose of total and ipsilateral lungs be kept less than 6 Gy and 20 Gy, respectively. Dosimetric factors of total or ipsilateral lung together with important clinical factors were significant risk factors for symptomatic radiation pneumonitis after SBRT. Constraining mean lung dose can limit clinically significant lung toxicity. [ABSTRACT FROM AUTHOR]

• Computer simulation showed a strong sparing effect on circulating immune cells. • Threshold FLASH dose rate consistent with reported FLASH dose rate in animal studies. • FLASH effect only with large dose per fraction. • Threshold FLASH dose rate for humans one order of magnitude less than that for mice. • Maybe not that challenging to develop a photon-based clinical FLASH-RT system. "FLASH" radiotherapy (RT) is a potential paradigm-changing RT technology with marked tumor killing and normal tissue sparing. However, the mechanism of the FLASH effect is not well understood. We hypothesize that the ultra-high dose rate FLASH-RT significantly reduces the killing of circulating immune cells which may partially contribute to the reported FLASH effect. This computation study directly models the effect of radiation dose rate on the killing of circulating immune cells. The model considers an irradiated volume that takes up A % of cardiac output and contains B % of total blood. The irradiated blood volume and dose were calculated for various A %, B %, blood circulation time, and irradiation time (which depends on the dose rate). The linear-quadratic model was used to calculate the extent of killing of circulating immune cells at ultra-high vs. conventional dose rates. A strong sparing effect on circulating blood cells by FLASH-RT was noticed; i.e., killing of circulating immune cells reduced from 90% to 100% at conventional dose rates to 5–10% at ultra-high dose rates. The threshold FLASH dose rate was determined to be ~40 Gy/s for mice in an average situation (A % = 50%), consistent with the reported FLASH dose rate in animal studies, and it was approximately one order of magnitude lower for humans than for mice. The magnitude of this sparing effect increased with the dose/fraction, reached a plateau at 30–50 Gy/fraction, and almost completely vanished at 2 Gy/fraction. We have calculated a strong sparing effect on circulating immune cells by FLASH-RT, which may contribute to the reported FLASH effects in animal studies. [ABSTRACT FROM AUTHOR]

• A 5-compartment immune OAR model with radiation dose to each compartment. • Incorporate lymphocyte radiosensitivity into the model. • First study to develop an immune OAR model that has a potential to guide personalized radiotherapy. • Test the model in 51 patients. • Potential to compare lymphocyte radiosensitivity in vivo and in vitro for each patient. Associations between radiation-induced lymphopenia (RIL) and survival have been extensively reported. However, the immune system is not considered as an organ-at-risk (OAR) in radiotherapy. This study aimed to develop the framework of an immune OAR model that may be utilized to predict and minimize RIL. A dynamic model was first developed for lymphocyte trafficking among 5 compartments of the immune system. Radiation dose to the circulating lymphocytes in each compartment was calculated based on the doses to fixed structures of each immune compartment and blood flow patterns. A RIL model was developed based on lymphocyte dynamics, lymphocyte radiosensitivity and reproductivity, and the dose to the lymphocytes. The model was tested in 51 patients by fitting it to weekly-measured absolute lymphocyte counts (ALC) for each patient, considering lymphocyte radiosensitivity and reproductivity as patient-dependent fitting parameters. The fitting was almost perfect for 20 patients, with sum of square of errors (SSE) between measured and predicted ALCs < 0.5. It was acceptable for another 27 patients, with SSE = 0.5~4.0. Only 4 patients had SSE > 4.0. The fitting also provided a method of in vivo estimation of radiosensitivity (α) for each patient. The median α was 0.40 Gy−1 for the 51 patients, consistent with in vitro measured data of 0.41 Gy−1 in the literature. We have presented a framework of developing an immune OAR model that has the potential to predict and minimize RIL in radiotherapy. [ABSTRACT FROM AUTHOR]

Highlights • Pericardial effusion is significantly associated with heart/pericardial dosimetric factors. • Pericardial effusion does not have a significant effect on survival. • The irradiated volume of pericardium, rather than the heart dose, is associated with inferior survival. • The risk of death may be decreased by minimizing the dose to pericardium. Abstract Background and purpose Higher cardiac dose was associated with worse overall survival in the RTOG0617 study. Pericardial effusion (PCE) is a common cardiac complication of thoracic radiation therapy (RT). We investigated whether doses of radiation to the heart and pericardium are associated with PCE and overall survival in patients treated with thoracic radiation for non-small cell lung cancer (NSCLC). Materials and methods A total of 94 patients with medically inoperable/unresectable NSCLC treated with definitive RT in prospective studies were reviewed for this secondary analysis. Heart and pericardium were contoured consistently according to the RTOG1106 Atlas, with the great vessels and thymus of the upper mediastinal structures included in the upper part of pericardium, only heart chambers included in the heart structure. Clinical factors and dose–volume parameters associated with PCE or survival were identified via Cox proportional hazards modeling. The risk of PCE and death were mapped using DVH atlases. Results Median follow-up for surviving patients was 58 months. The overall rate of PCE was 40.4%. On multivariable analysis, dosimetric factors of heart and pericardium were significantly associated with the risk of PCE. Pericardial V30 and V55 were significantly correlated with overall survival, but presence of PCE and heart dosimetric factors were not. Conclusion PCE was associated with both heart and pericardial doses. The significance of pericardial dosimetric parameters, but not heart chamber parameters, on survival suggests the potential significance of radiation damage to the cranial region of pericardium. [ABSTRACT FROM AUTHOR]

Highlights • Conventionally, metrics of pre-radiotherapy (RT) pulmonary function or post-RT pulmonary function changes have been used to predict outcomes in lung cancer patients receiving RT, but we hypothesized that parameters evaluated mid-treatment and used for replanning could provide accurate prediction of subsequent radiation-induced lung toxicity (RILT). • In the presented study, we tested this hypothesis in 42 patients receiving RT for high-risk, locally advanced non-small cell lung cancer (NSCLC) • Perfusion (Q)-single-photon emission computed tomography (SPECT) and Q-SPECT-CT were performed prior to RT and mid-treated after delivery of 40–50 Gy RT. • Our findings suggest that the mid-Tx dose–function histogram (DFH) parameters based on Q-SPECT were significantly elevated in patients who experienced grade 2 and above RILT. • Mid-Tx DFH seemed to be better for predicting RILT than traditional anatomical metrics in locally advanced NSCLC patients with significant functional lung changes mid-RT, though the difference did not reach a significant level, likely due to the limited sample size in this study. Abstract Purpose To investigate the predictive value of the perfusion (Q) single-photon emission computed tomography (SPECT)-weighted dose–function histogram (DFH) obtained mid-treatment (mid-Tx) with radiotherapy (RT) for radiation-induced lung toxicity (RILT) in patients with non-small cell lung cancer (NSCLC). Materials and methods The study population consisted of NSCLC patients who were undergoing RT treatment and enrolled in prospective imaging studies. Q-SPECT was performed prior to and during RT (at ∼40–45 Gy). A baseline dose–volume histogram (DVH) and mid-Tx DVH based on simulation CT as well as a baseline DFH and mid-Tx DFH based on Q-SPECT were calculated. Only patients with stage III NSCLC and visible functional lung (FL) changes on the mid-Tx scan were eligible for this enriched analysis. RILT was graded according to a reported scale. Results Forty-two stage III NSCLC patients met the criteria for inclusion. The accumulative incidence of grade ≥2 RILT was 31% in this high-risk population. Significant differences in functional metrics such as functional lung volume FV5–FV20 at increments of 5 Gy and functional MLD (FMLD) were observed between patients with and without grade ≥2 RILT (p < 0.05). Similar results were also obtained for anatomical metrics from V5–V20 and MLD (p < 0.05). The areas under the receiver operating characteristic curves (AUCs) ranged from 0.724to 0.812 for baseline DVH parameters, from 0.745 to 0.830 for mid-Tx DVH parameters, from 0.764 to 0.878 for baseline DFH parameters, and from 0.767 to 0.891 for mid-Tx DFH parameters. Further principal components analysis showed that the AUCs were 0.814/0.817 and 0.790/0.857 for baseline/mid-Tx DVH and baseline/mid-Tx DFH, respectively. Conclusions Mid-Tx DFH parameters based on Q-SPECT were significantly elevated in patients with grade ≥ 2 RILT in this study population. Among the metrics compared, mid-Tx DFH seemed to have better predictive accuracy, but this difference did not reach statistical difference. [ABSTRACT FROM AUTHOR]

Background and purpose To study whether cytokine markers may improve predictive accuracy of radiation esophagitis (RE) in non-small cell lung cancer (NSCLC) patients. Materials and methods A total of 129 patients with stage I–III NSCLC treated with radiotherapy (RT) from prospective studies were included. Thirty inflammatory cytokines were measured in platelet-poor plasma samples. Logistic regression was performed to evaluate the risk factors of RE. Stepwise Akaike information criterion (AIC) and likelihood ratio test were used to assess model predictions. Results Forty-nine of 129 patients (38.0%) developed grade ≥2 RE. Univariate analysis showed that age, stage, concurrent chemotherapy, and eight dosimetric parameters were significantly associated with grade ≥2 RE ( p  < 0.05). IL-4, IL-5, IL-8, IL-13, IL-15, IL-1α, TGFα and eotaxin were also associated with grade ≥2 RE ( p  < 0.1). Age, esophagus generalized equivalent uniform dose (EUD), and baseline IL-8 were independently associated grade ≥2 RE. The combination of these three factors had significantly higher predictive power than any single factor alone. Addition of IL-8 to toxicity model significantly improves RE predictive accuracy ( p  = 0.019). Conclusions Combining baseline level of IL-8, age and esophagus EUD may predict RE more accurately. Refinement of this model with larger sample sizes and validation from multicenter database are warranted. [ABSTRACT FROM AUTHOR]

Background and purpose Current methods to estimate risk of radiation-induced lung toxicity (RILT) rely on dosimetric parameters. We aimed to improve prognostication by incorporating clinical and cytokine data, and to investigate how these factors may interact with the effect of mean lung dose (MLD) on RILT. Materials and methods Data from 125 patients treated from 2004 to 2013 with definitive radiotherapy for stages I-III NSCLC on four prospective clinical trials were analyzed. Plasma levels of 30 cytokines were measured pretreatment, and at 2 and 4 weeks midtreatment. Penalized logistic regression models based on combinations of MLD, clinical factors, and cytokine levels were developed. Cross-validated estimates of log-likelihood and area under the receiver operating characteristic curve (AUC) were used to assess accuracy. Results In prognosticating grade 3 or greater RILT by MLD alone, cross-validated log-likelihood and AUC were −28.2 and 0.637, respectively. Incorporating clinical features and baseline cytokine levels increased log-likelihood to −27.6 and AUC to 0.669. Midtreatment cytokine data did not further increase log-likelihood or AUC. Of the 30 cytokines measured, higher levels of 13 decreased the effect of MLD on RILT, corresponding to a lower odds ratio for RILT per Gy MLD, while higher levels of 4 increased the association. Conclusions Although the added prognostic benefit from cytokine data in our model was modest, understanding how clinical and biologic factors interact with the MLD-RILT relationship represents a novel framework for understanding and investigating the multiple factors contributing to radiation-induced toxicity. [ABSTRACT FROM AUTHOR]

• NTCP modelled risks of RIBP after SBRT are ~10% with brachial plexus Dmax of ~32-34 Gy in 3 fractions. • NTCP modelled risks of RIBP after SBRT are ~10% with brachial plexus Dmax of ~40-43 Gy in 5 fractions. • RIBP dose-response from historic 2DRT, 3DRT or IMRT regimens appears much steeper than with SBRT. • The larger brachial plexus volume exposure with 2DRT/3DRT/IMRT may account for this difference. • Further study is needed to ascertain the effect of brachial plexus volume exposure on RIBP risks. Radiation-induced brachial plexopathy (RIBP), resulting in symptomatic motor or sensory deficits of the upper extremity, is a risk after exposure of the brachial plexus to therapeutic doses of radiation. We sought to model dosimetric factors associated with risks of RIBP after stereotactic body radiotherapy (SBRT). From a prior systematic review, 4 studies were identified that included individual patient data amenable to normal tissue complication probability (NTCP) modelling after SBRT for apical lung tumors. Two probit NTCP models were derived: one from 4 studies (including 221 patients with 229 targets and 18 events); and another from 3 studies (including 185 patients with 192 targets and 11 events) that similarly contoured the brachial plexus. NTCP models suggest ≈10% risks associated with brachial plexus maximum dose (D max) of ∼32–34 Gy in 3 fractions and ∼40–43 Gy in 5 fractions. RIBP risks increase with increasing brachial plexus D max. Compared to previously published data from conventionally-fractionated or moderately-hypofractionated radiotherapy for breast, lung and head and neck cancers (which tend to utilize radiation fields that circumferentially irradiate the brachial plexus), SBRT (characterized by steep dose gradients outside of the target volume) exhibits a much less steep dose–response with brachial plexus D max > 90–100 Gy in 2-Gy equivalents. A dose–response for risk of RIBP after SBRT is observed relative to brachial plexus D max. Comparisons to data from less conformal radiotherapy suggests potential dose-volume dependences of RIBP risks, though published data were not amenable to NTCP modelling of dose-volume measures associated with RIBP after SBRT. [ABSTRACT FROM AUTHOR]

Background In non-small-cell lung cancer radiotherapy, radiation pneumonitis ≥ grade 2 (RP2) depends on patients’ dosimetric, clinical, biological and genomic characteristics. Methods We developed a Bayesian network (BN) approach to explore its potential for interpreting biophysical signaling pathways influencing RP2 from a heterogeneous dataset including single nucleotide polymorphisms, micro RNAs, cytokines, clinical data, and radiation treatment plans before and during the course of radiotherapy. Model building utilized 79 patients (21 with RP2) with complete data, and model testing used 50 additional patients with incomplete data. A developed large-scale Markov blanket approach selected relevant predictors. Resampling by k -fold cross-validation determined the optimal BN structure. Area under the receiver-operating characteristics curve (AUC) measured performance. Results Pre- and during-treatment BNs identified biophysical signaling pathways from the patients’ relevant variables to RP2 risk. Internal cross-validation for the pre-BN yielded an AUC = 0.82 which improved to 0.87 by incorporating during treatment changes. In the testing dataset, the pre- and during AUCs were 0.78 and 0.82, respectively. Conclusions Our developed BN approach successfully handled a high number of heterogeneous variables in a small dataset, demonstrating potential for unraveling relevant biophysical features that could enhance prediction of RP2, although the current observations would require further independent validation. [ABSTRACT FROM AUTHOR]

This work is to analyze pooled clinical data using different radiobiological models and to understand the relationship between biologically effective dose (BED) and tumor control probability (TCP) for stereotactic body radiotherapy (SBRT) of early-stage non-small cell lung cancer (NSCLC). The clinical data of 1-, 2-, 3-, and 5-year actuarial or Kaplan–Meier TCP from 46 selected studies were collected for SBRT of NSCLC in the literature. The TCP data were separated for Stage T1 and T2 tumors if possible, otherwise collected for combined stages. BED was calculated at isocenters using six radiobiological models. For each model, the independent model parameters were determined from a fit to the TCP data using the least chi-square (χ 2 ) method with either one set of parameters regardless of tumor stages or two sets for T1 and T2 tumors separately. The fits to the clinic data yield consistent results of large α / β ratios of about 20 Gy for all models investigated. The regrowth model that accounts for the tumor repopulation and heterogeneity leads to a better fit to the data, compared to other 5 models where the fits were indistinguishable between the models. The models based on the fitting parameters predict that the T2 tumors require about additional 1 Gy physical dose at isocenters per fraction (⩽5 fractions) to achieve the optimal TCP when compared to the T1 tumors. In conclusion, this systematic analysis of a large set of published clinical data using different radiobiological models shows that local TCP for SBRT of early-stage NSCLC has strong dependence on BED with large α/ β ratios of about 20 Gy. The six models predict that a BED (calculated with α / β of 20) of 90 Gy is sufficient to achieve TCP ⩾ 95%. Among the models considered, the regrowth model leads to a better fit to the clinical data. [ABSTRACT FROM AUTHOR]

This study presents a MLC-based, 3D grid-therapy technique with characteristics of both 3D-conformal-radiotherapy and grid-therapy. It generates a brachytherapy-like dose distribution, with D50% of 20, 9.8, 5.4 and 2.9-Gy, for the spheres, target, 1 cm-outershell and 2 cm-outershell, respectively. It may provide a strategy to deliver ablative doses to large tumors safely. [ABSTRACT FROM AUTHOR]

Purpose This study utilizes a survival model and clinical data with various radiation doses from prospective trials to determine radiation dose–response parameters, such as radiosensitivity, and identify single-nucleotide-polymorphism (SNP) biomarkers that can potentially predict the dose response and guide personalized radiotherapy. Methods The study included 92 consecutive stage-III NSCLC patients with doses varying from 60 to 91 Gy. Logistic regression analysis of survival varying with SNP genotype and radiation dose was used to screen candidates for dose–response analysis. The dose–response parameter, represented by D 50 , was derived by fitting survival data into a model that takes into account both tumor control and treatment mortality. A candidate would be considered as a predictor if the 90% confident intervals (90% CIs) of D 50 for the 2 groups stratified by the SNP genotype were separated. Results One SNP-signature (combining ERCC2:rs238406 and ERCC1:rs11615) was found to predict dose–response. D 50 values are 63.7 (90% CI: 53.5–66.3) Gy and 76.1 (90% CI: 71.3, 84.6) Gy for the 2 groups stratified by the genotypes. Using this biomarker-based model, a personalized dose prescription may be generated to improve 2-year survival from ∼50% to 85% and ∼3% to 73% for hypothetical sensitive and resistant patients, respectively. Conclusions We have developed a survival model that may be used to identify genomic markers, such as ERCC1/2 SNPs, to predict radiation dose–response and potentially guide personalized radiotherapy. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: To exam factors associated with overall survival (OS) in patients with nasopharyngeal carcinoma (NPC). Materials and methods: This study is a retrospective study of a total of 1706 consecutive NPC patients from a single institution between January 1995 and December 1998. One thousand eighty-one patients were treated with radiotherapy (RT) alone and 625 with an intensive course of neoadjuvant chemotherapy followed by RT. Patient, tumor and treatment factors were analyzed for their significance on 5-year overall survival (OS). Results: Younger age, female gender, absence of anemia pre-RT, early tumor stage, interruption of RT, and neoadjuvant chemotherapy were significantly associated with survival under multivariate analysis (all P <0.05). The 5-year OS rates were 100%, 75.9% (95%CI 71.6–80.2%), 66.5% (95%CI 62.8–70.2%), and 49.3% (95%CI 45.0–53.6%) for stage I, II, III, and IV (P <0.05); 68.9% (95%CI 66.2–71.5%) and 63.7% (95%CI 61.5–65.8%), for patients treated with or without neoadjuvant chemotherapy (P =0.0051), and 51.7% (95%CI 45.0–58.4%) and 69.5% (95%CI 67.2–71.7%) for patients with or without treatment break (P <0.0001), respectively. Conclusion: Intensive neoadjuvant chemotherapy and absence of radiation break seem to be favorable factors associated with long-term survival in patients with NPC. [Copyright &y& Elsevier]

Abstract: Purpose: Clinical target volume (CTV), although present, is usually not considered during stereotactic body radiation therapy (SBRT) for non-small cell lung cancer. This study aimed to quantify the incidental dose to the potential CTV under different SBRT techniques. Materials and methods: Ten patients with various tumor motions were included in the study. Gated-4DCT was performed for all patients. Three treatment plans were generated. Plan A was based on free breathing gross tumor volume (GTV) from a regular CT. Plan B was based on internal target volume (ITV) from gated 4DCT. Plan C was a perfect gated treatment at the exhale phase. The hypothetical CTV was represented by three CTV shells (5, 10, and 15mm). Time-averaged dose for different respiratory phases was calculated for 18 representative points in each shell. Results: The minimum doses for plans A, B, and C were 84±20%, 94±3%, and 80±17% of the isocenter dose to the 5mm shell, 72±27%, 64±7%, and 20±11% to the 10mm shell, and 38±27%, 27±17%, and 6±7% to the 15mm shell, respectively. The caudal and cranial ends of each shell usually had lower dose compared to the other points on the shell. Plan B had the most uniform and reasonable doses to the CTV shells, and patients with large respiratory motion had significantly higher minimum dose than patients with less motion. Conclusion: The potential CTV may incidentally receive adequate and relatively homogeneous doses when ITV is used and the patients have large respiratory motion. However, it could be underdosed for gated treatment or for patients with little motion. [Copyright &y& Elsevier]

Abstract: Background and purpose: To determine the dose to regional nodal stations in patients with T1–3N0M0 non-small cell lung cancer (NSCLC) treated with three-dimensional conformal radiation therapy (3DCRT) without intentional elective nodal irradiation (ENI). Materials and methods: Twenty-three patients with medically inoperable T1–3N0M0 NSCLC were treated with 3DCRT without ENI. Hilar and mediastinal nodal regions were contoured on planning CT. The prescription dose was normalized to 70Gy. Equivalent uniform dose (EUD) and other dosimetric parameters (e.g., V 40) were calculated for each nodal station. Results: The median EUD for the whole group ranged from 0.4 to 4.4Gy for all elective nodal regions. Gross tumor volume (GTV) and the relationship between GTV and hilum were significantly correlated with irradiation dose to ipsilateral hilar nodal regions (P <.05). For patients with GTV⩾30.2cm3 (diameter≈4cm) and or having any overlap with hilum, the median EUDs were 9.6, 22.6, and 62.9Gy for ipsilateral lower paratracheal, subcarinal, and ipsilateral hilar regions, respectively. The corresponding median V40 were 32.5%, 39.3%, and 97.6%, respectively. Conclusions: Although incidental nodal irradiation dose is low in the whole group, the dose to high-risk nodal regions is considerable in patients with T1–3N0 NSCLC when the primary is large and/or centrally located. [Copyright &y& Elsevier]