Professional development through mentoring: Final evaluation of the pilot mentoring programme of the European society of radiotherapy and oncology.

The European SocieTy for Radiotherapy and Oncology (ESTRO) organized a one-year pilot mentoring programme. At evaluation after one year, both mentors and mentees scored the programme with a median score of 9 on a scale of 10. All of the mentors indicated that they wanted to participate again as mentors.

Severe radiation-induced lymphopenia during concurrent chemoradiotherapy for stage III non-small cell lung cancer: external validation of two prediction models.

Background: Severe radiation-induced lymphopenia (RIL) in patients undergoing chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC) is associated with decreased immunotherapy efficacy and survival. At The Christie and MD Anderson Cancer Center (MDACC), prediction models for lymphopenia were developed in lung and esophageal cancer patients, respectively. The aim of this study was to externally validate both models in patients with stage III NSCLC. Methods: Patients who underwent concurrent CRT for stage III NSCLC in 2019-2021 were studied. Outcomes were grade ≥3 and grade 4 lymphopenia during CRT. The Christie model predictors for grade ≥3 lymphopenia included age, baseline lymphocyte count, radiotherapy duration, chemotherapy, mean heart and lung doses, and thoracic vertebrae V20Gy. MDACC predictors for grade 4 lymphopenia were age, baseline lymphocyte count, planning target volume (PTV), and BMI. The external performance of both models was assessed. Results: Among 100 patients, 78 patients (78%) developed grade ≥3 lymphopenia, with grade 4 lymphopenia in 17 (17%). For predicting grade ≥3 lymphopenia, the Christie and MDACC models yielded c-statistics of 0.77 and 0.79, respectively. For predicting grade 4 lymphopenia, c-statistics were 0.69 and 0.80, respectively. Calibration for the Christie and MDACC models demonstrated moderate and good agreement, respectively. Conclusion: The PTV-based MDACC prediction model for severe RIL demonstrated superior external performance in NSCLC patients compared to the dosimetry-based Christie model. As such, the MDACC model can aid in identifying patients at high risk for severe lymphopenia. However, to optimize radiotherapy planning, further improvement and external validation of dosimetry-based models is desired.

Voxel-based analysis: Roadmap for clinical translation.

Voxel-based analysis (VBA) allows the full, 3-dimensional, dose distribution to be considered in radiotherapy outcome analysis. This provides new insights into anatomical variability of pathophysiology and radiosensitivity by removing the need for a priori definition of organs assumed to drive the dose response associated with patient outcomes. This approach may offer powerful biological insights demonstrating the heterogeneity of the radiobiology across tissues and potential associations of the radiotherapy dose with further factors. As this methodological approach becomes established, consideration needs to be given to translating VBA results to clinical implementation for patient benefit. Here, we present a comprehensive roadmap for VBA clinical translation. Technical validation needs to demonstrate robustness to methodology, where clinical validation must show generalisability to external datasets and link to a plausible pathophysiological hypothesis. Finally, clinical utility requires demonstration of potential benefit for patients in order for successful translation to be feasible. For each step on the roadmap, key considerations are discussed and recommendations provided for best practice.

Dysphagia at 1 Year is Associated With Mean Dose to the Inferior Section of the Brain Stem.

PURPOSE: Dysphagia is a common toxicity after head and neck (HN) radiation therapy that negatively affects quality of life. We explored the relationship between radiation therapy dose to normal HN structures and dysphagia 1 year after treatment using image-based datamining (IBDM), a voxel-based analysis technique. METHODS AND MATERIALS: We used data from 104 patients with oropharyngeal cancer treated with definitive (chemo)radiation therapy. Swallow function was assessed pretreatment and 1 year posttreatment using 3 validated measures: MD Anderson Dysphagia Inventory (MDADI), performance status scale for normalcy of diet (PSS-HN), and water swallowing test (WST). For IBDM, we spatially normalized all patients' planning dose matrices to 3 reference anatomies. Regions where the dose was associated with dysphagia measures at 1 year were found by performing voxel-wise statistics and permutation testing. Clinical factors, treatment variables, and pretreatment measures were used in multivariable analysis to predict each dysphagia measure at 1 year. Clinical baseline models were found using backward stepwise selection. Improvement in model discrimination after adding the mean dose to the identified region was quantified using the Akaike information criterion. We also compared the prediction performance of the identified region with a well-established association: mean doses to the pharyngeal constrictor muscles. RESULTS: IBDM revealed highly significant associations between dose to distinct regions and the 3 outcomes. These regions overlapped around the inferior section of the brain stem. All clinical models were significantly improved by including mean dose to the overlap region (P ≤ .006). Including pharyngeal dosimetry significantly improved WST (P = .04) but not PSS-HN or MDADI (P ≥ .06). CONCLUSIONS: In this hypothesis-generating study, we found that mean dose to the inferior section of the brain stem is strongly associated with dysphagia 1 year posttreatment. The identified region includes the swallowing centers in the medulla oblongata, providing a possible mechanistic explanation. Further work including validation in an independent cohort is required.

Demystifying the Results of RTOG 0617: Identification of Dose Sensitive Cardiac Subregions Associated With Overall Survival.

INTRODUCTION: The RTOG 0617 trial presented a worse survival for patients with lung cancer treated in the high-dose (74 Gy) arm. In multivariable models, radiation level and whole-heart volumetric dose parameters were associated with survival. In this work, we consider heart subregions to explain the observed survival difference between radiation levels. METHODS: Voxel-based analysis identified anatomical regions where the dose was associated with survival. Bootstrapping clinical and dosimetric variables into an elastic net model selected variables associated with survival. Multivariable Cox regression survival models assessed the significance of dose to the heart subregion, compared with whole heart v5 and v30. Finally, the trial outcome was assessed after propensity score matching of patients on lung dose, heart subregion dose, and tumor volume. RESULTS: A total of 458 patients were eligible for voxel-based analysis. A region of significance (p < 0.001) was identified in the base of the heart. Bootstrapping selected mean lung dose, radiation level, log tumor volume, and heart region dose. The multivariable Cox model exhibited dose to the heart region (p = 0.02), and tumor volume (p = 0.03) were significantly associated with survival, and radiation level was not significant (p = 0.07). The models exhibited that whole heart v5 and v30 were not associated with survival, with radiation level being significant (p < 0.05). In the matched cohort, no significant survival difference was seen between radiation levels. CONCLUSIONS: Dose to the base of the heart is associated with overall survival, partly removing the radiation level effect, and explaining that worse survival in the high-dose arm is owing, in part, to the heart subregion dose. By defining a heart avoidance region, future dose escalation trials may be feasible.

Qualitative Study on Diversity, Equity, and Inclusion Within Radiation Oncology in Europe.

PURPOSE: Organizational culture plays a major role in prioritizing diversity, equity, and inclusion (DEI) objectives by aligning individual values of employees with organizational values. However, effective strategies to create an inclusive organizational culture, in which these values are aligned, remain unclear. The European Society for Radiotherapy and Oncology (ESTRO) launched a qualitative study, as a follow-up of the previous project on DEI that highlighted low levels of inclusion and work engagement among radiation oncology (RO) professionals in Europe. The aim of the present study was to gain an understanding of how DEI could be improved within RO departments by creating a more inclusive organizational culture. METHODS AND MATERIALS: A qualitative research study was conducted by enrolling RO professionals from 4 selected European countries through an open call on the ESTRO platform. Respondents who completed an online survey and met the inclusion criteria, such as experiencing low DEI levels at work, were invited for an online semistructured interview. Interview transcripts were analyzed thematically with an abductive approach via concepts in relation to "DEI," "work engagement," "organizational culture," and "professional values." RESULTS: Twenty-six eligible respondents from Great Britain, Italy, Poland, and Switzerland were interviewed. The thematic analysis identified cases in which limited engagement at work emerged when the personal values of RO professionals conflicted with dominant organizational values, hampering DEI. Three conflicts were found between the following personal versus organizational values: (1) self-development versus efficiency, (2) togetherness versus competition, and (3) people-oriented versus task-oriented cultures. CONCLUSIONS: Awareness of how organizational values can conflict with professionals' values should be raised to improve inclusion and engagement in the workplace. Additionally, efforts should be focused on tackling existing power imbalances that hamper effective deliberation on organizational- versus personal-value conflicts.

The late effects of cranial irradiation in childhood on the hypothalamic-pituitary axis: a radiotherapist's perspective.

Brain tumours make up nearly one-third of paediatric malignancies. Over time, advancements in oncological treatments like radiotherapy have helped reduce normal-tissue toxicity when treating cancers in the brain. However, clinicians are still facing a trade-off between treatment efficacy and potential side effects. The aim of this review is to address the late effects of cranial irradiation on the neuroendocrine system and to identify factors that make patients more vulnerable to radiation-induced endocrine sequelae. Radiation damage to the hypothalamic-pituitary axis, which orchestrates hormone release, can lead to endocrinopathy; up to 48.8% of children who have undergone cranial irradiation develop a hormone deficiency. This may lead to further health complications that can appear up to decades after the last treatment, lowering the patients' quality of life and increasing long-term costs as lifelong hormone replacement therapy may be required. Growth hormone deficiency is the most common sequelae, followed by either thyroid or gonadotropic hormone deficiency. Adrenocorticotropic hormone deficiency tends to be the least common. Identified factors that increase the risk of late endocrine deficiency include total radiation dose, age at treatment, and time since last treatment. However, as there are various other factors that may potentiate the damage, a universal solution proven to be most effective in sparing the endocrine tissues is yet to be identified. Until then, accounting for the identified risk factors during treatment planning may in some cases help reduce the development of endocrine sequelae in childhood cancer survivors.

Heart dose and cardiac comorbidities influence death with a cardiac cause following hypofractionated radiotherapy for lung cancer.

Background: There is increasing evidence of cardiac toxicity of thoracic radiotherapy however, it is difficult to draw conclusions on cardiac dose constraints due to the heterogeneity of published studies. Moreover, few studies record data on cause of death. The aim of this paper is to investigate the relationship between conventional cardiac dosimetric parameters and death with cardiac causes using data from the UK national cause of death registry. Methods: Data on cancer diagnosis, treatment and cause of death following radical lung cancer radiotherapy were obtained from Public Health England for all patients treated at the Christie NHS Foundation Trust between 1/1/10 and 31/12/16. Individuals with metastatic disease and those who received multiple courses of thoracic radiotherapy where excluded. All patients who received > 45Gy in 20 fractions were included. Cardiac cause of death was defined as the following ICD-10 codes on death certificate: I20-I25; I30-I32; I34-I37; I40-I52. Cardiac V5Gy, V30Gy, V50Gy and mean heart dose (MHD) were extracted. Cumulative incidence of death with cardiac causes were plotted for each cardiac dosimetric parameter. Multi-variable Fine and Gray competing risk analysis was used to model predictors for cardiac death with non-cardiac death as a competing risk. Results: Cardiac dosimetric parameters were available for 967 individuals, 110 died with a cardiac cause (11.4%). Patients with a cardiac comorbidity had an increased risk of death with a cardiac cause compared with those without a cardiac comorbidity (2-year cumulative incidence 21.3% v 6.2%, p<0.001). In patients with a pre-existing cardiac comorbidity, heart V30Gy ≥ 15% was associated with higher cumulative incidence of death with a cardiac cause compared to patients with heart V30Gy <15% (2-year rate 25.8% v 17.3%, p=0.05). In patients without a cardiac comorbidity, after adjusting for tumour and cardiac risk factors, MHD (aHR 1.07, 1.01-1.13, p=0.021), heart V5Gy (aHR 1.01, 1-1.13, p=0.05) and heart V30Gy (aHR 1.04, 1-1.07, p=0.039) were associated with cardiac death. Conclusion: The effect of cardiac radiation dose on cardiac-related death following thoracic radiotherapy is different in patients with and without cardiac comorbidities. Therefore patients' cardiovascular risk factors should be identified and managed alongside radiotherapy for lung cancer.

Role of Real-World Data in Assessing Cardiac Toxicity After Lung Cancer Radiotherapy.

Radiation-induced heart disease (RIHD) is a recent concern in patients with lung cancer after being treated with radiotherapy. Most of information we have in the field of cardiac toxicity comes from studies utilizing real-world data (RWD) as randomized controlled trials (RCTs) are generally not practical in this field. This article is a narrative review of the literature using RWD to study RIHD in patients with lung cancer following radiotherapy, summarizing heart dosimetric factors associated with outcome, strength, and limitations of the RWD studies, and how RWD can be used to assess a change to cardiac dose constraints.

Predictive value of vascular calcification identified in 4D planning CT of lung cancer patients treated with stereotactic body radiation therapy.

PURPOSE: The aim was to identify vascular calcification in 4DCT scan of lung cancer patients and establish the association between overall survival (OS) and vascular calcification, as surrogate for vascular health. METHODS: Vascular calcification within the thoracic cavity were segmented in 334 lung cancer patients treated with stereotactic body radiation therapy (SBRT). This has been done automatically on 4D planning CT and average reconstruction scans. Correlation between cardiac comorbidity and calcification volumes was evaluated for patients with recorded Adult Co-Morbidity Evaluation (n = 303). Associations between the identified calcifications and OS were further investigated. RESULTS: The volume of calcification from the average scan was significantly lower than from each phase (p < 0.001). The highest level of correlations between cardiac comorbidity and volume of the calcifications were found for one phase representing inhale and two phases representing exhale with the least motion blurring due to respiration (p < 0.005). The volume of the calcifications was subsequently averaged over these three phases. The average of calcification volumes over the three phases (denoted by inhale-exhale) showed the highest likelihood in univariate analysis and was chosen as vascular calcification measure. Cox-model suggested that tumor volume (Hazard Ratio [HR] = 1.46, p < 0.01) and inhale-exhale volume (HR = 1.05, p < 0.05) are independent factors predicting OS after adjusting for age, sex, and performance status. CONCLUSION: It was feasible to use. It 4DCT scan for identifying thoracic calcifications in lung cancer patients treated with SBRT. Calcification volumes from inhale-exhale phases had the highest correlation with overall cardiac comorbidity and the average of the calcification volume obtained from these phases was an independent predictive factor for OS.

Novel Methodology to Investigate the Effect of Radiation Dose to Heart Substructures on Overall Survival.

PURPOSE: For patients with lung cancer treated with radiation therapy, a dose to the heart is associated with excess mortality; however, it is often not feasible to spare the whole heart. Our aim is to define cardiac substructures and dose thresholds that optimally reduce early mortality. METHODS AND MATERIALS: Fourteen cardiac substructures were delineated on 5 template patients with representative anatomies. One thousand one hundred sixty-one patients with non-small cell lung cancer were registered nonrigidly to these 5 template anatomies, and their radiation therapy doses were mapped. Mean and maximum dose to each substructure were extracted, and the means were evaluated as input to prediction models. The cohort was bootstrapped into 2 variable reduction techniques: elastic net least absolute shrinkage and selection operator and the random survival forest model. Each method was optimized to extract variables contributing most to overall survival, and model coefficients were evaluated to select these substructures. The most important variables common to both models were selected and evaluated in multivariable Cox-proportional hazard models. A threshold dose was defined, and Kaplan-Meier survival curves plotted. RESULTS: Nine hundred seventy-eight patients remained after visual quality assurance of the registration. Ranking the model coefficients across the bootstraps selected the maximum dose to the right atrium, right coronary artery, and ascending aorta as the most important factors associated with survival. The maximum dose to the combined cardiac region showed significance in the multivariable model, a hazard ratio of 1.01/Gy, and P = .03 after accounting for tumor volume (P < .001), N stage (P < .01), and performance status (P = .01). The optimal threshold for the maximum dose, equivalent dose in 2-Gy fractions, was 23 Gy. Kaplan-Meier survival curves showed a significant split (log-rank P = .008). CONCLUSIONS: The maximum dose to the combined cardiac region encompassing the right atrium, right coronary artery, and ascending aorta was found to have the greatest effect on patient survival. A maximum equivalent dose in 2-Gy fractions of 23 Gy was identified for consideration as a dose limit in future studies.

Radiotherapy-Related Lymphopenia Affects Overall Survival in Patients With Lung Cancer.

INTRODUCTION: Lymphopenia after radiotherapy has an adverse effect on the patient's outcome. However, the relationship between radiotherapy dose delivery and lymphopenia is not fully understood. This work used image-based data mining to identify anatomical regions where the received dose is correlated with severe lymphopenia. METHODS: A total of 901 patients with lung cancer were analyzed. A Cox model was used to assess prognostic factors of overall survival (OS). Two matched groups were defined-patients with lymphopenia of grade 3 or higher and patients without lymphopenia of grade 3-based on tumor volume, baseline lymphocytes, and prescribed dose. Then, data mining was used to identify regions where dose correlates significantly with lymphopenia of grade 3 or higher. For this, dose matrices were aligned using registration of the computed tomography images to one reference patient. Mean dose distributions were obtained for the two groups, and organs of significance were detected. Dosimetric parameters from the identified organs that had the highest correlation with lymphocytes at nadir were selected. Multivariable analysis was conducted for lymphopenia of grade 3 or higher on the full lung cohort, and the model was tested on 305 patients with esophageal cancer. RESULTS: Adjusted Cox regression revealed that lymphopenia of grade 3 or higher is an independent factor of OS. The anatomical regions identified were the heart, lung, and thoracic vertebrae. Dosimetric parameters for lymphopenia included thoracic vertebrae V20, mean lung dose, and mean heart dose, which were further validated in the esophageal cancer cohort. CONCLUSIONS: We report that severe lymphopenia during radiotherapy is a poor prognostic factor for OS in patients with lung cancer and could be mitigated by minimizing thoracic vertebrae V20, mean lung dose, and mean heart dose to limit the irradiation of stem cells and blood pool.

Radiotherapy-related lymphopenia in patients with advanced non-small cell lung cancer receiving palliative radiotherapy.

BACKGROUND: Lymphopenia during radiotherapy (RT) may have an adverse effect on treatment outcome. The aim of this study is to investigate associations between lymphopenia and RT parameters in patients with advanced lung cancer. Moreover, to investigate the prognostic role of lymphopenia, blood protein levels, and treatment and patient-related factors. MATERIAL AND METHODS: Sixty-two advanced stage non-small cell lung cancer (NSCLC) patients were retrospectively analyzed. Blood counts were available prior to, during, and after RT (3Gyx10). For each patient, a thoracic volume of interest (VOI) -including thoracic soft tissue and trabecular bone- was obtained by applying a CT window of -500 to 1200 HU in the planning CT. Dose parameters from thoracic VOI and other regions including lungs and vertebrae were calculated. Association between risk of lymphopenia ≥ G3 (lymphocytes at nadir according to CTCAE v4.0) and therapeutic parameters was investigated using Logistic regression. Relationships between overall survival (OS) and RT dose parameters, baseline blood counts and protein levels, and clinical factors were evaluated using Log-rank and Cox models. RESULT: Mean thoracic RT dose (odds ratio [OR] 1.67; p = 0.04), baseline lymphocytes (OR 0.65; p = 0.01), and corticosteroids use (OR 6.07; p = 0.02) were significantly associated with increased risk of lymphopenia ≥ G3 in multivariable analysis. Worse OS was associated with high mean thoracic RT dose, high CRP/Albumin, large tumor volume and corticosteroids use (p < 0.05, univariate analysis), but not with lymphopenia ≥ G3. CRP/Albumin ratio > 0.12 (hazard ratio [HR] 2.28, p = 0.03) and corticosteroid use (HR 2.52, p = 0.01) were independently associated with worse OS. CONCLUSION: High thoracic RT dose gave a higher risk of lymphopenia ≥ G3; hence limiting dose volume to the thorax may be valuable in preventing severe lymphopenia for patients receiving palliative fractionated RT. Still, lymphopenia ≥ G3 was not associated with worse OS. however, high baseline CRP/Albumin was associated with poorer OS and may carry important information as a prognostic factor of OS in advanced NSCLC receiving palliative RT.

Dose surface maps of the heart can identify regions associated with worse survival for lung cancer patients treated with radiotherapy.

BACKGROUND AND PURPOSE: For lung cancer patients treated with radiotherapy, radiation dose to the heart has been associated with overall survival, with volumetric dose statistics widely presented. However, critical cardiac structures are present on the hearts surface, where this approach may be sub-optimal. In this work we present a methodology for creating cardiac surface dose maps and identify regions where excess dose is associated with in worse overall survival. MATERIAL AND METHODS: A modified cylindrical coordinate system was implemented to map the cardiac surface dose for lung cancer patients. Validation was performed by mapping the cardiac chambers for 55 patients, fitting a point spread function (PSF) to the blurred edge. To account for this uncertainty, dose maps were blurred by a 2D-Gaussian with width described by the PSF. Permutation testing identified regions where excess dose was associated with worse patient survival. The 99th percentile of the max t-value then defined a cardiac surface region to extract dose, from each patient, to be analysed in a multivariable cox-proportional hazards survival model. RESULTS: Cardiac surface maps were created for 648 lung cancer patients. Cardiac surface dose maps were blurred with a 2D- Gaussian filter of size σφ = 4.3° and σy = 1.3units to account for mapping uncertainties. Permutation testing identified significant differences across the surface of the right atria, p < 0.001, at all timepoints. The median dose to the region defined by the 99th percentile of the maximum t-value was 18.5 Gy. Multivariable analysis showed the dose to this region was significantly associated with survival, hazard ratio 1.01 Gy-1, p = 0.03, controlling for confounding variables. CONCLUSIONS: Cardiac surface mapping was successfully implemented and identified a region where excess dose was associated with worse patient survival. This region extended over the right atria, potentially suggesting an interaction with the hearts electrical conduction system.

Mapping Bone Marrow Response in the Vertebral Column by Positron Emission Tomography Following Radiotherapy and Erlotinib Therapy of Lung Cancer.

PURPOSE: To map functional bone marrow (BM) by 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET) in the vertebral column of lung cancer patients prior to, during, and after treatment. Moreover, to identify radiation- and erlotinib-induced changes in the BM. PROCEDURES: Twenty-six patients with advanced non-small cell lung cancer, receiving radiotherapy (RT) alone or concomitantly with erlotinib, were examined by [18F]FDG PET before, during, and after treatment. A total of 61 [18F]FDG PET scans were analyzed. Vertebral column BM [18F]FDG standardized uptake value normalized to the liver (SUVBMLR) was used as uptake measure. Wilcoxon signed-rank test was used to assess changes in BM uptake of [18F]FDG between sessions. Effects of erlotinib on the BM activity during and after treatment were assessed using Mann-Whitney U test. RESULTS: A homogeneous uptake of [18F]FDG was observed within the vertebral column prior to treatment. Mean SUVBMLR (± S.E.M) in the body of thoracic vertebrae receiving a total RT dose of 10 Gy or higher was 0.64 ± 0.01, 0.56 ± 0.01, and 0.59 ± 0.01 at pre-, mid-, and post-therapy, respectively. A significant reduction in the mean SUVBMLR was observed from pre- to both mid- and post-therapy (p < 0.05). Mean SUVBMLR was significantly higher at post-therapy compared to mid-therapy for patients receiving erlotinib in addition to RT (p < 0.05). CONCLUSIONS: RT reduces BM [18F]FDG uptake in the vertebral column, especially in the high-dose region. Concomitant erlotinib may stimulate a recovery in BM [18F]FDG uptake from mid- to post-therapy. TRIAL REGISTRATION: NCT02714530. Registered 10 September 2015.

Serum cytokine profiles and metabolic tumor burden in patients with non-small cell lung cancer undergoing palliative thoracic radiation therapy.

PURPOSE: Radiation therapy effectively kills cancer cells and elicits local effects in the irradiated tissue. The aim of this study was to investigate the kinetics of cytokines in the serum of patients with lung cancer undergoing radiation therapy and to identify associations with metabolic tumor burden as determined by 2-deoxy-2-fluoro-D-glucose (18F-FDG) positron emission tomography (PET). METHODS AND MATERIALS: Forty-five patients with advanced non-small cell lung cancer were included in a phase 2 clinical trial and randomized between fractionated thoracic radiation therapy alone or concurrent with an epidermal growth factor receptor inhibitor. Blood was sampled at 4 different time points: prior to treatment, midtherapy, at the end of therapy, and 6 to 8 weeks after the start of treatment. The serum concentrations of 48 cytokines and 9 matrix metalloproteinases were measured with multiplex immunoassays. A subset of patients was examined by 18F-FDG PET/computed tomography before, during, and after radiation therapy. The maximum standardized uptake values (SUVmax) of the primary lung tumor, whole-body metabolic tumor volume, and total lesion glycolysis were calculated, and correlations between the PET parameters and cytokines were investigated. RESULTS: The SUVmax decreased from baseline through midtherapy to posttherapy 18F-FDG PET/computed tomography (P = .018). The serum levels of C-C motif chemokine ligand (CCL) 23, CCL24, C-X3-C motif chemokine ligand 1, and interleukin-8 (C-X-C motif ligand [CXCL]8) were significantly correlated to SUVmax, metabolic tumor volume, and total lesion glycolysis before, during, and after radiation therapy. CXCL2 (P = .030) and CXCL6 (P = .010) decreased after the start of therapy and changed significantly across the sample time points. Serum concentrations of CCL15 (P = .031), CXCL2 (P = .028), and interleukin-6 (P = .007) were positively correlated to the irradiated volume during the second week of treatment. CONCLUSIONS: Cytokine serum levels vary and correlate with metabolic tumor burden in patients with advanced non-small cell lung cancer undergoing palliative thoracic radiation therapy.

A new method to assess pulmonary changes using 18F-fluoro-2-deoxyglucose positron emission tomography for lung cancer patients following radiotherapy.

BACKGROUND: 18F-fluoro-2-deoxyglucose positron emission tomography (18F-FDG-PET) may be used for assessing radiation induced alterations in the lung. However, there is a need to further develop methodologies to improve quantification. Using computed tomography (CT), a local structure method has been shown to be superior to conventional CT-based analysis. Here, we investigate whether the local structure method based on 18F-FDG-PET improves radiotherapy (RT) dose-response quantification for lung cancer patients. MATERIAL AND METHODS: Sixteen patients with lung cancer undergoing fractionated RT were examined by 18F-FDG-PET/CT at three sessions (pre, mid, post) and the lung was delineated in the planning CT images. The RT dose matrix was co-registered with the PET images. For each PET image series, mean (µ) and standard deviation (σ) maps were calculated based on cubes in the lung (3 × 3 × 3 voxels), where the spread in pre-therapy µ and σ was characterized by a covariance ellipse in a sub-volume of 3 × 3 × 3 cubes. Mahalanobis distance was used to measure the distance of individual cube values to the origin of the ellipse and to further form local structure 'S' maps. The structural difference maps (ΔS) and mean difference maps (Δµ) were calculated by subtracting pre-therapy maps from maps at mid- and post-therapy. Corresponding maps based on CT images were also generated. RESULTS: ΔS identified new areas of interest in the lung compared to conventional Δµ maps. ΔS for PET and CT gave a significantly elevated lung signal compared to a control group during and post-RT (p < .05). Dose-response analyses by linear regression showed that ΔS between pre- and post-therapy for 18F-FDG-PET was the only parameter significantly associated with local lung dose (p = .04). CONCLUSIONS: The new method using local structures on 18F-FDG-PET provides a clearer uptake dose-response compared to conventional analysis and CT-based approaches and may be valuable in future studies addressing lung toxicity.

Assessment of pulmonary 18F-FDG-PET uptake and cytokine profiles in non-small cell lung cancer patients treated with radiotherapy and erlotinib.

PURPOSE: To investigate effects of radiotherapy (RT) and erlotinib on pulmonary glucose uptake using 2-deoxy-2-(18F)fluoro-D-glucose (18F-FDG) positron emission tomography (PET) during and after treatment of non-small cell lung cancer (NSCLC) and to identify associations between serum cytokine levels and lung glucose uptake. MATERIAL AND METHODS: Twenty-seven patients with advanced NSCLC, receiving RT alone or concomitant RT and erlotinib therapy, were examined by 18F-FDG PET before, during, and after treatment. A total of 57 18F-FDG PET scans were analyzed. Pulmonary 18F-FDG uptake and radiotherapy dose mapping were used to acquire dose-response curves for each patient, where subsequent linear regression gave a glucose uptake level in the un-irradiated parts of the lungs (SUV0) and a response slope (ΔSUV). Serum cytokine levels at corresponding time points were assessed using a multiplex bioassay. Correlations between the most robust cytokines and lung 18F-FDG dose response parameters were further investigated. RESULTS: From the dose response analysis, SUV0 at post-therapy was significantly higher (P < 0.001) than at mid- and pre-therapy (45% and 58%, respectively) for the group receiving RT + erlotinib. Also, SUV0 at post-therapy was higher for patients receiving RT + erlotinib compared to RT alone (42%; P < 0.001). No differences in ΔSUV were seen with treatments or time. SUV0 was positively associated (r = 0.47, P = 0.01) with serum levels of the chemokine C-C motif ligand 21 (CCL21) for patients receiving RT + erlotinib. CONCLUSIONS: Concomitant RT and erlotinib causes an elevation in pulmonary 18F-FDG uptake post treatment compared to RT alone. Pulmonary glucose uptake is associated with an upregulation of a chemokine (CCL21) involved in inflammatory reactions.