Heart and Lung Dose as Predictors of Overall Survival in Patients With Locally Advanced Lung Cancer. A National Multicenter Study.

Introduction: It is an ongoing debate how much lung and heart irradiation impact overall survival (OS) after definitive radiotherapy for lung cancer. This study uses a large national cohort of patients with locally advanced NSCLC to investigate the association between OS and irradiation of lung and heart. Methods: Treatment plans were acquired from six Danish radiotherapy centers, and patient characteristics were obtained from national registries. A hybrid segmentation tool automatically delineated the heart and substructures. Dose-volume histograms for all structures were extracted and analyzed using principal component analyses (PCAs). Parameter selection for a multivariable Cox model for OS prediction was performed using cross-validation based on bootstrapping. Results: The population consisted of 644 patients with a median survival of 26 months (95% confidence interval [CI]: 24-29). The cross-validation selected two PCA variables to be included in the multivariable model. PCA1 represented irradiation of the heart and affected OS negatively (hazard ratio, 1.14; 95% CI: 1.04-1.26). PCA2 characterized the left-right balance (right atrium and left ventricle) irradiation, showing better survival for tumors near the right side (hazard ratio, 0.92; 95% CI: 0.84-1.00). Besides the two PCA variables, the multivariable model included age, sex, body-mass index, performance status, tumor dose, and tumor volume. Conclusions: Besides the classic noncardiac risk factors, lung and heart doses had a negative impact on survival, while it is suggested that the left side of the heart is a more radiation dose-sensitive region. The data indicate that overall heart irradiation should be reduced to improve the OS if possible.

Radiation therapy in older patients with cancer.

The general population is aging, which expectedly will lead to a future increase in older patients with cancer. This review summarises the recent advances in radiotherapy. Technological advances have led radiotherapy to be an efficient and well-tolerated treatment option in older patient with cancer. Studies show no difference in toxicity and disease control rates compared with the ones in younger patients with cancer. MR-guided radiotherapy, proton therapy, and integration of artificial intelligence in treatment planning represent the latest advances in the field of radiotherapy and hold potential to further improve the treatment of older patients with cancer.

An open source auto-segmentation algorithm for delineating heart and substructures - Development and validation within a multicenter lung cancer cohort.

BACKGROUND AND PURPOSE: Irradiation of the heart in thoracic cancers raises toxicity concerns. For accurate dose estimation, automated heart and substructure segmentation is potentially useful. In this study, a hybrid automatic segmentation is developed. The accuracy of delineation and dose predictions were evaluated, testing the method's potential within heart toxicity studies. MATERIALS AND METHODS: The hybrid segmentation method delineated the heart, four chambers, three large vessels, and the coronary arteries. The method consisted of a nnU-net heart segmentation and partly atlas- and model-based segmentation of the substructures. The nnU-net training and atlas segmentation was based on lung cancer patients and was validated against a national consensus dataset of 12 patients with breast cancer. The accuracy of dose predictions between manual and auto-segmented heart and substructures was evaluated by transferring the dose distribution of 240 previously treated lung cancer patients to the consensus data set. RESULTS: The hybrid auto-segmentation method performed well with a heart dice similarity coefficient (DSC) of 0.95, with no statistically significant difference between the automatic and manual delineations. The DSC for the chambers varied from 0.78-0.86 for the automatic segmentation and was comparable with the inter-observer variability. Most importantly, the automatic segmentation was as precise as the clinical experts in predicting the dose distribution to the heart and all substructures. CONCLUSION: The hybrid segmentation method performed well in delineating the heart and substructures. The prediction of dose by the automatic segmentation was aligned with the manual delineations, enabling measurement of heart and substructure dose in large cohorts. The delineation algorithm will be available for download.

Impact of Stereotactic Body Radiotherapy on Thrombin Generation and Platelet Aggregation in Patients with Non-Small Cell Lung Cancer.

Patients with localized non-small cell lung cancer (NSCLC) considered unfit for surgery are at substantially increased risk of venous thromboembolism. Radiotherapy may further increase this risk. We aim to investigate the impact of stereotactic body radiotherapy (SBRT) on thrombin generation and platelet aggregation. We included 110 patients with localized NSCLC treated with SBRT. Blood samples were obtained prior to SBRT, immediately after SBRT completion, and 4-6 weeks following SBRT. Ex vivo and in vivo thrombin generations were analyzed using a calibrated automated thrombogram and commercial enzyme-linked immunosorbent assays. Platelet aggregation was evaluated using multiple electrode aggregometry. No significant differences were found in ex vivo or in vivo thrombin generation between blood samples before and immediately after SBRT treatment. Platelet aggregation was lower immediately after SBRT than before SBRT (TRAP: P = 0.04 and ASPI: P = 0.02) but remained within the reference interval. SBRT did not affect in vivo and ex vivo thrombin generation or platelet aggregation. SBRT did not cause prothrombotic changes in the coagulation in this study population of SBRT-treated patients with localized NSCLC.

Expanded HILUS Trial: A Pooled Analysis of Risk Factors for Toxicity From Stereotactic Body Radiation Therapy of Central and Ultracentral Lung Tumors.

PURPOSE: Stereotactic body radiation therapy for tumors near the central airways implies high-grade toxic effects, as concluded from the HILUS trial. However, the small sample size and relatively few events limited the statistical power of the study. We therefore pooled data from the prospective HILUS trial with retrospective data from patients in the Nordic countries treated outside the prospective study to evaluate toxicity and risk factors for high-grade toxic effects. METHODS AND MATERIALS: All patients were treated with 56 Gy in 8 fractions. Tumors within 2 cm of the trachea, the mainstem bronchi, the intermediate bronchus, or the lobar bronchi were included. The primary endpoint was toxicity, and the secondary endpoints were local control and overall survival. Clinical and dosimetric risk factors were analyzed for treatment-related fatal toxicity in univariable and multivariable Cox regression analyses. RESULTS: Of 230 patients evaluated, grade 5 toxicity developed in 30 patients (13%), of whom 20 patients had fatal bronchopulmonary bleeding. The multivariable analysis revealed tumor compression of the tracheobronchial tree and maximum dose to the mainstem or intermediate bronchus as significant risk factors for grade 5 bleeding and grade 5 toxicity. The 3-year local control and overall survival rates were 84% (95% CI, 80%-90%) and 40% (95% CI, 34%-47%), respectively. CONCLUSIONS: Tumor compression of the tracheobronchial tree and high maximum dose to the mainstem or intermediate bronchus increase the risk of fatal toxicity after stereotactic body radiation therapy in 8 fractions for central lung tumors. Similar dose constraints should be applied to the intermediate bronchus as to the mainstem bronchi.

Increased In Vivo Thrombin Generation in Patients with Localized Non-Small Cell Lung Cancer Unfit for Surgery.

Patients with lung cancer face a substantially increased risk of thromboembolic disease. Patients with localized non-small cell lung cancer (NSCLC) who are unfit for surgery due to age or comorbidity have additional thrombotic risk factors. Thus, we aimed to investigate markers of primary and secondary hemostasis, since this could assist in treatment decisions. We included 105 patients with localized NSCLC. Ex vivo thrombin generation was determined by calibrated automated thrombogram and in vivo thrombin generation was determined by measurement of thrombin-antithrombin complex (TAT) levels and prothrombin fragment F1 + 2 concentrations (F1 + 2). Platelet aggregation was investigated by impedance aggregometry. Healthy controls were used for comparison. TAT and F1 + 2 concentrations were significantly higher in NSCLC patients than in healthy controls (P < .001). The levels of ex vivo thrombin generation and platelet aggregation were not increased in the NSCLC patients. Patients with localized NSCLC considered unfit for surgery had significantly increased in vivo thrombin generation. This finding should be further investigated as it could be relevant for the choice of thromboprophylaxis in these patients.

Outcomes of prophylactic cranial irradiation in patients with small cell lung cancer in the modern era of baseline magnetic resonance imaging of the brain.

BACKGROUND: For decades many patients with small cell lung cancer (SCLC) have been offered prophylactic cranial irradiation (PCI) to prevent brain metastases (BM). However, the role of PCI is debated in the modern era of increased brain magnetic resonance imaging (MRI) availability. BM in SCLC patients may respond to chemotherapy, and if a negative MRI is used in the decision to use of PCI in the treatment strategy, the timing of brain MRI may be crucial when evaluating the effect of PCI. This retrospective study investigates the impact of PCI outcomes in patients with SCLC staged with brain MRI prior to chemotherapy. MATERIALS AND METHODS: This study included 245 patients diagnosed SCLC/mixed NSCLC-SCLC treated between 2012 and 2019. The population was analyzed separately for limited disease (LS-SCLC) and extensive disease (ES-SCLC). Patients were divided into groups based on baseline brain MRI prior to chemotherapy and PCI. The primary endpoint was time to symptomatic BM. Secondary endpoints were overall survival (OS), and progression-free survival (PFS). RESULTS: In patients with LS-SCLC staged with brain MRI the probability of developing symptomatic BM at one year was 4% vs. 22% (p < 0.05), median OS was 55 vs. 24 months (p < 0.05), and median PFS was 30 vs. 10 months (p < 0.05) with and without PCI, respectively. No differences in probability of symptomatic BM and survival outcomes were observed in ES-SCLC. In a multivariate regression analysis, no variables were statistically significant associated with the risk of developing symptomatic BM in patients with LS-SCLC and ES-SCLC. For patients with ES-SCLC staged with brain MRI, PS (HR = 3.33, CI; 1.41-7.89, p < 0.05) was associated with poor survival. CONCLUSION: This study found that PCI in LS-SCLC patients staged with brain MRI had lower incidence of symptomatic BM and improved survival outcomes suggesting PCI as standard of care. Similar benefit of PCI in patients with ES-SCLC was not found.

International efforts in geriatric radiation oncology.

INTRODUCTION: Geriatric assessment (GA) has been recommended to form part of treatment decision making for older adults with cancer. However despite consensus guidelines from various organizations, GA does not appear to be a part of routine practice in radiation oncology. The aim of the current study was to explore the implementation of GA in radiation oncology. MATERIALS AND METHODS: This anonymous international survey investigated current use of GA in patients presenting for radiation therapy aged 65 years and over, in accordance with Checklist for Reporting Results of Internet E-Surveys (CHERRIES) guidelines. The survey was designed, using Qualitrics™, an online survey tool. It was distributed via SIOG, social media and radiation oncology professional organizations. Survey responses were analyzed using simple descriptive statistics. An additional analysis by creating a dichotomous variable based on awareness of major clinical practice guidelines and current use of GA. RESULTS: Among 158 respondents, there was relatively low awareness of GA guidelines and low uptake of validated tools and processes. A minority of participants, only 16%, stated that they had a specialized geriatric oncology program in their institution. Approximately a third (34%) of respondents were unaware of any GA clinical practice guidelines. With regard to what way participants assess older patients differently to younger patients, 16% reported formally using specific validated tools, whereas 73% reported an informal assessment based on their own judgment, with 5% reporting no difference between younger and older patients. Regarding the use of validated screening tools for geriatric impairments, over half reported using none (57%). Regarding GA implementation, the main barriers highlighted included a lack of clinical/support staff, a lack of training, knowledge, understanding or experience about GA and a lack of time. DISCUSSION: Relatively low awareness of guidelines and low uptake of formal GA tools and processes were found. The integration of GA principles into radiation oncology appears to be ad hoc and very much in its infancy. There is a clear need for increased interdisciplinary education and collaboration between the disciplines of radiation oncology and geriatric medicine.

Tumour motion analysis from planning to end of treatment course for a large cohort of peripheral lung SBRT targets.

BACKGROUND: The aim is to quantify and analyse tumour motion during a course of treatment for lung SBRT patients. MATERIAL AND METHODS: Peak-to-peak motion of 483 tumours in 441 patients treated with peripheral lung SBRT at a single institution over a two year period was measured on planning CT and at all treatment fractions. Planning 4D-CT scans were analysed using our clinical workflow involving deformable propagation of the delineated target to all phases. Similarly, acquisition of the 4D-CBCT data followed the clinical workflow based on XVI 5.0 available on Elekta linacs. Differences and correlations of the peak-to-peak motion on the planning CT and at treatment were analysed. RESULTS: On the planning CT, a total of 81.4% of the tumours had a peak-to-peak motion <10 mm, and 96.1% had <20 mm. The largest motion was observed in the CC direction, with largest amplitude for tumours located in the caudal posterior part of the lung. The difference in amplitude in CC between planning CT and first fraction had a mean and standard deviation of 0.3 mm and 3.5 mm, respectively, and the largest differences were observed in the caudal posterior part of the lung. Patients with a difference in tumour motion amplitude exceeding two standard deviations (>7 mm) at the first fraction were evaluated individually, and they all had poor 4DCT image quality. The difference between the first and second/third fractions had a mean and standard deviation of 0.4 mm/0.5 mm and 2.0 mm/1.9 mm. CONCLUSION: Tumour motion at first treatment was similar to motion at planning, and motion at subsequent treatments was very similar to motion at first treatment. Large tumour motions are located towards the caudal posterior tumour locations. Patients with poor 4D-CT image quality should be closely followed at the first treatment to verify the motion.

Combination of the G-8 Screening Tool and Hand-Grip Strength to Predict Long-Term Overall Survival in Non-Small Cell Lung Cancer Patients Undergoing Stereotactic Body Radiotherapy.

The Geriatric 8 (G-8) is a known predictor of overall survival (OS) in older cancer patients, but is mainly based on nutritional aspects. This study aimed to assess if the G-8 combined with a hand-grip strength test (HGST) in patients with NSCLC treated with stereotactic body radiotherapy can predict long-term OS better than the G-8 alone. A total of 46 SBRT-treated patients with NSCLC of stage T1-T2N0M0 were included. Patients were divided into three groups: fit (normal G-8 and HGST), vulnerable (abnormal G-8 or HGST), or frail (abnormal G-8 and HGST). Statistically significant differences were found in 4-year OS between the fit, vulnerable, and frail groups (70% vs. 46% vs. 25%, p = 0.04), as well as between the normal and abnormal G-8 groups (69% vs. 39%, p = 0.02). In a multivariable analysis of OS, being vulnerable with a hazard ratio (HR) of 2.03 or frail with an HR of 3.80 indicated poorer OS, but this did not reach statistical significance. This study suggests that there might be a benefit of adding a physical test to the G-8 for more precisely predicting overall survival in SBRT-treated patients with localized NSCLC. However, this should be confirmed in a larger study population.

The HILUS-Trial-a Prospective Nordic Multicenter Phase 2 Study of Ultracentral Lung Tumors Treated With Stereotactic Body Radiotherapy.

INTRODUCTION: Stereotactic body radiation therapy of thoracic tumors close to the central airways implies risk of severe toxicity. We report a prospective multicenter phase 2 trial for tumors located less than or equal to 1 cm from the proximal bronchial tree with primary end point of local control and secondary end point of toxicity. METHODS: Stereotactic body radiation therapy with 7 Gy × 8 was prescribed to the 67% isodose encompassing the planning target volume. The patients were stratified to group A (tumors ≤ 1 cm from the main bronchi and trachea) or group B (all other tumors). Risk factors for treatment-related death were tested in univariate analysis, and a logistic regression model was developed for fatal bronchopulmonary bleeding versus dose to the main bronchi and trachea. RESULTS: A total of 65 patients (group A/group B, n = 39/26) were evaluated. The median distance between the tumor and the proximal bronchial tree was 0 mm (0-10 mm). The 2-year local control was 83%. Grade 3 to 5 toxicity was noted in 22 patients, including 10 cases of treatment-related death (bronchopulmonary hemorrhage, n = 8; pneumonitis, n = 1; fistula, n = 1). Dose to the combined structure main bronchi and trachea and tumor distance to the main bronchi were important risk factors. Dose modeling revealed minimum dose to the "hottest" 0.2 cc to the structure main bronchi and trachea as the strongest predictor for lethal bronchopulmonary hemorrhage. CONCLUSIONS: On the basis of the presented data, 7 Gy × 8, prescribed to the planning target volume-encompassing isodose, should not be used for tumors located within 1 cm from the main bronchi and trachea. Group B-type tumors may be considered for the treatment on the basis of an individual risk-benefit assessment and a maximum dose to the main bronchi and trachea in the order of 70 to 80 Gy (equivalent dose in 2 Gy fractions).

Health-related quality of life of patients with haematologic cancer during COVID-19 and their opinions on telehealth consultations - a Danish single site cross-sectional survey.

INTRODUCTION: During the COVID-19 pandemic, high-risk patient groups might have practiced social distancing and sheltering, and hospitals may have changed or postponed treatments and examinations. We aimed to explore health-related quality of life (QoL) in patients with haematological diseases during the early phase of the pandemic and their acceptability of using telehealth. PATIENTS AND METHODS: We performed a cross-sectional survey among patients at the Department of Haematology, Odense University Hospital, Denmark. Eligible participants were patients receiving either active treatment or survivors in a follow-up program. The survey was open from 22 May to 13 June 2020. The survey contained questions on concerns and the impact of COVID-19 and acceptability on telehealth in addition to the assessment of health-related QoL. The later was assessed by the European Organisation for Research and Treatment of Cancer core QoL (EORTC QLQ-C30) questionnaire with the subdomains Global QoL, emotional functioning (EF) and social functioning (SF) being of primary interest. Further, anxiety during COVID-19 was assessed by use of an adapted version of the generalised anxiety disorder (GAD-7) questionnaire. RESULTS: 4420 patients were eligible to participate. The response rate was 53% (n = 2239) of which 37% where in a treatment program and 63% where in a follow-up program. The majority (80%) of patients were concerned about contracting COVID-19. The global QoL score (69.0, ±SD 22.6) was markedly lower than EF (84.5, ±SD 18.9) and SF (85.0, ±SD 23.4). Regression analysis showed that being concerned (a little, moderately, very, extremely) about contracting COVID-19 correlated with lower scores of global QoL (-3.86 to -22.76), EF (-3.81 to -26.41) and SF (-1.14 to -22.49). The GAD-7 score showed that approximately 20% of patients had symptoms of COVID-19 associated generalised anxiety. Finally, 67% of the patients were positive towards replacing face-to-face consultancies with phone calls, but video consultations were less preferred (47%). CONCLUSION: Danish patients with haematological cancer presented with low global QoL during the early phase of COVID-19, and 20% of the patients showed symptoms of generalised anxiety. Patients were overall positive towards the implementation of telehealth consultancies.

Patients and family caregivers report high treatment expectations during palliative chemotherapy: a longitudinal prospective study.

BACKGROUND: When discussing treatment options and future care, it is important to understand the expectations of patients and family caregivers related to palliative chemotherapy and to identify patterns in patients' quality of life. The study aims were to evaluate differences in treatment expectations and quality of life between patients with thoracic cancer (non-small-cell lung cancer, small-cell lung cancer and mesothelioma) who were < 70 and ≥ 70 years of age and receiving palliative chemotherapy and to assess family caregivers' treatment expectations. METHODS: A prospective longitudinal study included patients with thoracic cancer receiving outpatient palliative chemotherapy at a university hospital in Denmark and their family caregivers. Patients' treatment expectations and quality of life were assessed three times during treatment with a survey of treatment expectations and the Functional Assessment of Cancer Therapy - General questionnaire. Family caregivers' treatment expectations were assessed once. RESULTS: A total of 48 patients and 36 family caregivers participated between 2018 and 2019. No statistically significant age-related differences in treatment expectations and quality of life were identified. 28% of patients aged < 70 years and 7% of those aged ≥70 years expected a cure. Among family caregivers, 36% expected a cure. Across both age groups, mean total quality of life scores significantly decreased from 73.2 at first palliative chemotherapy cycle to 70.5 at third cycle (p = 0.02). No meaningful changes were found in quality of life within either age group. A subgroup analysis found no significant between-group differences in quality of life. Mean physical well-being score for all patients decreased from 20.3 at first cycle to 18.4 at third cycle (p = 0.03) and mean emotional well-being score decreased from 15.4 at first cycle to 14.6 at third cycle (p = 0.04). CONCLUSION: This study emphasizes the importance of initiating conversations about treatment expectations and paying attention to expectations that may differ by the age of the patient and between patients and family caregivers. Addressing treatment expectations among patients and family caregivers and monitoring quality of life among patients is important in clinical practice.

The impact of comprehensive geriatric assessment for optimal treatment of older patients with cancer: A randomized parallel-group clinical trial.

OBJECTIVES: The aim was to investigate if oncologic treatment decision based on G8 screening followed by comprehensive geriatric assessment (CGA) and a multidisciplinary team conference in patients with G8 ≤ 14 was better than treatment decision based on standard assessment. ClinicalTrials.gov Identifier: NCT02671994. MATERIALS AND METHODS: From January 2016 to June 2018, 96 patients with cancer, aged ≥70 years, were included. Patients were randomized to treatment decision based on the oncologist's clinical judgement (control) or based on screening with G8. If G8 > 14 treatment decision was made as in the control group and if G8 ≤ 14, patients were referred to CGA including intervention as needed and treatment decision after a multidisciplinary team conference (MDT). RESULTS: The study was closed early. 47 patients were randomized to the control group and 49 to the intervention group; 28 had a G8 ≤ 14, 24 of whom attended CGA. In the intervention group 48% completed treatment as planned compared to 54% in the control group (p = .208). Thirty-eight percent experienced grade 3-4 toxicity in the control group compared with only 20% in the intervention group (p = .055). Median overall survival (OS) was 14.2 months in the control group and 19.1 months in the intervention group (p = .911). Median progression-free survival (PFS) was 9.0 months in the control group and 7.8 months for the intervention group (p = .838). CONCLUSION: Treatment decision based on G8 screening followed by CGA had no impact on completion rate of planned oncologic treatment, OS or PFS, but resulted in a borderline significant lower incidence of grade 3-4 toxicity.

The effect of tumor laterality on survival for non-small cell lung cancer patients treated with radiotherapy.

Background: The treatment of choice for patients with locally advanced non-small cell lung cancer (LA-NSCLC) in good performance status is definitive radiotherapy (RT), the five-year survival being approximately 25-30%. Advances in the diagnostic procedures and treatment modalities in NSCLC have increased the overall survival, making identifying factors with impact on survival increasingly relevant. Recent research indicates that tumor laterality has impact on the survival of patients with LA-NSCLC treated with definitive RT. The aim of this study was to investigate whether tumor laterality impacted overall survival. Material and methods: All patients with stage IIa-IIIb NSCLC planned for curative intended RT from 2008 to 2013 at Odense University Hospital were analyzed to compare overall survival of patients with right-sided vs. left-sided tumors. Log-rank test was performed to test for differences in survival rates and Cox regression analyses to test for possible confounders. No patients were lost to follow-up. Results: In total, 164 patients had a tumor in the right lung and 118 had tumor in the left lung. All patients had at least 4.5 years' follow-up. Median overall survival was 19 months (right) and 22.5 months (left) p = .729. Three-year overall survival was 31% (right) and 35% (left). In Cox regression analyses age, performances status and total mean lung dose were statistically significant with a hazard ratio (HR) = 1.03 (95% Cl: 1.01-1.05), HR = 1.60 (95% Cl: 1.12-2.28), and HR = 1.11 (95% Cl: 1.06-1.16), respectively. Conclusion: This study did not verify that laterality has a significant impact on survival in LA-NSCLC patients treated with curative intended RT.

Outcome of treatment in patients with small cell lung cancer in poor performance status.

Background: Patients with small cell lung cancer (SCLC) with poor performance status (PS) especially in the elderly may not benefit from chemotherapy. The aim of this study was to compare survival of treated patients with PS 3-4 with untreated patients.Material and methods: We reviewed the medical records and pathology data for 448 patients diagnosed with small cell carcinoma from 2010 to 2015 and selected all patients in PS 3-4 for review.Results: A total of 87 patients fulfilled the inclusion criteria. Of these, 53 (61%) received chemotherapy (CT), while 34 (39%) did not. The median overall survival (OS) was 5.1 months for the treated patients and 0.7 month for the untreated (p < .001). Multivariate analysis identified lack of treatment with chemotherapy, extensive disease, and PS 4 as independent factors associated with poor prognosis, while age and gender were not. Also, patients with aged ≥70 years who had extended disease had significant improved OS when treated with CT. However, the chance of being treated with CT was significantly influenced by age.Conclusion: CT was associated with improved survival in patients with SCLC with PS 3-4 independent of age and stage of disease. Neither ED, high age, nor poor PS should be used as criteria for omitting CT.