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.

Associations Between Mean Lung Dose and Prevalence of Radiation Pneumonitis in Elderly Lung Cancer Patients.

BACKGROUND/AIM: Pneumonitis is a serious radiotherapy complication. This study, which is a prerequisite for a prospective trial, aimed to identify the prevalence of pneumonitis and risk factors in elderly patients with lung cancer. PATIENTS AND METHODS: Ninety-eight lung cancer patients aged ≥65 years were included. Seventeen factors were investigated regarding grade ≥2 pneumonitis at 24 weeks following radiotherapy. RESULTS: The prevalence of grade ≥2 pneumonitis at 24 weeks was 27.3%. On univariate analysis, a significant association was observed for mean (ipsilateral) lung dose (MLD; ≤13.0 vs. 13.1-20.0 vs. >20.0 Gy; 0% vs. 24.9% vs. 48.7%). Results were significant also for ≤13.0 vs. >13.0 Gy (0% vs. 37.1%) or ≤20.0 vs. >20.0 Gy (13.4% vs. 48.7%). MLD achieved significance on multivariate analysis. CONCLUSION: Elderly patients receiving MLDs >13.0 Gy, particularly >20.0 Gy, have a high risk of grade ≥2 pneumonitis. These results are important for designing a prospective trial.

Clinically Significant Dermatitis During Adjuvant Radiotherapy for Invasive Breast Cancer.

BACKGROUND/AIM: Patients with breast cancer receiving adjuvant radiotherapy may experience grade ≥2 dermatitis. In the Interreg-project HeAT, a mobile application (app) reminding patients to perform skin care will be prospectively tested with the goal of decreasing clinically significant radiation dermatitis. This study aimed to identify the prevalence of grade ≥2 dermatitis and risk factors, required for designing the prospective trial. PATIENTS AND METHODS: In a retrospective study of 327 patients with breast cancer irradiated during 2022-2023, the prevalence of grade ≥2 dermatitis and 23 potential risk factors were investigated. RESULTS: The prevalence of grade ≥2 dermatitis was 31.2%. On multivariate analysis, it was significantly associated with chronic inflammatory disease (p=0.001), significant cardiovascular disease (p<0.001), smoking history >10 pack years (p<0.001), advanced T-stage (p=0.017), normo-fractionation (p<0.001), and radiation boost (p<0.001). CONCLUSION: The prevalence of grade ≥2 dermatitis and independent risk factors during adjuvant radiotherapy for invasive breast cancer were identified that contribute to improved patient care and the design of a prospective trial.

Radiotherapy for Metastatic Epidural Spinal Cord Compression with Increased Doses: Final Results of the RAMSES-01 Trial.

Patients with metastatic epidural spinal cord compression (MESCC) and favorable survival prognoses may benefit from radiation doses exceeding 10 × 3.0 Gy. In a multi-center phase 2 trial, patients receiving 15 × 2.633 Gy (41.6 Gy10) or 18 × 2.333 Gy (43.2 Gy10) were evaluated for local progression-free survival (LPFS), motor/sensory functions, ambulatory status, pain, distress, toxicity, and overall survival (OS). They were compared (propensity score-adjusted Cox regression) to a historical control group (n = 266) receiving 10 × 3.0 Gy (32.5 Gy10). In the phase 2 cohort, 50 (of 62 planned) patients were evaluated for LPFS. Twelve-month rates of LPFS and OS were 96.8% and 69.9%, respectively. Motor and sensory functions improved in 56% and 57.1% of patients, and 94.0% were ambulatory following radiotherapy. Pain and distress decreased in 84.4% and 78.0% of patients. Ten and two patients experienced grade 2 and 3 toxicities, respectively. Phase 2 patients showed significantly better LPFS than the control group (p = 0.039) and a trend for improved motor function (p = 0.057). Ambulatory and OS rates were not significantly different. Radiotherapy with 15 × 2.633 Gy or 18 × 2.333 Gy was well tolerated and appeared superior to 10 × 3.0 Gy.

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.

Clinical outcomes of ALK+ non-small cell lung cancer in Denmark.

BACKGROUND: Real-world clinical outcomes of anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC) patients vary. This study aimed to investigate the treatment and clinical outcomes of all ALK+ NSCLC patients in Denmark in the period 2011-2018, regardless of disease stage. MATERIALS AND METHODS: A national pathology database with complete coverage was used to identify ALK+ NSCLC patients diagnosed between 2011 and 2018. Clinical data were obtained through retrospective chart reviews. Overall survival (OS) and duration of treatment (DOT) were analyzed using Kaplan-Meier methodologies. RESULTS: A total of 209 ALK+ NSCLC patients were included. The cohort had a slight overrepresentation of female patients (56.5%) with a mean age of 61.6 years. Most patients were adenocarcinoma cases (97%) and presented with an ECOG performance status of 0-1 (79%). Stage IIIb-IVb patients comprised 70% of the cohort. The use of ALK-tyrosine kinase inhibitors (TKIs) as first-line treatment increased over time, with the 1st generation ALK-TKI crizotinib being the predominant treatment in the 1st line. In 1st line treatment, 2nd generation ALK-TKIs had a median DOT more than twice the median DOT of crizotinib (25.1 and 9.1 months, respectively). The median OS for the entire cohort was 44.0 months. Patients with stage I-IIIA disease had a median OS that had not been reached, while those with stage IIIb-IVb disease had a median OS of 31.8 months. Patients with stage IIIb-IVb disease receiving an ALK-TKI as 1st line treatment had a median OS of 42.5 months with immature follow-up. Brain metastases at diagnosis or choice of 1st line treatment did not statistically significantly impact OS. CONCLUSION: This study gives insights into the treatment and outcome of ALK+ NSCLC patients in Denmark and provides a real-world confirmation of the superior disease control provided by 2nd generation ALK-TKIs as compared to the 1st generation ALK-TKI crizotinib.

2-[18F]FDG-PET/CT in Cancer of Unknown Primary Tumor-A Retrospective Register-Based Cohort Study.

We investigated the impact of 2-[18F]FDG-PET/CT on detection rate (DR) of the primary tumor and survival in patients with suspected cancer of unknown primary tumor (CUP), comparing it to the conventional diagnostic imaging method, CT. Patients who received a tentative CUP diagnosis at Odense University Hospital from 2014-2017 were included. Patients receiving a 2-[18F]FDG-PET/CT were assigned to the 2-[18F]FDG-PET/CT group and patients receiving a CT only to the CT group. DR was calculated as the proportion of true positive findings of 2-[18F]FDG-PET/CT and CT scans, separately, using biopsy of the primary tumor, autopsy, or clinical decision as reference standard. Survival analyses included Kaplan-Meier estimates and Cox proportional hazards regression adjusted for age, sex, treatment, and propensity score. We included 193 patients. Of these, 159 were in the 2-[18F]FDG-PET/CT group and 34 were in the CT group. DR was 36.5% in the 2-[18F]FDG-PET/CT group and 17.6% in the CT group, respectively (p = 0.012). Median survival was 7.4 (95% CI 0.4-98.7) months in the 2-[18F]FDG-PET/CT group and 3.8 (95% CI 0.2-98.1) in the CT group. Survival analysis showed a crude hazard ratio of 0.63 (p = 0.024) and an adjusted hazard ratio of 0.68 (p = 0.087) for the 2-[18F]FDG-PET/CT group compared with CT. This study found a significantly higher DR of the primary tumor in suspected CUP patients using 2-[18F]FDG-PET/CT compared with patients receiving only CT, with possible immense clinical importance. No significant difference in survival was found, although a possible tendency towards longer survival in the 2-[18F]FDG-PET/CT group was observed.

5-Year survival in Danish patients with advanced non-small cell lung cancer treated with immune checkpoint inhibitor monotherapy.

BACKGROUND: Convincing results from randomized controlled trials (RCTs) have led to increasing use of immune checkpoint inhibitors (ICI) as part of standard therapies in real-world (RW) scenarios. However, RW patients differ clinically from RCT populations and might have reduced long-term survival. Currently, only sparse data on 3-5-year survival rate for RW patients with advanced non-small cell lung cancer (NSCLC) treated with ICI exist. MATERIALS AND METHODS: A multicenter study was performed including 729 patients with advanced NSCLC receiving monotherapy with ICI (retrospective data (n = 566) and prospective data (n = 163)). Detailed baseline clinical characteristics, programmed death-ligand 1 (PD-L1) tumor proportion score (TPS), and baseline haematological count were registered. Kaplan-Meier estimates and log-rank test were used for survival analyses, Cox regression for determination of prognostic factors. RESULTS: Median time of follow-up (FU) was 48.7 months (IQR 37.2-54.3). Median overall survival (OS) in first line treatment was 20.4 months (IQR 8.5-45.0) compared to 11.4 months (IQR 4.6-27.1) in ≥2nd line (HR 1.48, 95% CI 1.25-1.75). Estimated probability of OS was 30% at 3 years, 23% at 4 years, and 13% at 5 years in first line compared to 17, 13, and 11% in ≥2nd line, respectively. For those with performance status (PS) 2, the 2-year OS rate was 32% (95% CI 0.22-0.43) compared to 5% (95% CI 0.01-0.15) in patients with PD-L1 ≥ 50% versus <50%, respectively. CONCLUSIONS: Compared to RCTs, long-term OS and PFS rates are lower in real-world patients treated with ICI in first line but much improved compared to historic rates on chemotherapy. A promising flattening of both the OS and progression free survival curves illustrates that also a subset of real-world patients obtain long-term remission. Patients with PS 2 and PD-L1 ≥ 50% may obtain clinically meaningful 2-year PFS and OS rates.

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.

Does coronary artery calcium score have an impact on overall survival for locally advanced non-small cell lung cancer treated with definitive radiotherapy.

BACKGROUND AND PURPOSE: Coronary artery calcium score (CACs) is an excellent marker for survival in non-cancer patients, but its role in locally advanced non-small cell lung cancer (LA-NSCLC) patients remains uncertain. In this study, we hypothesize that CACs is a prognostic marker for survival in a competing risk analysis in LA-NSCLC patients treated with definitive radiotherapy. MATERIALS AND METHODS: We included 644 patients with LA-NSCLC treated in 2014-2015 in Denmark. Baseline patient characteristics were derived from the Danish Lung Cancer Registry. Radiotherapy planning CT scans were used for manual CACs measurements, and the patients were divided into four groups, CACs 0, 1-99, 100-399, and ≥400. A multivariable Cox model utilizing bootstrapping for cross-validation modeled overall survival (OS). RESULTS: The median follow-up time was seven years, and the median OS was 26 months (95% CI 24-29). Within each CAC group 0, 1-99, 100-399, and ≥400 were 172, 182, 143, and 147 patients, respectively. In the univariable analysis, the survival decreased with increasing CACs. However, after adjustment for age, PS, radiotherapy dose, and logarithmic GTV, CACs did not have a statistically significant impact on OS with hazard ratios of 1.04 (95% CI 0.85-1.28), 1.11 (95%CI 0.89-1.43), and 1.16 (95%CI 0.92-1.47) for CACs 1-99, CACs 100-399 and ≥400, respectively. Elevated CACs was observed in 73 % of the patients suggesting a high risk of cardiac comorbidity before radiotherapy. CONCLUSION: CACs did not add prognostic information to our population's classical risk factors, such as tumor volume, performance status, and age; the lung cancer has the highest priority despite the risk of baseline cardiac comorbidity.

Short Communication: Results of a Consensus Conference on Radiotherapy for Brain and Bone Metastases Within the Interreg-Project TreaT.

BACKGROUND/AIM: Differences between radiotherapy for metastases in Northern Germany and Southern Denmark were previously identified, which led to a consensus conference. PATIENTS AND METHODS: A consensus conference was held between three centers to harmonize radiotherapy regimens for bone and brain metastases. RESULTS: Centers agreed on 1×8 Gy for painful bone metastases in patients with poor or intermediate survival prognoses and 10×3 Gy for favorable-prognosis patients. For complicated bone metastases, 5-6×4 Gy was preferred for poor-prognosis, 10×3 Gy for intermediate-prognosis, and longer-course radiotherapy for favorable-prognosis patients. For ≥5 brain metastases, centers agreed on whole-brain irradiation (WBI) with 5×4 Gy in poor-prognosis and longer-course regimens in other patients. For single brain lesions and patients with 2-4 lesions and intermediate/favorable prognoses, fractionated stereotactic radiotherapy (FSRT) or radiosurgery were recommended. No consensus was reached for 2-4 lesions in poor-prognosis patients; two centers preferred FSRT, one center WBI. Preferred radiotherapy regimens were similar for different age groups including elderly and very elderly patients, but age-specific survival scores were recommended. CONCLUSION: The consensus conference was successful, since harmonization of radiotherapy regimens was achieved for 32 of 33 possible situations.

Current Radiotherapy Concepts Regarding Brain and Bone Metastases in Centers Participating in the German-Danish Interreg-Project TreaT.

BACKGROUND/AIM: Radiotherapy regimens for brain or bone metastases vary substantially. This study compared regimens utilized in Northern Germany and Denmark. PATIENTS AND METHODS: Three centers participating in the Interreg-Project TreaT completed questionnaires regarding preferred radiotherapy regimens for brain or bone metastases. RESULTS: Brain metastases: In poor-prognosis patients, all centers prefer short-course whole-brain irradiation (WBI) for multiple metastases. For oligometastatic disease, two centers prefer WBI, one center fractionated stereotactic radiotherapy (FSRT). For single lesions, all centers use FSRT. In intermediate- or favorable-prognosis patients, longer-course WBI is preferred for multiple lesions, sometimes with simultaneous-integrated boost. For oligo-metastasis, regimens vary. FSRT is preferred for single lesions. Bone metastases: For poor-prognosis patients, single-fraction radiotherapy is used for uncomplicated metastases and short-course radiotherapy for (impending) fractures, large soft-tissue components, and spinal cord compression. Multi-fraction regimens are preferred for intermediate-prognosis and longer-course regimens for favorable-prognosis patients. CONCLUSION: Regimens are relatively similar for bone metastases, single and multiple brain lesions, but vary considerably for few brain metastases. Further cross-border collaboration is required to provide more uniform and optimized treatment standards.

Comparison of Three Survival Scores in a Series of Patients ≥80 Years of Age Irradiated for Bone Metastases.

BACKGROUND/AIM: Very elderly patients irradiated for bone metastases likely benefit from individualized treatments. A specific survival score was created for this group and compared to existing instruments. PATIENTS AND METHODS: Ninety-six patients aged 80+ irradiated for bone metastases were retrospectively evaluated. Dose-fractionation regimen plus twelve characteristics were evaluated for survival. RESULTS: In the Cox regression model, performance status and tumor type were significant and used for the score, which included three groups (5-7, 8-12, and 14 points) with 6-month survival rates of 15%, 52%, and 90%. Positive predictive values (PPVs) regarding death ≤6 months were 85% (new score), 100% (previous 65+ score), and 84% (previous score for any age). The new instrument and the 65+ score were also very accurate regarding survival. Since PPV regarding death was calculated from only four patients for the 65+ score, this PPV may be less conclusive than that for the new instrument. CONCLUSION: The new score appears useful for patients aged 80+ irradiated for bone metastases.

Clinical impact of venous thromboembolism in non-small cell lung cancer patients receiving immunotherapy.

BACKGROUND: Prospective investigation on cancer-associated venous thromboembolism (VTE) in non-small cell lung cancer (NSCLC) during treatment with immune checkpoint inhibitors (ICIs) is lacking. PATIENTS AND METHODS: A prospective real-world study using combined computed tomography venography and pulmonary angiography (CTVPA) to screen patients with NSCLC for VTE (cohort A). A retrospective multicenter cohort without additional screening with CTVPA was included as control (cohort B). A model with VTE as a time-dependent event using competing risk analysis model with death as a competing event was used to evaluate outcomes and differences in cumulative VTE incidences. RESULTS: Cohort A (n = 146) and cohort B (n = 426) had median follow-up for VTE of 16.5 months (IQR 6.7-35.6). Cumulative VTE events at 1, 3, 6, and 12 months were 7.5 %, 9.6 %, 13.0 %, 14.4 % for cohort A and 1.9 %, 3.8 %, 4.9 %, 5.6 % for cohort B with SHR 2.42 (CI 95 % 1.37-4.27) p = 0.0024. Recurrent VTE comprised 52 % and 37 %, respectively. In multivariate overall survival analysis, VTE was significantly associated with impaired OS (HR 2.12 CI 95 % [1.49-3.03], p < 0.0001). Risk factors for VTE comprised prior VTE and ICI administered in first line. CONCLUSION: Cumulative VTE incidence in NSCLC patients following palliative ICI may be significantly higher than reported in randomised clinical trials and retrospective real-world reports. VTE development during ICI impair OS significantly. Thus, more focus on VTE during ICI is warranted to optimise both prevention and management of VTE. Whether there is a causal relationship between VTE and ICI remains to be explored.

The First Survival Score for Patients Aged ≥80 Years Irradiated for Brain Metastases.

Survival scores facilitate personalized cancer treatment. Due to demographic changes, very elderly patients are more prevalent than in the past. A score was developed in 94 patients aged ≥ 80 years undergoing whole-brain radiotherapy for brain metastases. Dose fractionation, treatment period, age, sex, performance score (ECOG-PS), tumor type, count of lesions, metastases outside the brain, and interval tumor diagnosis to radiotherapy were retrospectively evaluated. Independent predictors of survival were used for the score. Based on individual scoring points obtained from 3-month survival rates, prognostic groups were designed. Additionally, the score was compared to an existing tool developed in patients ≥ 65 years. ECOG-PS, count of lesions, and extra-cranial metastases were independent prognostic factors. Three groups were created (7, 10, and 13−16 points) with 3-month survival of 6%, 25%, and 67% (p < 0.001), respectively. Positive predictive values (PPVs) regarding death ≤ 3 and survival ≥ 3 months were 94% and 67% (new score) vs. 96% and 48% (existing tool), respectively. PPVs for survival ≥1 and ≥2 months were 88% and 79% vs. 63% and 58%, respectively. Both tools were accurate in predicting death ≤2, ≤3, and ≤6 months. The new score was more precise regarding death ≤1 month and survival (all time periods) and appeared preferable. However, it still needs to be validated.

A New Survival Score for Patients ≥65 Years Assigned to Radiotherapy of Bone Metastases.

Survival scores are important for personalized treatment of bone metastases. Elderly patients are considered a separate group. Therefore, a specific score was developed for these patients. Elderly patients (≥65 years) irradiated for bone metastases were randomly assigned to the test (n = 174) or validation (n = 174) cohorts. Thirteen factors were retrospectively analyzed for survival. Factors showing significance (p < 0.05) or a trend (p < 0.06) in the multivariate analysis were used for the score. Based on 6-month survival rates, prognostic groups were formed. The score was compared to an existing tool developed in patients of any age. In the multivariate analysis, performance score, tumor type, and visceral metastases showed significance and gender was a trend. Three groups were designed (17, 18−25 and 27−28 points) with 6-month survival rates of 0%, 51%, and 100%. In the validation cohort, these rates were 9%, 55%, and 86%. Comparisons of prognostic groups between both cohorts did not reveal significant differences. In the test cohort, positive predictive values regarding death ≤6 and survival ≥6 months were 100% with the new score vs. 80% and 88% with the existing tool. The new score was more accurate demonstrating the importance of specific scores for elderly patients.

A New Clinical Instrument for Estimating the Ambulatory Status after Irradiation for Malignant Spinal Cord Compression.

Estimating post-treatment ambulatory status can improve treatment personalization of patients irradiated for malignant spinal cord compression (MSCC). A new clinical score was developed from data of 283 patients treated with radiotherapy alone in prospective trials. Radiotherapy regimen, age, gender, tumor type, interval from tumor diagnosis to MSCC, number of affected vertebrae, other bone metastases, visceral metastases, time developing motor deficits, ambulatory status, performance score, sensory deficits, and sphincter dysfunction were evaluated. For factors with prognostic relevance in the multivariable logistic regression model after backward stepwise variable selection, scoring points were calculated (post-radiotherapy ambulatory rate in % divided by 10) and added for each patient. Four factors (primary tumor type, sensory deficits, sphincter dysfunction, ambulatory status) were used for the instrument that includes three prognostic groups (17-21, 22-31, and 32-37 points). Post-radiotherapy ambulatory rates were 10%, 65%, and 97%, respectively, and 2-year local control rates were 100%, 75%, and 88%, respectively. Positive predictive values to predict ambulatory and non-ambulatory status were 97% and 90% using the new score, and 98% and 79% using the previous instrument. The new score appeared more precise in predicting non-ambulatory status. Since patients with 32-37 points had high post-radiotherapy ambulatory and local control rates, they may not require surgery.

Clinical features affecting efficacy of immune checkpoint inhibitors in pretreated patients with advanced NSCLC: a Danish nationwide real-world study.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are implemented as standard treatment for patients with advanced non-small cell lung cancer (NSCLC) in first-line and subsequent-line treatment. However, certain subgroups such as patients with older age, poor performance status (PS), and severe comorbidity are underrepresented in the randomized controlled trials (RCTs). This study aimed to assess overall survival (OS), treatment data, and clinical features affecting second- or subsequent-line ICI efficacy in an unselected, Danish, nationwide NSCLC population. METHODS: Patients with advanced NSCLC who started nivolumab or pembrolizumab as second-line or subsequent-line treatment between 1 September 2015, and 1 October 2018, were identified from institutional records of all Danish oncology departments. Clinical and treatment data were retrospectively collected. Descriptive statistics and survival analyses were performed. RESULTS: Data were available for 840 patients; 49% females. The median age was 68 years (19% were ≥75 years), 19% had PS ≥2, and 36% had moderate to severe comorbidity. The median OS (mOS) was 12.2 months; 15.1 months and 10.0 months in females and males, respectively. The median time-to-treatment discontinuation (mTTD) and median progression-free survival (mPFS) was 3.2 and 5.2 months, respectively. Patients with PS ≥2 had a mOS of 4.5 months, mTTD of 1.1 month, and mPFS of 2.0 months. In multivariable Cox regression analysis, male sex (HR = 1.35, 95% CI 1.11-1.62), PS >0 (PS 1, HR = 1.88, 95% CI 1.52-2.33; PS ≥2, HR = 4.15, 95% CI 3.13-5.5), liver metastases (HR = 1.72, 95% CI 1.34-2.22), and bone metastases (HR = 1.27, 95% CI 1.03-1.58) were significant poor prognostic OS factors. CONCLUSIONS: Danish real-world patients with advanced NSCLC treated with second- or subsequent-line ICI had an OS comparable to results from RCTs. Women, frail and older patients constituted a higher proportion than in previous RCTs. Clinical features associated with poor OS were male sex, PS ≥1 (in particular PS ≥2), bone-, and liver metastases.

Nationwide Survival Benefit after Implementation of First-Line Immunotherapy for Patients with Advanced NSCLC-Real World Efficacy.

Background The selection of patients with non-small cell lung cancer (NSCLC) for immune checkpoint inhibitor (ICI) treatment remains challenging. This real-world study aimed to compare the overall survival (OS) before and after the implementation of ICIs, to identify OS prognostic factors, and to assess treatment data in first-line (1L) ICI-treated patients without epidermal growth factor receptor mutation or anaplastic lymphoma kinase translocation. Methods Data from the Danish NSCLC population initiated with 1L palliative antineoplastic treatment from 1 January 2013 to 1 October 2018, were extracted from the Danish Lung Cancer Registry (DLCR). Long-term survival and median OS pre- and post-approval of 1L ICI were compared. From electronic health records, additional clinical and treatment data were obtained for ICI-treated patients from 1 March 2017 to 1 October 2018. Results The OS was significantly improved in the DLCR post-approval cohort (n = 2055) compared to the pre-approval cohort (n = 1658). The 3-year OS rates were 18% (95% CI 15.6-20.0) and 6% (95% CI 5.1-7.4), respectively. On multivariable Cox regression, bone (HR = 1.63) and liver metastases (HR = 1.47), performance status (PS) 1 (HR = 1.86), and PS ≥ 2 (HR = 2.19) were significantly associated with poor OS in ICI-treated patients. Conclusion OS significantly improved in patients with advanced NSCLC after ICI implementation in Denmark. In ICI-treated patients, PS ≥ 1, and bone and liver metastases were associated with a worse prognosis.

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).