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.

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.

Test-retest repeatability and interobserver variation of healthy tissue metabolism using 18F-FDG PET/CT of the thorax among lung cancer patients.

OBJECTIVES: The aim of this study was to assess the test-retest repeatability and interobserver variation in healthy tissue (HT) metabolism using 2-deoxy-2-[18F]fluoro-d-glucose (18F-FDG) PET/computed tomography (PET/CT) of the thorax in lung cancer patients. METHODS: A retrospective analysis was conducted in 22 patients with non-small cell lung cancer who had two PET/CT scans of the thorax performed 3 days apart with no interval treatment. The maximum, mean and peak standardized uptake values (SUVs) in different HTs were measured by a single observer for the test-retest analysis and two observers for interobserver variation. Bland-Altman plots were used to assess the repeatability and interobserver variation. Intrasubject variability was evaluated using within-subject coefficients of variation (wCV). RESULTS: The wCV of test-retest SUVmean measurements in mediastinal blood pool, bone marrow, skeletal muscles and lungs was less than 20%. The left ventricle (LV) showed higher wCV (>60%) in all SUV parameters with wide limits of repeatability. High interobserver agreement was found with wCV of less than 10% in SUVmean of all HT, but up to 22% was noted in the LV. CONCLUSION: HT metabolism is stable in a test-retest scenario and has high interobserver agreement. SUVmean was the most stable metric in organs with low FDG uptake and SUVpeak in HTs with moderate uptake. Test-retest measurements in LV were highly variable irrespective of the SUV parameters used for measurements.

Outcome-based multiobjective optimization of lymphoma radiation therapy plans.

At its core, radiation therapy (RT) requires balancing therapeutic effects against risk of adverse events in cancer survivors. The radiation oncologist weighs numerous disease and patient-level factors when considering the expected risk-benefit ratio of combined treatment modalities. As part of this, RT plan optimization software is used to find a clinically acceptable RT plan delivering a prescribed dose to the target volume while respecting pre-defined radiation dose-volume constraints for selected organs at risk. The obvious limitation to the current approach is that it is virtually impossible to ensure the selected treatment plan could not be bettered by an alternative plan providing improved disease control and/or reduced risk of adverse events in this individual. Outcome-based optimization refers to a strategy where all planning objectives are defined by modeled estimates of a specific outcome's probability. Noting that various adverse events and disease control are generally incommensurable, leads to the concept of a Pareto-optimal plan: a plan where no single objective can be improved without degrading one or more of the remaining objectives. Further benefits of outcome-based multiobjective optimization are that quantitative estimates of risks and benefit are obtained as are the effects of choosing a different trade-off between competing objectives. Furthermore, patient-level risk factors and combined treatment modalities may be integrated directly into plan optimization. Here, we present this approach in the clinical setting of multimodality therapy for malignant lymphoma, a malignancy with marked heterogeneity in biology, target localization, and patient characteristics. We discuss future research priorities including the potential of artificial intelligence.

Circulating cell free DNA during definitive chemo-radiotherapy in non-small cell lung cancer patients - initial observations.

BACKGROUND: The overall aim was to investigate the change over time in circulating cell free DNA (cfDNA) in patients with locally advanced non-small cell lung cancer (NSCLC) undergoing concurrent chemo-radiotherapy. Furthermore, to assess the possibility of detecting circulating cell free tumor DNA (ctDNA) using shallow whole genome sequencing (sWGS) and size selection. METHODS: Ten patients were included in a two-phase study. The first four patients had blood samples taken prior to a radiation therapy (RT) dose fraction and at 30 minutes, 1 hour and 2 hours after RT to estimate the short-term dynamics of cfDNA concentration after irradiation. The remaining six patients had one blood sample taken on six treatment days 30 minutes post treatment to measure cfDNA levels. Presence of ctDNA as indicated by chromosomal aberrations was investigated using sWGS. The sensitivity of this method was further enhanced using in silico size selection. RESULTS: cfDNA concentration from baseline to 120 min after therapy was stable within 95% tolerance limits of +/- 2 ng/ml cfDNA. Changes in cfDNA were observed during therapy with an apparent qualitative difference between adenocarcinoma (average increase of 0.69 ng/ml) and squamous cell carcinoma (average increase of 4.0 ng/ml). Tumor shrinkage on daily cone beam computer tomography scans during radiotherapy did not correlate with changes in concentration of cfDNA. CONCLUSION: Concentrations of cfDNA remain stable during the first 2 hours after an RT fraction. However, based on the sWGS profiles, ctDNA represented only a minor fraction of cfDNA in this group of patients. The detection sensitivity of genomic alterations in ctDNA strongly increases by applying size selection.

Heterogeneity in tumours: Validating the use of radiomic features on 18F-FDG PET/CT scans of lung cancer patients as a prognostic tool.

AIM: The aim was to validate promising radiomic features (RFs)1 on 18F-flourodeoxyglucose positron emission tomography/computed tomography-scans (18F-FDG PET/CT) of non-small cell lung cancer (NSCLC) patients undergoing definitive chemo-radiotherapy. METHODS: 18F-FDG PET/CT scans performed for radiotherapy (RT) planning were retrieved. Auto-segmentation with visual adaption was used to define the primary tumour on PET images. Six pre-selected prognostic and reproducible PET texture -and shape-features were calculated using texture respectively shape analysis. The correlation between these RFs and metabolic active tumour volume (MTV)3, gross tumour volume (GTV)4 and maximum and mean of standardized uptake value (SUV)5 was tested with a Spearman's Rank test. The prognostic value of RFs was tested in a univariate cox regression analysis and a multivariate cox regression analysis with GTV, clinical stage and histology. P-value ≤ 0.05 were considered significant. RESULTS: Image analysis was performed for 233 patients: 145 males and 88 females, mean age of 65.7 and clinical stage II-IV. Mean GTV was 129.87 cm3 (SD 130.30 cm3). Texture and shape-features correlated more strongly to MTV and GTV compared to SUV-measurements. Four RFs predicted PFS in the univariate analysis. No RFs predicted PFS in the multivariate analysis, whereas GTV and clinical stage predicted PFS (p = 0.001 and p = 0.008 respectively). CONCLUSION: The pre-selected RFs were insignificant in predicting PFS in combination with GTV, clinical stage and histology. These results might be due to variations in technical parameters. However, it is relevant to question whether RFs are stable enough to provide clinically useful information.

Incorporating NTCP into Randomized Trials of Proton Versus Photon Therapy.

PURPOSE: We propose and simulate a model-based methodology to incorporate heterogeneous treatment benefit of proton therapy (PrT) versus photon therapy into randomized trial designs. We use radiation-induced pneumonitis (RP) as an exemplar. The aim is to obtain an unbiased estimate of how predicted difference in normal tissue complications probability (ΔNTCP) converts into clinical outcome on the patient level. MATERIALS AND METHODS: ΔNTCP data from in silico treatment plans for photon therapy and PrT for patients with locally advanced lung cancer as well as randomly sampled clinical risk factors were included in simulations of trial outcomes. The model used at point of analysis of the trials was an iQUANTEC model. Trial outcomes were examined with Cox proportional hazards models, both in case of a correctly specified model and in a scenario where there is discrepancy between the dose metric used for ΔNTCP and the dose metric associated with the "true" clinical outcome, that is, when the model is misspecified. We investigated how outcomes from such a randomized trial may feed into a model-based estimate of the patient-level benefit from PrT, by creating patient-specific predicted benefit probability distributions. RESULTS: Simulated trials showed benefit in accordance with that expected when the NTCP model was equal to the model for simulating outcome. When the model was misspecified, the benefit changed and we observed a reversal when the driver of outcome was high-dose dependent while the NTCP model was mean-dose dependent. By converting trial results into probability distributions, we demonstrated large heterogeneity in predicted benefit, and provided a randomized measure of the precision of individual benefit estimates. CONCLUSIONS: The design allows for quantifying the benefit of PrT referral, based on the combination of NTCP models, clinical risk factors, and traditional randomization. A misspecified model can be detected through a lower-than-expected hazard ratio per predicted ΔNTCP.

Deep inspiration breath hold in locally advanced lung cancer radiotherapy: validation of intrafractional geometric uncertainties in the INHALE trial.

OBJECTIVES: Patients with locally advanced non-small cell lung cancer (NSCLC) were included in a prospective trial for radiotherapy in deep inspiration breath hold (DIBH). We evaluated DIBH compliance and target position reproducibility. METHODS: Voluntary, visually guided DIBHs were performed with optical tracking. Patients underwent three consecutive DIBH CT scans for radiotherapy planning. We evaluated the intrafractional uncertainties in the position of the peripheral tumour, lymph nodes and differential motion between them, enabling PTV margins calculation. Patients who underwent all DIBH imaging and had tumour position reproducibility <8 mm were up-front DIBH compliant. Patients who performed DIBHs throughout the treatment course were overall DIBH compliant. Clinical parameters and DIBH-related uncertainties were validated against our earlier pilot study. RESULTS: 69 of 88 included patients received definitive radiotherapy. 60/69 patients (87%) were up-front DIBH compliant. DIBH plan was not superior in seven patients and three lost DIBH ability during the treatment, leaving 50/69 patients (72%) overall DIBH compliant.The systematic and random errors between consecutive DIBHs were small but differed from the pilot study findings. This led to slightly different PTV margins between the two studies. CONCLUSIONS: DIBH compliance and reproducibility was high. Still, this validation study highlighted the necessity of designing PTV margins in larger, representative patient cohorts. ADVANCES IN KNOWLEDGE: We demonstrated high DIBH compliance in locally advanced NSCLC patients. DIBH does not eliminate but mitigates the target position uncertainty, which needs to be accounted for in treatment margins. Margin design should be based on data from larger representative patient groups.

An investigative expansion of a competing risk model for first failure site in locally advanced non-small cell lung cancer.

Introduction: We hypothesized that gross tumor volume (GTV) of primary tumor (GTVT) and nodal volumes (GTVN) were predictors of first failure site in non-small cell lung cancer (NSCLC). We aimed at also comparing the prognostic model's complexity to its ability to generate absolute risk predictions with emphasis on variables available at the time of diagnosis. Materials and methods: Three hundred and forty-two patients treated with definitive chemoradiotherapy (CRT) for adenocarcinoma (AC) or squamous cell carcinoma (SCC) in 2009-2017 were analyzed. Clinical data, standardized uptake values on FDG-PET/CT, GTVT and GTVN were analyzed using multivariate competing risk models. Results: One hundred and thirty-seven patients had SCC. As first site of failure 49 had locoregional failure (LRF), 40 had distant metastasis (DM) and 24 died with no evidence of disease (NED). In 205 patients with AC, 34 had LRF, 118 had DM as first failure site and 17 died with NED. Performance status predicted LRF (p = .02) and UICC stage risk of DM (p = .05 for stage 3, p < .001 for stage 4). Adding histopathology changed predictions with much reduced risk of LRF in AC compared to SCC (HR = 0.5, 95% CI: (0.3-0.75), p = .001). Conversely, AC had a higher rate of DM than SCC (HR = 2.1, 95% CI: (1.5-3.0], p < .001). Addition of FDG metrics and tumor/nodal volume data predicted DM risk (p = .001), but with smaller impact on absolute risk compared to histopathology. Separation of GTV in nodal and tumor lesions did not improve risk predictions. Conclusions: We quantified the effect of adding volumetric and quantitative imaging to competing risk models of first failure site, but did not find tumor volume components to be important. Histopathology remains the simplest and most important factor in prognosticating failure patterns in NSCLC.

Repeatability of FDG PET/CT metrics assessed in free breathing and deep inspiration breath hold in lung cancer patients.

We measured the repeatability of FDG PET/CT uptake metrics when acquiring scans in free breathing (FB) conditions compared with deep inspiration breath hold (DIBH) for locally advanced lung cancer. Twenty patients were enrolled in this prospective study. Two FDG PET/CT scans per patient were conducted few days apart and in two breathing conditions (FB and DIBH). This resulted in four scans per patient. Up to four FDG PET avid lesions per patient were contoured. The following FDG metrics were measured in all lesions and in all four scans: Standardized uptake value (SUV)peak, SUVmax, SUVmean, metabolic tumor volume (MTV) and total lesion glycolysis (TLG), based on an isocontur of 50% of SUVmax. FDG PET avid volumes were delineated by a nuclear medicine physician. The gross tumor volumes (GTV) were contoured on the corresponding CT scans. Nineteen patients were available for analysis. Test-retest standard deviations of FDG uptake metrics in FB and DIBH were: SUVpeak FB/DIBH: 16.2%/16.5%; SUVmax: 18.2%/22.1%; SUVmean: 18.3%/22.1%; TLG: 32.4%/40.5%. DIBH compared to FB resulted in higher values with mean differences in SUVmax of 12.6%, SUVpeak 4.4% and SUVmean 11.9%. MTV, TLG and GTV were all significantly smaller on day 1 in DIBH compared to FB. However, the differences between metrics under FB and DIBH were in all cases smaller than 1 SD of the day to day repeatability. FDG acquisition in DIBH does not have a clinically relevant impact on the uptake metrics and does not improve the test-retest repeatability of FDG uptake metrics in lung cancer patients.

Fractionated palliative thoracic radiotherapy in non-small cell lung cancer - futile or worth-while?

BACKGROUND: Palliative thoracic radiotherapy (PTR) can relieve symptoms originating from intra-thoracic disease. The optimal timing and fractionation of PTR is unknown. Time to effect is 2 months. The primary aim of this retrospective study was to investigate survival after PTR, hypothesizing that a significant number of patients received futile fractionated PTR. The secondary aim was to find prognostic factors to guide treatment decisions. METHODS: Patients with non-small-cell lung cancer (NSCLC) planned for PTR in the period of 2010-2011 at the University Hospital of Copenhagen were included. We noted pathology, tumor, node and metastasis (TNM) classification of malignant tumors, stage, indication, start date, schedule for PTR, completed y/n, performance status (PS) and time of death. Analyses were performed as an intention-to-treat using Cox regression, Fishers exact test and Kaplan Meier. RESULTS: A total of 159 patients were included. Median overall survival (OS) was 4.2 months. Sixteen patients (10%) did either not begin or finish PTR. Of these, eight (5%) died prior to or during PTR. Of the 151 patients receiving PTR, sixteen patients (11%) died within 14 days, thirty-three (22%) within 30 days and fifty (33%) within 2 months. PS 0-1 and squamous cell carcinoma were correlated with a better survival. CONCLUSIONS: Our study show that a significant number of patients who received PTR died before they could achieve optimal effect of the treatment. PS and histology were significant prognostic factors favoring PS 0-1 and squamous cell carcinoma. Based on our study, we suggest that patients with PS 0-1 should be considered for fractionated PTR whereas patients with PS ≥ 2 should be considered for high dose single fraction only or supportive palliative care.

A Competing Risk Model of First Failure Site after Definitive Chemoradiation Therapy for Locally Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: The aim of the study was to build a model of first failure site- and lesion-specific failure probability after definitive chemoradiotherapy for inoperable NSCLC. METHODS: We retrospectively analyzed 251 patients receiving definitive chemoradiotherapy for NSCLC at a single institution between 2009 and 2015. All patients were scanned by fludeoxyglucose positron emission tomography/computed tomography for radiotherapy planning. Clinical patient data and fludeoxyglucose positron emission tomography standardized uptake values from primary tumor and nodal lesions were analyzed by using multivariate cause-specific Cox regression. In patients experiencing locoregional failure, multivariable logistic regression was applied to assess risk of each lesion being the first site of failure. The two models were used in combination to predict probability of lesion failure accounting for competing events. RESULTS: Adenocarcinoma had a lower hazard ratio (HR) of locoregional failure than squamous cell carcinoma (HR = 0.45, 95% confidence interval [CI]: 0.26-0.76, p = 0.003). Distant failures were more common in the adenocarcinoma group (HR = 2.21, 95% CI: 1.41-3.48, p < 0.001). Multivariable logistic regression of individual lesions at the time of first failure showed that primary tumors were more likely to fail than lymph nodes (OR = 12.8, 95% CI: 5.10-32.17, p < 0.001). Increasing peak standardized uptake value was significantly associated with lesion failure (OR = 1.26 per unit increase, 95% CI: 1.12-1.40, p < 0.001). The electronic model is available at http://bit.ly/LungModelFDG. CONCLUSIONS: We developed a failure site-specific competing risk model based on patient- and lesion-level characteristics. Failure patterns differed between adenocarcinoma and squamous cell carcinoma, illustrating the limitation of aggregating them into NSCLC. Failure site-specific models add complementary information to conventional prognostic models.

Early lesion-specific (18)F-FDG PET response to chemotherapy predicts time to lesion progression in locally advanced non-small cell lung cancer.

BACKGROUND AND PURPOSE: We hypothesize that the lesion-to-lesion variability in FDG-PET response after one cycle of chemotherapy for NSCLC in an individual patient may inform radiation dose redistribution. To test this hypothesis, we investigate if time to lesion-progression in patients with multiple lesions is dependent on lesion-specific response to chemotherapy. MATERIALS AND METHODS: We analyzed 81 patients with 184 lesions referred to curative chemo-radiotherapy for NSCLC 2010-2012. (18)F-FDG PET scans were performed at diagnosis and after one series of chemotherapy. Response of each lesion was assessed as the change in FDG peak standardized uptake value. Variance of lesion response was compared within and between patients. Time to progression for each lesion was analyzed using the Kaplan-Meier method and the Cox proportional hazards model. RESULTS: Within-patient variability in lesion responses was of the same magnitude as the between-patient variability. Lesion-specific time to progression was longer in lesions with a better response (log-rank p=0.038). Nodal lesions had a much lower risk of progression than T-site lesions (HR=0.09, p<0.0001). CONCLUSIONS: Recording an overall patient response involves a loss of biological information on heterogeneity between lesions. Poor lesion-specific response after one cycle chemotherapy may identify lesions that would benefit from an individualized radiotherapy strategy.