Stephanie Tanadini-Lang

Nomogram based overall survival prediction in stereotactic body radiotherapy for oligo-metastatic lung disease

BACKGROUND Radical local treatment of pulmonary metastases is practiced with increasing frequency due to acknowledgment and better understanding of oligo-metastatic disease. This study aimed to develop a nomogram predicting overall survival (OS) after stereotactic body radiotherapy (SBRT) for pulmonary metastases. PATIENTS AND METHODS A multi-institutional database of 670 patients treated with SBRT for pulmonary metastases was used as training cohort. Cox regression analysis with bidirectional variable elimination was performed to identify factors to be included into the nomogram model to predict 2-year OS. The calibration rate of the nomogram was assessed by plotting the actual Kaplan-Meier 2-year OS against the nomogram predicted survival. The nomogram was externally validated using two separate monocentric databases of 145 and 92 patients treated with SBRT for pulmonary metastases. RESULTS The median follow up of the trainings cohort was 14.3months, the 2-year and 5-year OS was 52.6% and 23.7%, respectively. Karnofsky performance index, type of the primary tumor, control of the primary tumor, maximum diameter of the largest treated metastasis and number of metastases (1 versus >1) were significant prognostic factors in the Cox model (all p<0.05). The calculated concordance-index for the nomogram was 0.73 (concordance indexes of all prognostic factors between 0.54 and 0.6). Based on the nomogram the training cohort was divided into 4 groups and 2-year OS ranged between 24.2% and 76.1% (predicted OS between 30.2% and 78.4%). The nomogram discriminated between risk groups in the two validation cohorts (concordance index 0.68 and 0.67). CONCLUSIONS A nomogram for prediction of OS after SBRT for pulmonary metastases was generated and externally validated. This tool might be helpful for interdisciplinary discussion and evaluation of local and systemic treatment options in the oligo-metastatic setting. KEY MESSAGE A nomogram for prediction of overall survival after stereotactic body radiotherapy (SBRT) for pulmonary metastases was developed and externally validated. This tool might be helpful for interdisciplinary discussion and evaluation of local and systemic treatment options in the oligo-metastatic setting.

Respiratory motion-management in stereotactic body radiation therapy for lung cancer – A dosimetric comparison in an anthropomorphic lung phantom (LuCa)

BACKGROUND AND PURPOSE The objective of this study was to compare the latest respiratory motion-management strategies, namely the internal-target-volume (ITV) concept, the mid-ventilation (MidV) principle, respiratory gating and dynamic couch tracking. MATERIALS AND METHODS An anthropomorphic, deformable and dynamic lung phantom was used for the dosimetric validation of these techniques. Stereotactic treatments were adapted to match the techniques and five distinct respiration patterns, and delivered to the phantom while radiographic film measurements were taken inside the tumor. To report on tumor coverage, these dose distributions were used to calculate mean doses (Dmean), changes in homogeneity indices (ΔH2-98), gamma agreement, and areas covered by the planned minimum dose (A>Dmin). RESULTS All techniques achieved good tumor coverage (A>Dmin>99.0%) and minor changes in Dmean (±3.2%). Gating and tracking strategies showed superior results in gamma agreement and ΔH2-98 compared to ITV and MidV concepts, which seem to be more influenced by the interplay and the gradient effect. For lung, heart and spinal cord, significant dose differences between the four techniques were found (p<0.05), with lowest doses for gating and tracking strategies. CONCLUSION Active motion-management techniques, such as gating or tracking, showed superior tumor dose coverage and better organ dose sparing than the passive techniques based on tumor margins.

Comparison of PET and CT radiomics for prediction of local tumor control in head and neck squamous cell carcinoma

Abstract Purpose: An association between radiomic features extracted from CT and local tumor control in the head and neck squamous cell carcinoma (HNSCC) has been shown. This study investigated the value of pretreatment functional imaging (18F-FDG PET) radiomics for modeling of local tumor control. Material and Methods: Data from HNSCC patients (n = 121) treated with definitive radiochemotherapy were used for model training. In total, 569 radiomic features were extracted from both contrast-enhanced CT and 18F-FDG PET images in the primary tumor region. CT, PET and combined PET/CT radiomic models to assess local tumor control were trained separately. Five feature selection and three classification methods were implemented. The performance of the models was quantified using concordance index (CI) in 5-fold cross validation in the training cohort. The best models, per image modality, were compared and verified in the independent validation cohort (n = 51). The difference in CI was investigated using bootstrapping. Additionally, the observed and radiomics-based estimated probabilities of local tumor control were compared between two risk groups. Results: The feature selection using principal component analysis and the classification based on the multivariabale Cox regression with backward selection of the variables resulted in the best models for all image modalities (CICT = 0.72, CIPET = 0.74, CIPET/CT = 0.77). Tumors more homogenous in CT density (decreased GLSZMsize_zone_entropy) and with a focused region of high FDG uptake (higher GLSZMSZLGE) indicated better prognosis. No significant difference in the performance of the models in the validation cohort was observed (CICT = 0.73, CIPET = 0.71, CIPET/CT = 0.73). However, the CT radiomics-based model overestimated the probability of tumor control in the poor prognostic group (predicted  = 68%, observed  = 56%). Conclusions: Both CT and PET radiomics showed equally good discriminative power for local tumor control modeling in HNSCC. However, CT-based predictions overestimated the local control rate in the poor prognostic validation cohort, and thus, we recommend to base the local control modeling on the 18F-FDG PET.

Stability of radiomic features in CT perfusion maps

This study aimed to identify a set of stable radiomic parameters in CT perfusion (CTP) maps with respect to CTP calculation factors and image discretization, as an input for future prognostic models for local tumor response to chemo-radiotherapy. Pre-treatment CTP images of eleven patients with oropharyngeal carcinoma and eleven patients with non-small cell lung cancer (NSCLC) were analyzed. 315 radiomic parameters were studied per perfusion map (blood volume, blood flow and mean transit time). Radiomics robustness was investigated regarding the potentially standardizable (image discretization method, Hounsfield unit (HU) threshold, voxel size and temporal resolution) and non-standardizable (artery contouring and noise threshold) perfusion calculation factors using the intraclass correlation (ICC). To gain added value for our model radiomic parameters correlated with tumor volume, a well-known predictive factor for local tumor response to chemo-radiotherapy, were excluded from the analysis. The remaining stable radiomic parameters were grouped according to inter-parameter Spearman correlations and for each group the parameter with the highest ICC was included in the final set. The acceptance level was 0.9 and 0.7 for the ICC and correlation, respectively. The image discretization method using fixed number of bins or fixed intervals gave a similar number of stable radiomic parameters (around 40%). The potentially standardizable factors introduced more variability into radiomic parameters than the non-standardizable ones with 56-98% and 43-58% instability rates, respectively. The highest variability was observed for voxel size (instability rate  >97% for both patient cohorts). Without standardization of CTP calculation factors none of the studied radiomic parameters were stable. After standardization with respect to non-standardizable factors ten radiomic parameters were stable for both patient cohorts after correction for inter-parameter correlations. Voxel size, image discretization, HU threshold and temporal resolution have to be standardized to build a reliable predictive model based on CTP radiomics analysis.

Validation of dynamic treatment-couch tracking for prostate SBRT

Purpose In stereotactic body radiation therapy (SBRT) of prostatic cancer, a high dose per fraction is applied to the target with steep dose gradients. Intrafractional prostate motion can occur unpredictably during the treatment and lead to target miss. This work investigated the dosimetric benefit of motion compensation with dynamic treatment‐couch tracking for prostate SBRT treatments in the presence of prostatic motion. Methods Ten SBRT treatment plans for prostate cancer patients with integrated boosts to their index lesion were prepared. The treatment plans were applied with a TrueBeam linear accelerator to a phantom in (a) static reference position, (b) moved with five prostate motion trajectories without any motion compensation, and (c) with real‐time compensation using transponder‐guided couch tracking. The geometrical position of the electromagnetic transponder was evaluated in the tracked and untracked situation. The dosimetric performance of couch tracking was evaluated, using Gamma agreement indices (GAI) and other dose parameters. These were evaluated within the phantoms biplanar diode array, as well as target‐ and organ‐specific. Results The root‐mean‐square error of the motion traces (range: 0.8–4.4 mm) was drastically reduced with couch tracking (0.2–0.4 mm). Residual motion was mainly observed at abrupt direction changes with steep motion gradients. The phantom measurements showed significantly better GAI1%/1mm with tracked (range: 83.4%–100.0%) than with untracked motion (28.9%–99.7%). Also GAI2%/2mm was significantly superior for the tracked (98.4%–100.0%) than the untracked motion (52.3%–100.0%). The organ‐specific evaluation showed significantly better target coverage with tracking. The dose to the rectum and bladder showed a dependency on the anterior–posterior motion direction. Conclusions Couch tracking clearly improved the dosimetric accuracy of prostate SBRT treatments. The treatment couch was able to compensate the prostatic motion with only some minor residual motion. Therefore, couch tracking combined with electromagnetic position monitoring for prostate SBRT is feasible and improves the accuracy in treatment delivery when prostate motion is present.

Post-radiochemotherapy PET radiomics in head and neck cancer - The influence of radiomics implementation on the reproducibility of local control tumor models

PURPOSE This study investigated an association of post-radiochemotherapy (RCT) PET radiomics with local tumor control in head and neck squamous cell carcinoma (HNSCC) and evaluated the models against two radiomics software implementations. MATERIALS AND METHODS 649 features, available in two radiomics implementations and based on the same definitions, were extracted from HNSCC primary tumor region in 18F-FDG PET scans 3 months post definitive RCT (training cohort n = 128, validation cohort n = 50) and compared using the intraclass correlation coefficient (ICC). Local recurrence models were trained, separately for both implementations, using principal component analysis (PCA) and the least absolute shrinkage and selection operator. The reproducibility of the concordance indexes (CI) in univariable Cox regression for features preselected in PCA and the final multivariable models was investigated using respective features from the other implementation. RESULTS Only 80 PET radiomic features yielded ICC > 0.8 in the comparison between the implementations. The change of implementation caused high variability of CI in the univariable analysis. However, both final multivariable models performed equally well in the training and validation cohorts (CI > 0.7) independent of radiomics implementation. CONCLUSION The two post-RCT PET radiomic models, based on two different software implementations, were prognostic for local tumor control in HNSCC. However, 88% of the features was not reproducible between the implementations.

ITV, mid-ventilation, gating or couch tracking – A comparison of respiratory motion-management techniques based on 4D dose calculations

PURPOSE Respiratory motion-management techniques (MMT) aim to ensure tumor dose coverage while sparing lung tissue. Dynamic treatment-couch tracking of the moving tumor is a promising new MMT and was compared to the internal-target-volume (ITV) concept, the mid-ventilation (MidV) principle and the gating approach in a planning study based on 4D dose calculations. METHODS For twenty patients with lung lesions, planning target volumes (PTV) were adapted to the MMT and stereotactic body radiotherapy treatments were prepared with the 65%-isodose enclosing the PTV. For tracking, three concepts for target volume definition were considered: Including the gross tumor volume of one phase (single-phase tracking), including deformations between phases (multi-phase tracking) and additionally including tracking latencies of a couch tracking system (reliable couch tracking). The accumulated tumor and lung doses were estimated with 4D dose calculations based on 4D-CT datasets and deformable image registration. RESULTS Single-phase tracking showed the lowest ipsilateral lung Dmean (median: 3.3Gy), followed by multi-phase tracking, gating, reliable couch tracking, MidV and ITV concepts (3.6, 3.8, 4.1, 4.3 and 4.8Gy). The 4D dose calculations showed the MidV and single-phase tracking overestimated the target mean dose (-2.3% and -1.3%), while it was slightly underestimated by the other MMT (<+1%). CONCLUSION The ITV concept ensures tumor coverage, but exposes the lung tissue to a higher dose. The MidV, gating and tracking concepts were shown to reduce the lung dose. Neglecting non-translational changes of the tumor in the target volume definition for tracking results in a slightly reduced target coverage. The slightly inferior dose coverage for MidV should be considered when applying this technique clinically.

The TRENDY multi-center randomized trial on hepatocellular carcinoma – Trial QA including automated treatment planning and benchmark-case results

BACKGROUND AND PURPOSE The TRENDY trial is an international multi-center phase-II study, randomizing hepatocellular carcinoma (HCC) patients between transarterial chemoembolization (TACE) and stereotactic body radiation therapy (SBRT) with a target dose of 48-54 Gy in six fractions. The radiotherapy quality assurance (QA) program, including prospective plan feedback based on automated treatment planning, is described and results are reported. MATERIALS AND METHODS Scans of a single patient were used as a benchmark case. Contours submitted by nine participating centers were compared with reference contours. The subsequent planning round was based on a single set of contours. A total of 20 plans from participating centers, including 12 from the benchmark case, 5 from a clinical pilot and 3 from the first study patients, were compared to automatically generated VMAT plans. RESULTS For the submitted liver contours, Dice Similarity Coefficients (DSC) with the reference delineation ranged from 0.925 to 0.954. For the GTV, the DSC varied between 0.721 and 0.876. For the 12 plans on the benchmark case, healthy liver normal-tissue complication probabilities (NTCPs) ranged from 0.2% to 22.2% with little correlation between NCTP and PTV-D95% (R2 < 0.3). Four protocol deviations were detected in the set of 20 treatment plans. Comparison with co-planar autoVMAT QA plans revealed these were due to too high target dose and suboptimal planning. Overall, autoVMAT resulted in an average liver NTCP reduction of 2.2 percent point (range: 16.2 percent point to -1.8 percent point, p = 0.03), and lower doses to the healthy liver (p < 0.01) and gastrointestinal organs at risk (p < 0.001). CONCLUSIONS Delineation variation resulted in feedback to participating centers. Automated treatment planning can play an important role in clinical trials for prospective plan QA as suboptimal plans were detected.

Comparison of multi-leaf collimator tracking and treatment-couch tracking during stereotactic body radiation therapy of prostate cancer

PURPOSE AND BACKGROUND Motion mitigation during prostate stereotactic body radiation therapy (SBRT) ensures optimal target coverage while reducing the risk of overdosage of nearby organs. The geometrical and dosimetrical performance of motion mitigation with the multileaf-collimator (MLC tracking) or the treatment couch (couch tracking) were compared. MATERIAL AND METHODS For ten prostate patients, SBRT treatment plans with integrated boosts were prepared using volumetric modulated arc technique. For the geometrical evaluation, a lead sphere at the beam isocenter was moved according to five prostate motion curves (i) without mitigation, (ii) with MLC tracking or (iii) with couch tracking. During irradiation, MV images were taken and the over-/underexposed areas were evaluated. For the dosimetrical evaluation, the plans were applied to a dosimetric phantom. Dose distributions with and without mitigation were evaluated inside the target structure and organs at risk. RESULTS The median over-/underexposed area was reduced significantly from 2.02cm2 without mitigation to 1.00cm2 and 0.45cm2 with MLC and couch tracking. Closest dosimetrical agreement to the static references was achieved with couch tracking. CONCLUSIONS MLC and couch tracking at a conventional linear accelerator significantly improved the accuracy of prostate SBRT in the presence of motion, whereby couch tracking showed slightly better performance than MLC tracking.

Modelling the immunosuppressive effect of liver SBRT by simulating the dose to circulating lymphocytes: an in-silico planning study

BackgroundTumor immune-evasion and associated failure of immunotherapy can potentially be overcome by radiotherapy, which however also has detrimental effects on tumor-infiltrating and circulating lymphocytes (CL). We therefore established a model to simulate the radiation-dose delivered to CL.MethodsA MATLAB-model was established to quantify the CL-dose during SBRT of liver metastases by considering the factors: hepatic blood-flow, −velocity and transition-time of individual hepatic segments, as well as probability-based recirculation. The effects of intra-hepatic tumor-location and size, fractionation and treatment planning parameters (VMAT, 3DCRT, photon-energy, dose-rate and beam-on-time) were analyzed. A threshold dose ≥0.5Gy was considered inactivating CL and CL0.5 (%) is the proportion of inactivated CL.ResultsMean liver dose was mostly influenced by treatment-modality, whereas CL0.5 was mostly influenced by beam-on-time. 3DCRT and VMAT (10MV-FFF) resulted in lowest CL0.5 values of 16 and 19%. Metastasis location influenced CL0.5, with a mean of 19% for both apical and basal and 31% for the central location. PTV-volume significantly increased CL0.5 from 27 to 67% (10MV-FFF) and from 31 to 98% (6MV-FFF) for PTV-volumes ranging from 14cm3 to 268cm3.ConclusionA simulation-model was established, quantifying the strong effects of treatment-technique, tumor-location and tumor-volume on dose to CL with potential implications for immune-optimized treatment-planning in the future.