Heike Peulen

Toxicity after reirradiation of pulmonary tumours with stereotactic body radiotherapy

PURPOSE To assess toxicity and feasibility of reirradiation with stereotactic body radiotherapy (SBRT) after prior lung SBRT for primary lung cancer or lung metastases. PATIENTS AND MATERIALS Twenty-nine patients reirradiated with SBRT on 32 lung lesions (11 central, 21 peripheral) were retrospectively reviewed. Median follow-up time was 12 months (range 1-97). The primary endpoint was toxicity, secondary endpoints were local control and overall survival time. Toxicity was scored according to the NCI-CTCAE version 3. RESULTS Grade 3-4 toxicity was scored 14 times in eight patients. Three patients died because of massive bleeding (grade 5). Larger clinical target volumes (CTV) and central tumour localization were associated with more severe toxicity. There was no correlation between mean lung dose (MLD) and lung toxicity. Local control at 5 months after reirradiation was 52%, as assessed by CT-scan (n=12) or X-thorax (n=3). A larger CTV was associated with poorer local control. Kaplan-Meier estimated 1- and 2-year survival rates were 59% and 43%, respectively. CONCLUSIONS Reirradiation with SBRT is feasible although increased risk of toxicity was reported in centrally located tumours. Further research is warranted for more accurate selection of patients suitable for reirradiation with SBRT.

Mid-ventilation based PTV margins in Stereotactic Body Radiotherapy (SBRT): A clinical evaluation

PURPOSE Large tumor motion leads to large treatment volumes with an Internal Target Volume (ITV) based approach, whereas mid-ventilation (MidV) based Planning Target Volumes (PTV) margins typically lead to smaller treatment volumes. The purpose of this study was to evaluate the MidV approach on clinical outcome data of Stereotactic Body Radiotherapy (SBRT) in NSCLC. METHODS AND MATERIALS 297 patients with 314 peripheral tumors treated from 2006 to 2012 were retrospectively analyzed. In all patients a 4D-CT was acquired and the MidV-CT-scan was selected. Tumor amplitudes were determined in left-right (LR), cranio-caudal (CC) and anterior-posterior (AP) direction, to calculate patient specific PTV margins. RESULTS The median LR, CC and AP tumor amplitudes were 2mm (0-16 mm), 4mm (0-39 mm) and 3mm (0-18 mm), respectively, yielding a median CTV-to-PTV margin of 8mm. An ITV+5mm based PTV margin would have been bigger in 47% of the patients. After a median follow up of 22 months, local recurrence occurred in six patients (2%). Two year LC and OS were 98% and 67%, respectively. CONCLUSIONS Using the MidV approach combined with online image guidance an excellent LC of 98% was established with SBRT. This provides clinical support that incorporating respiratory motion into the PTV margin is a safe approach.

Dealing with geometric uncertainties in dose painting by numbers: introducing the ΔVH.

PURPOSE Dose painting by numbers lacks the conventional margin approach for geometric uncertainties. Moreover, the DVH is unable to assess the geometric accuracy of a non-uniform dose distribution because spatial information is lost. In this work we present tools for planning and evaluation of non-uniform treatment dose which take geometric uncertainties into account. METHODS AND MATERIALS The IMRT optimization functions in the Pinnacle treatment planning software were extended to allow non-uniform prescription dose distributions, e.g., derived from a PET image set. Also, explicit handling of systematic and random geometric uncertainties was incorporated in the functions, enabling confidence level based probabilistic treatment planning. For plan evaluation the concept of ΔVH was introduced, which is the volume histogram of the difference between planned and prescribed doses. Probability distributions for ΔVH points were estimated using Monte Carlo methods. As a demonstration of these methods, two examples are presented; one plan for a lung cancer patient and one for a tumor in the head-and-neck region. RESULTS Dose distributions were obtained using the PET SUV, while allowing for geometric uncertainties. Optimization was performed such that the ΔVH evaluation indicated a 90% confidence of having under-dosage less than 5% of prescription dose maximum in 99% of the tumor volume. This corresponds to the clinical target constraint for margin based planning with uniform dose prescription. CONCLUSIONS Clinical treatment planning tools were extended to allow non-uniform prescription. For planning we introduced confidence level based probabilistic optimization with non-uniform target dose, while confidence levels of ΔVH points summarize the probability of proper target coverage.

Forward Intensity-Modulated Radiotherapy Planning in Breast Cancer to Improve Dose Homogeneity: Feasibility of Class Solutions

PURPOSE To explore forward planning methods for breast cancer treatment to obtain homogeneous dose distributions (using International Commission on Radiation Units and Measurements criteria) within normal tissue constraints and to determine the feasibility of class solutions. METHODS AND MATERIALS Treatment plans were optimized in a stepwise procedure for 60 patients referred for postlumpectomy irradiation using strict dose constraints: planning target volume (PTV)(95%) of >99%; V(107%) of <1.8 cc; heart V(5 Gy) of <10% and V(10 Gy) of <5%; and mean lung dose of <7 Gy. Treatment planning started with classic tangential beams. Optimization was done by adding a maximum of four segments before adding beams, in a second step. A breath-hold technique was used for heart sparing if necessary. RESULTS Dose constraints were met for all 60 patients. The classic tangential beam setup was not sufficient for any of the patients; in one-third of patients, additional segments were required (<3), and in two-thirds of patients, additional beams (<2) were required. Logistic regression analyses revealed central breast diameter (CD) and central lung distance as independent predictors for transition from additional segments to additional beams, with a CD cut-off point at 23.6 cm. CONCLUSIONS Treatment plans fulfilling strict dose homogeneity criteria and normal tissue constraints could be obtained for all patients by stepwise dose intensity modification using limited numbers of segments and additional beams. In patients with a CD of >23.6 cm, additional beams were always required.

Dose to heart substructures is associated with non-cancer death after SBRT in stage I–II NSCLC patients

BACKGROUND AND PURPOSE To investigate potential associations between dose to heart (sub)structures and non-cancer death, in early stage non-small cell lung cancer (NSCLC) patients treated with stereotactic body radiation therapy (SBRT). METHODS 803 patients with early stage NSCLC received SBRT with predominant schedules of 3×18Gy (59%) or 4×12Gy (19%). All patients were registered to an average anatomy, their planned dose deformed accordingly, and dosimetric parameters for heart substructures were obtained. Multivariate Cox regression and a sensitivity analysis were used to identify doses to heart substructures or heart region with a significant association with non-cancer death respectively. RESULTS Median follow-up was 34.8months. Two year Kaplan-Meier overall survival rate was 67%. Of the deceased patients, 26.8% died of cancer. Multivariate analysis showed that the maximum dose on the left atrium (median 6.5Gy EQD2, range=0.009-197, HR=1.005, p-value=0.035), and the dose to 90% of the superior vena cava (median 0.59Gy EQD2, range=0.003-70, HR=1.025, p-value=0.008) were significantly associated with non-cancer death. Sensitivity analysis identified the upper region of the heart (atria+vessels) to be significantly associated with non-cancer death. CONCLUSIONS Doses to mainly the upper region of the heart were significantly associated with non-cancer death. Consequently, dose sparing in particular of the upper region of the heart could potentially improve outcome, and should be further studied.

Dose–effect analysis of radiation induced rib fractures after thoracic SBRT

BACKGROUND AND PURPOSE To determine a dose-effect relation for radiation induced rib fractures after stereotactic body radiation therapy (SBRT) in early stage non-small cell lung cancer (NSCLC). Automatic rib delineation has enabled the analysis of a large patient group. MATERIAL AND METHODS Four-hundred and sixty-six patients with stage I/II NSCLC received SBRT with a median of 54Gy in 3 fractions. The optimal EQD2-corrected dose parameter to predict (a)symptomatic fractures was found using Cox regression. Three normal tissue complication probability (NTCP) models based on this optimal parameter were constructed: (1) at a median follow up (FU) of 26months, (2) for all data, with time to toxicity taken into account and (3) at a FU of 26months, excluding low dose ribs. RESULTS The median time to fracture was 22 (range 5-51) months. Maximum rib dose best predicted fractures. The TD50 (dose with 50% complication) of the second NTCP model was 375Gy. The TD50 was significantly higher for the other models indicating an under-estimation of the dose effect at the median follow-up time and/or when excluding low dose ribs. CONCLUSIONS The risk of symptomatic rib fractures after SBRT was significantly correlated to dose, and was <5% at 26months when Dmax<225Gy.

Prediction of Early Death in Patients with Early-Stage NSCLC—Can We Select Patients without a Potential Benefit of SBRT as a Curative Treatment Approach?

Introduction: Stereotactic body radiotherapy (SBRT) is the guideline‐recommended treatment for medically inoperable patients with peripheral stage I non–small cell lung cancer (NSCLC). This study analyzed whether short‐term (<6 months) death can be predicted reliably to select a subgroup of patients who will not have a benefit from SBRT. Methods: A total of 779 patients with early‐stage NSCLC who had been treated with cone beam computed tomography–guided SBRT in five institutes and for whom information on overall survival during the first 6 months after treatment was available were included in this analysis. The probability of dying within 6 months after treatment was defined as the end point “early death” and modeled by multivariate logistic regression. Model fitting was performed using the least absolute shrinkage and selection operator method, and model test performance was estimated using double 10‐fold cross validation. The variables age, sex, Eastern Cooperative Oncology Group performance status, operability, forced expiratory volume in 1 second, and Charlson comorbidity index were considered for model building. Results: Eastern Cooperative Oncology Group performance status and (to a lesser extent) operability were the most important predictors of early death, whereas the Charlson comorbidity index was associated only with the overall survival time. On the basis of the best expected test performance (area under the curve = 0.699), the risk for early death would be 8.8% (range 8.2%–13.7%) and 4.1% (3.0%–4.3%) for the 10% of patients with the highest and lowest risk, respectively. Overall, predictive performance was too low for clinical application. Conclusions: SBRT should be offered to all patients irrespective of their comorbidities, unless the performance status of the patients and the comorbidities prevent accurate SBRT planning and delivery.

Predictors and Patterns of Regional Recurrence Following Lung SBRT: A Report From the Elekta Lung Research Group

Introduction The objective of this study was to determine the predictors and patterns of regional recurrence (RR) following stereotactic body radiotherapy (SBRT) for primary lung cancers. Material and Methods Details of patient factors, treatment, and outcome factors were extracted from a multi‐institutional (5) database. All events were calculated from the end of radiotherapy. Estimates of local recurrence, RR, and distant metastases (DM) were calculated using the competing risk method. Cause‐specific and overall survival were calculated using the Kaplan‐Meier method. Details of locations and number of simultaneous RRs were categorized by lymph node anatomic station. Results A total of 734 patients were analyzed. The median follow‐up was 3.0 years in surviving patients. Four hundred seventy‐six (65%) patients had pathologic proof of disease. There were 64 patients with RR. The 2‐year local recurrence, RR, and distant metastases rates were 5.6%, 9.0%, and 14.6% respectively. The 2‐year cause‐specific and overall survival were 89.9% and 63.7%, respectively. There were 136 simultaneous sites of RR. There were 21 recurrences in stations 4R (15.4%), 9 (6.6%) in 4L, 30 (22%) in 7, 19 (13.9%) in 10R, and 14 (10.3%) in 10L. The most common stations for isolated recurrence (n = 19) were station 7 (n = 5; 26.3%) and station 10R (n = 6; 31.6%). The most common RR levels were stations 4 and 7 for right and left upper lobe, stations 5, 7, and 10 for left lower lobe tumors, and stations 7 and 10 for right lower lobe tumors. Conclusion Stations 4, 7, and 10 were the most common stations for RR. These patterns of recurrence may guide nodal staging procedures prior to SBRT. Micro‐Abstract This study explored the predictors and patterns of regional recurrence (RR) following stereotactic body radiotherapy (SBRT) in 734 cases from a multi‐institutional database. The 2‐year RR rate was 9%. Stations 4, 7, and 10 were the most common stations for RR following SBRT. These patterns of recurrence may guide nodal staging procedures prior to SBRT.

Validation of automatic segmentation of ribs for NTCP modeling.

BACKGROUND AND PURPOSE Determination of a dose-effect relation for rib fractures in a large patient group has been limited by the time consuming manual delineation of ribs. Automatic segmentation could facilitate such an analysis. We determine the accuracy of automatic rib segmentation in the context of normal tissue complication probability modeling (NTCP). MATERIALS AND METHODS Forty-one patients with stage I/II non-small cell lung cancer treated with SBRT to 54 Gy in 3 fractions were selected. Using the 4DCT derived mid-ventilation planning CT, all ribs were manually contoured and automatically segmented. Accuracy of segmentation was assessed using volumetric, shape and dosimetric measures. Manual and automatic dosimetric parameters Dx and EUD were tested for equivalence using the Two One-Sided T-test (TOST), and assessed for agreement using Bland-Altman analysis. NTCP models based on manual and automatic segmentation were compared. RESULTS Automatic segmentation was comparable with the manual delineation in radial direction, but larger near the costal cartilage and vertebrae. Manual and automatic Dx and EUD were significantly equivalent. The Bland-Altman analysis showed good agreement. The two NTCP models were very similar. CONCLUSIONS Automatic rib segmentation was significantly equivalent to manual delineation and can be used for NTCP modeling in a large patient group.

OC-0399: Dose to heart substructures is associated with non-cancer death after SBRT in stage I NSCLC patients

Material and Methods: From 2006-2013 801 patients with early stage NSCLC were treated with CBCT guided SBRT (median 54 Gy in 3 fractions) in 5 institutes for whom treatment plans were available. 565 patients were analyzed after exclusion of synchronous or metachronous tumors (n=80), follow-up<1y (n=63), or death from cancer (93).An average anatomy was constructed based on 109 patients of the 5 institutes using deformable image registration. Subsequently, all patients were registered to this average anatomy and the corresponding dose distribution was deformed accordingly [1]. The heart and substructures right atrium, left atrium, right ventricle, left ventricle, superior vena cava, descending aorta and left pulmonary artery were contoured on the average anatomy. For each (sub)structure dosimetric parameters DV (V: 0 cc-max), VD (D: 0 Gy-max), EUDn (n: 0.1-10) were obtained.Associations of these dosimetric parameters with death were evaluated using univariate Cox regression. Per (sub)structure the parameter with the lowest Akaike information criterion was selected and used in subsequent analyses. Correlations between all (sub)structures were assessed prior to inclusion in a multivariate Cox regression. Finally, the (sub)structure(s) that remained significant in the first multivariate analysis were included in a second multivariate analysis, also including; performance status, age, gender, biological dose, distance to bronchus, comorbidity index, lung-function, tumor diameter, T-stage, institute and pack years smoking.