Esophagus toxicity after stereotactic and hypofractionated radiotherapy for central lung tumors: Normal tissue complication probability modeling.

PURPOSE: To correlate esophagus toxicity and dose-volume histogram (DVH) parameters in order to assess risks, and derive a Normal Tissue Complication Probability (NTCP) model. METHODS AND MATERIALS: Patients with a central lung tumor from 2 centers, who underwent stereotactic or hypofractionated radiotherapy (≤12 fractions), were analyzed. Doses were recalculated to an equivalent dose of 2 Gy with an α/ß ratio of 10 (EQD210). The esophagus was manually delineated and DVH-parameters (Dmax,EQD2, D1cc,EQD2, D2cc,EQD2, D5cc,EQD2) were analyzed and used for NTCP modeling based on logistic regression analysis. RESULTS: Two-hundred-and-thirty-one patients with 252 tumors were eligible. No acute or late grade 3-5 esophageal toxicity was reported. Acute grade 1-2 esophagus toxicity was recorded in 38 patients (17%). All DVH-parameters were significantly higher in patients with toxicity. NTCP models showed a 50% probability of acute grade 1-2 toxicity at a Dmax of 67 Gy EQD210 and D1cc of 42 Gy EQD210. No difference in overall survival was observed between patients with and without toxicity (p = 0.428). CONCLUSION: As no grade 3-5 esophageal toxicity was observed in our cohort, a Dmax of 56 Gy EQD210 and a D5cc of 35.5 Gy EQD210 could be delivered without high risks of severe toxicity. The NTCP models of this study might be used as practical guidelines for the treatment of central lung tumors with stereotactic radiotherapy.

Normal Tissue Complication Probability Modeling of Pulmonary Toxicity After Stereotactic and Hypofractionated Radiation Therapy for Central Lung Tumors.

PURPOSE: To evaluate clinical pulmonary and radiographic bronchial toxicity after stereotactic ablative radiation therapy and hypofractionated radiation therapy for central lung tumors, and perform normal tissue complication probability modeling and multivariable analyses to identify predictors for toxicity. METHODS AND MATERIALS: A pooled analysis was performed of patients with a central lung tumor treated using ≤12 fractions at 2 centers between 2006 and 2015. Airways were manually contoured on planning computed tomography scans, and doses were recalculated to an equivalent dose of 2 Gy per fraction with an α/ß ratio of 3. Grade ≥3 (≥G3) clinical pulmonary toxicity was evaluated by 2 or more physicians. Radiographic toxicity was defined as a stenosis or an occlusion with or without atelectasis using follow-up computed tomography scans. Logistic regression analyses were used for statistical analyses. RESULTS: A total of 585 bronchial structures were studied in 195 patients who were mainly treated using 5 or 8 fractions (60%). Median patient survival was 27.9 months (95% confidence interval 22.3-33.6 months). Clinical ≥G3 toxicity was observed in 24 patients (12%) and radiographic bronchial toxicity in 55 patients (28%), both mainly manifesting ≤12 months after treatment. All analyzed dosimetric parameters correlated with clinical and lobar bronchial radiographic toxicity, with V130Gy,EQD having the highest odds ratio. Normal tissue complication probability modeling showed a volume dependency for the development of both clinical and radiographic toxicity. On multivariate analyses, significant predictors for ≥G3 toxicity were a planning target volume overlapping the trachea or main stem bronchus (P = .005), chronic obstructive pulmonary disease (P = .034), and the total V130Gy,EQD (P = .012). Radiographic bronchial toxicity did not significantly correlate with clinical toxicity (P = .663). CONCLUSIONS: We identified patient and dosimetric factors associated with clinical and radiographic toxicity after high-dose radiation therapy for central lung tumors. Additional data from prospective studies are needed to validate these findings.

Dose and Volume of the Irradiated Main Bronchi and Related Side Effects in the Treatment of Central Lung Tumors With Stereotactic Radiotherapy.

High radiation dose to the main bronchi can result in stenosis, occlusion or fistula formation, and death. Only 8 articles have reported side effects to the main bronchi from stereotactic body radiation therapy (SBRT), mostly with only one symptomatic complication per article. Therefore, we calculated the dose to the bronchial structures, such as trachea; mainstem bronchi; intermediate bronchus; upper-, middle-, and lower-lobe bronchus; and the segmental bronchi in 134 patients with central tumors and calculated the normal tissue complication probability (NTCP) for each of these structures, with toxicity determination based upon computed tomography imaging. No side effects were found in the trachea, and only stenosis occurred in the main bronchus and bronchus intermedius. Higher grades of side effects, such as occlusion and atelectasis, were only seen in the upper-, middle-, and lower bronchi and the segmental bronchi. When 0.5cc of a segmental bronchi was irradiated to 50Gy in 5 fractions, it was about 50% likely to be occluded radiographically. For grade 1 radiographically evident side effects, the 50% risk level for a 5-fraction Dmax was 55Gy for mid-bronchi and 65Gy for mainstem bronchi. To assure the relationship between clinical toxicity and side effects to the bronchi, further investigation is needed.

Improved efficiency of multi-criteria IMPT treatment planning using iterative resampling of randomly placed pencil beams.

This study investigates whether 'pencil beam resampling', i.e. iterative selection and weight optimization of randomly placed pencil beams (PBs), reduces optimization time and improves plan quality for multi-criteria optimization in intensity-modulated proton therapy, compared with traditional modes in which PBs are distributed over a regular grid. Resampling consisted of repeatedly performing: (1) random selection of candidate PBs from a very fine grid, (2) inverse multi-criteria optimization, and (3) exclusion of low-weight PBs. The newly selected candidate PBs were added to the PBs in the existing solution, causing the solution to improve with each iteration. Resampling and traditional regular grid planning were implemented into our in-house developed multi-criteria treatment planning system 'Erasmus iCycle'. The system optimizes objectives successively according to their priorities as defined in the so-called 'wish-list'. For five head-and-neck cancer patients and two PB widths (3 and 6 mm sigma at 230 MeV), treatment plans were generated using: (1) resampling, (2) anisotropic regular grids and (3) isotropic regular grids, while using varying sample sizes (resampling) or grid spacings (regular grid). We assessed differences in optimization time (for comparable plan quality) and in plan quality parameters (for comparable optimization time). Resampling reduced optimization time by a factor of 2.8 and 5.6 on average (7.8 and 17.0 at maximum) compared with the use of anisotropic and isotropic grids, respectively. Doses to organs-at-risk were generally reduced when using resampling, with median dose reductions ranging from 0.0 to 3.0 Gy (maximum: 14.3 Gy, relative: 0%-42%) compared with anisotropic grids and from -0.3 to 2.6 Gy (maximum: 11.4 Gy, relative: -4%-19%) compared with isotropic grids. Resampling was especially effective when using thin PBs (3 mm sigma). Resampling plans contained on average fewer PBs, energy layers and protons than anisotropic grid plans and more energy layers and protons than isotropic grid plans. In conclusion, resampling resulted in improved plan quality and in considerable optimization time reduction compared with traditional regular grid planning.