Substantial Sparing of Organs at Risk with Modern Proton Therapy in Lung Cancer, but Altered Breathing Patterns Can Jeopardize Target Coverage.

Enhancing treatment of locally advanced non-small cell lung cancer (LA-NSCLC) by using pencil beam scanning proton therapy (PBS-PT) is attractive, but little knowledge exists on the effects of uncertainties occurring between the planning (Plan) and the start of treatment (Start). In this prospective simulation study, we investigated the clinical potential for PBS-PT under the influence of such uncertainties. Imaging with 4DCT at Plan and Start was carried out for 15 patients that received state-of-the-art intensity-modulated radiotherapy (IMRT). Three PBS-PT plans were created per patient: 3D robust single-field uniform dose (SFUD), 3D robust intensity-modulated proton therapy (IMPT), and 4D robust IMPT (4DIMPT). These were exposed to setup and range uncertainties and breathing motion at Plan, and changes in breathing motion and anatomy at Start. Target coverage and dose-volume parameters relevant for toxicity were compared. The organ at risk sparing at Plan was greatest with IMPT, followed by 4DIMPT, SFUD and IMRT, and persisted at Start. All plans met the preset criteria for target robustness at Plan. At Start, three patients had a lack of CTV coverage with PBS-PT. In conclusion, the clinical potential for heart and lung toxicity reduction with PBS-PT was substantial and persistent. Altered breathing patterns between Plan and Start jeopardized target coverage for all PBS-PT techniques.

Impact of RBE variations on risk estimates of temporal lobe necrosis in patients treated with intensity-modulated proton therapy for head and neck cancer.

BACKGROUND: Temporal lobe necrosis (TLN) is a potential late effect after radiotherapy for skull base head and neck cancer (HNC). Several photon-derived dose constraints and normal tissue complication probability (NTCP) models have been proposed, however variation in relative biological effectiveness (RBE) may challenge the applicability of these dose constraints and models in proton therapy. The purpose of this study was therefore to investigate the influence of RBE variations on risk estimates of TLN after Intensity-Modulated Proton Therapy for HNC. MATERIAL AND METHODS: Seventy-five temporal lobes from 45 previously treated patients were included in the analysis. Sixteen temporal lobes had radiation associated Magnetic Resonance image changes (TLIC) suspected to be early signs of TLN. Fixed (RWDFix) and variable RBE-weighed doses (RWDVar) were calculated using RBE = 1.1 and two RBE models, respectively. RWDFix and RWDVar for temporal lobes were compared using Friedman's test. Based on RWDFix, six NTCP models were fitted and internally validated through bootstrapping. Estimated probabilities from RWDFix and RWDVar were compared using paired Wilcoxon test. Seven dose constraints were evaluated separately for RWDFix and RWDVar by calculating the observed proportion of TLIC in temporal lobes meeting the specific dose constraints. RESULTS: RWDVar were significantly higher than RWDFix (p < 0.01). NTCP model performance was good (AUC:0.79-0.84). The median difference in estimated probability between RWDFix and RWDVar ranged between 5.3% and 20.0% points (p < 0.01), with V60GyRBE and DMax at the smallest and largest differences, respectively. The proportion of TLIC was higher for RWDFix (4.0%-13.1%) versus RWDVar (1.3%-5.3%). For V65GyRBE ≤ 0.03 cc the proportion of TLIC was less than 5% for both RWDFix and RWDVar. CONCLUSION: NTCP estimates were significantly influenced by RBE variations. Dmax as model predictor resulted in the largest deviations in risk estimates between RWDFix and RWDVar. V65GyRBE ≤ 0.03 cc was the most consistent dose constraint for RWDFix and RWDVar.

Mixed Effect Modeling of Dose and Linear Energy Transfer Correlations With Brain Image Changes After Intensity Modulated Proton Therapy for Skull Base Head and Neck Cancer.

PURPOSE: Intensity modulated proton therapy (IMPT) could yield high linear energy transfer (LET) in critical structures and increased biological effect. For head and neck cancers at the skull base this could potentially result in radiation-associated brain image change (RAIC). The purpose of the current study was to investigate voxel-wise dose and LET correlations with RAIC after IMPT. METHODS AND MATERIALS: For 15 patients with RAIC after IMPT, contrast enhancement observed on T1-weighted magnetic resonance imaging was contoured and coregistered to the planning computed tomography. Monte Carlo calculated dose and dose-averaged LET (LETd) distributions were extracted at voxel level and associations with RAIC were modelled using uni- and multivariate mixed effect logistic regression. Model performance was evaluated using the area under the receiver operating characteristic curve and precision-recall curve. RESULTS: An overall statistically significant RAIC association with dose and LETd was found in both the uni- and multivariate analysis. Patient heterogeneity was considerable, with standard deviation of the random effects of 1.81 (1.30-2.72) for dose and 2.68 (1.93-4.93) for LETd, respectively. Area under the receiver operating characteristic curve was 0.93 and 0.95 for the univariate dose-response model and multivariate model, respectively. Analysis of the LETd effect demonstrated increased risk of RAIC with increasing LETd for the majority of patients. Estimated probability of RAIC with LETd = 1 keV/µm was 4% (95% confidence interval, 0%, 0.44%) and 29% (95% confidence interval, 0.01%, 0.92%) for 60 and 70 Gy, respectively. The TD15 were estimated to be 63.6 and 50.1 Gy with LETd equal to 2 and 5 keV/µm, respectively. CONCLUSIONS: Our results suggest that the LETd effect could be of clinical significance for some patients; LETd assessment in clinical treatment plans should therefore be taken into consideration.

Outcomes and patterns of radiation associated brain image changes after proton therapy for head and neck skull base cancers.

BACKGROUND AND PURPOSE: To characterize patterns and outcomes of brain MR image changes after proton therapy (PT) for skull base head and neck cancer (HNC). MATERIAL AND METHODS: Post-treatment MRIs ≥6 months were reviewed for radiation-associated image changes (RAIC) in 127 patients. All patients had received at least a point dose of 40 Gy(RBE) to the brain. The MRIs were rigidly registered to planning CTs and RAIC lesions were contoured both on T1 weighted (post-contrast) and T2 weighted sequences, and dose-volume parameters extracted. Probability of RAIC was calculated using multistate survival analysis. Univariate/multivariate analyses were performed using Cox Regression. Recursive partitioning analysis was used to investigate dose-volume correlates of RAIC development. RESULTS: 17.3% developed RAIC. All RAIC events were asymptomatic and occurred in the temporal lobe (14), frontal lobe (6) and cerebellum (2). The median volume of the contrast enhanced RAIC lesion was 0.5 cc at their maximum size. The RAIC resolved or improved in 45.5% of the patients and were stable or progressed in 36.4%. The 3-year actuarial rate of developing RAIC was 14.3%. RAIC was observed in 63% of patients when V67 Gy(RBE) of the brain ≥0.17 cc. CONCLUSION: Small RAIC lesions after PT occurred in 17.3% of the patients; the majority in nasopharyngeal or sinonasal cancer. The estimated dose-volume correlations confirm the importance of minimizing focal high doses to brain when achievable.

Plan Selection in Proton Therapy of Locally Advanced Prostate Cancer with Simultaneous Treatment of Multiple Targets.

PURPOSE: Intensity modulated proton therapy (IMPT) of locally advanced prostate cancer can spare the bowel considerably compared with modern photon therapy, but simultaneous treatment of the prostate (p), seminal vesicles (sv), and lymph nodes is challenging owing to day-to-day organ motion and range uncertainties. Our purpose was, therefore, to generate a plan library for use in adaptive IMPT to mitigate these uncertainties. METHODS AND MATERIALS: We retrospectively included 27 patients with a series of computed tomography scans throughout their treatment representing day-to-day variation. In 18 of the patients, target motion was analyzed using rigid shifts of prostate gold markers relative to bony anatomy. A plan library with different p and sv planning target volume (p/sv-PTV) positions was defined from the distribution and direction of these shifts. Delivery of IMPT using plan selection from the library was simulated for image guidance on bony anatomy, in the remaining patients and compared with nonadaptive IMPT. RESULTS: The plan library consisted of 3 small margin p/sv-PTVs: (1) p/sv-PTV shifted 1.5 systematic error (Σ) of the population mean in the anterior and cranial directions, (2) p/sv-PTV shifted 1.5Σ in the posterior and caudal directions, and (3) p/sv-PTV in the planning position. The conventional p/sv-PTV was also available for backup. Plan selection compared with nonadaptive IMPT resulted in a reduction of the rectum volume receiving 60 Gy relative biological effect (RBE) (V60GyRBE) from on average 12 mL to 9 mL. For the bladder the average V45GyRBE was reduced from 36% to 30%. Large and small bowel doses were also reduced, whereas target coverage was comparable or improved compared with nonadaptive IMPT. CONCLUSIONS: Plan selection based on a population model of rigid target motion was feasible for all patients. Compared with conventional IMPT, plan selection resulted in significant dosimetric sparing of rectum and bladder without compromising target coverage.

Imaging for Target Delineation and Treatment Planning in Radiation Oncology: Current and Emerging Techniques.

Imaging in radiation oncology has a wide range of applications. It is necessary not only for tumor staging and treatment response assessment after therapy but also for the treatment planning process, including definition of target and organs at risk, as well as treatment plan calculation. This article provides a comprehensive overview of the main imaging modalities currently used for target delineation and treatment planning and gives insight into new and promising techniques.

Exploration and application of phenomenological RBE models for proton therapy.

The relative biological effectiveness (RBE) of protons varies with multiple physical and biological factors. Phenomenological RBE models have been developed to include such factors in the estimation of a variable RBE, in contrast to the clinically applied constant RBE of 1.1. In this study, eleven published phenomenological RBE models and two plan-based models were explored and applied to simulated patient cases. All models were analysed with respect to the distribution and range of linear energy transfer (LET) and reference radiation fractionation sensitivity ((α/ß) x ) of their respective experimental databases. Proton therapy plans for a spread-out Bragg peak in water and three patient cases (prostate adenocarcinoma, pituitary adenoma and thoracic sarcoma) were optimised using an RBE of 1.1 in the Eclipse™ treatment planning system prior to recalculation and modelling in the FLUKA Monte Carlo code. Model estimated dose-volume parameters for the planning target volumes (PTVs) and organs at risk (OAR) were compared. The experimental in vitro databases for the various models differed greatly in the range of (α/ß) x values and dose-averaged LET (LETd). There were significant variations between the model estimations, which arose from fundamental differences in the database definitions and model assumptions. The greatest variations appeared in organs with low (α/ß) x and high LETd, e.g. biological doses given to late responding OARs located distal to the target in the treatment field. In general, the variation in maximum dose (D2%) was larger than the variation in mean dose and other dose metrics, with D2% of the left optic nerve ((α/ß) x = 2.1 Gy) in the pituitary adenoma case showing the greatest discrepancies between models: 28-52 Gy(RBE), while D2% for RBE1.1 was 30 Gy(RBE). For all patient cases, the estimated mean RBE to the PTV was in the range 1.09-1.29 ((α/ß) x = 1.5/3.1/10.6 Gy). There were considerable variations between the estimations of RBE and RBE-weighted doses from the different models. These variations were a consequence of fundamental differences in experimental databases, model assumptions and regression techniques. The results from the implementation of RBE models in dose planning studies should be evaluated in light of these deviations.

The influence of inter-fractional anatomy variation on secondary cancer risk estimates following radiotherapy.

PURPOSE: In silico studies comparing estimated risks of radiation-induced secondary cancer (SC) are frequently performed in assessment of radiotherapy techniques. Since inter-patient anatomy variations can result in considerable differences in estimated risk we aimed to explore the influence of inter-fractional organ motion patterns on SC risk. METHODS: Volumetric modulated arc therapy (VMAT) and intensity-modulated proton therapy (IMPT) plans were generated on the planning CT (pCT) scans of eight prostate cancer patients. In addition, the treatment plans were re-calculated on 8-9 repeat CTs (rCTs) of each patient acquired throughout the treatment course. Relative risk (RR) of SC (VMAT/IMPT) was calculated for the planned and the re-calculated dose distributions using the organ equivalent dose concept adapted to a linear and a bell-shaped competition dose-response model. RESULTS: Day-to-day variations in anatomy lead to fluctuations in SC risk estimates of the same order of magnitude as those caused by inter-patient variations. Using the competition model, the RR range for bladder cancer based on the pCTs was 0.4-3.4, while a considerably wider range was found when including all rCTs (0.2-6.7). There was nevertheless a correlation in RR based on repeat CTs for individual patients, indicating that patient-specific SC risks could be estimated. CONCLUSIONS: The estimated relative risks varied considerably across rCTs and could change the risk in favour of VMAT/IMPT depending on the anatomy of the day. The results demonstrate the importance of performing in silico studies of SC risk on a cohort of patients or multiple CTs when structures subject to organ motion are involved.

Linear energy transfer distributions in the brainstem depending on tumour location in intensity-modulated proton therapy of paediatric cancer.

BACKGROUND: For tumours near organs at risk, there is concern about unintended increase in biological dose from elevated linear energy transfer (LET) at the distal end of treatment fields. The objective of this study was therefore to investigate how different paediatric posterior fossa tumour locations impact LET and biological dose to the brainstem during intensity-modulated proton therapy (IMPT). MATERIAL AND METHODS: Multiple IMPT plans were generated for four different simulated tumour locations relative to the brainstem for a five-year-old male patient. A prescribed dose of 59.4 Gy(RBE) was applied to the planning target volumes (PTVs). Plans with two lateral and one posterior non-coplanar fields were created, along with plans with modified field arrangements. The dose-averaged LET (LETd) and the physical dose × RBELET (D × RBELET), where RBELET=1+c × LETd, were calculated using the FLUKA Monte Carlo code. A scaling parameter c was applied to make the RBELET represent variations in the biological effect due to LET. RESULTS: High LETd values surrounded parts of the PTV and encompassed portions of the brainstem. Mean LETd values in the brainstem were 3.2-6.6 keV/µm. The highest absolute brainstem LETd values were seen with the tumour located most distant from the brainstem, whereas lower and more homogeneous LETd values were seen when the tumour invaded the brainstem. In contrast, the highest mean D × RBELET values were found in the latter case (54.0 Gy(RBE)), while the case with largest distance between tumour and brainstem had a mean D × RBELET of 1.8 Gy(RBE). CONCLUSIONS: Using IMPT to treat posterior fossa tumours may result in high LETd values within the brainstem, particularly if the tumour volume is separated from the brainstem. However, the D × RBELET was greater for tumours that approached or invaded the brainstem. Changing field angles showed a reduction of LETd and D × RBELET in the brainstem.

Modelling of organ-specific radiation-induced secondary cancer risks following particle therapy.

BACKGROUND AND PURPOSE: Radiation-induced cancer is a serious late effect that may follow radiotherapy. A considerable uncertainty is associated with carcinogenesis from photon-based treatment, and even less established when including relative biological effectiveness (RBE) for particle therapy. The aim of this work was therefore to estimate and in particular explore relative risks (RR) of secondary cancer (SC) following particle therapy as applied in treatment of prostate cancer. MATERIAL AND METHODS: RRs of radiation-induced SC in the bladder and rectum were estimated using a bell-shaped dose-response model incorporating RBE and fractionation effects. The risks from volumetric modulated arc therapy (VMAT) were compared to intensity-modulated proton therapy (IMPT) and scanning carbon ions for ten patients. RESULTS: The mean estimated RR (95% CI) of SC for VMAT/C-ion was 1.31 (0.65-2.18) for the bladder and 0.58 (0.41-0.80) for the rectum. Corresponding values for VMAT/IMPT were 1.72 (1.06-2.37) and 1.10 (0.78-1.43). The radio-sensitivity parameter α had the strongest influence on the results with decreasing RR for increasing values of α. CONCLUSION: Based on the wide spread in RR between patients and variations across the included parameter values, the risk profiles of the rectum and bladder were not dramatically different for the investigated radiotherapy techniques.

Estimated risk of radiation-induced cancer following paediatric cranio-spinal irradiation with electron, photon and proton therapy.

BACKGROUND: Improvement in radiotherapy during the past decades has made the risk of developing a radiation-induced secondary cancer as a result of dose to normal tissue a highly relevant survivorship issue. Important factors expected to influence secondary cancer risk include dose level and dose heterogeneity, as well as gender and type of tissue irradiated. The elevated radio-sensitivity in children calls for models particularly tailored to paediatric cancer patients. MATERIAL AND METHODS: Treatment plans of six paediatric medulloblastoma patients were analysed with respect to secondary cancer risk following cranio-spinal irradiation (CSI), using either: 1) electrons and photons combined; 2) conformal photons; 3) double-scattering (DS) protons; or 4) intensity-modulated proton therapy (IMPT). The relative organ equivalent dose (OED) concept was applied in three dose-risk scenarios: a linear response model, a plateau response and an organ specific linear-exponential response. Life attributable risk (LAR) was calculated based on the BEIR VII committee's preferred models for estimating age- and site-specific solid cancer incidence. Uncertainties in the model input parameters were evaluated by error propagation using a Monte Carlo sampling procedure. RESULTS: Both DS protons and IMPT achieved a significantly better dose conformity compared to the photon and electron irradiation techniques resulting in a six times lower overall risk of radiation-induced cancer. Secondary cancer risk in the thyroid and lungs contributed most to the overall risk in all compared modalities, while no significant difference was observed for the bones. Variations between DS protons and IMPT were small, as were differences between electrons and photons. CONCLUSION: Regardless of technique, using protons decreases the estimated risk of secondary cancer following paediatric CSI compared to conventional photon and electron techniques. Substantial uncertainties in the LAR estimates support relative risk comparisons by OED.