Martijn Engelsman

How much margin reduction is possible through gating or breath hold

We determined the relationship between intra-fractional breathing motion and safety margins, using daily real-time tumour tracking data of 40 patients (43 tumour locations), treated with radiosurgery at Hokkaido University. We limited our study to the dose-blurring effect of intra-fractional breathing motion, and did not consider differences in positioning accuracy or systematic errors. The additional shift in the prescribed isodose level (e.g. 95 %) was determined by convolving a one-dimensional dose profile, having a dose gradient representing an 8 MV beam through either lung or water, with the probability density function (PDF) of breathing. This additional shift is a measure for the additional margin that should be applied in order to maintain the same probability of tumour control as without intra-fractional breathing. We show that the required safety margin is a nonlinear function of the peak-to-peak breathing motion. Only a small reduction in the shift of isodose curves was observed for breathing motion up to 10 mm. For larger motion, 20 or 30 mm, control of patient breathing during irradiation, using either gating or breath hold, can allow a substantial reduction in safety margins of about 7 or 12 mm depending on the dose gradient prior to blurring. Clinically relevant random setup uncertainties, which also have a blurring effect on the dose distribution, have only a small effect on the margin needed for intra-fractional breathing motion. Because of the one-dimensional nature of our analysis, the resulting margins are mainly applicable in the superior-inferior direction. Most measured breathing PDFs were not consistent with the PDF of a simple parametric curve such as cos4, either because of irregular breathing or base-line shifts. Instead, our analysis shows that breathing motion can be modelled as Gaussian with a standard deviation of about 0.4 times the peak-to-peak breathing motion.

Advanced-technology radiation therapy in the management of bone and soft tissue sarcomas.

BACKGROUND For patients with sarcomas, radiotherapy can be used as neoadjuvant, adjuvant, or primary local therapy, depending on the site and type of sarcoma, the surgical approach, and the efficacy of chemotherapy. METHODS The authors review the current status of advanced technology radiation therapy in the management of bone and soft tissue sarcoma. RESULTS Advances in radiotherapy have resulted in improved treatment for bone and soft tissue sarcomas. Intensity-modulated radiation therapy (IMRT) uses modifications in the intensity of the photon-beam from a linear accelerator across the irradiated fields to enhance dose conformation in three dimensions. For proton-beam radiation therapy, the nuclei of hydrogen atoms are accelerated in cyclotrons or synchrotrons, extracted, and transported to treatment rooms where the proton beam undergoes a series of modifications that conform the dose in a particular patient to the tumor target. Brachytherapy and intraoperative radiation therapy have generally been used to treat microscopic residual disease in patients with sarcomas. These technologies deliver dose to tumor cells with irradiation of limited volumes of normal tissue. Patients who may benefit from technically advanced radiotherapy include those with skull base and spine/paraspinal sarcomas, Ewings sarcoma, and retroperitoneal/extremity sarcomas. CONCLUSIONS Advances in radiation therapy technology, particularly IMRT, proton-beam or other charged-particle radiation therapy, brachytherapy, and intraoperative radiation therapy, have led to improved treatment for patients with bone and soft tissue sarcomas.

Target volume dose considerations in proton beam treatment planning for lung tumors.

We performed a treatment planning study in order to gather basic insight in the effect of setup errors and breathing motion on the cumulative proton dose to a lung tumor. We used a simplified geometry that simulates a 50 mm diameter gross tumor volume (GTV) located centrally inside lung tissue. The GTV was expanded with a uniform 5 mm margin into a clinical target volume (CTV) and into a variety of planning target volume (PTVs). Proton beam apertures were designed to conform the prescribed dose laterally to the PTV while the range compensator was designed to provide distal coverage of the CTV. Different smearing distances were applied to the range compensators, and the cumulative dose in the CTV was evaluated for different combinations of breathing motion and systematic setup errors. Evaluation parameters were the dose to 99% of the CTV (D99) and the equivalent uniform dose (EUD), with a surviving fraction at 2 Gy of SF2 = 0.5. For a single proton field designed to a 15 mm expansion of the CTV and without smearing applied to the range compensator, D99 of the CTV reduced from 96% for no tumor displacement to 41% and 13% for systematic setup errors of 5 and 10 mm, respectively. For a representative clinical combination, of 5 mm systematic error and 10 mm breathing amplitude, the EUD of the CTV was about 40 Gy (prescribed dose 70 Gy) regardless the CTV to PTV margin, and without smearing. Smearing the range compensator increases the dose to the CTV substantially with a lateral margin and smearing distance of 7.5 mm providing ample tumor coverage. In this latter case, D99 of the target volume increased to 87% for a single field treatment plan. Smearing does, however, lead to an increase in dose to normal tissues distal to the clinical target volume. Next to countering geometric mismatches due to patient setup, smearing can also be used to counter the detrimental effects of breathing motion on the dose to the clinical target volume. We show that the lateral margin and smearing distance can be substantially smaller than the maximum tumor displacement due to setup errors and patient breathing, as measured by the D99 and the EUD.

Results of a Multicentric In Silico Clinical Trial (ROCOCO): Comparing Radiotherapy with Photons and Protons for Non-small Cell Lung Cancer

Introduction: This multicentric in silico trial compares photon and proton radiotherapy for non-small cell lung cancer patients. The hypothesis is that proton radiotherapy decreases the dose and the volume of irradiated normal tissues even when escalating to the maximum tolerable dose of one or more of the organs at risk (OAR). Methods: Twenty-five patients, stage IA-IIIB, were prospectively included. On 4D F18-labeled fluorodeoxyglucose-positron emission tomography-computed tomography scans, the gross tumor, clinical and planning target volumes, and OAR were delineated. Three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT) photon and passive scattered conformal proton therapy (PSPT) plans were created to give 70 Gy to the tumor in 35 fractions. Dose (de-)escalation was performed by rescaling to the maximum tolerable dose. Results: Protons resulted in the lowest dose to the OAR, while keeping the dose to the target at 70 Gy. The integral dose (ID) was higher for 3DCRT (59%) and IMRT (43%) than for PSPT. The mean lung dose reduced from 18.9 Gy for 3DCRT and 16.4 Gy for IMRT to 13.5 Gy for PSPT. For 10 patients, escalation to 87 Gy was possible for all 3 modalities. The mean lung dose and ID were 40 and 65% higher for photons than for protons, respectively. Conclusions: The treatment planning results of the Radiation Oncology Collaborative Comparison trial show a reduction of ID and the dose to the OAR when treating with protons instead of photons, even with dose escalation. This shows that PSPT is able to give a high tumor dose, while keeping the OAR dose lower than with the photon modalities.

Accuracy of Proton Beam Range Verification Using Post-Treatment Positron Emission Tomography/Computed Tomography as Function of Treatment Site

PURPOSE For 23 patients, an off-line positron emission tomography scan and a computed tomography scan after proton radiotherapy was performed at the Massachusetts General Hospital to assess in vivo treatment verification. A well-balanced population of patients was investigated to assess the effect of the tumor location on the accuracy of the technique. METHODS AND MATERIALS Range verification was achieved by comparing the measured positron emission tomography activity distributions with the corresponding Monte Carlo-simulated distributions. Observed differences in the distal end of the activity distributions were analyzed as potential indicators for the range differences between the actual delivered and planned dose. RESULTS The average spatial agreement between the measured and simulated activity distribution was within ±3 mm, and the corresponding average absolute agreement was within ±45% (derived from gamma index analysis). The mean absolute range deviation at 93 randomly chosen positions in 17 treatment fields delivered to 11 patients was 3.6 mm. Characteristic differences in the agreement of the measured and simulated activity distribution for the different tumor/target sites were found. This resulted from the different effect of factors such as biologic washout effects, motion, or limitations in the Monte Carlo-simulated activity patterns. CONCLUSION We found that intracranial and cervical spine patients can greatly benefit from off-line positron emission tomography and computed tomography range verification. However, for the successful application of the method to patients with abdominopelvic tumors, major technological and methodologic improvements are needed. Among the intracranial and cervical spine target sites, patients with arteriovenous malformations or metal implants represent groups that could especially benefit from the approach.

Comparison between the lateral penumbra of a collimated double-scattered beam and uncollimated scanning beam in proton radiotherapy.

Intensity modulated proton radiotherapy (IMPT) can reduce the dose to critical structures by optimizing the distribution and intensity of individual pencil beams. The IMPT can be delivered by dynamically scanning a pencil beam with variable intensity and energy across the tumor target volume. The lateral penumbra of an uncollimated pencil beam is compromised, however, by the scattering in air between the vacuum window and the patient, and by the initial beam size. In this study, we compare the transversal penumbra of a pencil beam to the one of a collimated Gaussian broad divergent beam, such as the one produced by the double scattering system, for different range compensator thicknesses, collimator-to-surface distances (CSD), proton range and pencil beam sizes (sigma0). The effect of vacuum and helium in the nozzle on the pencil beam lateral profile further downstream is also investigated. The lateral spatial intensity distribution for the collimated Gaussian broad divergent proton beam is modeled using the generalized Fermi-Eyges theory. The model is validated with measurements of the lateral profile in water at different depths for two different ranges (7.7 cm and 22.1 cm, respectively). Nearly 2500 treatment fields are analyzed to establish typical clinical beam configurations, such as the range compensator thicknesses, CSD and range, which we use to predict the 80%-20% lateral penumbra. The penumbra of the collimated broad divergent beam is calculated for fixed source-to-surface distance (SSD) of 220 cm and source size of 2.5 cm (sigma). The results show that the model predicts the penumbra at different water depths with accuracy better than 0.2 mm. At depths larger than 7.6 cm (minimum range of the clinical fields analyzed), the accuracy is better than 3%. The treatment fields feature the following average configuration: the range compensator thickness of 6.5+/-2.8 cm (max 19.4 cm), CSD 11.9+/-3.8 cm (max 29.4 cm) and range of 16.0+/-6.1 cm. The penumbra of a pencil beam at shallow depth is in general larger (i.e., worse) than the penumbra of a collimated beam, but better at larger depths. The depth at which the two penumbras are identical exhibits only a small dependence on the proton range, but is strongly affected by the collimator-to-surface distance. For CSD 10 cm, range compensator thickness 6 cm, SSD 220 cm and source size 2.5 cm, this depth is 11.5 cm for a 5 mm pencil beam, and 9.1 cm for a 3 mm pencil beam. For most of the clinical sites considered, assuming the beam configurations of this study, the pencil beam penumbra is larger (i.e., worse). By moving the vacuum window downstream or by replacing air with helium in the gantry nozzle, the dosimetrical benefit of scanning would be drastically improved, especially for small sigma0 (5 mm or less).

The prediction of output factors for spread-out proton Bragg peak fields in clinical practice

The reliable prediction of output factors for spread-out proton Bragg peak (SOBP) fields in clinical practice remained unrealized due to a lack of a consistent theoretical framework and the great number of variables introduced by the mechanical devices necessary for the production of such fields. These limitations necessitated an almost exclusive reliance on manual calibration for individual fields and empirical, ad hoc, models. We recently reported on a theoretical framework for the prediction of output factors for such fields. In this work, we describe the implementation of this framework in our clinical practice. In our practice, we use a treatment delivery nozzle that uses a limited, and constant, set of mechanical devices to produce SOBP fields over the full extent of clinical penetration depths, or ranges, and modulation widths. This use of a limited set of mechanical devices allows us to unfold the physical effects that affect the output factor. We describe these effects and their incorporation into the theoretical framework. We describe the calibration and protocol for SOBP fields, the effects of apertures and range-compensators and the use of output factors in the treatment planning process.

Interfractional Variations in the Setup of Pelvic Bony Anatomy and Soft Tissue, and Their Implications on the Delivery of Proton Therapy for Localized Prostate Cancer

PURPOSE To quantify daily variations in the anatomy of patients undergoing radiation therapy for prostate carcinoma, to estimate their effect on dose distribution, and to evaluate the effectiveness of current standard planning and setup approaches employed in proton therapy. METHODS We used series of computed tomography data, which included the pretreatment scan, and between 21 and 43 in-room scans acquired on different treatment days, from 10 patients treated with intensity-modulated radiation therapy at Morristown Memorial Hospital. Variations in femur rotation angles, thickness of subcutaneous adipose tissue, and physical depth to the distal surface of the prostate for lateral beam arrangement were recorded. Proton dose distributions were planned with the standard approach. Daily variations in the location of the prescription isodose were evaluated. RESULTS In all 10 datasets, substantial variation was observed in the lateral tissue thickness (standard deviation of 1.7-3.6 mm for individual patients, variations of >5 mm from the planning computed tomography observed in all series), and femur rotation angle (standard deviation between 1.3° and 4.8°, with the maximum excursion exceeding 10° in 6 of 10 datasets). Shifts in the position of treated volume (98% isodose) were correlated with the variations in the lateral tissue thickness. CONCLUSIONS Analysis suggests that, combined with image-guided setup verification, the range compensator expansion technique prevents loss of dose to target from femur rotation and soft-tissue deformation, in the majority of cases. Anatomic changes coupled with the uncertainties of particle penetration in tissue restrict possibilities for margin reduction in proton therapy of prostate cancer.

Proton SBRT for medically inoperable stage i NSCLC

Introduction: The physical properties of proton beam radiation may offer advantages for treating patients with non–small-cell lung cancer (NSCLC). However, its utility for the treatment of medically inoperable stage I NSCLC patients with stereotactic body radiation therapy (SBRT) is unknown. Methods: Outcomes for patients with medically inoperable stage I NSCLC treated with proton SBRT were retrospectively analyzed. Proton SBRT was selected as the treatment modality based on pulmonary comorbidities (n = 5), prior chest radiation or/and multiple primary tumors (n = 7), or other reasons (n = 3). Treatments were administered using 2 to 3 proton beams. Treatment toxicity was scored according to common toxicity criteria for adverse events version 4 criteria. Results: Fifteen consecutive patients and 20 tumors were treated with proton SBRT to 42 to 50 Gy(relative biological effectiveness) in 3 to 5 fractions between July 2008 and September 2010. Treatments were well tolerated with only one case of grade 2 fatigue, one case of grade 2 dermatitis, three cases of rib fracture (maximum grade 2), and one case of grade 3 pneumonitis in a patient with severe chronic obstructive pulmonary disease. With a median follow-up of 24.1 months, 2-year overall survival and local control rates were 64% (95% confidence limits, 34%–83%) and 100% (83%–100%), respectively. Conclusions: We conclude that proton SBRT is effective and well tolerated in this unfavorable group of patients. Prospective clinical trials testing the utility of proton SBRT in stage I NSCLC are warranted.

Design of and technical challenges involved in a framework for multicentric radiotherapy treatment planning studies

This report introduces a framework for comparing radiotherapy treatment planning in multicentric in silico clinical trials. Quality assurance, data incompatibility, transfer and storage issues, and uniform analysis of results are discussed. The solutions that are given provide a useful guide for the set-up of future multicentric planning studies or public repositories of high quality data.