Dosimetric Comparison of Conventional Radiotherapy, Volumetric Modulated Arc Therapy, and Proton Beam Therapy for Palliation of Thoracic Spine Metastases Secondary to Breast or Prostate Cancer.

The aim of this planning study was to compare the dosimetric outcomes of Volumetric Modulated Arc Therapy (VMAT), Proton Beam Therapy (PBT), and conventional External Beam Radiation Therapy (cEBRT) in the treatment of thoracic spinal metastases originating from breast or prostate cancer. Our study utilized data from 30 different treatment plans and evaluated target coverage and doses to vital organs at risk (OARs), such as the spinal cord, heart, esophagus, and lungs. The results showed that VMAT and PBT achieved superior target coverage and significantly lower doses to the spinal cord compared to cEBRT (target: median PTVD95%: 75.2 for cEBRT vs. 92.9 and 91.7 for VMAT (p < 0.001) and PBT (p < 0.001), respectively; spinal cord: median Dmax%: 105.1 for cEBRT vs. 100.4 and 103.6 for VMAT (p < 0.001) and PBT (p = 0.002), respectively). Specifically, VMAT was notable for its superior target coverage and PBT for significantly lower doses to heart, lungs, and esophagus. However, VMAT resulted in higher lung doses, indicating potential trade-offs among different techniques. The study demonstrated the relative advantages of VMAT and PBT over traditional RT in the palliative treatment of spinal metastases using conventional fractionation. These findings underscore the potential of VMAT and PBT to improve dosimetric outcomes, suggesting that they may be more suitable for certain patient groups for whom the sparing of specific OARs is especially important.

Modeling secondary cancer risk ratios for proton versus carbon ion beam therapy: A comparative study based on the local effect model.

BACKGROUND: Ion beam therapy allows for substantial sparing of normal tissues. Besides deterministic normal-tissue complications, stochastic long-term effects like secondary cancer (SC) induction are of importance when comparing different treatment modalities. PURPOSE: To develop a modeling approach for comparison of SC risk in proton and carbon ion therapy. METHODS AND MATERIALS: The local effect model (LEM) is used to predict the relative biological effectiveness (RBE) of SC induction after particle therapy. A key feature of the new approach is the double use of the LEM, reflecting the competition between the two processes of mutation induction (leading to cancer development) and cell inactivation (leading to suppression of cancer development). Based on previous investigations, treatment plans were in this work analyzed for an idealized geometry in order to assess the underlying systematic dependencies of cancer induction. In a further step, relative SC risks were predicted for proton and carbon ion treatment plans prepared for 10 prostate cancer patients. RESULTS: We investigated the impact of factors such as treatment plan geometry, fractionation scheme, and tissue radiosensitivity to photon irradiation on the ion beam SC risk. Our model studies do not result in a clear preference for either protons or carbon ions, but rather indicate a complex interplay of different aspects. Reduced lateral scattering leads to a lower SC risk for carbon ions compared to protons at the lateral field margins in the entrance channel, while an increased risk was found closely behind the tumor due to projectile fragmentation. The fractionation scheme had little impact on the expected risk ratio. With respect to sensitivity parameters, those characterizing RBE for cell killing of potentially cancerous cells as well as of the primary tumor had the most significant impact. The observed general systematic dependencies are in agreement with results from previous model studies. The prostate patient study reveals reduced SC risks predictions for skin and bones for carbon ions as compared to protons, but higher mean risks for bladder and rectum. CONCLUSION: The methods established in this work provide a basis for further investigating treatment optimizing strategies for ion beam therapy with regard to SC risk comparisons.

Estimated Risk of Radiation-Induced Cancer after Thymoma Treatments with Proton- or X-ray Beams.

We compared the calculated risks of radiation-induced secondary malignant neoplasms (SMNs) for patients treated for thymic tumors with 3D-CRT, IMRT, or single-field uniform dose (SFUD) proton beam therapy (PBT) using the pencil beam scanning (PBS) technique. A cancer-induction model based on the organ equivalent dose (OED) concept was used. For twelve patients, treated with 3D-CRT for thymic tumors, alternative IMRT and SFUD plans were retrospectively prepared. The resulting DVHs for organs at risk (OARs) were extracted and used to estimate the risk of SMNs. The OED was calculated using a mechanistic model for carcinoma induction. Two limit cases were considered; the linear-exponential model, in which the repopulation/repair of the cells is neglected, and the plateau model, in which full repopulation/repair of the irradiated cells is assumed. The calculated risks for SMNs for the different radiation modalities and dose-relation models were used to calculate relative risks, which were compared pairwise. The risks for developing SMNs were reduced for all OARs, and for both dose-relation models, if SFUD was used, compared to 3D-CRT and IMRT. In conclusion, PBS shows a potential benefit to reduce the risk of SMNs compared to 3D-CRT and IMRT in the treatment of thymic tumors.

Locomotion and eating behavior changes in Yucatan minipigs after unilateral radio-induced ablation of the caudate nucleus.

The functional roles of the Caudate nucleus (Cd) are well known. Selective Cd lesions can be found in neurological disorders. However, little is known about the dynamics of the behavioral changes during progressive Cd ablation. Current stereotactic radiosurgery technologies allow the progressive ablation of a brain region with limited adverse effects in surrounding normal tissues. This could be of high interest for the study of the modified behavioral functions in relation with the degree of impairment of the brain structures. Using hypofractionated stereotactic radiotherapy combined with synchrotron microbeam radiation, we investigated, during one year after irradiation, the effects of unilateral radio-ablation of the right Cd on the behavior of Yucatan minipigs. The right Cd was irradiated to a minimal dose of 35.5 Gy delivered in three fractions. MRI-based morphological brain integrity and behavioral functions, i.e. locomotion, motivation/hedonism were assessed. We detected a progressive radio-necrosis leading to a quasi-total ablation one year after irradiation, with an additional alteration of surrounding areas. Transitory changes in the motivation/hedonism were firstly detected, then on locomotion, suggesting the influence of different compensatory mechanisms depending on the functions related to Cd and possibly some surrounding areas. We concluded that early behavioral changes related to eating functions are relevant markers for the early detection of ongoing lesions occurring in Cd-related neurological disorders.

An in silico planning study comparing doses and estimated risk of toxicity in 3D-CRT, IMRT and proton beam therapy of patients with thymic tumours.

PURPOSE: To compare the dose distributions produced in patients (pts) treated for thymic tumours with spot-scanning proton beam therapy (PBT) implemented with single-field uniform dose (SFUD), intensity-modulated radiation therapy (IMRT) and three-dimensional conformal photon-beam based radiotherapy (3D-CRT). METHODS: Twelve pts, treated with 3D-CRT, were included. Alternative IMRT and SFUD plans were constructed. The IMRT plans were created using a setup with beams incident from 5 to 6 different angles. For the SFUD plans, a field-specific planning target volume (PTV) was created for each patient and a clinical target volume (CTV)-based robust optimization was performed. A robustness evaluation was performed for the CTV for all SFUD plans. A dosimetric evaluation was conducted for the doses to the CTV and organs at risk (OARs) for all plans. The normal tissue complication probability (NTCP), for different endpoints, was calculated using the Lyman-Kutcher-Burman (LKB)-model and compared between plans. RESULTS: SFUD was associated with significantly lower mean doses to the oesophagus, the heart, the left anterior descending coronary artery (LAD), lungs and breasts compared to 3D-CRT and IMRT. The maximum dose given to the spinal cord was significantly lower with SFUD. The risks for pneumonitis, esophagitis and myelopathy were significantly reduced in the SFUD plans. CONCLUSIONS: The present study showed dosimetric advantages of using scanned-beam PBT for the treatment of thymic tumours, as compared to 3D-CRT and IMRT, especially in regard to lower doses to the oesophagus and lungs. The risk of toxicity was reduced with SFUD.

Estimation of the risk for radiation-induced liver disease following photon- or proton-beam radiosurgery of liver metastases.

BACKGROUND: Radiotherapy of liver metastases is commonly being performed with photon-beam based stereotactic body radiation therapy (SBRT). The high risk for radiation-induced liver disease (RILD) is a limiting factor in these treatments. The use of proton-beam based SBRT could potentially improve the sparing of the healthy part of the liver. The aim of this study was to use estimations of normal tissue complication probability (NTCP) to identify liver-metastases patients that could benefit from being treated with intensity-modulated proton therapy (IMPT), based on the reduction of the risk for RILD. METHODS: Ten liver metastases patients, previously treated with photon-beam based SBRT, were retrospectively planned with IMPT. A CTV-based robust optimisation (accounting for setup and range uncertainties), combined with a PTV-based conventional optimisation, was performed. A robustness criterion was defined for the CTV (V95% > 98% for at least 10 of the 12 simulated scenarios). The NTCP was estimated for different endpoints using the Lyman-Kutcher-Burman model. The ΔNTCP (NTCPIMPT - NTCPSBRT) for RILD was registered for each patient. The patients for which the NTCP (RILD) < 5% were also identified. A generic relative biological effectiveness of 1.1 was assumed for the proton beams. RESULTS: For all patients, the objectives set for the PTV and the robustness criterion set for the CTV were fulfilled with the IMPT plans. An improved sparing of the healthy part of the liver, right kidney, lungs, spinal cord and the skin was achieved with the IMPT plans, compared to the SBRT plans. Mean liver doses larger than the threshold value of 32 Gy led to NTCP values for RILD exceeding 5% (7 patients with SBRT and 3 patients with the IMPT plans). ΔNTCP values (RILD) ranging between - 98% and - 17% (7 patients) and between 0 and 2% (3 patients), were calculated. CONCLUSIONS: In this study, liver metastases patients that could benefit from being treated with IMPT, based on the NTCP reductions, were identified. The clinical implementation of such a model-based approach to select liver metastases patients to proton therapy needs to be made with caution while considering the uncertainties involved in the NTCP estimations.

Estimation of Risk of Normal-tissue Toxicity Following Gastric Cancer Radiotherapy with Photon- or Scanned Proton-beams.

BACKGROUND/AIM: Gastric cancer (GC) radiotherapy involves irradiation of large tumour volumes located in the proximities of critical structures. The advantageous dose distributions produced by scanned-proton beams could reduce the irradiated volumes of the organs at risk (OARs). However, treatment-induced side-effects may still appear. The aim of this study was to estimate the normal tissue complication probability (NTCP) following proton therapy of GC, compared to photon radiotherapy. PATIENTS AND METHODS: Eight GC patients, previously treated with volumetric-modulated arc therapy (VMAT), were retrospectively planned with scanned proton beams carried out with the single-field uniform-dose (SFUD) method. A beam-specific planning target volume was used for spot positioning and a clinical target volume (CTV) based robust optimisation was performed considering setup- and range-uncertainties. The dosimetric and NTCP values obtained with the VMAT and SFUD plans were compared. RESULTS: With SFUD, lower or similar dose-volume values were obtained for OARs, compared to VMAT. NTCP values of 0% were determined with the VMAT and SFUD plans for all OARs (p>0.05), except for the left kidney (p<0.05), for which lower toxicity was estimated with SFUD. CONCLUSION: The NTCP reduction, determined for the left kidney with SFUD, can be of clinical relevance for preserving renal function after radiotherapy of GC.

Quantitative evaluation of potential irradiation geometries for carbon-ion beam grid therapy.

PURPOSE: Radiotherapy using grids containing cm-wide beam elements has been carried out sporadically for more than a century. During the past two decades, preclinical research on radiotherapy with grids containing small beam elements, 25 µm-0.7 mm wide, has been performed. Grid therapy with larger beam elements is technically easier to implement, but the normal tissue tolerance to the treatment is decreasing. In this work, a new approach in grid therapy, based on irradiations with grids containing narrow carbon-ion beam elements was evaluated dosimetrically. The aim formulated for the suggested treatment was to obtain a uniform target dose combined with well-defined grids in the irradiated normal tissue. The gain, obtained by crossfiring the carbon-ion beam grids over a simulated target volume, was quantitatively evaluated. METHODS: The dose distributions produced by narrow rectangular carbon-ion beams in a water phantom were simulated with the PHITS Monte Carlo code. The beam-element height was set to 2.0 cm in the simulations, while the widths varied from 0.5 to 10.0 mm. A spread-out Bragg peak (SOBP) was then created for each beam element in the grid, to cover the target volume with dose in the depth direction. The dose distributions produced by the beam-grid irradiations were thereafter constructed by adding the dose profiles simulated for single beam elements. The variation of the valley-to-peak dose ratio (VPDR) with depth in water was thereafter evaluated. The separation of the beam elements inside the grids were determined for different irradiation geometries with a selection criterion. RESULTS: The simulated carbon-ion beams remained narrow down to the depths of the Bragg peaks. With the formulated selection criterion, a beam-element separation which was close to the beam-element width was found optimal for grids containing 3.0-mm-wide beam elements, while a separation which was considerably larger than the beam-element width was found advantageous for grids containing 0.5-mm-wide beam elements. With the single-grid irradiation setup, the VPDRs were close to 1.0 already at a distance of several cm from the target. The valley doses given to the normal tissue at 0.5 cm distance from the target volume could be limited to less than 10% of the mean target dose if a crossfiring setup with four interlaced grids was used. CONCLUSIONS: The dose distributions produced by grids containing 0.5- and 3.0-mm wide beam elements had characteristics which could be useful for grid therapy. Grids containing mm-wide carbon-ion beam elements could be advantageous due to the technical ease with which these beams can be produced and delivered, despite the reduced threshold doses observed for early and late responding normal tissue for beams of millimeter width, compared to submillimetric beams. The treatment simulations showed that nearly homogeneous dose distributions could be created inside the target volumes, combined with low valley doses in the normal tissue located close to the target volume, if the carbon-ion beam grids were crossfired in an interlaced manner with optimally selected beam-element separations. The formulated selection criterion was found useful for the quantitative evaluation of the dose distributions produced by the different irradiation setups.

Development of an interlaced-crossfiring geometry for proton grid therapy.

BACKGROUND: Grid therapy has in the past normally been performed with single field photon-beam grids. In this work, we evaluated a method to deliver grid therapy based on interlacing and crossfiring grids of mm-wide proton beamlets over a target volume, by Monte Carlo simulations. MATERIAL AND METHODS: Dose profiles for single mm-wide proton beamlets (1, 2 and 3 mm FWHM) in water were simulated with the Monte Carlo code TOPAS. Thereafter, grids of proton beamlets were directed toward a cubic target volume, located at the center of a water tank. The aim was to deliver a nearly homogeneous dose to the target, while creating high dose heterogeneity in the normal tissue, i.e., high gradients between valley and peak doses in the grids, down to the close vicinity of the target. RESULTS: The relative increase of the beam width with depth was largest for the smallest beams (+6.9 mm for 1 mm wide and 150 MeV proton beamlets). Satisfying dose coverage of the cubic target volume (σ < ±5%) was obtained with the interlaced-crossfiring setup, while keeping the grid pattern of the dose distribution down to the target (valley-to-peak dose ratio <0.5 less than 1 cm before the target). Center-to-center distances around 7-8 mm between the beams were found to give the best compromise between target dose homogeneity and low peak doses outside of the target. CONCLUSIONS: A nearly homogeneous dose distribution can be obtained in a target volume by crossfiring grids of mm-wide proton-beamlets, while maintaining the grid pattern of the dose distribution at large depths in the normal tissue, close to the target volume. We expect that the use of this method will increase the tumor control probability and improve the normal tissue sparing in grid therapy.

Proton Grid Therapy: A Proof-of-Concept Study.

In this work, we studied the possibility of merging proton therapy with grid therapy. We hypothesized that patients with larger targets containing solid tumor growth could benefit from being treated with this method, proton grid therapy. We performed treatment planning for 2 patients with abdominal cancer with the suggested proton grid therapy technique. The proton beam arrays were cross-fired over the target volume. Circular or rectangular beam element shapes (building up the beam grids) were evaluated in the planning. An optimization was performed to calculate the fluence from each beam grid element. The optimization objectives were set to create a homogeneous dose inside the target volume with the constraint of maintaining the grid structure of the dose distribution in the surrounding tissue. The proton beam elements constituting the grid remained narrow and parallel down to large depths in the tissue. The calculation results showed that it is possible to produce target doses ranging between 100% and 130% of the prescribed dose by cross-firing beam grids, incident from 4 directions. A sensitivity test showed that a small rotation or translation of one of the used grids, due to setup errors, had only a limited influence on the dose distribution produced in the target, if 4 beam arrays were used for the irradiation. Proton grid therapy is technically feasible at proton therapy centers equipped with spot scanning systems using existing tools. By cross-firing the proton beam grids, a low tissue dose in between the paths of the elemental beams can be maintained down to the vicinity of a deep-seated target. With proton grid therapy, it is possible to produce a dose distribution inside the target volume of similar uniformity as can be created with current clinical methods.

Comparative study of the calculated risk of radiation-induced cancer after photon- and proton-beam based radiosurgery of liver metastases.

INTRODUCTION: The potential of proton therapy to improve the sparing of the healthy tissue has been demonstrated in several studies. However, even small doses delivered to the organs at risk (OAR) may induce long-term detriments after radiotherapy. In this study, we investigated the possibility to reduce the risk of radiation-induced secondary cancers with intensity modulated proton therapy (IMPT), when used for radiosurgery of liver metastases. MATERIAL AND METHODS: Ten patients, previously treated for liver metastases with photon-beam based stereotactic body radiation therapy (SBRT) were retrospectively planned for radiosurgery with IMPT. A treatment plan comparison was then performed in terms of calculated risk of radiation-induced secondary cancer. The risks were estimated using two distinct models (Dasu et al., 2005; Schneider et al., 2005, 2009). The plans were compared pairwise with a two-sided Wilcoxon signed-rank test with a significance level of 0.05. RESULTS: Reduced risks for induction of fatal and other types of cancers were estimated for the IMPT plans (p<0.05) with the Dasu et al. MODEL: Using the Schneider et al. model, lower risks for carcinoma-induction with IMPT were estimated for the skin, lungs, healthy part of the liver, esophagus and the remaining part of the body (p<0.05). The risk of observing sarcomas in the bone was also reduced with IMPT (p<0.05). CONCLUSION: The findings of this study indicate that the risks of radiation-induced secondary cancers after radiosurgery of liver metastases may be reduced, if IMPT is used instead of photon-beam based SBRT.

Comparison of gastric-cancer radiotherapy performed with volumetric modulated arc therapy or single-field uniform-dose proton therapy.

BACKGROUND: Proton-beam therapy of large abdominal cancers has been questioned due to the large variations in tissue density in the abdomen. The aim of this study was to evaluate the importance of these variations for the dose distributions produced in adjuvant radiotherapy of gastric cancer (GC), implemented with photon-based volumetric modulated arc therapy (VMAT) or with proton-beam single-field uniform-dose (SFUD) method. MATERIAL AND METHODS: Eight GC patients were included in this study. For each patient, a VMAT- and an SFUD-plan were created. The prescription dose was 45 Gy (IsoE) given in 25 fractions. The plans were prepared on the original CT studies and the doses were thereafter recalculated on two modified CT studies (one with extra water filling and the other with expanded abdominal air-cavity volumes). RESULTS: Compared to the original VMAT plans, the SFUD plans resulted in reduced median values for the V18 of the left kidney (26%), the liver mean dose (14.8 Gy (IsoE)) and the maximum dose given to the spinal cord (26.6 Gy (IsoE)). However, the PTV coverage decreased when the SFUD plans were recalculated on CT sets with extra air- (86%) and water-filling (87%). The added water filling only led to minor dosimetric changes for the OARs, but the extra air caused significant increases of the median values of V18 for the right and left kidneys (10% and 12%, respectively) and of V10 for the liver (12%). The density changes influenced the dose distributions in the VMAT plans to a minor extent. CONCLUSIONS: SFUD was found to be superior to VMAT for the plans prepared on the original CT sets. However, SFUD was inferior to VMAT for the modified CT sets.

Dosimetric Comparison of Plans for Photon- or Proton-Beam Based Radiosurgery of Liver Metastases.

PURPOSE: Radiosurgery treatment of liver metastases with photon beams has been an established method for more than a decade. One method commonly used is the stereotactic body radiation therapy (SBRT) technique. The aim of this study was to investigate the potential sparing of the organs at risk (OARs) that the use of intensity-modulated proton therapy (IMPT), instead of SBRT, could enable. PATIENTS AND METHODS: A comparative treatment-planning study of photon-beam and proton-beam based liver-cancer radiosurgery was performed. Ten patients diagnosed with liver metastasis and previously treated with SBRT at the Karolinska University Hospital were included in the study. New IMPT plans were prepared for all patients, while the original plans were set as reference plans. The IMPT planning was performed with the objective of achieving the same target dose coverage as with the SBRT plans. Pairwise dosimetric comparisons of the treatment plans were then performed for the OARs. A 2-sided Wilcoxon signed-rank test with significance level of 5% was carried out. RESULTS: Improved sparing of the OARs was made possible with the IMPT plans. There was a significant decrease of the mean doses delivered to the following risk organs: the nontargeted part of the liver (P = .002), the esophagus (P = .002), the right kidney (P = .008), the spinal cord (P = .004), and the lungs (P = .002). The volume of the liver receiving less than 15 Gy was significantly increased with the IMPT plans (P = .004). CONCLUSION: The IMPT-based radiosurgery plans provided similar target coverage and significant dose reductions for the OARs compared with the photon-beam based SBRT plans. Further studies including detailed information about varying tissue heterogeneities in the beam path, due to organ motion, are required to evaluate more accurately whether IMPT is preferable for the radiosurgical treatment of liver metastases.

Response of the rat spinal cord to X-ray microbeams.

BACKGROUND AND PURPOSE: To quantify the late dose-related responses of the rat cervical spinal cord to X-ray irradiations by an array of microbeams or by a single millimeter beam. MATERIALS AND METHODS: Necks of anesthetized rats were irradiated transversely by an 11 mm wide array of 52 parallel, 35 µm wide, vertical X-ray microbeams, separated by 210 µm intervals between centers. Comparison was made with rats irradiated with a 1.35 mm wide single beam of similar X-rays. Rats were killed when paresis developed, or up to 383 days post irradiation (dpi). RESULTS: Microbeam peak/valley doses of ≈357/12.7 Gy to 715/25.4 Gy to an 11 mm long segment of the spinal cord, or single beam doses of ≈146-454 Gy to a 1.35 mm long segment caused foreleg paresis and histopathologically verified spinal cord damage; rats exposed to peak/valley doses up to 253/9 Gy were paresis-free at 383 dpi. CONCLUSIONS: Whereas microbeam radiation therapy [MRT] for malignant gliomas implanted in rat brains can be safe, palliative or curative, the high tolerance of normal rat spinal cords to similar microbeam exposures justifies testing MRT for autochthonous malignancies in the central nervous system of larger animals with a view to subsequent clinical applications.

Delineation of gross tumor volume (GTV) for radiation treatment planning of locally advanced rectal cancer using information from MRI or FDG-PET/CT: a prospective study.

PURPOSE: Accurate delineation of target volumes is important to maximize radiation dose to the tumor and minimize it to nontumor tissue. Computed tomography (CT) and magnetic resonance imaging (MRI) are standard imaging modalities in rectal cancer. The aim was to explore whether functional imaging with F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET), combined with CT (FDG-PET/CT) gives additional information to standard pretreatment evaluation and changes the shape and size of the gross tumor volume (GTV). METHODS AND MATERIALS: From 2007 to 2009, 77 consecutive patients with locally advanced rectal cancer were prospectively screened for inclusion in the study at two university hospitals in Sweden, and 68 patients were eligible. Standard GTV was delineated using information from clinical examination, CT, and MRI (GTV-MRI). Thereafter, a GTV-PET was defined in the fused PET-CT, and the target volume delineations were compared for total volume, overlap, and mismatch. Pathologic uptake suspect of metastases was also registered. RESULTS: The median volume of GTV-MRI was larger than that of GTV-PET: 111 cm(3) vs. 87 cm(3) (p < 0.001). In many cases, the GTV-MRI contained the GTV defined on the PET/CT images as subvolumes, but when a GTV total was calculated after the addition of GTV-PET to GTV-MRI, the volume increased, with median 11% (range, 0.5-72%). New lesions were seen in 15% of the patients for whom PET/CT was used. CONCLUSIONS: FDG-PET/CT facilitates and adds important information to the standard delineation procedure of locally advanced rectal cancer, mostly resulting in a smaller GTV, but a larger total GTV using the union of GTV-MRI and GTV-PET. New lesions were sometimes seen, potentially changing the treatment strategy.