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.
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 (V
> 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 (NTCP
- NTCP
) 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.
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.
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.
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.
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).
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.
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.
•Dose distributions was compared between SFUD, 3D-CRT and IMRT in pts with thymic tumours.•NTCP for different endpoints was calculated and compared between plans.•SFUD was associated with ...significantly lower doses to organs at risk.•The risk of toxicity was reduced with SFUD for several endpoints.
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).
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.
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.
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.
Highlights • Comparison of risks for cancer induction after SBRT and IMPT of liver metastases. • With the Dasu-model, the highest risks were estimated for the skin. • With the Schneider-model, the ...highest risk-ratios were estimated for the liver. • Both the fatal- and total-cancer risks were lower when the IMPT method was used. • Both the carcinoma- and sarcoma risks were lower when the IMPT method was used.
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.
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.
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 (
= .002), the esophagus (
= .002), the right kidney (
= .008), the spinal cord (
= .004), and the lungs (
= .002). The volume of the liver receiving less than 15 Gy was significantly increased with the IMPT plans (
= .004).
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.
Recently, there has been an increase in the number of proton beam therapy (PBT) centers operating worldwide. For certain cases, proton beams have been shown to provide dosimetric and radiobiological ...advantages when used for cancer treatment, compared to the regular photon-beam based treatments. Under ideal circumstances, the dose given to the tissues surrounding a target can be reduced with PBT. The risk for side effects following treatment is then expected to decrease. Until present, mainly stationary targets, e.g. targets in the brain, have been treated with PBT. There is currently a growing interest to treat also target volumes in other parts of the body with PBT. However, there are sources of uncertainties, which must be more carefully considered when PBT is used, especially for PBT carried out with scanned proton beams. PBT is more sensitive to anatomical changes, e.g. organ motion or a variable gas content in the intestines, which requires that special precautions are taken prior to treating new tumour sites. In photon beam radiotherapy (RT) of moving targets, the main consequence of organ motion is the loss of sharpness of the dose gradients (dose smearing). When scanned proton beams are used, dose deformation caused by the fluctuations in the proton beam range, due to varying tissue heterogeneities (e.g., the ribs moving in and out of the beam path) and the so-called interplay effect, can be expected to impact the dose distributions in addition to the dose smearing. The dosimetric uncertainties, if not accounted for, may cause the planned and accurately calculated dose distribution to be distorted, compromising the main goal of RT of achieving the maximal local disease control while accepting certain risks for normal tissue complications. Currently there is a lack of clinical follow-up data regarding the outcome of PBT for different tumour sites, in particular for extra-cranial tumour sites in moving organs. On the other hand, the use of photon beams for this kind of cancer treatment is well-stablished. A treatment planning comparison between RT carried out with photons and with protons may provide guidelines for when PBT could be more suitable. New clinical applications of particle beams in cancer therapy can also be transferred from photon-beam treatments, for which there is a vast clinical experience. The evaluation of the different uncertainties influencing RT of different tumour sites carried out with photon- and with proton-beams, will hopefully create an understanding for the feasibility of treating cancers with scanned proton beams instead of photon beams. The comparison of two distinct RT modalities is normally performed by studying the dosimetric values obtained from the dose volume histograms (DVH). However, in dosimetric evaluations, the outcome of the treatments in terms of local disease control and healthy tissue toxicity are not estimated. In this regard, radiobiological models can be an indispensable tool for the prediction of the outcome of cancer treatments performed with different types of ionising radiation. In this thesis, different factors that should be taken into consideration in PBT, for treatments influenced by organ motion and density heterogeneities, were studied and their importance quantified. This thesis consists of three published articles (Articles I, II and III). In these reports, the dosimetric and biological evaluations of photon-beam and scanned proton-beam RT were performed and the results obtained were compared. The studies were made for two tumour sites influenced by organ motion and density changes, gastric cancer (GC) and liver metastases. For the GC cases, the impact of changes in tissue density, resulting from variable gas content (which can be observed inter-fractionally), was also studied. In this thesis, both conventional fractionations (implemented in the planning for GC treatments) and hypofractionated regimens (implemented in the planning for the liver metastases cases) were considered. In this work, it was found that proton therapy provided the possibility to reduce the irradiations of the normal tissue located near the target volumes, compared to photon beam RT. However, the effects of density changes were found to be more pronounced in the plans for PBT. Furthermore, with proton beams, the reduction of the integral dose given to the OARs resulted in reduced risks of treatment-induced secondary malignancies.
There has been an increasing interest in proton beam therapy (PBT) in recent years related to the advantageous depth-dose characteristics of proton beams compared to what is achievable with standard ...external photon beam radiotherapy (RT). With PBT, improved target dose conformity can be achieved together with a reduction in the dose to the organs at risk (OARs). This can for certain cases lead to an increased tumour control probability (TCP) at the same time as the probabilities for normal tissue complications (NTCP) and radiation-induced secondary cancers are reduced. However, there are challenges with PBT, in the form of uncertainties in the dose delivery to the patient, due to different influencing factors. These perturbing factors are contributing to the uncertainties during different steps in the RT flow process, from the treatment planning to the irradiation. In the present work, a comparative treatment planning study of PBT and photon RT for a few clinical liver- and stomach-cancer cases were performed with the aim of determining possible advantages of PBT. The treatment planning comparisons were performed by means of dosimetric evaluations and by use of tissue response models. The later included the calculation of TCP and NTCP as well as the assessment of risk of radiation-induced secondary cancer for the two compared RT techniques. A total of eleven patients previously treated with RT at Karolinska University Hospital were included in the study. Three of these patients had been treated for liver cancer and eight for stomach cancer. The photon plans which had been used in the real treatments at the hospital were taken as reference plans. The treatment planning for the liver cancer cases had been performed on conventional CT images, but 4D-CT images were used for target definition to account for the target motion. Three distinct CT images were used in the planning of the stomach cancer cases, the original CT image study on which the photon plans had been done and two CT image studies with artificially changed physical density for some of the internal organs to simulate different possible fillings of the stomach. The extra- or reduced gas filling was drawn on the CT slices by the radiation oncologist to estimate two worst-case scenarios for changes in density within the irradiated volume. The results indicate an improved target dose conformity, dose homogeneity and sparing of OARs for the PBT plans compared to the photon RT plans for the two clinical cases studied. The sparing of the OARs was also observed in the form of decreased NTCP for the PBT plans. The PBT plans showed to be worse than the photon plans when some structures were replaced by air and water. In the case of extra air there was a shift of the higher doses beyond the distal edge of the planned proton range which caused both an increase of the irradiated volumes of sensitive normal tissues and of the maximum doses to the OARs. In the case of extra water in the stomach, the maximum range of the protons was reduced causing target underdosage. The calculations of probabilities for radiation-induced secondary malignancies indicated a reduced risk for all the OARs with the proton plans for the liver cancer cases. For the stomach cancer cases, reduced risks were obtained for induction of cancer in the liver but an increased risk was calculated for the bowel(-)PTV, with the proton- compared to the photon-plans. The results of the calculations of risk for radiation-induced cancer in the kidneys were inconclusive. The assessment of risk of secondary cancer for other organs, not delineated in this work (to obtain the whole body risk), is needed in order to obtain more comprehensive and clinically useful results.
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