Experimental assessment of inter-centre variation in stopping-power and range prediction in particle therapy.

PURPOSE: Experimental assessment of inter-centre variation and absolute accuracy of stopping-power-ratio (SPR) prediction within 17 particle therapy centres of the European Particle Therapy Network. MATERIAL AND METHODS: A head and body phantom with seventeen tissue-equivalent materials were scanned consecutively at the participating centres using their individual clinical CT scan protocol and translated into SPR with their in-house CT-number-to-SPR conversion. Inter-centre variation and absolute accuracy in SPR prediction were quantified for three tissue groups: lung, soft tissues and bones. The integral effect on range prediction for typical clinical beams traversing different tissues was determined for representative beam paths for the treatment of primary brain tumours as well as lung and prostate cancer. RESULTS: An inter-centre variation in SPR prediction (2σ) of 8.7%, 6.3% and 1.5% relative to water was determined for bone, lung and soft-tissue surrogates in the head setup, respectively. Slightly smaller variations were observed in the body phantom (6.2%, 3.1%, 1.3%). This translated into inter-centre variation of integral range prediction (2σ) of 2.9%, 2.6% and 1.3% for typical beam paths of prostate-, lung- and primary brain-tumour treatments, respectively. The absolute error in range exceeded 2% in every fourth participating centre. The consideration of beam hardening and the execution of an independent HLUT validation had a positive effect, on average. CONCLUSION: The large inter-centre variations in SPR and range prediction justify the currently clinically used margins accounting for range uncertainty, which are of the same magnitude as the inter-centre variation. This study underlines the necessity of higher standardisation in CT-number-to-SPR conversion.

Risk of Cardiac Implantable Electronic Device Malfunctioning During Pencil Beam Proton Scanning in an In Vitro Setting.

PURPOSE: Cardiac implantable electronic devices (CIED) are sensitive to scattered secondary neutrons from proton beam irradiation. This experimental in vitro study investigated risk of CIED errors during pencil beam proton therapy. METHODS AND MATERIALS: We used 62 explanted CIEDs from 4 manufacturers; 49 CIEDs were subjected to a simulated clinical protocol with daily 2 Gy relative biological effectiveness fractions prescribed to the phantom. Devices were located at 3 different lateral distances from the spread-out Bragg peak to investigate the risk of permanent or temporary device errors. Additionally, 13 devices with leads connected were monitored live during consecutive irradiations to investigate the risk of noise, over- or undersense, pace inhibition, and inappropriate shock therapy. RESULTS: We detected 61 reset errors in 1728 fractions, and all except 1 CIED were reprogrammed to normal function. All, except 1 reset, occurred in devices from the same manufacturer. These were successfully reprogrammed to normal function. The 1 remaining CIED was locked in permanent safety mode. Secondary neutron dose, as estimated by Monte Carlo simulations, was found to significantly increase the odds of CIED resets by 55% per mSv. Clinically significant battery depletion was observed in 5 devices. We observed no noise, over- or undersense, pace inhibition, or inappropriate shock therapy during 362 fractions of live monitoring. CONCLUSIONS: Reprogrammable CIED reset was the most commonly observed malfunction during proton therapy, and reset risk depended on secondary neutron exposure. The benefits of proton therapy are expected to outweigh the risk of CIED malfunctioning for most patients.

Impact of interfractional target motion in locally advanced cervical cancer patients treated with spot scanning proton therapy using an internal target volume strategy.

BACKGROUND AND PURPOSE: The more localized dose deposition of proton therapy (PT) compared to photon therapy might allow a reduction in treatment-related side effects but induces additional challenges to address. The aim of this study was to evaluate the impact of interfractional motion on the target and organs at risk (OARs) in cervical cancer patients treated with spot scanning PT using an internal target volume (ITV) strategy. METHODS AND MATERIALS: For ten locally advanced cervical cancer patients, empty and full bladder planning computed tomography (pCT) as well as 25 daily cone beam CTs (CBCTs) were available. The Clinical Target Volume (CTV), the High Risk CTV (CTVHR) (gross tumor volume and whole cervix), the non-involved uterus as well as the OARs (bowel, bladder and rectum) were contoured on the daily CBCTs and transferred to the pCT through rigid bony match. Using synthetic CTs derived from pCTs, four-beam spot scanning PT plans were generated to target the patient-specific ITV with 45 Gy(RBE) in 25 fractions. This structure was defined based on pre-treatment MRI and CT to anticipate potential target motion throughout the treatment. D98% of the targets and V40Gy(RBE) of the OARs were extracted from the daily anatomies, accumulated and analyzed. In addition, the impact of bladder volume deviations from planning values on target and bowel dose was investigated. RESULTS: The ITV strategy ensured a total accumulated dose >42.75 Gy(RBE) to the CTVHR for all ten patients. Two patients with large bladder-related uterus motion had accumulated dose to the non-involved uterus of 35.7 Gy(RBE) and 41.1 Gy(RBE). Variations in bowel V40Gy(RBE) were found to be correlated (Pearson r = -0.55; p-value <0.0001) with changes in bladder volume during treatment. CONCLUSION: The ITV concept ensured adequate dose to the CTVHR, but was insufficient for the non-involved uterus of patients subject to large target interfractional motion. CBCT monitoring and occasional replanning is recommended along the same lines as with photon radiotherapy in cervical cancer.

Roadmap: proton therapy physics and biology.

The treatment of cancer with proton radiation therapy was first suggested in 1946 followed by the first treatments in the 1950s. As of 2020, almost 200 000 patients have been treated with proton beams worldwide and the number of operating proton therapy (PT) facilities will soon reach one hundred. PT has long moved from research institutions into hospital-based facilities that are increasingly being utilized with workflows similar to conventional radiation therapy. While PT has become mainstream and has established itself as a treatment option for many cancers, it is still an area of active research for various reasons: the advanced dose shaping capabilities of PT cause susceptibility to uncertainties, the high degrees of freedom in dose delivery offer room for further improvements, the limited experience and understanding of optimizing pencil beam scanning, and the biological effect difference compared to photon radiation. In addition to these challenges and opportunities currently being investigated, there is an economic aspect because PT treatments are, on average, still more expensive compared to conventional photon based treatment options. This roadmap highlights the current state and future direction in PT categorized into four different themes, 'improving efficiency', 'improving planning and delivery', 'improving imaging', and 'improving patient selection'.

RBE for proton radiation therapy - a Nordic view in the international perspective.

BACKGROUND: This paper presents an insight into the critical discussions and the current strategies of the Nordic countries for handling the variable proton relative biological effectiveness (RBE) as presented at The Nordic Collaborative Workshop for Particle Therapy that took place at the Skandion Clinic on 14th and 15th of November 2019. MATERIAL AND METHODS: In the current clinical practice at the two proton centres in operation at the date, Skandion Clinic, and the Danish Centre for Particle Therapy, a constant proton RBE of 1.1 is applied. The potentially increased effectiveness at the end of the particle range is however considered at the stage of treatment planning at both places based on empirical observations and knowledge. More elaborated strategies to evaluate the plans and mitigate the problem are intensely investigated internationally as well at the two centres. They involve the calculation of the dose-averaged linear energy transfer (LETd) values and the assessment of their distributions corroborated with the distribution of the dose and the location of the critical clinical structures. RESULTS: Methods and tools for LETd calculations are under different stages of development as well as models to account for the variation of the RBE with LETd, dose per fraction, and type of tissue. The way they are currently used for evaluation and optimisation of the plans and their robustness are summarised. A critical but not exhaustive discussion of their potential future implementation in the clinical practice is also presented. CONCLUSIONS: The need for collaboration between the clinical proton centres in establishing common platforms and perspectives for treatment planning evaluation and optimisation is highlighted as well as the need of close interaction with the research academic groups that could offer a complementary perspective and actively help developing methods and tools for clinical implementation of the more complex metrics for considering the variable effectiveness of the proton beams.

FRoG: An independent dose and LETd prediction tool for proton therapy at ProBeam® facilities.

PURPOSE: Particle therapy is becoming increasingly available world-wide for precise tumor targeting, its favorable depth dose deposition, and increased biological damage to tumor tissue compared to conventional photon therapy. As demand increases for improved robustness and conformality, next-generation secondary dose calculation engines are needed to verify treatment plans independently and provide estimates for clinical decision-making factors, such as dose-averaged linear energy transfer (LETd ) and relative biological effectiveness (RBE). METHOD: FRoG (Fast dose Recalculation on GPU) has been installed and commissioned at the Danish Centre for Particle Therapy (DCPT). FRoG was developed for synchrotron-based facilities and has previously demonstrated good agreement with gold-standard Monte Carlo simulations and measurements. In this work, additions and modifications to FRoG's pencil beam algorithm to support the ion beam delivery with cyclotron-based technology as used at the DCPT, range shifter (RS) implementation, and robustness analysis methods are presented. FRoG dose predictions are compared to measurements and predictions of the clinical treatment planning system (TPS) Eclipse (Varian Medical Systems, Palo Alto, United States of America, CA, v.13.7.16) in both homogenous and heterogeneous scenarios using a solid-water/water and a half-head anthropomorphic phantom, respectively. Additional capabilities of FRoG are explored by performing a plan robustness analysis, analyzing dose and LETd for ten patients. RESULTS: Mid-target measurements in spread-out Bragg Peaks (SOBP) were on average within -0.19% ± 0.30% and ≤0.5% of FRoG predictions for irradiations without and with RS, respectively. Average 3%/2mm 3D γ-analysis passing rates were 99.1% for ~200 patient plan QA comparisons. Measurement with an anthropomorphic head-phantom yielded a γ-passing rate >98%. Overall, maximum target differences in D02% of <2% between the TPS and FRoG were observed for patient plans. The robustness analysis study accounting for range, delivery, and positioning uncertainties revealed small differences in target dose and a maximum LETd VH02% (LETd received by 2% of the volume having dose larger than 1% of maximum dose) values below 10.1 keV/µm to the brain stem. CONCLUSION: We demonstrate that auxiliary dose calculation systems like FRoG can yield excellent agreement to measurements comparable to clinical beam models. Through this work, application of FRoG as a secondary engine at third party cyclotron-based particle treatment facilities is now established for dose verification as well as providing further insight on LETd and variable RBE distributions for protons, currently absent from the standard clinical TPS.

Treatment planning for proton therapy: what is needed in the next 10 years?

Treatment planning is the process where the prescription of the radiation oncologist is translated into a deliverable treatment. With the complexity of contemporary radiotherapy, treatment planning cannot be performed without a computerized treatment planning system. Proton therapy (PT) enables highly conformal treatment plans with a minimum of dose to tissues outside the target volume, but to obtain the most optimal plan for the treatment, there are a multitude of parameters that need to be addressed. In this review areas of ongoing improvements and research in the field of PT treatment planning are identified and discussed. The main focus is on issues of immediate clinical and practical relevance to the PT community highlighting the needs for the near future but also in a longer perspective. We anticipate that the manual tasks performed by treatment planners in the future will involve a high degree of computational thinking, as many issues can be solved much better by e.g. scripting. More accurate and faster dose calculation algorithms are needed, automation for contouring and planning is required and practical tools to handle the variable biological efficiency in PT is urgently demanded just to mention a few of the expected improvements over the coming 10 years.

Quenching-free fluorescence signal from plastic-fibres in proton dosimetry: understanding the influence of Cerenkov radiation.

The origin of photons emitted in optical fibres under proton irradiation has been attributed to either entirely Cerenkov radiation or light consisting of fluorescence with a substantial amount of Cerenkov radiation. The source of the light emission is assessed in order to understand why the signal from optical fibres irradiated with protons is reportedly quenching-free. The present study uses the directional emittance of Cerenkov photons in 12 MeV and 20 MeV electron beams to validate a Monte Carlo model for simulating the emittance and transmission of Cerenkov radiation in optical fibres. We show that fewer than 0.01 Cerenkov photons are emitted and guided per 225 MeV proton penetrating the optical fibre, and that the Cerenkov signal in the optical fibre is completely negligible at the Bragg peak. Furthermore, on taking the emittance and guidance of both fluorescence and Cerenkov photons into account, it becomes evident that the reported quenching-free signal in PMMA-based optical fibres during proton irradiation is due to fluorescence.

The role of protons in modern and biologically-guided radiotherapy.

With the introduction of new biologically based imaging possibilities, a higher degree of individualisation and adaptation of radiotherapy will be possible. Better knowledge of the biology of the target and its sub-volumes will enable dose prescriptions tailored to the individual patients, tissues and sub-volumes. Repeated imaging during the course of treatment will in addition enable adaptation of the treatment to cope with anatomical, as well as biological changes of the patient and of the target tissues. To translate these bright future perspectives into significant improvements in clinical outcome, advanced tools to tailor the physical dose distributions are needed. The most conformal radiotherapy technique known to mankind and clinically available today is proton therapy; in particular Intensity Modulated Proton Therapy (IMPT) with active spot scanning can not only tailor the dose to the desired target, but also effectively avoid sensitive structures in the proximity of the target to a degree far better than other conformal techniques such as Intensity Modulated Radiotherapy with photons (IMRT). The development of IMPT is now mature enough for clinical introduction on a broad scale. Proton therapy is still more expensive than conventional radiotherapy, but with the present rapid increase in the number of proton facilities worldwide and new initiatives to improve efficiency, the difference in affordability will continue to decrease and in comparison with the benefits, soon diminish even further. Contrary to what is sometimes claimed, the demands for better physical dose distributions and better avoidance of non-target tissue, has never been higher. Prolonged expected survival in many groups of patients emphasises the need to reduce late toxicities. The success of concomitant systemic therapies, with their tendency to cause higher morbidity stresses even further the increased need for subtle dose-sculpting methodologies and tools. There is no contradiction between striving for better physical dose distributions and a more biologically based approach. On the contrary, physical dose distributions are the tools to which achieve a treatment that can meet the biological demands.

A treatment planning study of the potential of geometrical tracking for intensity modulated proton therapy of lung cancer.

BACKGROUND: Proton therapy of lung cancer holds the potential for a reduction of the volume of irradiated normal lung tissue. In this work we investigate the robustness of intensity modulated proton therapy (IMPT) plans to motion, and evaluate a geometrical tumour tracking method to compensate for tumour motion. MATERIAL AND METHODS: Seven patients with a nine targets with 4DCT scans were selected. IMPT plans were made on the midventilation phase using a 3-field technique. The plans were transferred and calculated on the remaining nine phases of the 4DCT, and the combined dose distribution was summed using deformable image registration (DIR). An additional set of plans were made in which the proton beam was simply geometrically shifted to the centre of the gross tumour volume (GTV), i.e. simulating tracking of the tumour motion but without on-line adjustment of the proton energies. A possible interplay effect between the dynamics of the spot scanning delivery and the tumour motion has not been considered in this work. RESULTS: Around 97-100% of the GTV was covered by 95% of the prescribed dose (V95) for a tumour displacement of less than about 1 cm with a static beam. For the remaining three of nine targets with a larger motion the tracking method studied provided a marked improvement over static beam; raising the GTV V95 from 95 to 100%, 82 to 98% and 51 to 97%, respectively. CONCLUSION: The possibility of performing DIR and summing the dose on the 4DCT data set was shown to be feasible. The fairly simplistic tracking method suggested here resulted in a marked improvement in GTV coverage for tumours with large intra-fractional motion (>1 cm displacement), indicating that on-line adjustment of the proton energies may be redundant.

IMRT in a pregnant patient: how to reduce the fetal dose?

The purpose of our study was to find a solution for fetal dose reduction during head-and-neck intensity modulated radiation therapy (IMRT) of a pregnant patient. The first step was optimization of the IMRT treatment plan with as few monitor units (MUs) as possible, while maintaining an acceptable dose distribution. The peripheral dose originating from the final IMRT plan was measured at distances reaching from the most proximal to the most distal fetal position, along the accelerator's longitudinal axis, using an anthropomorphic phantom extended with water-equivalent plastic. The measured peripheral dose was divided into leakage, and internal and collimator scatter, to find the degree to which each component influences the peripheral dose to build an appropriate shield. Collimator scatter was the greatest contributor to the peripheral dose throughout the range of the growing fetus. A shield was built and placed beneath the accelerator head, extending caudally from the field edge, to function as an extra collimator jaw. This shield reduced the fetal dose by a factor of 3.5. The peripheral dose components were also measured for simple rectangular fields and also here the collimator scatter was the greatest contributor to the peripheral dose. Therefore, the shielding used for the IMRT treatment of our patient could also be used when shielding in conventional radiotherapy. It is important for a radiation therapy department to be prepared for treatment of a pregnant patient to shield the fetus efficiently.

The effect of different lung densities on the accuracy of various radiotherapy dose calculation methods: implications for tumour coverage.

PURPOSE: To evaluate against Monte-Carlo the performance of various dose calculations algorithms regarding lung tumour coverage in stereotactic body radiotherapy (SBRT) conditions. MATERIALS AND METHODS: Dose distributions in virtual lung phantoms have been calculated using four commercial Treatment Planning System (TPS) algorithms and one Monte Carlo (MC) system (EGSnrc). We compared the performance of the algorithms in calculating the target dose for different degrees of lung inflation. The phantoms had a cubic 'body' and 'lung' and a central 2-cm diameter spherical 'tumour' (the body and tumour have unit density). The lung tissue was assigned five densities (rho(lung)): 0.01, 0.1, 0.2, 0.4 and 1g/cm(3). Four-field treatment plans were calculated with 6- and 18 MV narrow beams for each value of rho(lung). We considered the Pencil Beam Convolution (PBC(Ecl)) and the Analytical Anisotropic Algorithm (AAA(Ecl)) from Varian Eclipse and the Pencil Beam Convolution (PBC(OMP)) and the Collapsed Cone Convolution (CCC(OMP)) algorithms from Oncentra MasterPlan. RESULTS: When changing rho(lung) from 0.4 to 0.1g/cm(3), the MC median target dose decreased from 89.2% to 74.9% for 6 MV and from 83.3% to 61.6% for 18 MV (of dose maximum in the homogenous case at both energies), while for both PB algorithms the median target dose was virtually independent of lung density. CONCLUSIONS: Both PB algorithms overestimated the target dose, the overestimation increasing as rho(lung) decreased. Concerning target dose, the AAA(Ecl) and CCC(OMP) algorithms appear to be adequate alternatives to MC.

Interfractional changes in tumour volume and position during entire radiotherapy courses for lung cancer with respiratory gating and image guidance.

INTRODUCTION: With the purpose of implementing gated radiotherapy for lung cancer patients, this study investigated the interfraction variations in tumour size and internal displacement over entire treatment courses. To explore the potential of image guided radiotherapy (IGRT) the variations were measured using a set-up strategy based on imaging of bony landmarks and compared to a strategy using in room lasers, skin tattoos and cupper landmarks. MATERIALS AND METHODS: During their six week treatment course of 60Gy in 2Gy fractions, ten patients underwent 3 respiratory gated CT scans. The tumours were contoured on each CT scan to evaluate the variations in volumes and position. The lung tumours and the mediastinal tumours were contoured separately. The positional variations were measured as 3D mobility vectors and correlated to matching of the scans using the two different strategies. RESULTS: The tumour size was significantly reduced from the first to the last CT scan. For the lung tumours the reduction was 19%, p=0.03, and for the mediastinal tumours the reduction was 34%, p=0.0007. The mean 3D mobility vector and the SD for the lung tumours was 0.51 cm (+/-0.21) for matching using bony landmarks and 0.85 cm (+/-0.54) for matching using skin tattoos. For the mediastinal tumours the corresponding vectors and SD's were 0.55 cm (+/-0.19) and 0.72 cm (+/-0.43). The differences between the vectors were significant for the lung tumours p=0.004. The interfractional overlap of lung tumours was 80-87% when matched using bony landmarks and 70-76% when matched using skin tattoos. The overlap of the mediastinal tumours were 60-65% and 41-47%, respectively. CONCLUSIONS: Despite the use of gating the tumours varied considerably, regarding both position and volume. The variations in position were dependent on the set-up strategy. Set-up using IGRT was superior to set-up using skin tattoos.

The role of image guidance in respiratory gated radiotherapy.

Respiratory gating for radiotherapy beam delivery is a widely available technique, manufactured and sold by most of the major radiotherapy machine vendors. Respiratory gated beam delivery is intended to limit the irradiation of tumours moving with respiration to selected parts of the respiratory cycle, and thereby enable dose escalation and/or reduction of dose to organs at risk. Without adequate use of respiratory correlated image guidance on a regular basis, respiratory beam gating may however have a detrimental effect on target coverage. Image guidance of tumour respiratory motion is therefore of utmost importance for the safe introduction of respiratory gating. In this short overview, suitable image guidance strategies for respiratory gated radiotherapy are reviewed for two cancer sites; breast cancer and lung tumours.

Clinical evaluation of monitor unit software and the application of action levels.

PURPOSE: The aim of this study was the clinical evaluation of an independent dose and monitor unit verification (MUV) software which is based on sophisticated semi-analytical modelling. The software was developed within the framework of an ESTRO project. Finally, consistent handling of dose calculation deviations applying individual action levels is discussed. MATERIALS AND METHODS: A Matlab-based software ("MUV") was distributed to five well-established treatment centres in Europe (Vienna, Graz, Basel, Copenhagen, and Umeå) and evaluated as a quality assurance (QA) tool in clinical routine. Results were acquired for 226 individual treatment plans including a total of 815 radiation fields. About 150 beam verification measurements were performed for a portion of the individual treatment plans, mainly with time variable fluence patterns. The deviations between dose calculations performed with a treatment planning system (TPS) and the MUV software were scored with respect to treatment area, treatment technique, geometrical depth, radiological depth, etc. RESULTS: In general good agreement was found between calculations performed with the different TPSs and MUV, with a mean deviation per field of 0.2+/-3.5% (1 SD) and mean deviations of 0.2+/-2.2% for composite treatment plans. For pelvic treatments less than 10% of all fields showed deviations larger than 3%. In general, when using the radiological depth for verification calculations the results and the spread in the results improved significantly, especially for head-and-neck and for thorax treatments. For IMRT head-and-neck beams, mean deviations between MUV and the local TPS were -1.0+/-7.3% for dynamic, and -1.3+/-3.2% for step-and-shoot IMRT delivery. For dynamic IMRT beams in the pelvis good agreement was obtained between MUV and the local TPS (mean: -1.6+/-1.5%). Treatment site and treatment technique dependent action levels between +/-3% and +/-5% seem to be clinically realistic if a radiological depth correction is performed, even for dynamic wedges and IMRT. CONCLUSION: The software MUV is well suited for patient specific treatment plan QA applications and can handle all currently available treatment techniques that can be applied with standard linear accelerators. The highly sophisticated dose calculation model implemented in MUV allows investigation of systematic TPS deviations by performing calculations in homogeneous conditions.

Intra- and interfraction breathing variations during curative radiotherapy for lung cancer.

BACKGROUND AND PURPOSE: This study aimed at quantifying the breathing variations among lung cancer patients over full courses of fractionated radiotherapy. The intention was to relate these variations to the margins assigned to lung tumours, to account for respiratory motion, in fractionated radiotherapy. MATERIALS AND METHODS: Eleven lung cancer patients were included in the study. The patients' chest wall motions were monitored as a surrogate measure for breathing motion during each fraction of radiotherapy by use of an external optical marker. The exhale level variations were evaluated with respect to exhale points and fraction-baseline, defined for intra- and interfraction variations respectively. The breathing amplitude was evaluated as breathing cycle amplitudes and fraction-max-amplitudes defined for intra- and interfraction breathing, respectively. RESULTS: The breathing variations over a full treatment course, including both intra- and interfraction variations, were 15.2mm (median over the patient population), range 5.5-26.7mm, with the variations in exhale level as the major contributing factor. The median interfraction span in exhale level was 14.8mm, whereas the median fraction-max-amplitude was 6.1mm (median of patient individual SD 1.4). The median intrafraction span in exhale level was 1.6mm, and the median breathing cycle amplitude was 4.0mm (median of patient individual SD 1.4). CONCLUSIONS: The variations in externally measured exhale levels are larger than variations in breathing amplitude. The interfraction variations in exhale level are in general are up to 10 times larger than intrafraction variations. Margins to account for respiratory motion cannot safely be based on one planning session, especially not if relying on measuring external marker motion. Margins for lung tumours should include interfraction variations in breathing.