In radiotherapy, hypoxia is a known negative factor, occurring especially in solid malignant tumours. Nitroimidazole-based positron emission tomography (PET) tracers, due to their selective binding to hypoxic cells, could be used as surrogates to image and quantify the underlying oxygen distributions in tissues. The spatial resolution of a clinical PET image, however, is much larger than the cellular spatial scale where hypoxia occurs. A question therefore arises regarding the possibility of quantifying different hypoxia levels based on PET images, and the aim of the present study is the prescription of corresponding therapeutic doses and its exploration.

A tumour oxygenation model was created consisting of two concentric spheres with different oxygen partial pressure (pO2) distributions. In order to mimic a PET image of the simulated tumour, given the relation between uptake and pO2, fundamental effects that limit spatial resolution in a PET imaging system were considered: the uptake distribution was processed with a Gaussian 3D filter, and a re-binning to reach a typical PET image voxel size was performed. Prescription doses to overcome tumour hypoxia and predicted tumour control probability (TCP) were calculated based on the processed images for several fractionation schemes. Knowing the underlying oxygenation at microscopic scale, the actual TCP expected after the delivery of the calculated prescription doses was evaluated. Results are presented for three different dose painting strategies: by numbers, by contours and by using a voxel grouping-based approach.

The differences between predicted TCP and evaluated TCP indicate that careful consideration must be taken on the dose prescription strategy and the selection of the number of fractions, depending on the severity of hypoxia.

Background/Aim: The problem of lack of standardisation in target delineation and herewith the variability of target contours in Gamma Knife radiosurgery is as severe as in linac-based radiotherapy in general. The first aim of this study was to quantify the contouring variability for a group of five radiosurgery targets and estimate their true-volume based on multiple delineations using the Simultaneous Truth and Performance Level Estimation (STAPLE) algorithm. The second aim was to assess the robustness of the STAPLE method for the assessment of the true-volume, with respect to the number of contours available as input. Patients and Methods: A multicentre analysis of the variability in contouring of five cases was performed. Twelve contours were provided for each case by experienced planners for Gamma Knife. To assess the robustness of the STAPLE method with respect to the number of contours used as input, sets of contours were randomly selected in the analysis. Results: A high similarity was observed between the STAPLE generated true-volume and the 50%-agreement volume when all 12 available contours were used as input (90-100%). Lower similarity was observed with smaller sets of contours (10-70%). Conclusion: If a high number of input contours is available, the STAPLE method provides a valuable tool in the estimation of the true volume of a target based on multiple contours as well as the sensitivity and specificity for each input contour relative to the true volume of that structure. The robustness of the STAPLE method for rendering the true target volume depends on the number of contours provided as input and their variability with respect to shape, size and position.

Background: The reduced normal tissue dose burden from protons can reduce the risk of second cancer for breast cancer patients. Breathing motion and the impact of variable relative biological effectiveness (RBE) are however concerns for proton dose distributions. This study aimed to quantify the impact of these factors on risk predictions from proton and photon therapy.

Materials and methods: Twelve patients were planned in free breathing with protons and photons to deliver 50 Gy (RBE) in 25 fractions (assuming RBE = 1.1 for protons) to the left breast. Second cancer risk was evaluated with several models for the lungs, contralateral breast, heart and esophagus as organs at risk (OARs). Plans were recalculated on CT-datasets acquired in extreme phases to account for breathing motion. Proton plans were also recalculated assuming variable RBE for a range of radiobiological parameters.

Results: The OARs received substantially lower doses from protons compared to photons. The highest risks were for the lungs (average second cancer risks of 0.31% and 0.12% from photon and proton plans, respectively). The reduced risk with protons was maintained, even when breathing and/or RBE variation were taken into account. Furthermore, while the total risks from the photon plans were seen to increase with the integral dose, no such correlation was observed for the proton plans.

Conclusions: Protons have an advantage over the photons with respect to the induction of cancer. Uncertainties in physiological movements and radiobiological parameters affected the absolute risk estimates, but not the general trend of lower risk associated with proton therapy.

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.

Purpose: The enhanced relative biological effectiveness (RBE) at the end of the proton range might increase the risk of radiation-induced toxicities. This is of special concern for intracranial treatments where several critical organs at risk (OARs) surround the tumor.  In the light of this, a retrospective analysis of dose-averaged linear energy transfer (LET_d) and RBE-weighted dose (D_RBE) distributions was conducted for three clinical cases with suspected treatment related toxicities following intracranial proton therapy. Alternative treatment strategies aiming to reduce toxicity risks are also presented.

Methods: The clinical single-field optimized (SFO) plans were recalculated for 81 error scenarios with a Monte Carlo dose engine. The fractionation D_RBE was 1.8 Gy (RBE) in 28 or 30 fractions assuming a constant RBE of 1.1. Two LET_d- and α/β-dependent variable RBE models were used for evaluation, including a sensitivity analysis of the α/β parameter. Resulting distributions of D_RBE and LET_d were analyzed together with normal tissue complication probabilities (NTCPs). Subsequently, four multi-field optimized (MFO) plans, with an additional beam and/or objectives penalizing protons stopping in OARs, were created to investigate the potential reduction of LET_d, D_RBE and NTCP.

Results: The two variable RBE models agreed well and predicted average RBE values around 1.3 in the toxicity volumes, resulting in increased near-maximum D_RBE of 7-11 Gy (RBE) compared to RBE=1.1 in the nominal scenario. The corresponding NTCP estimates increased from 0.8%, 0.0% and 3.7% (RBE=1.1) to 15.5%, 1.8% and 45.7% (Wedenberg RBE model) for the three patients, respectively. The MFO plans generally allowed for LET_d, D_RBE and NTCP reductions in OARs, without compromising the target dose. Compared to the clinical SFO plans, the maximum reduction of the near-maximum LET_d was 56%, 63% and 72% in the OAR exhibiting the toxicity for the three patients, respectively.

Conclusions: Although a direct causality between RBE and toxicity cannot be established here, high LET_d and D_RBE correlated spatially with the observed toxicities, whereas setup and range uncertainties had a minor impact. Individual factors, which might affect the patient-specific radiosensitivity, were however not included in these calculations. The MFO plans using both an additional beam and proton track-end objectives allowed the largest reductions in LET_d, D_RBE and NTCP, and might be future tools for similar cases.

Background/Aim: This study investigated the impact of temporary vascular collapse on tumour control probability (TCP) in stereotactic body radiotherapy (SBRT), taking into account different radiosensitivities of chronically and acutely hypoxic cells. Materials and Methods: Three-dimensional tumours with heterogeneous oxygenation were simulated assuming different fractions of collapsed vessels at every treatment fraction. The modelled tumours contained a chronically hypoxic subvolume of 30-60% of the tumour diameter, and a hypoxic fraction ≤5 mm Hg of 30-50%. The rest of the tumours were well-oxygenated at the start of the simulated treatment. Results: For all simulated cases, the largest reduction in TCP from 97% to 2% was found in a tumour with a small chronically hypoxic core treated with 60 Gy in eight fractions and assuming a treatment-induced vascular collapse of 35% in the well-oxygenated region. Conclusion: The timing of SBRT fractions should be considered together with the tumour oxygenation to avoid loss of TCP in SBRT.

Purpose

Tumor hypoxia, often found in nonsmall cell lung cancer (NSCLC), implies an increased resistance to radiotherapy. Pretreatment assessment of tumor oxygenation is, therefore, warranted in these patients, as functional imaging of hypoxia could be used as a basis for dose painting. This study aimed at investigating the feasibility of using a method for calculating the dose required in hypoxic subvolumes segmented on ¹⁸F‐HX4 positron emission tomography (PET) imaging of NSCLC.

Methods

Positron emission tomography imaging data based on the hypoxia tracer ¹⁸F‐HX4 of 19 NSCLC patients were included in the study. Normalized tracer uptake was converted to oxygen partial pressure (pO₂) and hypoxic target volumes (HTVs) were segmented using a threshold of 10 mmHg. Uniform doses required to overcome the hypoxic resistance in the target volumes were calculated based on a previously proposed method taking into account the effect of interfraction reoxygenation, for fractionation schedules ranging from extremely hypofractionated stereotactic body radiotherapy (SBRT) to conventionally fractionated radiotherapy.

Results

Gross target volumes ranged between 6.2 and 859.6 cm³, and the hypoxic fraction < 10 mmHg between 1.2% and 72.4%. The calculated doses for overcoming the resistance of cells in the HTVs were comparable to those currently prescribed in clinical practice as well as those previously tested in feasibility studies on dose escalation in NSCLC. Depending on the size of the HTV and the distribution of pO₂, HTV doses were calculated as 43.6–48.4 Gy for a three‐fraction schedule, 51.7–57.6 Gy for five fractions, and 59.5–66.4 Gy for eight fractions. For patients in whom the HTV pO₂ distribution was more favorable, a lower dose was required despite a bigger volume. Tumor control probability was lower for single‐fraction schedules, while higher levels of tumor control probability were found for schedules employing several fractions.

Conclusions

The method to account for heterogeneous and dynamic hypoxia in target volume segmentation and dose prescription based on ¹⁸F‐HX4‐PET imaging appears feasible in NSCLC patients. The distribution of oxygen partial pressure within HTV could impact the required prescribed dose more than the size of the volume.

Background/Aim: The aim of this study was to investigate radiation-induced tumour vascular damage and its impact thereof on the outcome of stereotactic body radiotherapy (SBRT). Materials and Methods: Vessel densities in animal tumours before and after a single dose of 20 Gy were quantified and used as input for simulations of three-dimensional tumours with heterogeneous oxygenation. SBRT treatments of the modelled tumours in 1-8 fractions were simulated. The impact of vessel collapse on the outcome of SBRT was investigated by calculating tumour control probability (TCP) and the dose required to obtain a TCP of 50% (D₅₀). Results: A radiation-induced increase of acute hypoxia in tumours during SBRT treatment could be simulated based on the experimental data. The D₅₀ values for these tumours were higher than for the simulated tumours without vessel collapse. Conclusion: The vascular changes after high doses of radiation could compromise the outcome of SBRT by increasing tumour hypoxia.

The progress in functional imaging and dose delivery has opened the possibility of targeting tumour hypoxia with radiotherapy. Advanced approaches apply quantitative information on tumour oxygenation retrieved from imaging in dose prescription. These do not, however, take into account the potential difference in radiosensitivity of chronically and acutely hypoxic cells. It was the aim of this study to evaluate the implications of assuming the same or different sensitivities for the hypoxic cells. An in silico 3D-model of a hypoxic tumour with heterogeneous oxygenation was used to model the probabilities of tumour control with different radiotherapy regimens. The results show that by taking into account the potential lower radioresistance of chronically hypoxic cells deprived of oxygen and nutrients, the total dose required to achieve a certain level of control is substantially reduced for a given fractionation scheme in comparison to the case when chronically and acutely hypoxic cells are assumed to have similar features. The results also suggest that the presence of chronic hypoxia could explain the success of radiotherapy for some hypoxic tumours. Given the implications for clinical dose escalation trials, further exploration of the influence of the different forms of hypoxia on treatment outcome is therefore warranted.

Purpose: Early assessment of tumour response to treatment with repeated FDG-PET-CT imaging has potential for treatment adaptation but it is unclear what the optimal time window for this evaluation is. Previous studies indicate that changes in SUVmean and the effective radiosensitivity (alpha(eff), accounting for uptake variations and accumulated dose until the second FDG-PET-CT scan) are predictive of 2-year overall survival (OS) when imaging is performed before radiotherapy and during the second week. This study aims to investigate if multiple FDG-PET-derived quantities determined during the third treatment week have stronger predictive power.

Methods: Twenty-eight lung cancer patients were imaged with FDG-PET-CT before radiotherapy (PET1) and during the third week (PET2). SUVmean, SUVmax, SUVpeak, MTV41%-50% (Metabolic Tumour Volume), TLG41%-50% (Total Lesion Glycolysis) in PET1 and PET2 and their change (), as well as average alpha(eff) (<(alpha)over bar >(eff)) and the negative fraction of alpha(eff) values (f(alpha eff) (< 0)) were determined. Correlations were sought between FDG-PET-derived quantities and OS with ROC analysis.

Results: Neither SUVmean, SUVmax, SUVpeak in PET1 and PET2 (AUC = 0.5-0.6), nor their changes (AUC = 0.5-0.6) were significant for outcome prediction purposes. Lack of correlation with OS was also found for (alpha) over bar (eff) (AUC = 0.5) and f(alpha eff) (<) 0 (AUC = 0.5). Threshold-based quantities (MTV41%-50%, TLG41%-50%) and their changes had AUC= 0.5-0.7. P-values were in all cases >> 0.05.

Conclusions: The poor OS predictive power of the quantities determined from repeated FDG-PET-CT images indicates that the third week of treatment might not be suitable for treatment response assessment. Comparatively, the second week during the treatment appears to be a better time window.