Salvage Reirradiation for Locally Recurrent Prostate Cancer: Results From a Prospective Study With 7.2 Years of Follow-Up.

PURPOSE: There are no well-established re-treatment options for local recurrence after primary curative radiation therapy for prostate cancer (PCa), as prospective studies with long-term follow-up are lacking. Here, we present results from a prospective study on focal salvage reirradiation with external-beam radiation therapy with a median follow-up of 7.2 years. MATERIALS AND METHODS: From 2013 to 2017, 38 patients with biopsy-proven locally recurrent PCa >2 years after previous treatment and absence of grade 2-3 toxicity from the first course of radiation were included. The treatment was 35 Gy in five fractions to the MRI-based target volume and 6 months of androgen-deprivation therapy starting 3 months before radiation. The Phoenix criteria defined biochemical recurrence-free survival (bRFS), and toxicity was scored according to Radiation Therapy Oncology Group criteria. RESULTS: Median age was 70 years, and median time from primary radiation to prostate-specific antigen (PSA) recurrence was 83 months. The actuarial 2-year and 5-year bRFS were 81% (95% CI, 69 to 94) and 58% (95% CI, 49 to 74), respectively. The actuarial 5-year local recurrence-free survival was 93% (95% CI, 82 to 100), metastasis-free survival was 82% (95% CI, 69 to 95), and overall survival was 87% (95% CI, 76 to 98). Two patients (5%) had durable grade 3 genitourinary toxicity, one combined with GI grade 3 toxicity. A PSA doubling time ≤6 months at salvage, a Gleason score >7, and a PSA nadir ≥0.1 ng/mL predicted a worse outcome. CONCLUSION: Reirradiation with EBRT for locally recurrent PCa after primary curative radiation therapy is clinically feasible and demonstrated a favorable outcome with acceptable toxicity in this prospective study with long-term follow-up.

Reduction of PTV margins for elective pelvic lymph nodes in online adaptive radiotherapy of prostate cancer patients.

BACKGROUND: Cone beam CT (CBCT) based online adaptive radiotherapy (oART) is a new development in radiotherapy. With oART, the requirements for planning target volume (PTV) margins differ from standard therapy because motion occurs during a session. In this study, we aim to evaluate a margin reduction for locally advanced prostate patients treated with oART. MATERIAL AND METHODS: Intrafraction motion of the elective pelvic lymph nodes was evaluated by two radiation therapists (RTTs) for 150 fractions from 10 prostate patients treated with oART. PTV margins of 3, 4 and 5 mm where added to these lymph nodes for all patients. The seven first patients were treated with 5 mm PTV margin, while the last three patients were treated with 4 mm margin. After treatment, the RTTs reviewed the verification CBCTs and evaluated whether the various PTV margins would have covered the adapted clinical target volume, scoring each fraction as approved, inconclusive or rejected. Couch shifts corresponding to the rigid prostate match between the CBCTs were analyzed with respect to the RTT evaluation. RESULTS: The RTTs approved a 4 mm margin in 95% of the fractions, while 2% of the fractions were rejected. For a 3 mm margin, 57% of the fractions were approved, while 5% were rejected. The scoring from the two RTTs was consistent; e.g., for 3 mm, one RTT approved 58% of the fractions, while the other approved 55%. If the couch was moved less than 2 mm in any direction, 70% of the fractions were approved for a 3 mm margin, compared to 32% for shifts greater than 2 mm. CONCLUSION: It is safe to reduce the PTV margin from 5 to 4 mm for the elective pelvic lymph nodes for prostate patients treated with oART. Further margin reductions can be motivated for patients presenting little intrafraction motion.

Influence of beam pruning techniques on LET and RBE in proton arc therapy.

Introduction: Proton arc therapy (PAT) is an emerging treatment modality that holds promise to improve target volume coverage and reduce linear energy transfer (LET) in organs at risk. We aimed to investigate if pruning the highest energy layers in each beam direction could increase the LET in the target and reduce LET in tissue and organs at risk (OAR) surrounding the target volume, thus reducing the relative biological effectiveness (RBE)-weighted dose and sparing healthy tissue. Methods: PAT plans for a germinoma, an ependymoma and a rhabdomyosarcoma patient were created in the Eclipse treatment planning system with a prescribed dose of 54 Gy(RBE) using a constant RBE of 1.1 (RBE1.1). The PAT plans was pruned for high energy spots, creating several PAT plans with different amounts of pruning while maintaining tumor coverage, denoted PX-PAT plans, where X represents the amount of pruning. All plans were recalculated in the FLUKA Monte Carlo software, and the LET, physical dose, and variable RBE-weighted dose from the phenomenological Rørvik (ROR) model and an LET weighted dose (LWD) model were evaluated. Results and discussion: For the germinoma case, all plans but the P6-PAT reduced the mean RBE-weighted dose to the surrounding healthy tissue compared to the PAT plan. The LET was increasingly higher within the PTV for each pruning iteration, where the mean LET from the P6-PAT plan was 1.5 keV/µm higher than for the PAT plan, while the P4- and P5-PAT plans provided an increase of 0.4 and 0.7 keV/µm, respectively. The other plans increased the LET by a smaller margin compared to the PAT plan. Likewise, the LET values to the healthy tissue were reduced for each degree of pruning. Similar results were found for the ependymoma and the rhabdomyosarcoma case. We demonstrated a PAT pruning technique that can increase both LET and RBE in the target volume and at the same time decreased values in healthy tissue, without affecting the target volume dose coverage.

Combined RBE and OER optimization in proton therapy with FLUKA based on EF5-PET.

INTRODUCTION: Tumor hypoxia is associated with poor treatment outcome. Hypoxic regions are more radioresistant than well-oxygenated regions, as quantified by the oxygen enhancement ratio (OER). In optimization of proton therapy, including OER in addition to the relative biological effectiveness (RBE) could therefore be used to adapt to patient-specific radioresistance governed by intrinsic radiosensitivity and hypoxia. METHODS: A combined RBE and OER weighted dose (ROWD) calculation method was implemented in a FLUKA Monte Carlo (MC) based treatment planning tool. The method is based on the linear quadratic model, with α and ß parameters as a function of the OER, and therefore a function of the linear energy transfer (LET) and partial oxygen pressure (pO2 ). Proton therapy plans for two head and neck cancer (HNC) patients were optimized with pO2 estimated from [18 F]-EF5 positron emission tomography (PET) images. For the ROWD calculations, an RBE of 1.1 (RBE1.1,OER ) and two variable RBE models, Rørvik (ROR) and McNamara (MCN), were used, alongside a reference plan without incorporation of OER (RBE1.1 ). RESULTS: For the HNC patients, treatment plans in line with the prescription dose and with acceptable target ROWD could be generated with the established tool. The physical dose was the main factor modulated in the ROWD. The impact of incorporating OER during optimization of HNC patients was demonstrated by the substantial difference found between ROWD and physical dose in the hypoxic tumor region. The largest physical dose differences between the ROWD optimized plans and the reference plan was 12.2 Gy. CONCLUSION: The FLUKA MC based tool was able to optimize proton treatment plans taking the tumor pO2 distribution from hypoxia PET images into account. Independent of RBE-model, both elevated LET and physical dose were found in the hypoxic regions, which shows the potential to increase the tumor control compared to a conventional optimization approach.

An organ deformation model using Bayesian inference to combine population and patient-specific data.

Objective.Organ deformation models have the potential to improve delivery and reduce toxicity of radiotherapy, but existing data-driven motion models are based on either patient-specific or population data. We propose to combine population and patient-specific data using a Bayesian framework. Our goal is to accurately predict individual motion patterns while using fewer scans than previous models.Approach.We have derived and evaluated two Bayesian deformation models. The models were applied retrospectively to the rectal wall from a cohort of prostate cancer patients. These patients had repeat CT scans evenly acquired throughout radiotherapy. Each model was used to create coverage probability matrices (CPMs). The spatial correlations between these estimated CPMs and the ground truth, derived from independent scans of the same patient, were calculated.Main results.Spatial correlation with ground truth were significantly higher for the Bayesian deformation models than both patient-specific and population-derived models with 1, 2 or 3 patient-specific scans as input. Statistical motion simulations indicate that this result will also hold for more than 3 scans.Significance.The improvement over previous models means that fewer scans per patient are needed to achieve accurate deformation predictions. The models have applications in robust radiotherapy planning and evaluation, among others.

Towards range-guidance in proton therapy to detect organ motion-induced dose degradations.

Introduction.Internal organ motion and deformations may cause dose degradations in proton therapy (PT) that are challenging to resolve using conventional image-guidance strategies. This study aimed to investigate the potential ofrange guidanceusing water-equivalent path length (WEPL) calculations to detect dose degradations occurring in PT.Materials and methods. Proton ranges were estimated using WEPL calculations. Field-specific isodose surfaces in the planning CT (pCT), from robustly optimised five-field proton plans (opposing lateral and three posterior/posterior oblique beams) for locally advanced prostate cancer patients, were used as starting points. WEPLs to each point on the field-specific isodoses in the pCT were calculated. The corresponding range for each point was found in the repeat CTs (rCTs). The spatial agreement between the resulting surfaces in the rCTs (hereafter referred to as iso-WEPLs) and the isodoses re-calculated in rCTs was evaluated for different dose levels and Hausdorff thresholds (2-5 mm). Finally, the sensitivity and specificity of detecting target dose degradation (V95% < 95%) using spatial agreement measures between the iso-WEPLs and isodoses in the pCT was evaluated.Results. The spatial agreement between the iso-WEPLs and isodoses in the rCTs depended on the Hausdorff threshold. The agreement was 65%-88% for a 2 mm threshold, 83%-96% for 3 mm, 90%-99% for 4 mm, and 94%-99% for 5 mm, across all fields and isodose levels. Minor differences were observed between the different isodose levels investigated. Target dose degradations were detected with 82%-100% sensitivity and 75%-80% specificity using a 2 mm Hausdorff threshold for the lateral fields.Conclusion. Iso-WEPLs were comparable to isodoses re-calculated in the rCTs. The proposed strategy could detect target dose degradations occurring in the rCTs and could be an alternative to a fully-fledged dose re-calculation to detect anatomical variations severely influencing the proton range.

The Organ Sparing Potential of Different Biological Optimization Strategies in Proton Therapy.

PURPOSE: Variable relative biological effectiveness (RBE) models allow for differences in linear energy transfer (LET), physical dose, and tissue type to be accounted for when quantifying and optimizing the biological damage of protons. These models are complex and fraught with uncertainties, and therefore, simpler RBE optimization strategies have also been suggested. Our aim was to compare several biological optimization strategies for proton therapy by evaluating their performance in different clinical cases. METHODS AND MATERIALS: Two different optimization strategies were compared: full variable RBE optimization and differential RBE optimization, which involve applying fixed RBE for the planning target volume (PTV) and variable RBE in organs at risk (OARs). The optimization strategies were coupled to 2 variable RBE models and 1 LET-weighted dose model, with performance demonstrated on 3 different clinical cases: brain, head and neck, and prostate tumors. RESULTS: In cases with low ( α / ß ) x in the tumor, the full RBE optimization strategies had a large effect, with up to 10% reduction in RBE-weighted dose to the PTV and OARs compared with the reference plan, whereas smaller variations (<5%) were obtained with differential optimization. For tumors with high ( α / ß ) x , the differential RBE optimization strategy showed a greater reduction in RBE-weighted dose to the OARs compared with the reference plan and the full RBE optimization strategy. CONCLUSIONS: Differences between the optimization strategies varied across the studied cases, influenced by both biological and physical parameters. Whereas full RBE optimization showed greater OAR sparing, awareness of underdosage to the target must be carefully considered.

Reducing systematic errors due to deformation of organs at risk in radiotherapy.

PURPOSE: In radiotherapy (RT), the planning CT (pCT) is commonly used to plan the full RT-course. Due to organ deformation and motion, the organ shapes seen at the pCT will not be identical to their shapes during RT. Any difference between the pCT organ shape and the organ's mean shape during RT will cause systematic errors. We propose to use statistical shrinkage estimation to reduce this error using only the pCT and the population mean shape computed from training data. METHODS: The method was evaluated for the rectum in a cohort of 37 prostate cancer patients that had a pCT and 7-10 treatment CTs with rectum delineations. Deformable registration was performed both within-patient and between patients, resulting in point-to-point correspondence between all rectum shapes, which enabled us to compute a population mean rectum. Shrinkage estimates were found by combining the pCTs linearly with the population mean. The method was trained and evaluated using leave-one-out cross validation. The shrinkage estimates and the patient mean shapes were compared geometrically using the Dice similarity index (DSI), Hausdorff distance (HD), and bidirectional local distance. Clinical dose/volume histograms, equivalent uniform dose (EUD) and minimum dose to the hottest 5% volume (D5%) were compared for the shrinkage estimate and the pCT. RESULTS: The method resulted in moderate but statistically significant increase in similarity to the patient mean shape over the pCT. On average, the HD was reduced from 15.6 to 13.4 mm, while the DSI was increased from 0.74 to 0.78. Significant reduction in the bias of volume estimates was found in the DVH-range of 52.5-65 Gy, where the bias was reduced from -1.3 to -0.2 percentage points, but no significant improvement was found in EUD or D5%, CONCLUSIONS: The results suggest that shrinkage estimation can reduce systematic errors due to organ deformations in RT. The method has potential to increase the accuracy in RT of deformable organs and can improve motion modeling.

Anatomically robust proton therapy using multiple planning computed tomography scans for locally advanced prostate cancer.

BACKGROUND: Proton therapy (PT) is sensitive towards anatomical changes that may occur during a treatment course. The aim of this study was to investigate if anatomically robust PT (ARPT) plans incorporating patient-specific target motion improved target coverage while still sparing normal tissues, when applied on locally advanced prostate cancer patients where pelvic irradiation is indicated. MATERIAL AND METHODS: A planning computed tomography (CT) scan used for dose calculation and two additional CTs (acquired on different days) were used to make patient-specific targets for the ARPT plans on the eight included patients. The plans were compared to a conventional robust PT plan and a volumetric modulated arc therapy (VMAT) photon plan, which were derived from the planning CT (pCT). Worst-case robust optimisation was used for all proton plans with a setup uncertainty of 5 mm and a range uncertainty of 3.5%. Target coverage (V95% and D95%) and normal tissue doses (V5-75 Gy) were evaluated on 6-8 rCTs per patient. RESULTS: The ARPT plans improved the prostate target coverage for the most challenging patient compared to conventional robust PT plans (20% point increase for V95% and 31 Gy increase for D95%). Across the whole cohort the estimated mean value for V95% was 97% for the ARPT plans and 95% for the conventional robust PT plans. The ARPT plans had a slight, statistically insignificant increase in normal tissue doses compared to the conventional robust proton plans. Compared to VMAT, the ARPT plans significantly reduced the normal tissue doses in the low-to-intermediate dose range. CONCLUSIONS: While both proton plans reduced the low-to-intermediate normal tissue doses compared to VMAT, ARPT plans improved the target coverage for the most challenging patient without significantly increasing the normal tissue doses compared to conventional robust PT plans.

Variation in relative biological effectiveness for cognitive structures in proton therapy of pediatric brain tumors.

BACKGROUND: Clinically, a constant value of 1.1 is used for the relative biological effectiveness (RBE) of protons, whereas in vitro the RBE has been shown to vary depending on physical dose, tissue type, and linear energy transfer (LET). As the LET increases at the distal end of the proton beam, concerns exist for an elevated RBE in normal tissues. The aim of this study was therefore to investigate the heterogeneity of RBE to brain structures associated with cognition (BSCs) in pediatric suprasellar tumors. MATERIAL AND METHODS: Intensity-modulated proton therapy (IMPT) plans for 10 pediatric craniopharyngioma patients were re-calculated using 11 phenomenological and two plan-based variable RBE models. Based on LET, tissue dependence and number of data points used to fit the models, the three RBE models considered the most relevant for the studied endpoint were selected. Thirty BSCs were investigated in terms of RBE and dose/volume parameters. RESULTS: For a representative patient, the median (range) dose-weighted mean RBE (RBEd) across all BSCs from the plan-based models was among the lowest (1.09 (1.02-1.52) vs. the phenomenological models at 1.21 (0.78-2.24)). Omitting tissue dependency resulted in RBEd at 1.21 (1.04-2.24). Across all patients, the narrower RBE model selection gave median RBEd values from 1.22 to 1.30. CONCLUSION: For all BSCs, there was a systematic model-dependent variation in RBEd, mirroring the uncertainty in biological effects of protons. According to a refined selection of in vitro models, the RBE variation across BSCs was in effect underestimated when using a fixed RBE of 1.1.

Patterns of practice for adaptive and real-time radiation therapy (POP-ART RT) part II: Offline and online plan adaption for interfractional changes.

PURPOSE: The POP-ART RT study aims to determine to what extent and how intrafractional real-time respiratory motion management (RRMM), and plan adaptation for interfractional anatomical changes (ART) are used in clinical practice and to understand barriers to implementation. Here we report on part II: ART using more than one plan per target per treatment course. MATERIALS AND METHODS: A questionnaire on the current practice of ART, wishes for expansion or implementation, and barriers to implementation was distributed worldwide. Four types of ART were discriminated: daily online replanning, online plan library, protocolled offline replanning (all three based on a protocol), and ad-hoc offline replanning. RESULTS: The questionnaire was completed by 177 centres from 40 countries. ART was used by 61% of respondents (31% with protocol) for a median (range) of 3 (1-8) tumour sites. CBCT/MVCT was the main imaging modality except for online daily replanning (11 users) where 10 users used MR. Two thirds of respondents wished to implement ART for a new tumour site; 40% of these had plans to do it in the next 2 years. Human/material resources and technical limitations were the main barriers to further use and implementation. CONCLUSIONS: ART was used for a broad range of tumour sites, mainly with ad-hoc offline replanning and for a median of 3 tumour sites. There was a large interest in implementing ART for more tumour sites, mainly limited by human/material resources and technical limitations. Daily online replanning was primarily performed on MR-linacs.

Inter-patient variations in relative biological effectiveness for cranio-spinal irradiation with protons.

Cranio-spinal irradiation (CSI) using protons has dosimetric advantages compared to photons and is expected to reduce risk of adverse effects. The proton relative biological effectiveness (RBE) varies with linear energy transfer (LET), tissue type and dose, but a variable RBE has not replaced the constant RBE of 1.1 in clinical treatment planning. We examined inter-patient variations in RBE for ten proton CSI patients. Variable RBE models were used to obtain RBE and RBE-weighted doses. RBE was quantified in terms of dose weighted organ-mean RBE ([Formula: see text] = mean RBE-weighted dose/mean physical dose) and effective RBE of the near maximum dose (D2%), i.e. RBED2% = [Formula: see text], where subscripts RBE and phys indicate that the D2% is calculated based on an RBE model and the physical dose, respectively. Compared to the median [Formula: see text] of the patient population, differences up to 15% were observed for the individual [Formula: see text] values found for the thyroid, while more modest variations were seen for the heart (6%), lungs (2%) and brainstem (<1%). Large inter-patient variation in RBE could be correlated to large spread in LET and dose for these organs at risk (OARs). For OARs with small inter-patient variations, the results show that applying a population based RBE in treatment planning may be a step forward compared to using RBE of 1.1. OARs with large inter-patient RBE variations should ideally be selected for patient-specific biological or RBE robustness analysis if the physical doses are close to known dose thresholds.

Plan Selection in Proton Therapy of Locally Advanced Prostate Cancer with Simultaneous Treatment of Multiple Targets.

PURPOSE: Intensity modulated proton therapy (IMPT) of locally advanced prostate cancer can spare the bowel considerably compared with modern photon therapy, but simultaneous treatment of the prostate (p), seminal vesicles (sv), and lymph nodes is challenging owing to day-to-day organ motion and range uncertainties. Our purpose was, therefore, to generate a plan library for use in adaptive IMPT to mitigate these uncertainties. METHODS AND MATERIALS: We retrospectively included 27 patients with a series of computed tomography scans throughout their treatment representing day-to-day variation. In 18 of the patients, target motion was analyzed using rigid shifts of prostate gold markers relative to bony anatomy. A plan library with different p and sv planning target volume (p/sv-PTV) positions was defined from the distribution and direction of these shifts. Delivery of IMPT using plan selection from the library was simulated for image guidance on bony anatomy, in the remaining patients and compared with nonadaptive IMPT. RESULTS: The plan library consisted of 3 small margin p/sv-PTVs: (1) p/sv-PTV shifted 1.5 systematic error (Σ) of the population mean in the anterior and cranial directions, (2) p/sv-PTV shifted 1.5Σ in the posterior and caudal directions, and (3) p/sv-PTV in the planning position. The conventional p/sv-PTV was also available for backup. Plan selection compared with nonadaptive IMPT resulted in a reduction of the rectum volume receiving 60 Gy relative biological effect (RBE) (V60GyRBE) from on average 12 mL to 9 mL. For the bladder the average V45GyRBE was reduced from 36% to 30%. Large and small bowel doses were also reduced, whereas target coverage was comparable or improved compared with nonadaptive IMPT. CONCLUSIONS: Plan selection based on a population model of rigid target motion was feasible for all patients. Compared with conventional IMPT, plan selection resulted in significant dosimetric sparing of rectum and bladder without compromising target coverage.