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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.

Background and Purpose: For locally advanced non-small cell lung cancer (LA-NSCLC), intensity-modulated proton therapy (IMPT) can reduce organ at risk (OAR) doses compared to intensity-modulated radiotherapy (IMRT). Deep inspiration breath hold (DIBH) reduces OAR doses compared to free breathing (FB) in IMRT. In IMPT, differences in dose distributions and robustness between DIBH and FB are unclear. In this study, we compare DIBH to FB in IMPT, and IMPT to IMRT., Materials and Methods: Fortyone LA-NSCLC patients were prospectively included. 4D computed tomography images (4DCTs) and DIBH CTs were acquired for treatment planning and during weeks 1 and 3 of treatment. A new system for automated robust planning was developed and used to generate a FB and a DIBH IMPT plan for each patient. Plans were compared in terms of dose-volume parameters and normal tissue complication probabilities (NTCPs). Dose recalculations on repeat CTs were used to compare inter-fraction plan robustness., Results: In IMPT, DIBH reduced median lungs D mean from 9.3 Gy(RBE) to 8.0 Gy(RBE) compared to FB, and radiation pneumonitis NTCP from 10.9 % to 9.4 % ( p  < 0.001). Inter-fraction plan robustness for DIBH and FB was similar. Median NTCPs for radiation pneumonitis and mortality were around 9 percentage points lower with IMPT than IMRT ( p  < 0.001). These differences were much larger than between FB and DIBH within each modality., Conclusion: DIBH IMPT resulted in reduced lung dose and radiation pneumonitis NTCP compared to FB IMPT. Inter-fraction robustness was comparable. OAR doses were far lower in IMPT than IMRT., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: BJMH, SB: Erasmus MC Cancer Institute has research collaborations with Elekta AB (Stockholm, Sweden), Accuray, Inc (Sunnyvale, USA) and Varian Medical Systems, Inc (Palo Alto, USA). The other authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (© 2024 Published by Elsevier B.V. on behalf of European Society of Radiotherapy & Oncology.)

Background: Knowledge-based planning (KBP) is a method for automated radiotherapy treatment planning where appropriate optimization objectives for new patients are predicted based on a library of training plans. KBP can save time and improve organ at-risk sparing and inter-patient consistency compared to manual planning, but its performance depends on the quality of the training plans. We used another system for automated planning, which generates multi-criteria optimized (MCO) plans based on a wish list, to create training plans for the KBP model, to allow seamless integration of knowledge from a new system into clinical routine. Model performance was compared for KBP models trained with manually created and automatic MCO treatment plans., Material and Methods: Two RapidPlan models with the same 30 locally advanced non-small cell lung cancer patients included were created, one containing manually created clinical plans (RP&#95;CLIN) and one containing fully automatic multi-criteria optimized plans (RP&#95;MCO). For 15 validation patients, model performance was compared in terms of dose-volume parameters and normal tissue complication probabilities, and an oncologist performed a blind comparison of the clinical (CLIN), RP&#95;CLIN, and RP&#95;MCO plans., Results: The heart and esophagus doses were lower for RP&#95;MCO compared to RP&#95;CLIN, resulting in an average reduction in the risk of 2-year mortality by 0.9 percentage points and the risk of acute esophageal toxicity by 1.6 percentage points with RP&#95;MCO. The oncologist preferred the RP&#95;MCO plan for 8 patients and the CLIN plan for 7 patients, while the RP&#95;CLIN plan was not preferred for any patients., Conclusion: RP&#95;MCO improved OAR sparing compared to RP&#95;CLIN and was selected for implementation in the clinic. Training a KBP model with clinical plans may lead to suboptimal output plans, and making an extra effort to optimize the library plans in the KBP model creation phase can improve the plan quality for many future patients.

Particle therapy (PT) used for cancer treatment can spare healthy tissue and reduce treatment toxicity. However, full exploitation of the dosimetric advantages of PT is not yet possible due to range uncertainties, warranting development of range-monitoring techniques. This study proposes a novel range-monitoring technique introducing the yet unexplored concept of simultaneous detection and imaging of fast neutrons and prompt-gamma rays produced in beam-tissue interactions. A quasi-monolithic organic detector array is proposed, and its feasibility for detecting range shifts in the context of proton therapy is explored through Monte Carlo simulations of realistic patient models and detector resolution effects. The results indicate that range shifts of [Formula: see text] can be detected at relatively low proton intensities ([Formula: see text] protons/spot) when spatial information obtained through imaging of both particle species are used simultaneously. This study lays the foundation for multi-particle detection and imaging systems in the context of range verification in PT., (© 2023. The Author(s).)

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., (Creative Commons Attribution license.)

Background: State-of-the-art radiotherapy of locally advanced non-small cell lung cancer (LA-NSCLC) is performed with intensity-modulation during free breathing (FB). Previous studies have found encouraging geometric reproducibility and patient compliance of deep inspiration breath hold (DIBH) radiotherapy for LA-NSCLC patients. However, dosimetric comparisons of DIBH with FB are sparse, and DIBH is not routinely used for this patient group. The objective of this simulation study was therefore to compare DIBH and FB in a prospective cohort of LA-NSCLC patients treated with intensity-modulated radiotherapy (IMRT)., Methods: For 38 LA-NSCLC patients, 4DCTs and DIBH CTs were acquired for treatment planning and during the first and third week of radiotherapy treatment. Using automated planning, one FB and one DIBH IMRT plan were generated for each patient. FB and DIBH was compared in terms of dosimetric parameters and NTCP. The treatment plans were recalculated on the repeat CTs to evaluate robustness. Correlations between ΔNTCPs and patient characteristics that could potentially predict the benefit of DIBH were explored., Results: DIBH reduced the median D mean to the lungs and heart by 1.4 Gy and 1.1 Gy, respectively. This translated into reductions in NTCP for radiation pneumonitis grade ≥2 from 20.3% to 18.3%, and for 2-year mortality from 51.4% to 50.3%. The organ at risk sparing with DIBH remained significant in week 1 and week 3 of treatment, and the robustness of the target coverage was similar for FB and DIBH. While the risk of radiation pneumonitis was consistently reduced with DIBH regardless of patient characteristics, the ability to reduce the risk of 2-year mortality was evident among patients with upper and left lower lobe tumors but not right lower lobe tumors., Conclusion: Compared to FB, DIBH allowed for smaller target volumes and similar target coverage. DIBH reduced the lung and heart dose, as well as the risk of radiation pneumonitis and 2-year mortality, for 92% and 74% of LA-NSCLC patients, respectively. However, the advantages varied considerably between patients, and the ability to reduce the risk of 2-year mortality was dependent on tumor location. Evaluation of repeat CTs showed similar robustness of the dose distributions with each technique., Competing Interests: LR, BH and SB: Erasmus MC Cancer Institute has research collaborations with Elekta AB (Stockholm, Sweden), Accuray, Inc. (Sunnyvale, USA) and Varian Medical Systems, Inc. (Palo Alto, USA). The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fjellanger, Rossi, Heijmen, Pettersen, Sandvik, Breedveld, Sulen and Hysing.)

Enhancing treatment of locally advanced non-small cell lung cancer (LA-NSCLC) by using pencil beam scanning proton therapy (PBS-PT) is attractive, but little knowledge exists on the effects of uncertainties occurring between the planning (Plan) and the start of treatment (Start). In this prospective simulation study, we investigated the clinical potential for PBS-PT under the influence of such uncertainties. Imaging with 4DCT at Plan and Start was carried out for 15 patients that received state-of-the-art intensity-modulated radiotherapy (IMRT). Three PBS-PT plans were created per patient: 3D robust single-field uniform dose (SFUD), 3D robust intensity-modulated proton therapy (IMPT), and 4D robust IMPT (4DIMPT). These were exposed to setup and range uncertainties and breathing motion at Plan, and changes in breathing motion and anatomy at Start. Target coverage and dose-volume parameters relevant for toxicity were compared. The organ at risk sparing at Plan was greatest with IMPT, followed by 4DIMPT, SFUD and IMRT, and persisted at Start. All plans met the preset criteria for target robustness at Plan. At Start, three patients had a lack of CTV coverage with PBS-PT. In conclusion, the clinical potential for heart and lung toxicity reduction with PBS-PT was substantial and persistent. Altered breathing patterns between Plan and Start jeopardized target coverage for all PBS-PT techniques.

Background: Temporal lobe necrosis (TLN) is a potential late effect after radiotherapy for skull base head and neck cancer (HNC). Several photon-derived dose constraints and normal tissue complication probability (NTCP) models have been proposed, however variation in relative biological effectiveness (RBE) may challenge the applicability of these dose constraints and models in proton therapy. The purpose of this study was therefore to investigate the influence of RBE variations on risk estimates of TLN after Intensity-Modulated Proton Therapy for HNC., Material and Methods: Seventy-five temporal lobes from 45 previously treated patients were included in the analysis. Sixteen temporal lobes had radiation associated Magnetic Resonance image changes (TLIC) suspected to be early signs of TLN. Fixed (RWD Fix ) and variable RBE-weighed doses (RWD Var ) were calculated using RBE = 1.1 and two RBE models, respectively. RWD Fix and RWD Var for temporal lobes were compared using Friedman's test. Based on RWD Fix , six NTCP models were fitted and internally validated through bootstrapping. Estimated probabilities from RWD Fix and RWD Var were compared using paired Wilcoxon test. Seven dose constraints were evaluated separately for RWD Fix and RWD Var by calculating the observed proportion of TLIC in temporal lobes meeting the specific dose constraints., Results: RWD Var were significantly higher than RWD Fix ( p  < 0.01). NTCP model performance was good (AUC:0.79-0.84). The median difference in estimated probability between RWD Fix and RWD Var ranged between 5.3% and 20.0% points ( p  < 0.01), with V 60GyRBE and D Max at the smallest and largest differences, respectively. The proportion of TLIC was higher for RWD Fix (4.0%-13.1%) versus RWD Var (1.3%-5.3%). For V 65GyRBE ≤ 0.03 cc the proportion of TLIC was less than 5% for both RWD Fix and RWD Var., Conclusion: NTCP estimates were significantly influenced by RBE variations. D max as model predictor resulted in the largest deviations in risk estimates between RWD Fix and RWD Var . V 65GyRBE ≤ 0.03 cc was the most consistent dose constraint for RWD Fix and RWD Var.

In this study, the novel iCE radiotherapy treatment planning system (TPS) for automated multi-criterial planning with integrated beam angle optimization (BAO) was developed, and applied to optimize organ at risk (OAR) sparing and systematically investigate the impact of beam angles on radiotherapy dose in locally advanced non-small cell lung cancer (LA-NSCLC). iCE consists of an in-house, sophisticated multi-criterial optimizer with integrated BAO, coupled to a broadly used commercial TPS. The in-house optimizer performs fluence map optimization to automatically generate an intensity-modulated radiotherapy (IMRT) plan with optimal beam angles for each patient. The obtained angles and dose-volume histograms are then used to automatically generate the final deliverable plan with the commercial TPS. For the majority of 26 LA-NSCLC patients, iCE achieved improved heart and esophagus sparing compared to the manually created clinical plans, with significant reductions in the median heart D mean (8.1 vs. 9.0 Gy, p = 0.02) and esophagus D mean (18.5 vs. 20.3 Gy, p = 0.02), and reductions of up to 6.7 Gy and 5.8 Gy for individual patients. iCE was superior to automated planning using manually selected beam angles. Differences in the OAR doses of iCE plans with 6 beams compared to 4 and 8 beams were statistically significant overall, but highly patient-specific. In conclusion, automated planning with integrated BAO can further enhance and individualize radiotherapy for LA-NSCLC.

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., (© 2021 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Purpose: Intensity modulated proton therapy (IMPT) could yield high linear energy transfer (LET) in critical structures and increased biological effect. For head and neck cancers at the skull base this could potentially result in radiation-associated brain image change (RAIC). The purpose of the current study was to investigate voxel-wise dose and LET correlations with RAIC after IMPT., Methods and Materials: For 15 patients with RAIC after IMPT, contrast enhancement observed on T1-weighted magnetic resonance imaging was contoured and coregistered to the planning computed tomography. Monte Carlo calculated dose and dose-averaged LET (LET d ) distributions were extracted at voxel level and associations with RAIC were modelled using uni- and multivariate mixed effect logistic regression. Model performance was evaluated using the area under the receiver operating characteristic curve and precision-recall curve., Results: An overall statistically significant RAIC association with dose and LET d was found in both the uni- and multivariate analysis. Patient heterogeneity was considerable, with standard deviation of the random effects of 1.81 (1.30-2.72) for dose and 2.68 (1.93-4.93) for LET d , respectively. Area under the receiver operating characteristic curve was 0.93 and 0.95 for the univariate dose-response model and multivariate model, respectively. Analysis of the LET d effect demonstrated increased risk of RAIC with increasing LET d for the majority of patients. Estimated probability of RAIC with LET d  = 1 keV/µm was 4% (95% confidence interval, 0%, 0.44%) and 29% (95% confidence interval, 0.01%, 0.92%) for 60 and 70 Gy, respectively. The TD 15 were estimated to be 63.6 and 50.1 Gy with LET d equal to 2 and 5 keV/µm, respectively., Conclusions: Our results suggest that the LET d effect could be of clinical significance for some patients; LET d assessment in clinical treatment plans should therefore be taken into consideration., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Manual volumetric modulated arc therapy (VMAT) treatment planning for high-risk prostate cancer receiving whole pelvic radiotherapy (WPRT) with four integrated dose levels is complex and time consuming. We have investigated if the radiotherapy planning process and plan quality can be improved using a well-tuned model developed through a commercial system for knowledge-based planning (KBP)., Material and Methods: Treatment plans from 69 patients treated for high-risk prostate cancer with manually planned VMAT were used to develop an initial KBP model (RapidPlan, RP). Prescribed doses were 50, 60, 67.5, and 72.5 Gy in 25 fractions to the pelvic lymph nodes, prostate and seminal vesicles, prostate gland, and prostate tumour(s), respectively. This RP model was in clinical use from July 2019 to February 2020, producing another set of 69 clinically delivered treatment plans for a new patient group, which were used to develop a second RP model. Both models were validated on an independent group of 40 patients. Plan quality was compared by D 98% and the Paddick conformity index for targets, mean dose ( D mean ) and generalised equivalent uniform dose (gEUD) for bladder, bowel bag and rectum, and number of monitor units (MU)., Results: Target coverage and conformity was similar between manually created and RP treatment plans. Compared to the manually created treatment plans, the final RP model reduced average D mean and gEUD with 2.7 Gy and 1.3 Gy for bladder, 1.2 Gy and 0.9 Gy for bowel bag, and 2.7 Gy and 0.8 Gy for rectum, respectively ( p < .05). For rectum, the interpatient variation (i.e., 95% confidence interval) of DVHs was reduced by 23%., Conclusion: KBP improved plan quality and consistency among treatment plans for high-risk prostate cancer. Model tuning using KBP-based clinical plans further improved model outcome.

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) (V60 GyRBE ) from on average 12 mL to 9 mL. For the bladder the average V45 GyRBE 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., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: There is no consensus on how to treat high-risk prostate cancer, and long-term results from hypofractionated radiation therapy are lacking. We report 10-year results after image guided, intensity modulated radiation therapy with hypofractionated simultaneous integrated boost and elective pelvic field., Methods and Materials: Between 2007 and 2009, 97 consecutive patients with high-risk prostate cancer were included, treated with 2.7 to 2.0 Gy × 25 Gy to the prostate, seminal vesicles, and elective pelvic field. Toxicity was scored according to Radiation Therapy Oncology Group criteria and biochemical disease-free survival (BFS) defined by the Phoenix definition. Patients were subsequently divided into 3 groups: high risk (HR; n = 32), very high risk (VHR; n = 50), and N+/s-prostate-specific antigen (PSA) ≥100 (n = 15). Differences in outcomes were examined using Kaplan-Meier analyses., Results: BFS in the patients at HR and VHR was 64%, metastasis-free survival 80%, prostate cancer-specific survival 90%, and overall survival (OS) 72%. VHR versus HR subgroups demonstrated significantly different BFS, 54% versus 79% ( P = .01). Metastasis-free survival and prostate cancer-specific survival in the VHR group versus HR group were 76% versus 87% ( P = .108) and 74% versus 100% ( P = .157). Patients reaching nadir PSA <0.1 (n = 80) had significantly better outcomes than the rest (n = 17), with BFS 70% versus 7% ( P < .001). Acute grade 2 gastrointestinal tract (GI) and genitourinary tract (GU) toxicity occurred in 27% and 40%, grade 3 GI and GU toxicity in 1% and 3%. Late GI and GU grade 2 toxicity occurred in 1% and 8%., Conclusions: High-risk prostate cancer patients obtained favorable 10-year outcomes with low toxicity. There were significantly better results in the HR versus the VHR group, both better than the N+/PSA ≥100 group. A nadir PSA value < 0.1 predicted good prognosis., (© 2019 The Author(s).)

Background and Purpose: Planned doses are used as surrogate for the actually delivered dose in radiotherapy. We have estimated the delivered dose in a dose-escalation trial of locally advanced prostate cancer by statistical dose-accumulation and by DVH-summation, and compared to planned dose., Materials and Method: Prescribed dose-escalation to the prostate was 67.5 Gy/25fr., corresponding to 81GyEQD2 assuming α/β = 1.5. The 21 patients had three targets (i.e. CTV67.5 + 2 mm, CTV60 + 5 mm, CTV50 + 10 mm) irradiated by a simultaneous-integrated-boost technique. Analysis was based on 213 CT scans and 5-years of follow-up. For statistical dose-accumulation, we modelled 10000 possible treatment courses based on planned dose and deformation-vector-fields from contour-based registration. For DVH-summation we recalculated dose on repeat-CTs and estimated median D98%/EUD. Groups with/without disease recurrence were compared., Results: Discrepancies between planned and accumulated dose were mostly seen for CTV67.5, where under-dosage was found at different locations in the prostate in 12/21 patients. Delivered dose-escalation (D98%) was on average 73.9GyEQD2 (range: 68.3-78.7GyEQD2). No significant difference in accumulated-D98% was found in patients with (n = 8) and without (n = 13) recurrence (p > 0.05). Average D98%/EUD with statistical dose-accumulation vs DVH-summation was significantly different in CTV60, CTV50, rectum and bladder but not in CTV67.5., Conclusion: The planned dose escalation was not received by more than half-of-the patients. Robustness of the prostate target (CTV67.5) should therefore be better prioritized in these patients given the low toxicity profile. Estimates of delivered dose were less conservative for dose-accumulation due to interaction of random organ motion with the dose matrix., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: In silico studies comparing estimated risks of radiation-induced secondary cancer (SC) are frequently performed in assessment of radiotherapy techniques. Since inter-patient anatomy variations can result in considerable differences in estimated risk we aimed to explore the influence of inter-fractional organ motion patterns on SC risk., Methods: Volumetric modulated arc therapy (VMAT) and intensity-modulated proton therapy (IMPT) plans were generated on the planning CT (pCT) scans of eight prostate cancer patients. In addition, the treatment plans were re-calculated on 8-9 repeat CTs (rCTs) of each patient acquired throughout the treatment course. Relative risk (RR) of SC (VMAT/IMPT) was calculated for the planned and the re-calculated dose distributions using the organ equivalent dose concept adapted to a linear and a bell-shaped competition dose-response model., Results: Day-to-day variations in anatomy lead to fluctuations in SC risk estimates of the same order of magnitude as those caused by inter-patient variations. Using the competition model, the RR range for bladder cancer based on the pCTs was 0.4-3.4, while a considerably wider range was found when including all rCTs (0.2-6.7). There was nevertheless a correlation in RR based on repeat CTs for individual patients, indicating that patient-specific SC risks could be estimated., Conclusions: The estimated relative risks varied considerably across rCTs and could change the risk in favour of VMAT/IMPT depending on the anatomy of the day. The results demonstrate the importance of performing in silico studies of SC risk on a cohort of patients or multiple CTs when structures subject to organ motion are involved., (Copyright © 2017 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Background and Purpose: Radiation-induced cancer is a serious late effect that may follow radiotherapy. A considerable uncertainty is associated with carcinogenesis from photon-based treatment, and even less established when including relative biological effectiveness (RBE) for particle therapy. The aim of this work was therefore to estimate and in particular explore relative risks (RR) of secondary cancer (SC) following particle therapy as applied in treatment of prostate cancer., Material and Methods: RRs of radiation-induced SC in the bladder and rectum were estimated using a bell-shaped dose-response model incorporating RBE and fractionation effects. The risks from volumetric modulated arc therapy (VMAT) were compared to intensity-modulated proton therapy (IMPT) and scanning carbon ions for ten patients., Results: The mean estimated RR (95% CI) of SC for VMAT/C-ion was 1.31 (0.65-2.18) for the bladder and 0.58 (0.41-0.80) for the rectum. Corresponding values for VMAT/IMPT were 1.72 (1.06-2.37) and 1.10 (0.78-1.43). The radio-sensitivity parameter α had the strongest influence on the results with decreasing RR for increasing values of α., Conclusion: Based on the wide spread in RR between patients and variations across the included parameter values, the risk profiles of the rectum and bladder were not dramatically different for the investigated radiotherapy techniques., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: Introdution: Variation in shape, position and treatment response of both tumor and organs at risk are major challenges for accurate dose delivery in radiotherapy. Adaptive radiotherapy (ART) has been proposed to customize the treatment to these motion/response patterns of the individual patients, but increases workload and thereby challenges clinical implementation. This paper reviews strategies and workflows for clinical and in silico implemented ART for prostate, bladder, gynecological (gyne) and ano-rectal cancers., Material and Methods: Initial identification of papers was based on searches in PubMed. For each tumor site, the identified papers were screened independently by two researches for selection of studies describing all processes of an ART workflow: treatment monitoring and evaluation, decision and execution of adaptations. Both brachytherapy and external beam studies were eligible for review., Results: The review consisted of 43 clinical studies and 51 in silico studies. For prostate, 1219 patients were treated with offline re-planning, mainly to adapt prostate motion relative to bony anatomy. For gyne 1155 patients were treated with online brachytherapy re-planning while 25 ano-rectal cancer patients were treated with offline re-planning, all to account for tumor regression detected by magnetic resonance imaging (MRI)/computed tomography (CT). For bladder and gyne, 161 and 64 patients, respectively, were treated with library-based online plan selection to account for target volume and shape variations. The studies reported sparing of rectum (prostate and bladder cancer), bladder (ano-rectal cancer) and bowel cavity (gyne and bladder cancer) as compared to non-ART., Conclusion: Implementations of ART were dominated by offline re-planning and online brachytherapy re-planning strategies, although recently online plan selection workflows have increased with the availability of cone-beam CT. Advantageous dosimetric and outcome patterns using ART was documented by the studies of this review. Despite this, clinical implementations were scarce due to challenges in target/organ re-contouring and suboptimal patient selection in the ART workflows.

During pelvic radiotherapy bowel loops (BL) are subject to inter-fraction changes. MVCT images have the potential to provide daily bowel segmentation. We assess the feasibility of deformable registration and contour propagation in replacing manual BL segmentation on MVCT. Four observers delineated BL on the planning kVCT and on one therapy MVCT in eight patients. Inter-observer variations in BLs contouring were quantified using DICE index. BLs were then automatically propagated onto MVCT by a commercial software for image deformation and subsequently manually corrected. The agreement between propagated BL/propagated+manually corrected BL vs manual were quantified using the DICE. Contouring times were also compared. The impact on DVH of using the deformable-registration method was assessed. The same procedures were repeated on high-resolution planning-kVCT and therapy-kVCT. MVCTs are adequate to visualize BL (average DICE: 0.815), although worse than kVCT (average DICE:0.889). When comparing propagated vs manual BL, a poor agreement was found (average DICE: 0.564/0.646 for MVCT/KVCT). After manual correction, average DICE indexes increased to 0.810/0.897. The contouring time was reduced to 15min with the semi-automatic approach from 30min with manual contouring. DVH parameters of propagated BL were significantly different from manual BL (p<0.0001); after manual correction, no significant differences were seen. MVCT are suitable for BL visualization. The use of a software to segment BL on MVCT starting from BL-kVCT contours was feasible if followed by manual correction. The method resulted in a substantial reduction of contouring time without detrimental effect on the quality of bowel segmentation and DVH estimates., (Copyright © 2016 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Background: An elevated risk of radiation-induced secondary cancer (SC) has been observed in prostate cancer patients after radiotherapy (RT), rising to as high as one in 70 patients with more than 10 years follow-up. In this study we have estimated SC risks following RT with both previous and contemporary techniques, including proton therapy, using risk models based on different dose-response relationships., Material and Methods: RT plans treating the prostate and seminal vesicles with either conformal radiotherapy (CRT), volumetric modulated arc therapy (VMAT) or intensity-modulated proton therapy (IMPT) were created for 10 patients. The risks of radiation-induced cancer were estimated for the bladder and rectum using dose-response models reflecting varying degrees of cell sterilisation: a linear model, a linear-plateau model and a bell-shaped model also accounting for fractionated RT., Results: The choice of risk models was found to rank the plans quite differently, with the CRT plans having the lowest SC risk using the bell-shaped model, while resulting in the highest risk applying the linear model. Considering all dose-response scenarios, median relative risks of VMAT versus IMPT were 1.1-1.7 for the bladder and 0.9-1.8 for the rectum. Risks of radiation-induced bladder and rectal cancers were lower from VMAT if exposed at 80 years versus IMPT if exposed at 50 years., Conclusions: The SC risk estimations for the bladder and rectum revealed no clear relative relationship between the contemporary techniques and CRT, with divergent results depending on choice of model. However, the SC risks for these organs when using IMPT were lower or comparable to VMAT. SC risks could be assessed when considering referral of prostate cancer patients to proton therapy, taking also general patient characteristics, such as age, into account.

Background: Improvement in radiotherapy during the past decades has made the risk of developing a radiation-induced secondary cancer as a result of dose to normal tissue a highly relevant survivorship issue. Important factors expected to influence secondary cancer risk include dose level and dose heterogeneity, as well as gender and type of tissue irradiated. The elevated radio-sensitivity in children calls for models particularly tailored to paediatric cancer patients., Material and Methods: Treatment plans of six paediatric medulloblastoma patients were analysed with respect to secondary cancer risk following cranio-spinal irradiation (CSI), using either: 1) electrons and photons combined; 2) conformal photons; 3) double-scattering (DS) protons; or 4) intensity-modulated proton therapy (IMPT). The relative organ equivalent dose (OED) concept was applied in three dose-risk scenarios: a linear response model, a plateau response and an organ specific linear-exponential response. Life attributable risk (LAR) was calculated based on the BEIR VII committee's preferred models for estimating age- and site-specific solid cancer incidence. Uncertainties in the model input parameters were evaluated by error propagation using a Monte Carlo sampling procedure., Results: Both DS protons and IMPT achieved a significantly better dose conformity compared to the photon and electron irradiation techniques resulting in a six times lower overall risk of radiation-induced cancer. Secondary cancer risk in the thyroid and lungs contributed most to the overall risk in all compared modalities, while no significant difference was observed for the bones. Variations between DS protons and IMPT were small, as were differences between electrons and photons., Conclusion: Regardless of technique, using protons decreases the estimated risk of secondary cancer following paediatric CSI compared to conventional photon and electron techniques. Substantial uncertainties in the LAR estimates support relative risk comparisons by OED.

Background and Purpose: Deformation and correlated target motion remain challenges for margin recipes in radiotherapy (RT). This study presents a statistical deformable motion model for multiple targets and applies it to margin evaluations for locally advanced prostate cancer i.e. RT of the prostate (CTV-p), seminal vesicles (CTV-sv) and pelvic lymph nodes (CTV-ln)., Material and Methods: The 19 patients included in this study, all had 7-10 repeat CT-scans available that were rigidly aligned with the planning CT-scan using intra-prostatic implanted markers, followed by deformable registrations. The displacement vectors from the deformable registrations were used to create patient-specific statistical motion models. The models were applied in treatment simulations to determine probabilities for adequate target coverage, e.g. by establishing distributions of the accumulated dose to 99% of the target volumes (D99) for various CTV-PTV expansions in the planning-CTs., Results: The method allowed for estimation of the expected accumulated dose and its variance of different DVH parameters for each patient. Simulations of inter-fractional motion resulted in 7, 10, and 18 patients with an average D99 >95% of the prescribed dose for CTV-p expansions of 3mm, 4mm and 5mm, respectively. For CTV-sv and CTV-ln, expansions of 3mm, 5mm and 7 mm resulted in 1, 11 and 15 vs. 8, 18 and 18 patients respectively with an average D99 >95% of the prescription., Conclusions: Treatment simulations of target motion revealed large individual differences in accumulated dose mainly for CTV-sv, demanding the largest margins whereas those required for CTV-p and CTV-ln were comparable., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: Daily treatment plan selection from a plan library is a major adaptive radiotherapy strategy to account for individual internal anatomy variations. This strategy depends on the initial input images being representative for the variations observed later in the treatment course. Focusing on locally advanced prostate cancer, our aim was to evaluate if residual motion of the prostate (CTV-p) and the elective targets (CTV-sv, CTV-ln) can be prospectively accounted for with a statistical deformable model based on images acquired in the initial part of treatment., Methods: Thirteen patients with locally advanced prostate cancer, each with 9-10 repeat CT scans, were included. Displacement vectors fields (DVF) obtained from contour-based deformable registration of delineations in the repeat- and planning CT scans were used to create patient-specific statistical motion models using principal component analysis (PCA). For each patient and CTV, four PCA-models were created: one with all 9-10 DVF as input in addition to models with only four, five or six DVFs as input. Simulations of target shapes from each PCA-model were used to calculate iso-coverage levels, which were converted to contours. The levels were analyzed for sensitivity and precision., Results: A union of the simulated shapes was able to cover at least 97%, 97% and 95% of the volumes of the evaluated CTV shapes for PCA-models using six, five and four DVFs as input, respectively. There was a decrease in sensitivity with higher iso-coverage levels, with a sharper decline for greater target movements. Apart from having the steepest decline in sensitivity, CTV-sv also displayed the greatest influence on the number of geometries used in the PCA-model., Conclusions: PCA-based simulations of residual motion derived from four to six DVFs as input could account for the majority of the target shapes present during the latter part of the treatment. CTV-sv displayed the greatest range in both sensitivity and precision.

Background and Purpose: In radiotherapy (RT) of prostate cancer the key organs at risk (ORs) - the rectum and the bladder - display considerable motion, which may influence the dose/volume parameters predicting for morbidity. In this study we compare motion-inclusive doses to planned doses for the rectum and bladder and explore their associations with prospectively recorded morbidity., Materials and Methods: The study included 38 prostate cancer patients treated with hypo-fractionated image-guided intensity-modulated RT that had an average of nine repeat CT scans acquired during treatment. These scans were registered to the respective treatment planning CT (pCT) followed by a new dose calculation from which motion-inclusive dose distributions were derived. The pCT volumes, the treatment course averaged volumes as well as the planned and motion-inclusive doses were associated with acute and late morbidity (morbidity cut-off: ≥ Grade 2)., Results: Acute rectal morbidity (observed in 29% of cases) was significantly associated with both smaller treatment course averaged rectal volumes (population median: 75 vs. 94 cm(3)) and the motion-inclusive volume receiving doses close to the prescription dose (2 Gy-equivalent dose of 76 Gy)., Conclusion: Variation in rectum and bladder volumes leads to deviations between planned and delivered dose/volume parameters that should be accounted for to improve the ability to predict morbidity following RT., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: Internal target and organ motion during treatment is a challenge in radiotherapy (RT) of the prostate and the involved elective targets, with residual motion being present also following image-guidance strategies. The aim of this study was to investigate organ motion-induced dose degradations for the prostate, seminal vesicle and the pelvic lymph node when treating these targets with proton therapy, using different image-guidance and delivery strategies., Material and Methods: Four patients were selected from a larger series as they displayed large inter-fractional variation in bladder and rectum volume. Intensity-modulated proton therapy plans were generated using both simultaneous integrated and sequential boost delivery. For each technique, three isotropic margin expansions (in the range of 4-10 mm) were evaluated for the clinical target volume of prostate (CTV-p), seminal vesicles (CTV-sv) and lymph nodes (CTV-ln). Simulation of the dose degradations for all treatment plans were based on dose re-calculations for the 8-9 repeat CTs available for each patient, after applying rigid registrations to reproduce set-up based on either intra-prostatic fiducials or bony anatomy., Results: The simulated dose received by 99% of the target volume (D(99)) and generalized equivalent dose (gEUD) showed substantial inter-patient variations. For 40% of the investigated scenarios, the patient average simulated D(99) for all targets were within 2 GyE from the planned dose. The largest difference between simulated and planned dose was seen for the CTV-sv when using SIB delivery, with an average relative reduction in D(99) of 13% and 15% for the largest margin expansion, when positioned using fiducials and bony anatomy, respectively., Conclusions: The most severe dose degradations were found for CTV-sv, but they were also evident for CTV-ln. The degradations could not be completely resolved, neither by using the largest margin expansion nor with the choice of set-up. With fiducial set-up CTV-p was robust against the inter-fraction changes.

Background and Purpose: The aim of this work was to develop a statistical method for generation of patient-specific planning organ-at-risk volumes (PRVs) for the small bowel (SB), by efficient use of a few repeat CT scans., Materials and Methods: The PRVs are generated from a coverage probability (CP) matrix of the small bowel wall (SBW) by thresholding. To estimate the CPs, we extend a previously published 'relative frequency of coverage' approach by adding a 'soft margin' around each SBW instance. This prevents the CP matrix from containing any holes, thus making it more robust. As the number of CTs approach infinity, the 'soft margin' approaches zero and the CP matrix converges to the 'relative frequency of coverage'. The PRVs were evaluated by using the bootstrap method in three patients with different degrees of SB motion: The PRVs from randomly sampled subsets of CTs were compared to the PRVs generated from all 10-11 CT scans, by analysis of sensitivity and specificity. Furthermore, the PRVs generated for CP=0.005 (i.e. generous patient-specific PRVs) and for CP=0.03 (i.e. tight patient-specific PRVs) were compared to an intestinal cavity (IC) approach and a population based PRV approach of 10 and 30 mm isotropic planning margins around SB., Results: The sensitivity and specificity of the PRVs depend on the number of CT scans and the CP threshold. With three CT scans and a threshold of 0.03, an average sensitivity of 94-96% and specificity of 86-97% was obtained. All investigated SB planning volumes had an average overlap >89% of both SB and SBW. The tight patient-specific PRVs and the 10mm margins had the lowest relative volumes, followed by the generous patient-specific PRVs, the 30 mm margins and the ICs., Conclusions: Based on a few CTs, our method generates patient-specific SB PRVs which are both sensitive and specific. Compared to conventional approaches, the patient-specific PRVs are either similar or better in predicting for SB voxels, and at the same time they occupy a smaller or similar volume in the patient., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: Uncorrelated motion of targets and large deformations of organs at risk represent challenges for image-guidance in simultaneous integrated boost (SIB) radiotherapy (RT) of pelvic tumour sites. This study aims to evaluate the robustness towards geometrical uncertainties in prostate cancer using two image-guided RT (IGRT) set-up strategies for two SIB delivery methods. Secondly, we evaluate the ability of geometrical parameters to predict when the applied margins are insufficient, resulting in target underdosage (TUD)., Material and Methods: The study included nine patients with eight to nine repeat computed tomography (CT)-scans evenly distributed throughout their treatment course. The prostate target (CTV-p) and the lymph node target including seminal vesicles (CTV-ln/sv) were delineated in all scans. SIB treatment plans for intensity-modulated RT and volumetric modulated arc therapy were generated on the planning CT and transferred to the repeat CTs for dose re-calculation using registration based on either anatomy or intra-prostatic fiducial markers. Receiving operator characteristic analysis was used to deduce the ability of the parameters to predict TUD., Results: The dosimetric differences between the two positioning strategies were small for all parameters evaluated and significant only for the dose to rectum. Anatomy based registration resulted in inferior target coverage with a larger number of TUDs, mostly seen in the seminal vesicles. For both targets the highest sensitivity and specificity of predicting TUD was seen for the relative volume and the lowest was found for the displacement vector., Conclusions: Positioning based on fiducials gave the best trade-off between coverage of the targets although resulting in the highest dose to rectum. Target underdosage occurred mostly in the seminal vesicles. For both targets, the best parameter to predict TUD was the relative volume.

A fast and accurate segmentation of organs at risk, such as the healthy colon, would be of benefit for planning of radiotherapy, in particular in an adaptive scenario. For the treatment of pelvic tumours, a great challenge is the segmentation of the most adjacent and sensitive parts of the gastrointestinal tract, the sigmoid and descending colon. We propose a semi-automated method to segment these bowel parts using the fast marching (FM) method. Standard 3D computed tomography (CT) image data obtained from routine radiotherapy planning were used. Our pre-processing steps distinguish the intestine, muscles and air from connective tissue. The core part of our method separates the sigmoid and descending colon from the muscles and other segments of the intestine. This is done by utilizing the ability of the FM method to compute a specified minimal energy functional integrated along a path, and thereby extracting the colon centre line between user-defined control points in the sigmoid and descending colon. Further, we reconstruct the tube-shaped geometry of the sigmoid and descending colon by fitting ellipsoids to points on the path and by adding adjacent voxels that are likely voxels belonging to these bowel parts. Our results were compared to manually outlined sigmoid and descending colon, and evaluated using the Dice coefficient (DC). Tests on 11 patients gave an average DC of 0.83 (+/-0.07) with little user interaction. We conclude that the proposed method makes it possible to fast and accurately segment the sigmoid and descending colon from routine CT image data.

Purpose: To compare an intensity-modulated radiotherapy (IMRT) planning approach for prostate pelvic RT with a conformal RT (CRT) approach taking into account the influence of organ-at-risk (OAR) motion., Methods and Materials: A total of 20 male patients, each with one planning computed tomography scan and five to eight treatment computed tomography scans, were used for simulation of IMRT and CRT for delivery of a prescribed dose of 50 Gy to the prostate, seminal vesicles, and pelvic lymph nodes. Planning was done in Eclipse without correcting for OAR motion. Evaluation was performed using the CRT and IMRT dose matrices and the planning and treatment OAR outlines. The generalized equivalent uniform dose (gEUD) was calculated for 894 OAR volumes using a volume-effect parameter of 4, 12, and 8 for bowel, rectum and bladder, respectively. For the bowel, the gEUD was normalized to a reference volume of 200 cm(3). For each patient and each OAR, an average of the treatment gEUDs (gEUD(treat)) was calculated for CRT and IMRT. The paired t test was used to compare IMRT with CRT and gEUD(treat) with gEUD(plan)., Results: The mean gEUD(treat) was reduced from 43 to 40 Gy, 47 to 46 Gy, and 48 to 45 Gy with IMRT for the bowel, rectum, and bladder, respectively (p < 0.001). Differences between the gEUD(plan) and gEUD(treat) were not significant (p > 0.05) for any OAR but was >6% for the bowel in 6 of 20 patients., Conclusion: Intensity-modulated RT reduced the bowel, rectum, and bladder gEUDs also under influence of OAR motion. Neither CRT nor IMRT was robust against bowel motion, but IMRT was not less robust than CRT.

Purpose: We present planning and early clinical outcomes of a study of intensity-modulated radiotherapy (IMRT) for locally advanced prostate cancer., Methods and Materials: A total of 43 patients initially treated with an IMRT plan delivering 50 Gy to the prostate, seminal vesicles, and pelvic lymph nodes, followed by a conformal radiotherapy (CRT) plan delivering 20 Gy to the prostate and seminal vesicles, were studied. Dose-volume histogram (DVH) data for the added plans were compared with dose-volume histogram data for the sum of two CRT plans for 15 cases. Gastrointestinal (GI) and genitourinary (GU) toxicity, based on the Radiation Therapy Oncology Group scoring system, was recorded weekly throughout treatment as well as 3 to 18 months after treatment and are presented., Results: Treatment with IMRT both reduced normal tissue doses and increased the minimum target doses. Intestine volumes receiving more than 40 and 50 Gy were significantly reduced (e.g., at 50 Gy, from 81 to 19 cm(3); p = 0.026), as were bladder volumes above 40, 50, and 60 Gy, rectum volumes above 30, 50, and 60 Gy, and hip joint muscle volumes above 20, 30, and 40 Gy. During treatment, Grade 2 GI toxicity was reported by 12 of 43 patients (28%), and Grade 2 to 4 GU toxicity was also observed among 12 patients (28%). With 6 to 18 months of follow-up, 2 patients (5%) experienced Grade 2 GI effects and 7 patients (16%) experienced Grade 2 GU effects., Conclusions: Use of IMRT for pelvic irradiation in prostate cancer reduces normal tissue doses, improves target coverage, and has a promising toxicity profile.

Background and Purpose: To account for internal organ motion and set-up uncertainties around organs at risk (OR) in radiotherapy (RT), the ICRU report no 62 introduced the planning organ at risk volume (PRV). In the present study, we have quantified PRV margins for the intestine, which is an important OR in pelvic RT., Materials and Methods: The present study was based on intestine contours outlined in a total of 149 CT scans of 20 male bladder cancer patients (20 planning scans, 129 during treatment). From these data, we created location probability maps of the intestine for each patient. A commercial treatment planning system was used to add 3D isotropic intestine PRV margins (from 5 to 30 mm, in intervals of 5 mm) around the intestine planning outline. We then derived the fraction of patients for which a given PRV encompassed various degrees of intestine motion (85%, 90% and 95% of volumes with different probabilities of intestinal occupancy). As a measure of the specificity of the PRV, we also derived the fraction of the PRV containing volumes with zero probability of intestinal occupancy., Results: Isotropic margins of up to 30 mm are required to account for all intestine motion in 90% of the patients, while isotropic margins of 5 - 10 mm will encompass 85 - 95% of the volumes having a probability of intestinal occupancy of > or = 75% in the same fraction of patients. Intestine PRVs are not very specific and will also include volumes where the intestine will rarely or never be located., Conclusions: Large intestinal motion was found, but isotropic PRV margins of 5-10 mm will include the major part of volumes with a large probability of intestinal occupancy in most patients.