The impact of baseline health factors on second primary cancer risk after radiotherapy for prostate cancer.

PURPOSE: In evaluating second primary cancers (SPCs) following External Beam Radiotherapy (EBRT), the role of lifestyle factors is frequently not considered due to data limitations. We investigated the association between smoking, comorbidities, and SPC risks within EBRT-treated patients for localized prostate cancer (PCa). PATIENTS & METHODS: The study included 1,883 PCa survivors aged 50-79, treated between 2006 and 2013, with intensity-modulated radiotherapy (IMRT) or three-dimensional conformal radiotherapy (3D-CRT). Clinical data were combined with SPC and survival data from the Netherlands Cancer Registry with a 12-month latency period. Standardized Incidence Ratios (SIRs) were calculated comparing the EBRT cohort with the general Dutch population. To explore the effect of patient and treatment characteristics on SPCs we conducted a Cox regression analysis. Lastly, we estimated cumulative incidences of developing solid SPC, pelvis SPC, and non-pelvis SPC using a competing risk analysis. RESULTS: Significantly increased SIRs were observed for all SPC (SIR = 1.21, 95% confidence interval [CI]: 1.08-1.34), pelvis SPC (SIR = 1.46, 95% CI: 1.18-1.78), and non-pelvis SPC (SIR = 1.18, 95% CI [1.04-1.34]). Smoking status was significantly associated with pelvic and non-pelvic SPCs. Charlson comorbidity index (CCI) ≥ 1 (Hazard Ratio [HR] = 1.45, 95% CI: 1.10-1.91), cardiovascular disease (HR = 1.41, 95% CI: 1.05-1.88), and chronic obstructive pulmonary disease (COPD) (HR = 1.91, 95% CI: 1.30-2.79) were significantly associated with non-pelvis SPC. The proportion of active smoking numbers in the cohort was similar to the general population. INTERPRETATION: We conclude that the presence of comorbidities in the EBRT population might be a relevant factor in observed excess non-pelvis SPC risk, but not for excess pelvis SPC risk.

Multidelay pseudocontinuous arterial spin labeling to measure blood flow in the head and neck.

Perfusion MRI is promising for the assessment, prediction, and monitoring of radiation toxicity in organs at risk in head and neck cancer. Arterial spin labeling (ASL) may be an attractive alternative for conventional perfusion MRI, that does not require the administration of contrast agents. However, currently, little is known about the characteristics and performance of ASL in healthy tissues in the head and neck region. Therefore, the purpose of this study was to optimize and evaluate multidelay pseudocontinuous ASL (pCASL) for the head and neck region and to explore nominal values and measurement repeatability for the blood flow (BF), and the transit time and T1 values needed for BF quantification in healthy tissues. Twenty healthy volunteers underwent a scan session consisting of four repeats of multidelay pCASL (postlabel delays: 1000, 1632, 2479 ms). Regions of interest were defined in the parotid glands, submandibular glands, tonsils, and the cerebellum (as a reference). Nominal values of BF were calculated as the average over four repeats per volunteer. The repeatability coefficient and within-subject coefficient of repeatability (wCV) of BF were calculated. The effect of T1 (map vs. cohort average) and transit time correction on BF was investigated. The mean BF (± SE) was 55.7 ± 3.1 ml/100 g/min for the parotid glands, 41.2 ± 2.8 ml/100 g/min for the submandibular glands, and 32.3 ± 2.2 ml/100 g/min for the tonsils. The best repeatability was found in the parotid glands (wCV = 13.3%-16.1%), followed by the submandibular glands and tonsils (wCV = 20.0%-24.6%). On average, the effect of T1 and transit time correction on BF was limited, although substantial bias occurred in individual acquisitions. In conclusion, we demonstrated the feasibility of BF measurements in the head and neck region using multidelay pCASL and reported on nominal BF values, BF repeatability, the effect of T1, and transit time in various tissues in the head and neck region.

HYpofractionated, dose-redistributed RAdiotherapy with protons and photons to combat radiation-induced immunosuppression in head and neck squamous cell carcinoma: study protocol of the phase I HYDRA trial.

BACKGROUND: Radiotherapy (RT) is the standard of care for most advanced head and neck squamous cell carcinoma (HNSCC) and results in an unfavorable 5-year overall survival of 40%. Despite strong biological rationale, combining RT with immune checkpoint inhibitors does not result in a survival benefit. Our hypothesis is that the combination of these individually effective treatments fails because of radiation-induced immunosuppression and lymphodepletion. By integrating modern radiobiology and innovative radiotherapy concepts, the patient's immune system could be maximally retained by (1) increasing the dose per fraction so that the total dose and number of fractions can be reduced (HYpofractionation), (2) redistributing the radiation dose towards a higher peak dose within the tumor center and a lowered elective lymphatic field dose (Dose-redistribution), and (3) using RAdiotherapy with protons instead of photons (HYDRA). METHODS: The primary aim of this multicenter study is to determine the safety of HYDRA proton- and photon radiotherapy by conducting two parallel phase I trials. Both HYDRA arms are randomized with the standard of care for longitudinal immune profiling. There will be a specific focus on actionable immune targets and their temporal patterns that can be tested in future hypofractionated immunoradiotherapy trials. The HYDRA dose prescriptions (in 20 fractions) are 40 Gy elective dose and 55 Gy simultaneous integrated boost on the clinical target volume with a 59 Gy focal boost on the tumor center. A total of 100 patients (25 per treatment group) will be recruited, and the final analysis will be performed one year after the last patient has been included. DISCUSSION: In the context of HNSCC, hypofractionation has historically only been reserved for small tumors out of fear for late normal tissue toxicity. To date, hypofractionated radiotherapy may also be safe for larger tumors, as both the radiation dose and volume can be reduced by the combination of advanced imaging for better target definition, novel accelerated repopulation models and high-precision radiation treatment planning and dose delivery. HYDRA's expected immune-sparing effect may lead to improved outcomes by allowing for future effective combination treatment with immunotherapy. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov; NCT05364411 (registered on May 6th, 2022).

Post radiation mucosal ulcer risk after a hypofractionated stereotactic boost and conventional fractionated radiotherapy for oropharyngeal carcinoma.

BACKGROUND/PURPOSE: Post radiation mucosal ulcers (PRMU) after treatment for oropharyngeal squamous cell carcinoma (OPSCC) can have a huge negative impact on patients' quality of life, but little is known concerning risk factors and the impact of fraction size. Therefore, the goal of this study was to determine the pattern of PRMU development and to identify risk factors after a hypofractionated stereotactic body radiotherapy boost (SBRT) compared to conventionally fractionated radiotherapy for OPSCC. MATERIAL AND METHODS: We performed a retrospective cohort study (N = 332) of OPSCC patients with ≥ 1-year disease-free survival, treated with 46 Gy Intensity Modulated Radiotherapy (IMRT) (2 Gy fractions) followed by either an SBRT boost of 16.5 Gy (5.5 Gy fractions) (N = 180), or 24 Gy IMRT (2 Gy fractions) (N = 152). PRMU (grade ≥ 2) was scored when observed > three months after the last radiotherapy (RT) fraction (CTCAE v5.0). Potential risk factors were analyzed with Cox regression models using death as competing risk. Dose at the PRMU site was calculated by projecting delineated PRMU on the planning CT. RESULTS: All cases of PRMU (N = 64) occurred within 24 months; all were grade 2. The cumulative incidence at 2 years in the SBRT boost group was 26% (N = 46) vs. 12% (N = 18) for conventional fractionation (p = 0.003). Most PRMU developed within nine months (N = 48). PRMU occurring > nine months (N = 16) were mainly observed in the SBRT boost group (N = 15). Sex (p = 0.048), acute tube feeding (p = < 0.001), tumor subsite tonsil (p = 0.001), and N stage (p = 0.017) were associated with PRMU risk at multivariable regression in the hypofractionated SBRT boost group. All 25 delineated PRMU were located within the high dose regions. CONCLUSION: The risk of PRMU should be included in the cost benefit analysis when considering future research using a hypofractionated SBRT boost for OPSCC patients.

An optimal acquisition and post-processing pipeline for hybrid IVIM-DKI in head and neck.

PURPOSE: To optimize the diffusion-weighting b values and postprocessing pipeline for hybrid intravoxel incoherent motion diffusion kurtosis imaging in the head and neck region. METHODS: Optimized diffusion-weighting b value sets ranging between 5 and 30 b values were constructed by optimizing the Cramér-Rao lower bound of the hybrid intravoxel incoherent motion diffusion kurtosis imaging model. With this model, the perfusion fraction, pseudodiffusion coefficient, diffusion coefficient, and kurtosis were estimated. Sixteen volunteers were scanned with a reference b value set and 3 repeats of the optimized sets, of which 1 with volunteers swallowing on purpose. The effects of (1) b value optimization and number of b values, (2) registration type (none vs. intervolume vs. intra- and intervolume registration), and (3) manual swallowing artifact rejection on the parameter precision were assessed. RESULTS: The SD was higher in the reference set for perfusion fraction, diffusion coefficient, and kurtosis by a factor of 1.7, 1.5, and 2.3 compared to the optimized set, respectively. A smaller SD (factor 0.7) was seen in pseudodiffusion coefficient. The sets containing 15, 20, and 30 b values had comparable repeatability in all parameters, except pseudodiffusion coefficient, for which set size 30 was worse. Equal repeatability for the registration approaches was seen in all parameters of interest. Swallowing artifact rejection removed the bias when present. CONCLUSION: To achieve optimal hybrid intravoxel incoherent motion diffusion kurtosis imaging in the head and neck region, b value optimization and swallowing artifact image rejection are beneficial. The optimized set of 15 b values yielded the optimal protocol efficiency, with a precision comparable to larger b value sets and a 50% reduction in scan time.

Prognostic factors of local control and disease free survival in centrally located non-small cell lung cancer treated with stereotactic body radiation therapy.

Background: Stereotactic body radiation therapy (SBRT) results in high local control (LC) rates in patients with non-small cell lung cancer (NSCLC). For central lung tumors, risk-adapted fractionation schedules are used and underdosage to the Planned Target Volume (PTV) is often accepted to respect the dose constraints of the organs at risk in order to avoid high rates of toxicity. The purpose of this study was to analyze the effect of PTV underdosage and other possible prognostic factors on local- and disease control after SBRT in patients with central lung tumors.Material and Methods: Patients with centrally located NSCLC treated with SBRT were included. The doses were converted into biologically equivalent dose using α/ß-value of 10 Gy (BED10). Underdosage to the PTV was defined as the (percentage of) PTV receiving less than 100 Gy BED10; (%)PTV < 100 BED10. Potential prognostic factors for LC and Disease Free Survival (DFS) were evaluated using Cox regression analysis.Results: Two hundred and twenty patients received ≤12 fractions of SBRT. LC-rates were 88% at 2 years and 81% at 3 years. Twenty-seven patients developed a local recurrence. Both the PTV < 100 BED10 and %PTV < 100 BED10 were not prognostic for LC. Tumor size and forced expiratory volume in 1 second (FEV1) were independently prognostic for LC. Disease progression was reported in 75 patients with DFS-rates of 66% at 2 years and 56% at 3 years. Disease recurrence was independent significantly associated with larger tumor diameter, lower lobe tumor location and decreased FEV1. Grade 4-5 toxicity was reported in 10 patients (8 with ultra-central tumors) and was fatal in at least 3 patients.Conclusion: Decrease in tumor coverage was not correlated with the local recurrence probability. The LC and DFS were promising after SBRT of centrally located NSCLC with tumor size, FEV1 and tumor location (for DFS only) as prognostic factors.

Commissioning and clinical implementation of the first commercial independent Monte Carlo 3D dose calculation to replace CyberKnife M6™ patient-specific QA measurements.

PURPOSE: To report on the commissioning and clinical validation of the first commercially available independent Monte Carlo (MC) three-dimensional (3D) dose calculation for CyberKnife robotic radiosurgery system® (Accuray, Sunnyvale, CA). METHODS: The independent dose calculation (IDC) by SciMoCa® (Scientific RT, Munich, Germany) was validated based on water measurements of output factors and dose profiles (unshielded diode, field-size dependent corrections). A set of 84 patient-specific quality assurance (QA) measurements for multi-leaf collimator (MLC) plans, using an Octavius two-dimensional SRS1000 array (PTW, Freiburg, Germany), was compared to results of respective calculations. Statistical process control (SPC) was used to detect plans outside action levels. RESULTS: Of all output factors for the three collimator systems of the CyberKnife, 99% agreed within 2% and 81% within 1%, with a maximum deviation of 3.2% for a 5-mm fixed cone. The profiles were compared using a one-dimensional gamma evaluation with 2% dose difference and 0.5 mm distance-to-agreement (Γ(2,0.5)). The off-centre ratios showed an average pass rate >99% (92-100%). The agreement of the depth dose profiles depended on field size, with lowest pass rates for the smallest MLC field sizes. The average depth dose pass rate was 88% (35-99%). The IDCs showed a Γ(2,1) pass rate of 98%. Statistical process control detected six plans outside tolerance levels in the measurements, all of which could be attributed the measurement setup. Independent dose calculations showed problems in five plans, all due to differences in the algorithm between TPS and IDC. Based on these results changes were made in the class solution for treatment plans. CONCLUSION: The first commercially available MC 3D dose IDC was successfully commissioned and validated for the CyberKnife and replaced all routine patient-specific QA measurements in our clinic.

Survival and prognostic factors of pulmonary oligometastases treated with stereotactic body radiotherapy.

BACKGROUND: Stereotactic body radiotherapy (SBRT) for pulmonary oligometastatic disease achieves excellent treatment outcomes in terms of local control and toxicity. Patients treated with SBRT are often elderly and have multiple co-morbidities. This subset of patients may experience different survival as compared to young and fit patients subjected to radical metastasectomies. The purpose of this retrospective study was to evaluate OS and identify factors associated with OS for inoperable pulmonary oligometastases treated with SBRT. MATERIAL AND METHODS: Criteria used for selection of patients with oligometastases included: metastases limited to ≤2 organs and in total ≤5 metastases at the time of treatment. Peripheral tumors were treated with 51 Gy to 60 Gy in three fractions or a single fraction of 30 Gy. Central tumors received a dose of 45-60 Gy in 5-8 fractions. Survival probabilities were estimated by means of Kaplan-Meier method and the relation between potential prognostic factors and OS was studied by means of Cox regression analyses. RESULTS: In this study, 327 inoperable pulmonary oligometastases in 206 patients were treated with SBRT from the year 2005 to 2015. Primary sites of pulmonary oligometastases included colorectal carcinoma (n = 118), lung carcinoma (n = 36), melanoma (n = 11), sarcoma (n = 10), breast carcinoma (n = 7), and other tumors sites (n = 24). Median follow-up was 26 months. Median survival was 33 months. The 2-year and 5-year OS rates were 63% and 30%, respectively. On univariate analysis synchronous oligometastases (HR 0.59) and colorectal primary (HR 0.64) were associated with improved OS. On multivariable analysis synchronous oligometastases (HR 0.56), colorectal primary (HR 0.62) and tumor size <3 cm (HR 0.68) were independently associated with OS. CONCLUSIONS: SBRT to pulmonary oligometastases was associated with a 2-year OS of 63%. Tumor size <3 cm and colorectal primary tumors experienced improved OS compared to tumors >3 cm and non-colorectal primary tumors.

Plan-library supported automated replanning for online-adaptive intensity-modulated proton therapy of cervical cancer.

Background: Intensity-modulated proton therapy is sensitive to inter-fraction variations, including density changes along the pencil-beam paths and variations in organ-shape and location. Large day-to-day variations are seen for cervical cancer patients. The purpose of this study was to develop and evaluate a novel method for online selection of a plan from a patient-specific library of prior plans for different anatomies, and adapt it for the daily anatomy. Material and methods: The patient-specific library of prior plans accounting for altered target geometries was generated using a pretreatment established target motion model. Each fraction, the best fitting prior plan was selected. This prior plan was adapted using (1) a restoration of spot-positions (Bragg peaks) by adapting the energies to the new water equivalent path lengths; and (2) a spot addition to fully cover the target of the day, followed by a fast optimization of the spot-weights with the reference point method (RPM) to obtain a Pareto-optimal plan for the daily anatomy. Spot addition and spot-weight optimization could be repeated iteratively. The patient cohort consisted of six patients with in total 23 repeat-CT scans, with a prescribed dose of 45 Gy(RBE) to the primary tumor and the nodal CTV. Using a 1-plan-library (one prior plan based on all motion in the motion model) was compared to choosing from a 2-plan-library (two prior plans based on part of the motion). Results: Applying the prior-plan adaptation method with one iteration of adding spots resulted in clinically acceptable target coverage ( V95%≥95% and V107%≤2% ) for 37/46 plans using the 1-plan-library and 41/46 plans for the 2-plan-library. When adding spots twice, the 2-plan-library approach could obtain acceptable coverage for all scans, while the 1-plan-library approach showed V107%>2% for 3/46 plans. Similar OAR results were obtained. Conclusion: The automated prior-plan adaptation method can successfully adapt for the large day-to-day variations observed in cervical cancer patients.

Acute toxicity of the bowel after stereotactic robotic radiotherapy for abdominopelvic oligometastases.

AIM: To correlate dose-volume histogram (DVH) parameters with appearance of grade ≥2 acute and late gastrointestinal toxicity of stereotactic body radiotherapy (SBRT) in patients with abdominopelvic solitary or oligometastatic disease outside the liver. MATERIAL AND METHODS: Acute and late bowel toxicity of 84 abdominopelvic oligometastatic patients was registered. A logistic regression was performed between different DVH parameters and presence of grade ≥2 acute and late toxicity. A Normal Tissue Complication Probability (NTCP) model was built with significant parameters to determine complication probabilities (CP). RESULTS: Thirteen (15%) of 84 patients experienced of grade ≥2 acute toxicity, while 8 (10%) reported late toxicity complications. A significant relationship was found for EQD2 (V30Gy, V40Gy, V50Gy and V65Gy) and grade ≥2 acute toxicity. Dmax and D2 were not significant. Late grade ≥2 toxicity was not significantly correlated with any DVH parameter. According to our NTCP model for V40Gy, an irradiated bowel volume of 10 cm3 of V40Gy resulted in CP of grade ≥2 acute toxicity of less than 10%. Local control was 87% at 2 years and 82% at 5 years. Overall survival was 61% at 2 years and 32% at 5 years. CONCLUSIONS: After SBRT for abdominopelvic oligometastases, in general, the presence of acute and late toxicity was low. A significant relationship was found for V30Gy, V40Gy, V50Gy and V65Gy and grade ≥2 acute toxicity. We estimated acute complication probabilities per volume of irradiated bowel by V40Gy and V50Gy.

Factors affecting local control of pulmonary oligometastases treated with stereotactic body radiotherapy.

BACKGROUND: Oligometastases refers to a state of limited metastatic disease. The use of local ablative therapies to patients with oligometastases can result in durable state of remission or long-term cure. Stereotactic body radiotherapy (SBRT) is a highly conformal radiation technique that delivers ablative doses to the target. The study aimed to evaluate local control (LC) and identify factors associated with poor LC in patients with pulmonary oligometastases treated with SBRT. Primary endpoint of the study was to assess LC; secondary endpoint was to determine factors associated with LC. MATERIAL AND METHODS: Criteria used for selection of patients with oligometastases included: metastatic disease limited to a maximum of two organs and no more than five metastatic lesions at time of treatment. Peripheral tumors were treated with 51-60 Gy in three fractions or a single fraction of 30 Gy. Central tumors received a dose of 45-60 Gy in 5-8 fractions. RESULTS: In 206 patients, 327 pulmonary oligometastases were treated with SBRT. Median follow-up was 22 months (range 2-100). LC at 2 and 3 years was 85% and 83%, respectively. On univariate analysis, biological equivalent dose assuming an α/ß ratio of 10 (BED10) < 100 Gy (HR 3.09), single-fraction SBRT (HR 2.83), synchronous metastasis (HR 1.99), and pre-SBRT chemotherapy (HR 2.79) were significantly associated with inferior LC. In the multivariable analysis BED10 <100 Gy (HR 3.59), pre-SBRT chemotherapy (HR 2.61) and presence of synchronous metastasis (HR 2.21) remained independently associated with poor LC. CONCLUSIONS: SBRT achieved an excellent LC of 85% at 2 years. Although retrospective in nature, our study identified three factors associated with inferior LC. These factors may help to refine SBRT practice for pulmonary oligometastases in the future.

Impact of model and dose uncertainty on model-based selection of oropharyngeal cancer patients for proton therapy.

BACKGROUND: Proton therapy is becoming increasingly available, so it is important to apply objective and individualized patient selection to identify those who are expected to benefit most from proton therapy compared to conventional intensity modulated radiation therapy (IMRT). Comparative treatment planning using normal tissue complication probability (NTCP) evaluation has recently been proposed. This work investigates the impact of NTCP model and dose uncertainties on model-based patient selection. MATERIAL AND METHODS: We used IMRT and intensity modulated proton therapy (IMPT) treatment plans of 78 oropharyngeal cancer patients, which were generated based on automated treatment planning and evaluated based on three published NTCP models. A reduction in NTCP of more than a certain threshold (e.g. 10% lower NTCP) leads to patient selection for IMPT, referred to as 'nominal' selection. To simulate the effect of uncertainties in NTCP-model coefficients (based on reported confidence intervals) and planned doses on the accuracy of model-based patient selection, the Monte Carlo method was used to sample NTCP-model coefficients and doses from a probability distribution centered at their nominal values. Patient selection accuracy within a certain sample was defined as the fraction of patients which had similar selection in both the 'nominal' and 'sampled' scenario. RESULTS: For all three NTCP models, the median patient selection accuracy was found to be above 70% when only NTCP-model uncertainty was considered. Selection accuracy decreased with increasing uncertainty resulting from differences between planned and delivered dose. In case of excessive dose uncertainty, selection accuracy decreased to 60%. CONCLUSION: Model and dose uncertainty highly influence the accuracy of model-based patient selection for proton therapy. A reduction of NTCP-model uncertainty is necessary to reach more accurate model-based patient selection.

Repeat CT-scan assessment of lymph node motion in locally advanced cervical cancer patients.

PURPOSE: In cervical cancer patients the nodal clinical target volume (CTV, defined using the major pelvic blood vessels and enlarged lymph nodes) is assumed to move synchronously with the bony anatomy. The aim of this study was to verify this assumption by investigating the motion of the major pelvic blood vessels and enlarged lymph nodes visible in CT scans. METHODS AND MATERIALS: For 13 patients treated in prone position, four variable bladder-filling CT scans per patient, acquired at planning and after 40 Gy, were selected from an available dataset of 9-10 CT scans. The bladder, rectum, and the nodal-vessels structure containing the iliac vessels and all visible enlarged nodes were delineated in each selected CT scan. Two online patient setup correction protocols were simulated. The first corrected bony anatomy translations and the second corrected translations and rotations. The efficacy of each correction was calculated as the overlap between the nodal-vessels structure in the reference and repeat CT scans. The motion magnitude between delineated structures was quantified using nonrigid registration. RESULTS: Translational corrections resulted in an average overlap of 58 ± 13% and in a range of motion between 9.9 and 27.3 mm. Translational and rotational corrections significantly improved the overlap (64 ± 13%, p value = 0.007) and moderately reduced the range of motion to 7.6-23.8 mm (p value = 0.03). Bladder filling changes significantly correlated with the nodal-vessels motion (p < 0.001). CONCLUSION: The motion of the nodal-vessels was large, nonrigid, patient-specific, and only moderately synchronous with the bony anatomy. This study highlights the need for caution when reducing the CTV-to-PTV (PTV planning target volume) margin of the nodal CTV for highly conformal radiation techniques.

CyberKnife robotic spinal radiosurgery in prone position: dosimetric advantage due to posterior radiation access?

CyberKnife spinal radiosurgery suffers from a lack of posterior beams due to workspace limitations. This is remedied by a newly available tracking modality for fiducial-free, respiration-compensated spine tracking in prone patient position. We analyzed the potential dosimetric benefit in a planning study. Fourteen exemplary cases were compared in three scenarios: supine (PTV=CTV), prone (PTV=CTV), and prone position with an additional margin (PTV=CTV+2 mm), to incorporate reduced accuracy of respiration-compensated tracking. Target and spinal cord constraints were chosen according to RTOG 0631 protocol for spinal metastases. Plan quality was scored based on four predefined parameters: dose to cord (D0.1cc and D1cc), high dose (V10Gy), and low dose (V4Gy) volume of healthy tissue. Prescription dose was 16 Gy to the highest isodose line encompassing 90% of the target. Results were related to target size and position. All plans fulfilled RTOG 0631 constraints for coverage and dose to cord. When no additional margin was applied, a majority of eight cases benefitted from prone position, mainly due to a reduction of V4Gy by 23% ± 26%. In the 2 mm prone scenario, the benefit was nullified by an average increase of V10Gy by 43% ± 24%, and an increase of D1cc to cord (four cases). Spinal cord D0.1cc was unchanged (< ± 1 Gy) in all but two cases for both prone scenarios. Conformity (nCI) and number of beams were equivalent in all scenarios, but supine plans used a significantly higher number of monitor units (+16%) than prone. Posterior beam access can reduce dose to healthy tissue in CyberKnife spinal radiosurgery when no additional margin is applied. When a target margin of 2 mm is added, this potential gain is lost. Relative anterior-posterior position and size of the target are selection criteria for prone treatment.

Robust optimization of a radiotherapy pretreatment preparation workflow.

Objective. Increasing cancer incidence, staff shortage and high burnout rate among radiation oncologists, medical physicists and radiation technicians are putting many departments under strain. Operations research (OR) tools could optimize radiotherapy processes, however, clinical implementation of OR-tools in radiotherapy is scarce since most investigated optimization methods lack robustness against patient-to-patient variation in duration of tasks. By combining OR-tools, a method was developed that optimized deployment of radiotherapy resources by generating robust pretreatment preparation schedules that balance the expected average patient preparation time (Fmean) with the risk of working overtime (RoO). The method was evaluated for various settings of an one-stop shop (OSS) outpatient clinic for palliative radiotherapy.Approach. The OSS at our institute sees, scans and treats 3-5 patients within one day. The OSS pretreatment preparation workflow consists of a fixed sequence of tasks, which was manually optimized for radiation oncologist and CT availability. To find more optimal sequences, with shorterFmeanand lowerRoO, a genetic algorithm was developed which regards these sequences as DNA-strands. The genetic algorithm applied natural selection principles to produce new sequences. A decoder translated sequences to schedules to find the conflicting fitness parametersFmeanandRoO. For every generation, fitness of sequences was determined by the distance to the estimated Pareto front ofFmeanandRoO. Experiments were run in various OSS-settings.Main results. According to our approach, the expectedFmeanof the current clinical schedule could be reduced with 37%, without increasingRoO. Additional experiments provided insights in trade-offs betweenFmean,RoO, working shift length, number of patients treated on a single day and staff composition.Significance. Our approach demonstrated that OR-tools could optimize radiotherapy resources by robust pretreatment workflow scheduling. The results strongly support further exploration of scheduling optimization for treatment preparation also outside a one-stop shop or radiotherapy setting.

Nine years of plan of the day for cervical cancer: Plan library remains effective compared to fully online-adaptive techniques.

BACKGROUND AND PURPOSE: Since 2011, our center has been using a library-based Plan-of-the-Day (PotD) strategy for external beam radiotherapy of cervical cancer patients to reduce normal tissue dose while maintaining adequate target coverage. With the advent of fully online-adaptive techniques such as daily online-adaptive replanning, further dose reduction may be possible. However, it is unknown how this reduction relates to plan library approaches, and how the most recent PotD strategies relate to no adaptation. In this study we compare the performance of our current PotD strategy with non-adaptive and fully online-adaptive techniques in terms of target volume size and normal tissue sparing. MATERIALS AND METHODS: Treatment data of 376 patients treated with the PotD protocol between June 2011 and April 2020 were included. The size of the Planning Target Volumes (PTVs) was reconstructed for different strategies: full online adaptation, no adaptation, and the latest clinical version of the PotD protocol. Normal tissue sparing was estimated by the difference in margin volume to construct the PTV and the volume overlap of the PTV with bladder and rectum. RESULTS: The current version of our PotD approach reduced the PTV margin volume by a median of 250 cm3 compared to no adaptation. Bladder-PTV overlap decreased from a median of 142 to 71 cm3, and from 39 to 16 cm3 for rectum-PTV. Fully online-adaptive approaches could further decrease the PTV volume by 144 cm3 using a 5 mm margin for residual errors. In this scenario, bladder-PTV overlap was reduced to 35 cm3 and rectum-PTV overlap to 11 cm3. CONCLUSION: The current version of the PotD protocol is an effective technique to improve normal tissue sparing compared to no adaptation. Further sparing can be achieved using fully online-adaptive techniques, but at the cost of a more complex workflow and with a potentially limited impact. PotD-type protocols can therefore be considered as a suitable alternative to fully online-adaptive approaches.

Two-dimensional oxygen-diffusion modelling for FLASH proton therapy with pencil beam scanning - impact of diffusive tissue properties, dose, dose rate and scan patterns.

Oxygen depletion is generally believed to play an important role in the FLASH effect - a differential reduction of the radiosensitivity of healthy tissues, relative to that of the tumour under ultra-high dose-rate (UHDR) irradiation conditions. In proton therapy (PT) with pencil-beam scanning (PBS), the deposition of dose, and, hence, the degree of (radiolytic) oxygen depletion varies both spatially and temporally. Therefore, the resulting oxygen concentration and the healthy-tissue sparing effect through radiation-induced hypoxia varies both spatially and temporally as well. We propose and numerically solve a physical oxygen diffusion model to study these effects and their dependence on tissue parameters and the scan pattern in pencil-beam delivery. Since current clinical FLASH proton therapy (FLASH-PT) is based on 250 MeV shoot-through (transmission) beams, for which dose and dose rate hardly vary with depth compared to the variation transverse to the beam axis, we focus on the two-dimensional case. We numerically integrate the model to obtain the oxygen concentration in each voxel as a function of time and extract voxel-based and spatially and temporarily integrated metrics for oxygen (FLASH) enhanced dose. Furthermore, we evaluate the impact on oxygen enhancement of standard pencil-beam delivery patterns and patterns that were optimised on dose-rate. Our model can contribute to the identification of tissue properties and pencil-beam delivery parameters that are critical for FLASH-PT and it may be used for the optimisation of FLASH-PT treatment plans and their delivery. Our main findings are that: (i) the diffusive properties of oxygen are critical for the steady state concentration and therefore the FLASH effect, even more so in two dimensions when compared to one dimension. (ii) The FLASH effect through oxygen depletion depends primarily on dose and less on other parameters. (iii) At a fixed fraction dose there is a slight dependence on dose rate. (iv) Scan patterns optimised on dose rate slightly increase the oxygen induced FLASH effect.

A generalized model for monitor units determination in ocular proton therapy using machine learning: A proof-of-concept study.

Objective.Determining and verifying the number of monitor units is crucial to achieving the desired dose distribution in radiotherapy and maintaining treatment efficacy. However, current commercial treatment planning system(s) dedicated to ocular passive eyelines in proton therapy do not provide the number of monitor units for patient-specific plan delivery. Performing specific pre-treatment field measurements, which is time and resource consuming, is usually gold-standard practice. This proof-of-concept study reports on the development of a multi-institutional-based generalized model for monitor units determination in proton therapy for eye melanoma treatments.Approach.To cope with the small number of patients being treated in proton centers, three European institutes participated in this study. Measurements data were collected to address output factor differences across the institutes, especially as function of field size, spread-out Bragg peak modulation width, residual range, and air gap. A generic model for monitor units prediction using a large number of 3748 patients and broad diversity in tumor patterns, was evaluated using six popular machine learning algorithms: (i) decision tree; (ii) random forest, (iii) extra trees, (iv) K-nearest neighbors, (v) gradient boosting, and (vi) the support vector regression. Features used as inputs into each machine learning pipeline were: Spread-out Bragg peak width, range, air gap, fraction and calibration doses. Performance measure was scored using the mean absolute error, which was the difference between predicted and real monitor units, as collected from institutional gold-standard methods.Main results.Predictions across algorithms were accurate within 3% uncertainty for up to 85.2% of the plans and within 10% uncertainty for up to 98.6% of the plans with the extra trees algorithm.Significance.A proof-of-concept of using machine learning-based generic monitor units determination in ocular proton therapy has been demonstrated. This could trigger the development of an independent monitor units calculation tool for clinical use.

Evaluating AI-generated CBCT-based synthetic CT images for target delineation in palliative treatments of pelvic bone metastasis at conventional C-arm linacs.

PURPOSE: One-table treatments with treatment imaging, preparation and delivery occurring at one treatment couch, could increase patients' comfort and throughput for palliative treatments. On regular C-arm linacs, however, cone-beam CT (CBCT) imaging quality is currently insufficient. Therefore, our goal was to assess the suitability of AI-generated CBCT based synthetic CT (sCT) images for target delineation and treatment planning for palliative radiotherapy. MATERIALS AND METHODS: CBCTs and planning CT-scans of 22 female patients with pelvic bone metastasis were included. For each CBCT, a corresponding sCT image was generated by a deep learning model in ADMIRE 3.38.0. Radiation oncologists delineated 23 target volumes (TV) on the sCTs (TVsCT) and scored their delineation confidence. The delineations were transferred to planning CTs and manually adjusted if needed to yield gold standard target volumes (TVclin). TVsCT were geometrically compared to TVclin using Dice coefficient (DC) and Hausdorff Distance (HD). The dosimetric impact of TVsCT inaccuracies was evaluated for VMAT plans with different PTV margins. RESULTS: Radiation oncologists scored the sCT quality as sufficient for 13/23 TVsCT (median: DC = 0.9, HD = 11 mm) and insufficient for 10/23 TVsCT (median: DC = 0.7, HD = 34 mm). For the sufficient category, remaining inaccuracies could be compensated by +1 to +4 mm additional margin to achieve coverage of V95% > 95% and V95% > 98%, respectively in 12/13 TVsCT. CONCLUSION: The evaluated sCT quality allowed for accurate delineation for most targets. sCTs with insufficient quality could be identified accurately upfront. A moderate PTV margin expansion could address remaining delineation inaccuracies. Therefore, these findings support further exploration of CBCT based one-table treatments on C-arm linacs.