Highlights•A practical method is described to assess robustness of CTV dose in both photon and proton treatments. •By a calibration procedure consistency with historic PTV-based evaluations is ...achieved. •The method has been clinically introduced in the Dutch proton centres and replaced PTV-based evaluations, solving its inaccuracies caused by the ‘static dose cloud approximation’.
•Probabilistic dose to near-minimum volume v = 99.8% correlated best with clinical PTV-D98% for VMAT and VWmin-D98%,CTV doses for IMPT.•Despite differences between photons and protons, the planning ...comparison between VMAT and IMPT leads to consistent CTV dose, NTCP and TCP results.•The nominal NTCP is a good estimator to qualify patients for IMPT.
In the Netherlands, head-and-neck cancer (HNC) patients are referred for proton therapy (PT) through model-based selection (MBS). However, treatment errors may compromise adequate CTV dose. Our aims are: (i) to derive probabilistic plan evaluation metrics on the CTV consistent with clinical metrics; (ii) to evaluate plan consistency between photon (VMAT) and proton (IMPT) planning in terms of CTV dose iso-effectiveness and (iii) to assess the robustness of the OAR doses and of the risk toxicities involved in the MBS.
Sixty HNC plans (30 IMPT/30 VMAT) were included. A robustness evaluation with 100,000 treatment scenarios per plan was performed using Polynomial Chaos Expansion (PCE). PCE was applied to determine scenario distributions of clinically relevant dosimetric parameters, which were compared between the 2 modalities. Finally, PCE-based probabilistic dose parameters were derived and compared to clinical PTV-based photon and voxel-wise proton evaluation metrics.
Probabilistic dose to near-minimum volume v = 99.8% for the CTV correlated best with clinical PTV-D98% and VWmin-D98%,CTV doses for VMAT and IMPT respectively. IMPT showed slightly higher nominal CTV doses, with an average increase of 0.8 GyRBE in the median of the D99.8%,CTV distribution. Most patients qualified for IMPT through the dysphagia grade II model, for which an average NTCP gain of 10.5 percentages points (%-point) was found. For all complications, uncertainties resulted in moderate NTCP spreads lower than 3 p.p. on average for both modalities.
Despite the differences between photon and proton planning, the comparison between PTV-based VMAT and robust IMPT is consistent. Treatment errors had a moderate impact on NTCPs, showing that the nominal plans are a good estimator to qualify patients for PT.
FLASH dose rates >40 Gy/s are readily available in proton therapy (PT) with cyclotron-accelerated beams and pencil-beam scanning (PBS). The PBS delivery pattern will affect the local dose rate, as ...quantified by the PBS dose rate (PBS-DR), and therefore needs to be accounted for in FLASH-PT with PBS, but it is not yet clear how. Our aim was to optimize patient-specific scan patterns for stereotactic FLASH-PT of early-stage lung cancer and lung metastases, maximizing the volume irradiated with PBS-DR >40 Gy/s of the organs at risk voxels irradiated to >8 Gy (FLASH coverage).
Plans to 54 Gy/3 fractions with 3 equiangular coplanar 244 MeV proton shoot-through transmission beams for 20 patients were optimized with in-house developed software. Planning target volume-based planning with a 5 mm margin was used. Planning target volume ranged from 4.4 to 84 cc. Scan-pattern optimization was performed with a Genetic Algorithm, run in parallel for 20 independent populations (islands). Mapped crossover, inversion, swap, and shift operators were applied to achieve (local) optimality on each island, with migration between them for global optimality. The cost function was chosen to maximize the FLASH coverage per beam at >8 Gy, >40 Gy/s, and 40 nA beam current. The optimized patterns were evaluated on FLASH coverage, PBS-DR distribution, and population PBS-DR-volume histograms, compared with standard line-by-line scanning. Robustness against beam current variation was investigated.
The optimized patterns have a snowflake-like structure, combined with outward swirling for larger targets. A population median FLASH coverage of 29.0% was obtained for optimized patterns compared with 6.9% for standard patterns, illustrating a significant increase in FLASH coverage for optimized patterns. For beam current variations of 5 nA, FLASH coverage varied between –6.1%-point and 2.2%-point for optimized patterns.
Significant improvements on the PBS-DR and, hence, on FLASH coverage and potential healthy-tissue sparing are obtained by sequential scan-pattern optimization. The optimizer is flexible and may be further fine-tuned, based on the exact conditions for FLASH.
Intensity modulated proton therapy (IMPT) is an emerging treatment modality for cancer. However, treatment planning for IMPT is labour-intensive and time-consuming. We have developed a novel approach ...for multi-criteria optimisation (MCO) of robust IMPT plans (SISS-MCO) that is fully automated and fast, and we compare it for head and neck, cervix, and prostate tumours to a previously published method for automated robust MCO (IPBR-MCO, van de Water 2013).
In both auto-planning approaches, the applied automated MCO of spot weights was performed with wish-list driven prioritised optimisation (Breedveld 2012). In SISS-MCO, spot weight MCO was applied once for every patient after sparsity-induced spot selection (SISS) for pre-selection of the most relevant spots from a large input set of candidate spots. IPBR-MCO had several iterations of spot re-sampling, each followed by MCO of the weights of the current spots.
Compared to the published IPBR-MCO, the novel SISS-MCO resulted in similar or slightly superior plan quality. Optimisation times were reduced by a factor of 6 i.e. from 287 to 47 min. Numbers of spots and energy layers in the final plans were similar.
The novel SISS-MCO automatically generated high-quality robust IMPT plans. Compared to a published algorithm for automated robust IMPT planning, optimisation times were reduced on average by a factor of 6. Moreover, SISS-MCO is a large scale approach; this enables optimisation of more complex wish-lists, and novel research opportunities in proton therapy.
We derive a general expression that quantifies the total entanglement production rate in continuous variable systems, where a source emits two entangled Gaussian beams with arbitrary correlators. ...This expression is especially useful for situations where the source emits an arbitrary frequency spectrum, e.g. when cavities are involved. To exemplify its meaning and potential, we apply it to a four-mode optomechanical setup that enables the simultaneous up- and down-conversion of photons from a drive laser into entangled photon pairs. This setup is efficient in that both the drive and the optomechanical up- and down-conversion can be fully resonant.
•Despite its consistency in terms of TCP, the Dutch RE protocol lead to substantial inter-patient and inter-center variation in terms of CTV dose.•The Dutch MBS protocol for PT patient selection is ...robust against treatment errors.•Probabilistic evaluations could aid in the harmonization and consensus of robustness evaluation protocols.•Polynomial Chaos Expansion (PCE) allows for a better comprehension of the robustness of treatment plans and evaluation protocols.
In the Netherlands, 2 protocols have been standardized for PT among the 3 proton centers: a robustness evaluation (RE) to ensure adequate CTV dose and a model-based selection (MBS) approach for IMPT patient-selection. This multi-institutional study investigates (i) inter-patient and inter-center variation of target dose from the RE protocol and (ii) the robustness of the MBS protocol against treatment errors for a cohort of head-and-neck cancer (HNC) patients treated in the 3 Dutch proton centers.
Clinical treatment plans of 100 HNC patients were evaluated. Polynomial Chaos Expansion (PCE) was used to perform a comprehensive robustness evaluation per plan, enabling the probabilistic evaluation of 100,000 complete fractionated treatments. PCE allowed to derive scenario distributions of clinically relevant dosimetric parameters to assess CTV dose (D99.8%/D0.2%, based on a prior photon plan calibration) and tumour control probabilities (TCP) as well as the evaluation of the dose to OARs and normal tissue complication probabilities (NTCP) per center.
For the CTV70.00, doses from the RE protocol were consistent with the clinical plan evaluation metrics used in the 3 centers. For the CTV54.25, D99.8% were consistent with the clinical plan evaluation metrics at center 1 and 2 while, for center 3, a reduction of 1 GyRBE was found on average. This difference did not impact modelled TCP at center 3. Differences between expected and nominal NTCP were below 0.3 percentage point for most patients.
The standardization of the RE and MBS protocol lead to comparable results in terms of TCP and the NTCPs. Still, significant inter-patient and inter-center variation in dosimetric parameters remained due to clinical practice differences at each institution. The MBS approach is a robust protocol to qualify patients for PT.
•PCE allows comprehensive robustness evaluation for clinical neuro-oncological targets.•The Dutch protocol realizes in more than adequate target expected dose.•PCE analysis provides valuable insights ...if target coverage has to be compromised.
Scenario-based robust optimization and evaluation are commonly used in proton therapy (PT) with pencil beam scanning (PBS) to ensure adequate dose to the clinical target volume (CTV). However, a statistically accurate assessment of the clinical application of this approach is lacking. In this study, we assess target dose in a clinical cohort of neuro-oncological patients, planned according to the DUPROTON robustness evaluation consensus, using polynomial chaos expansion (PCE).
A cohort of the first 27 neuro-oncological patients treated at HollandPTC was used, including realistic error distributions derived from geometrical and stopping-power prediction (SPP) errors. After validating the model, PCE-based robustness evaluations were performed by simulating 100.000 complete fractionated treatments per patient to obtain accurate statistics on clinically relevant dosimetric parameters and population-dose histograms.
Treatment plans that were robust according to clinical protocol and treatment plansin which robustness was sacrificed are easily identified. For robust treatment plans on average, a CTV dose of 3 percentage points (p.p.) more than prescribed was realized (range +2.7 p.p. to +3.5 p.p.) for 98% of the sampled fractionated treatments. For the entire patient cohort on average, a CTV dose of 0.1 p.p. less than prescribed was achieved (range −2.4 p.p. to +0.5 p.p.). For the 6 treatment plans in which robustness was clinically sacrificed, normalized CTV doses of 0.98, 0.94(7)11To indicate that the value is just below the constraint of 0.95, it was not rounded to two decimal digits, but it is displayed with the third decimal digit between parentheses., 0.94, 0.91, 0.90 and 0.89 were realized. The first of these was clinically borderline non-robust.
The clinical robustness evaluation protocol is safe in terms of CTV dose as all plans that fulfilled the clinical robustness criteria were also robust in the PCE evaluation. Moreover, for plans that were non-robust in the PCE-based evaluation, CTV dose was also lower than prescribed in the clinical evaluation.
•In this cohort, the cumulative incidence of psPD increases from 13% in the first year to 28% at 10 years.•psPD is asymptomatic in 83% of patients.•1p/19q codeletion and biopsy are associated with an ...increased risk of psPD.•When analyzed as a time-dependent covariate, psPD is not associated with overall survival.•An uniform definition and analysis method for psPD in diffuse glioma is needed for comparisons between photon - and proton beam radiotherapy.
The interpretation of new enhancing lesions after radiotherapy for diffuse glioma remains a clinical challenge. We sought to characterize and classify new contrast enhancing lesions in a historical multicenter cohort of patients with IDH mutated grade 2 diffuse glioma treated with photon therapy.
We reviewed all follow-up MRI’s of all patients treated with radiotherapy for histologically confirmed, IDH mutated diffuse grade 2 glioma between 1–1-2007 and 31–12-2018 in two tertiary referral centers. Disease progression (PD) was defined in accordance with the RANO criteria for progressive disease in low grade glioma. Pseudoprogression (psPD) was defined as any transient contrast-enhancing lesion between the end of radiotherapy and PD, or any new contrast-enhancing lesion that remained stable over a period of 12 months in patients who did not exhibit PD.
A total of 860 MRI’s of 106 patients were reviewed. psPD was identified in 24 patients (23%) on 76 MRI’s. The cumulative incidence of psPD was 13% at 1 year, 22% at 5 years, and 28% at 10 years. The mean of the observed maximal volume of psPD was 2.4 cc. The median Dmin in psPD lesions was 50.1 Gy. The presence of an 1p/19q codeletion was associated with an increased risk of psPD (subhazard ratio 2.34, p = 0.048). psPD was asymptomatic in 83% of patients.
The cumulative incidence of psPD in grade 2 diffuse glioma increases over time. Consensus regarding event definition and statistical analysis is needed for comparisons between series investigating psPD.
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