Publications by authors named "Frank Van den Heuvel"

46 Publications

Incorporating oxygenation levels in analytical DNA-damage models-quantifying the oxygen fixation mechanism.

Phys Med Biol 2021 Jul 9;66(14). Epub 2021 Jul 9.

University of Oxford, Department of Oncology, Oxford, United Kingdom.

To develop a framework to include oxygenation effects in radiation therapy treatment planning which is valid for all modalities, energy spectra and oxygen levels. The framework is based on predicting the difference in DNA-damage resulting from ionising radiation at variable oxygenation levels.Oxygen fixation is treated as a statistical process in a simplified model of complex and simple damage. We show that a linear transformation of the microscopic oxygen fixation process allows to extend this to all energies and modalities, resulting in a relatively simple rational polynomial expression. The model is expanded such that it can be applied for polyenergetic beams. The methodology is validated using Microdosimetric Monte Carlo Damage Simulation code (MCDS). This serves as a bootstrap to determine relevant parameters in the analytical expression, as MCDS is shown to be extensively verified with published empirical data. Double-strand break induction as calculated by this methodology is compared to published proton experiments. Finally, an example is worked out where the oxygen enhancement ratio (OER) is calculated at different positions in a clinically relevant spread out Bragg peak (SOBP) dose deposition in water. This dose deposition is obtained using a general Monte Carlo code (FLUKA) to determine dose deposition and locate fluence spectra.For all modalities (electrons, protons), the damage categorised as complex could be parameterised to within 0.3% of the value calculated using microdosimetric Monte Carlo. The proton beam implementation showed some variation in OERs which differed slightly depending on where the assessment was made; before the SOBP, mid-SOBP or at the distal edge. Environment oxygenation was seen to be the more important variable.An analytic expression calculating complex damage depending on modality, energy spectrum, and oxygenation levels was shown to be effective and can be readily incorporated in treatment planning software, to take into account the impact of variable oxygenation, forming a first step to an optimised treatment based on biological factors.
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http://dx.doi.org/10.1088/1361-6560/ac0b80DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273901PMC
July 2021

High Quality Clinical Stereotactic Radiosurgery Planning and Delivery With Standard Resolution (5 mm) Multileaf Collimation and Multiple Isocenters.

Pract Radiat Oncol 2020 Jul - Aug;10(4):293-300. Epub 2020 Mar 19.

Department of Clinical Oncology, Oxford University Hospitals NHS Trust, Oxford, United Kingdom.

Purpose: Our purpose was to demonstrate the use of novel planning techniques in producing high-quality stereotactic radiosurgery (SRS) plans using a standard 5 mm multileaf collimator (MLC) and multiple isocenters delivered clinically at a local institution.

Methods And Materials: Novel planning techniques consisted of offset isocenter, variable asymmetrical jaws, and Digital Imagine and Communications in Medicine (DICOM) edits to reduce leaf tip transmission, all with the aim of maximizing dose conformity. A local institution clinical cohort was planned (1-4 targets), and plan conformity metrics common to SRS were compared against conformity metrics from selected previous publications comparing Gamma Knife to linear accelerator SRS using high-definition MLC (2.5 mm). Additionally, local institution plan conformity metrics for 2 benchmark SRS planning cases (3 and 7 targets) were compared with metrics from other centers treating SRS clinically in England. Pretreatment quality assurance results, both point dose measurement and film analysis, are presented to demonstrate plan deliverability.

Results: Clinical conformity metrics are shown to be comparable to previously published results using either Gamma Knife or linear accelerator with high-definition MLC. Metrics from benchmark planning cases are shown to be comparable and to have better prescription dose conformity than average nationally in England. Pretreatment quality assurance results demonstrate suitable plan deliverability.

Conclusions: SRS planning using standard 5 mm MLC and multiple isocenters produces high-quality treatment plans for a limited number of targets with a high degree of dose conformity and dose fall off when employing novel planning techniques to compensate for MLC leaf size and multiple isocenters.
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http://dx.doi.org/10.1016/j.prro.2020.03.004DOI Listing
March 2021

Stereotactic body radiotherapy for moderately central and ultra-central oligometastatic disease: Initial outcomes.

Tech Innov Patient Support Radiat Oncol 2020 Mar 17;13:24-30. Epub 2020 Feb 17.

Medical Physics and Biomedical Engineering, Malet Place Engineering Building, University College London, Gower Street, London WC1E 6BT, United Kingdom.

Background: Delivery of SBRT to central thoracic tumours within 2 cm of the proximal bronchial tree (PBT), and especially ultra-central tumours which directly abut the PBT, has been controversial due to concerns about high risk of toxicity and treatment-related death when delivering high doses close to critical mediastinal structures. We present dosimetric and clinical outcomes from a group of oligometastatic patients treated with a risk-adapted SBRT approach.

Methods: Between September 2015 and October 2018, 27 patients with 28 central thoracic oligometastases (6 moderately central, 22 ultra-central) were treated with 60 Gy in 8 fractions under online CBCT guidance. PTV dose was compromised where necessary to meet mandatory OAR constraints. Patients were followed up for toxicity and disease status.

Results: Mandatory OAR constraints were met in all cases; this required PTV coverage compromise in 23 cases, with V100% reduced to <70% in 11 cases. No acute or late toxicities of Grade ≥ 3 were reported. One and 2 year in-field control rates were 95.2% and 85.7% respectively, progression-free survival rates were 42.8% and 23.4% respectively, and overall survival rates were 82.7% and 69.5% respectively. No significant differences were seen in control or survival rates by extent of PTV underdosage or between moderately and ultra-central cases.

Conclusion: It appears that compromising PTV coverage to meet OAR constraints allows safe and effective delivery of SBRT to moderately and ultra-central tumours, with low toxicity rates and high in-field control rates. This treatment can be delivered on standard linear accelerators with widely available imaging technology.
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http://dx.doi.org/10.1016/j.tipsro.2020.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042153PMC
March 2020

Impact of abdominal compression on setup error and image matching during radical abdominal radiotherapy.

Tech Innov Patient Support Radiat Oncol 2019 Dec 16;12:28-33. Epub 2019 Dec 16.

CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom.

Purpose: To determine the impact of abdominal compression (AC) on setup error and image matching time.

Materials And Methods: This study included 72 liver, pancreas and abdominal node patients treated radically from 2016 to 2019 in a single centre. Patients received either SBRT or conventional radical fractionation (CRF). Compressed patients were supine, arms up with kneefix and AC equipment. Uncompressed patients were supine, arms up with kneefix. All patients received daily online-matched CBCTs before treatment. Initial setup error was determined for all patients. Registration error was assessed for 10 liver and 10 pancreas patients. Image matching times were determined using beam on times. Statistical tests conducted were an F-test to compare variances in setup error, Student's t-tests for setup error and average image analysis, and a Wilcoxon Mann Whitney test for imaging matching time analysis.

Results: Initial setup displacement was similar between compressed and uncompressed patients. Displacements > 1 cm occurred more frequently in the longitudinal direction for most patients. SBRT patients required more additional manual positioning following imaging. Mean absolute registration error in the SI direction was 5.4 mm and 3.3 mm for uncompressed and compressed pancreas patients respectively and 1.7 mm and 0.8 mm for uncompressed and compressed liver patients respectively. Compressed patients required less time for image matching and fewer images per fraction on average. Repeat imaging occurred more frequently in SBRT and uncompressed patients.

Conclusions: Although abdominal compression has no significant impact on setup error, it can reduce imaging matching times resulting in improved treatment accuracy.
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http://dx.doi.org/10.1016/j.tipsro.2019.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033789PMC
December 2019

Assessment of robustness against setup uncertainties using probabilistic scenarios in lung cancer: a comparison of proton with photon therapy.

Br J Radiol 2020 Mar 4;93(1107):20190584. Epub 2020 Feb 4.

CRUK and MRC Oxford Institute for Radiation Oncology, Old Road Campus Research Building, Off Roosevelt Drive, University of Oxford, Oxford, OX3 7DQ, UK.

Objective: We compared the sensitivity of intensity modulated proton therapy (IMPT) and photon volumetric modulated arc therapy (VMAT) plans to setup uncertainties in locally advanced non-small cell lung cancer (NSCLC) using probabilistic scenarios.

Methods: Minimax robust (MM) and planning target volume (PTV) optimised IMPT and VMAT nominal plans were created with physical dose of 70 Gy in 35 fractions in 10 representative patients. Using population data of setup errors, a fractionated treatment course was simulated, summed (D) and compared to the nominal plan. Three treatment-course simulations were done for each plan. Target robustness criteria were: dose deviation of ≤5% to clinical target volume (CTV) D and CTV V ≥ 99.9%. Voxelwise simulation repeatability was analysed using Bland-Altman plots. Acceptable limits of agreement were 2% of the prescription dose.

Results: All D met target robustness criteria. While fraction VMAT and MM-IMPT doses were excellent, simulated fraction doses in PTV-IMPT were suboptimal. Almost all (>99%) of VMAT and MM-IMPT fraction doses met both target robustness criteria. For PTV-IMPT, only 96.9 and 80.3% of fractions met CTVD and V criteria respectively. Simulation repeatability was excellent (limits of agreement range: 0.41-1.1 Gy) with strong positive correlations.

Conclusion: When considering the whole treatment course, setup errors do not influence robustness irrespective of planning techniques used. However, on a fraction level, VMAT and MM-IMPT plans are superior compared to PTV-IMPT plans.

Advances In Knowledge: Probabilistic analysis provides a fast and practical method for evaluating VMAT and IMPT plan sensitivity against setup uncertainty. VMAT and robust-optimised IMPT plans have comparable sensitivity to setup uncertainties in conventionally fractionated treatment for NSCLC.
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http://dx.doi.org/10.1259/bjr.20190584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066956PMC
March 2020

A systematic review of health economic evaluations of proton beam therapy for adult cancer: Appraising methodology and quality.

Clin Transl Radiat Oncol 2020 Jan 31;20:19-26. Epub 2019 Oct 31.

Health Economics Research Centre, Nuffield Department of Population Health, University of Oxford, UK.

Background And Purpose: With high treatment costs and limited capacity, decisions on which adult patients to treat with proton beam therapy (PBT) must be based on the relative value compared to the current standard of care. Cost-utility analyses (CUAs) are the gold-standard method for doing this. We aimed to appraise the methodology and quality of CUAs in this area.

Materials And Methods: We performed a systematic review of the literature to identify CUA studies of PBT in adult disease using MEDLINE, EMBASE, EconLIT, NHS Economic Evaluation Database (NHS EED), Web of Science, and the Tufts Medical Center Cost-Effectiveness Analysis Registry from 1st January 2010 up to 6th June 2018. General characteristics, information relating to modelling approaches, and methodological quality were extracted and synthesized narratively.

Results: Seven PBT CUA studies in adult disease were identified. Without randomised controlled trials to inform the comparative effectiveness of PBT, studies used either results from one-armed studies, or dose-response models derived from radiobiological and epidemiological studies of PBT. Costing methods varied widely. The assessment of model quality highlighted a lack of transparency in the identification of model parameters, and absence of external validation of model outcomes. Furthermore, appropriate assessment of uncertainty was often deficient.

Conclusion: In order to foster credibility, future CUA studies must be more systematic in their approach to evidence synthesis and expansive in their consideration of uncertainties in light of the lack of clinical evidence.
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http://dx.doi.org/10.1016/j.ctro.2019.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854069PMC
January 2020

Is an analytical dose engine sufficient for intensity modulated proton therapy in lung cancer?

Br J Radiol 2020 Mar 20;93(1107):20190583. Epub 2019 Nov 20.

CRUK and MRC Oxford Institute for Radiation Oncology, Old Road Campus Research Building, Off Roosevelt Drive, University of Oxford, Oxford, OX3 7DQ, UK.

Objective: To identify a subgroup of lung cancer plans where the analytical dose calculation (ADC) algorithm may be clinically acceptable compared to Monte Carlo (MC) dose calculation in intensity modulated proton therapy (IMPT).

Methods: Robust-optimised IMPT plans were generated for 20 patients to a dose of 70 Gy (relative biological effectiveness) in 35 fractions in Raystation. For each case, four plans were generated: three with ADC optimisation using the pencil beam (PB) algorithm followed by a final dose calculation with the following algorithms: PB (PB-PB), MC (PB-MC) and MC normalised to prescription dose (PB-MC scaled). A fourth plan was generated where MC optimisation and final dose calculation was performed (MC-MC). Dose comparison and γ analysis (PB-PB PB-MC) at two dose thresholds were performed: 20% (D20) and 99% (D99) with PB-PB plans as reference.

Results: Overestimation of the dose to 99% and mean dose of the clinical target volume was observed in all PB-MC compared to PB-PB plans (median: 3.7 Gy(RBE) (5%) (range: 2.3 to 6.9 Gy(RBE)) and 1.8 Gy(RBE) (3%) (0.5 to 4.6 Gy(RBE))). PB-MC scaled plans resulted in significantly higher CTVD2 compared to PB-PB (median difference: -4 Gy(RBE) (-6%) (-5.3 to -2.4 Gy(RBE)), ≤ .001). The overall median γ pass rates (3%-3 mm) at D20 and D99 were 93.2% (range:62.2-97.5%) and 71.3 (15.4-92.0%). On multivariate analysis, presence of mediastinal disease and absence of range shifters were significantly associated with high pass rates. Median D20 and D99 pass rates with these predictors were 96.0% (95.3-97.5%) and 85.4% (75.1-92.0%). MC-MC achieved similar target coverage and doses to OAR compared to PB-PB plans.

Conclusion: In the presence of mediastinal involvement and absence of range shifters Raystation ADC may be clinically acceptable in lung IMPT. Otherwise, MC algorithm would be recommended to ensure accuracy of treatment plans.

Advances In Knowledge: Although MC algorithm is more accurate compared to ADC in lung IMPT, ADC may be clinically acceptable where there is mediastinal involvement and absence of range shifters.
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http://dx.doi.org/10.1259/bjr.20190583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066954PMC
March 2020

Response of FDG avid pelvic bone marrow to concurrent chemoradiation for anal cancer.

Radiother Oncol 2020 02 7;143:19-23. Epub 2019 Sep 7.

CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, UK. Electronic address:

Background And Purpose: To determine if suppression of active bone marrow, as defined on FDG PETCT, is seen in on-treatment imaging of anal cancer patients receiving concurrent chemoradiation.

Methods And Materials: Scans from 26 patients participating in the ART trial (full title: Anal squamous cell carcinoma: Investigation of functional imaging during chemoRadioTherapy), a single center observational study with FDG PETCT prior to radiotherapy and at fraction 8-10 of concurrent chemoradiation were analysed. Active bone marrow was contoured in both the pelvis and un-irradiated thoracic spine. SUV and volume of active bone marrow after 8-10 fractions of treatment were compared to baseline. Dose metrics to pelvic active bone marrow were extracted and compared to reduction in SUV/active bone marrow volume and to blood count nadir using linear regression.

Results: Suppression of active bone marrow is seen in the pelvis by a reduction in mean SUV and volume of active bone marrow after 8-10 fractions of treatment. Suppression is not seen in un-irradiated thoracic spine. Dose metrics were associated with reduced SUV and reduced volume of active bone marrow. Volume of active bone marrow receiving <20 Gy was associated with WCC/ANC nadir. 20 Gy was identified as the most likely clinically meaningful dose threshold for toxicity. Volume of active bone marrow receiving <20 Gy correlated to WCC and ANC with an increase of 100 cc being associated with an increase of 0.4 and 0.3 respectively.

Conclusion: The effect of concurrent chemoradiation in suppression of active bone marrow is seen in on-treatment FDG PETCT scans. Chemotherapy appears well tolerated after 2 weeks of treatment.
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http://dx.doi.org/10.1016/j.radonc.2019.08.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077746PMC
February 2020

In modern linacs monitor units should be defined in water at 10 cm depth rather than at d.

Med Phys 2018 Nov 20;45(11):4789-4792. Epub 2018 Jun 20.

Department of Radiation Oncology, Duke University, Durham, North Carolina, 27710, USA.

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http://dx.doi.org/10.1002/mp.13015DOI Listing
November 2018

Using stable distributions to characterize proton pencil beams.

Med Phys 2018 May 15;45(5):2278-2288. Epub 2018 Apr 15.

CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.

Purpose: To introduce and evaluate the use of stable distributions as a methodology to quantify the behavior of proton pencil beams in a medium.

Methods: The proton pencil beams of a clinically commissioned proton treatment facility are replicated in a Monte Carlo simulation system (FLUKA). For each available energy, the beam deposition in water medium is characterized by the dose deposition. Using a stable distribution methodology, each beam with a nominal energy E is characterized by the lateral spread at depth z: S(z; α, γ, E) and a total energy deposition I (z, E). The parameter α describes the tailedness of the distributions, while γ is used to scale the size of the function. The beams can then be described completely by a function of the variation of the parameters with depth.

Results: Quantitatively, the fit of the stable distributions, compared to those implemented in some standard treatment planning systems, are equivalent for all but the highest energies (i.e., 230 MeV/u). The decrease in goodness of fit makes this methodology comparable to a double Gaussian approach. The introduction of restricted linear combinations of stable distributions also resolves that particular case. More importantly, the meta-parameterization (i.e., the description of the dose deposition by only providing the fitted parameters) allows for interpolation of nonmeasured data. In the case of the clinical commissioning data used in this paper, it was possible to only commission one out of five nominal energies to obtain a viable dataset, valid for all energies. An additional parameter β allows to describe asymmetric beam profiles as well.

Conclusions: Stable distributions are intrinsically suited to describe proton pencil beams in a medium and provide a tool to quantify the propagation of proton beams in a medium.
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http://dx.doi.org/10.1002/mp.12876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6571675PMC
May 2018

Technical Note: Defining cyclotron-based clinical scanning proton machines in a FLUKA Monte Carlo system.

Med Phys 2018 Feb 22;45(2):963-970. Epub 2017 Dec 22.

CRUK - MRC Oxford Institute for Radiation Oncology University of Oxford, Oxford, UK.

Purpose: Cyclotron-based pencil beam scanning (PBS) proton machines represent nowadays the majority and most affordable choice for proton therapy facilities, however, their representation in Monte Carlo (MC) codes is more complex than passively scattered proton system- or synchrotron-based PBS machines. This is because degraders are used to decrease the energy from the cyclotron maximum energy to the desired energy, resulting in a unique spot size, divergence, and energy spread depending on the amount of degradation. This manuscript outlines a generalized methodology to characterize a cyclotron-based PBS machine in a general-purpose MC code. The code can then be used to generate clinically relevant plans starting from commercial TPS plans.

Methods: The described beam is produced at the Provision Proton Therapy Center (Knoxville, TN, USA) using a cyclotron-based IBA Proteus Plus equipment. We characterized the Provision beam in the MC FLUKA using the experimental commissioning data. The code was then validated using experimental data in water phantoms for single pencil beams and larger irregular fields. Comparisons with RayStation TPS plans are also presented.

Results: Comparisons of experimental, simulated, and planned dose depositions in water plans show that same doses are calculated by both programs inside the target areas, while penumbrae differences are found at the field edges. These differences are lower for the MC, with a γ(3%-3 mm) index never below 95%.

Conclusions: Extensive explanations on how MC codes can be adapted to simulate cyclotron-based scanning proton machines are given with the aim of using the MC as a TPS verification tool to check and improve clinical plans. For all the tested cases, we showed that dose differences with experimental data are lower for the MC than TPS, implying that the created FLUKA beam model is better able to describe the experimental beam.
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http://dx.doi.org/10.1002/mp.12701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6571526PMC
February 2018

Quantifying target-specific motion in anal cancer patients treated with intensity modulated radiotherapy (IMRT).

Radiother Oncol 2016 10 28;121(1):92-97. Epub 2016 Aug 28.

CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, UK. Electronic address:

Background And Purpose: Intensity modulated radiotherapy requires all target areas to be treated by a single radiotherapy plan. In anal cancer, the pelvic nodes, inguinal nodes and primary tumour represent three different targets. We aim to calculate target-specific motion in anal cancer radiotherapy, when delivered using a single pelvic online auto-match.

Materials And Methods: Twenty consecutive patients treated using IMRT at a single institution were studied. CBCTs were retrospectively re-matched around the inguinal nodes and primary tumour. Match values were recorded relative to origin, defined as pelvic CBCT auto-match. Systematic and random errors were quantified to determine target-specific motion and suggested margins calculated using van Herk formulae.

Results: The suggested margins to cover the independent motion of the inguinal and anal targets for LR, CC and AP set up around the inguinal nodes were 1.5mm, 2.7mm and 2.8mm; and the primary tumour were, 4.6mm, 8.9mm and 5.2mm respectively.

Conclusions: Target-specific set up will likely result in reduced treatment volumes and as such reduced toxicity. This is the first time a relationship has been described between pelvic bones, inguinal nodes and primary tumour. The PLATO study will prospectively assess the toxicity and outcomes of this target-specific margins strategy.
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http://dx.doi.org/10.1016/j.radonc.2016.08.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5100804PMC
October 2016

Potential benefits of dosimetric VMAT tracking verified with 3D film measurements.

Med Phys 2016 May;43(5):2162

Department of Oncology, MRC-CR-UK Gray Institute of Radiation Oncology and Biology, University of Oxford, Oxford OX1 2JD, United Kingdom.

Purpose: To evaluate three different plan adaptation strategies using 3D film-stack dose measurements of both focal boost and hypofractionated prostate VMAT treatments. The adaptation strategies (a couch shift, geometric tracking, and dosimetric tracking) were applied for three realistic intrafraction prostate motions.

Methods: A focal boost (35 × 2.2 and 35 × 2.7 Gy) and a hypofractionated (5 × 7.25 Gy) prostate VMAT plan were created for a heterogeneous phantom that allows for internal prostate motion. For these plans geometric tracking and dosimetric tracking were evaluated by ionization chamber (IC) point dose measurements (zero-D) and measurements using a stack of EBT3 films (3D). The geometric tracking applied translations, rotations, and scaling of the MLC aperture in response to realistic prostate motions. The dosimetric tracking additionally corrected the monitor units to resolve variations due to difference in depth, tissue heterogeneity, and MLC-aperture. The tracking was based on the positions of four fiducial points only. The film measurements were compared to the gold standard (i.e., IC measurements) and the planned dose distribution. Additionally, the 3D measurements were converted to dose volume histograms, tumor control probability, and normal tissue complication probability parameters (DVH/TCP/NTCP) as a direct estimate of clinical relevance of the proposed tracking.

Results: Compared to the planned dose distribution, measurements without prostate motion and tracking showed already a reduced homogeneity of the dose distribution. Adding prostate motion further blurs the DVHs for all treatment approaches. The clinical practice (no tracking) delivered the dose distribution inside the PTV but off target (CTV), resulting in boost dose errors up to 10%. The geometric and dosimetric tracking corrected the dose distribution's position. Moreover, the dosimetric tracking could achieve the planned boost DVH, but not the DVH of the more homogeneously irradiated prostate. A drawback of both the geometric and dosimetric tracking was a reduced MLC blocking caused by the rotational component of the MLC aperture corrections. Because of the used CTV to PTV margins and the high doses in the considered fractionation schemes, the TCP differed less than 0.02 from the planned value for all targets and all correction methods. The rectal NTCP constraints, however, could not be realized using any of these methods.

Conclusions: The geometric and dosimetric tracking use only a limited input, but they deposit the dose distribution with higher geometric accuracy than the clinical practice. The latter case has boost dose errors up to 10%. The increased accuracy has a modest impact [Δ(NT)CP < 0.02] because of the applied margins and the high dose levels used. To allow further margin reduction tracking methods are vital. The proposed methodology could further be improved by implementing a rotational correction using collimator rotations.
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http://dx.doi.org/10.1118/1.4945024DOI Listing
May 2016

Dependence of Gold Nanoparticle Radiosensitization on Functionalizing Layer Thickness.

Radiat Res 2016 04 7;185(4):384-92. Epub 2016 Mar 7.

a   Departments of Physics and Astronomy.

Gold nanoparticles functionalized with polyethylene glycol of different chain lengths are used to determine the influence of the capping layer thickness on the radiosensitizing effect of the particles. The size variations in organic coating, built up with polyethylene glycol polymers of molecular weight 1-20 kDa, allow an evaluation of the decrease in dose enhancement percentages caused by the gold nanoparticles at different radial distances from their surface. With localized eradication of malignant cells as a primary focus, radiosensitization is most effective after internalization in the nucleus. For this reason, we performed controlled radiation experiments, with doses up to 20 Gy and particle diameters in a range of 5-30 nm, and studied the relaxation pattern of supercoiled DNA. Subsequent gel electrophoresis of the suspensions was performed to evaluate the molecular damage and consecutively quantify the gold nanoparticle sensitization. In conclusion, on average up to 58.4% of the radiosensitizing efficiency was lost when the radial dimensions of the functionalizing layer were increased from 4.1 to 15.3 nm. These results serve as an experimental supplement for biophysical simulations and demonstrate the influence of an important parameter in the development of nanomaterials for targeted therapies in cancer radiotherapy.
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http://dx.doi.org/10.1667/RR14207.1DOI Listing
April 2016

Hematologic Malignancies in Pregnancy: Management Guidelines From an International Consensus Meeting.

J Clin Oncol 2016 Feb 30;34(5):501-8. Epub 2015 Nov 30.

Michael Lishner, Meir Medical Center, Kfar Saba, and Tel Aviv University; Irit Avivi, Ichilov Medical Center, Tel Aviv, Israel; Jane F. Apperley, Hammersmith Hospital; Susan Robinson, Guy's and St Thomas' National Health Service Foundation Trust, London; Frank Van den Heuvel, University of Oxford, Oxford, United Kingdom; Andrew M. Evens, Tufts Medical Center, Boston, MA; Monica Fumagalli, University of Milan; Fedro Alessandro Peccatori, European Institute of Oncology, Milan, Italy; Irena Nulman, University of Toronto, and The Hospital for Sick Children, Toronto, Ontario, Canada; Fuat S. Oduncu, University of Munich, Munich, Germany; Kristel Van Calsteren, University Hospital Gasthuisberg; Tineke Vandenbroucke and Frederic Amant, Katholieke Universiteit Leuven; Daan Dierickx, University of Leuven; and Tineke Vandenbroucke, University Hospitals Leuven, Leuven, Belgium.

Purpose: The incidence of hematologic malignancies during pregnancy is 0.02%. However, this figure is increasing, as women delay conception until a later age. Systemic symptoms attributed to the development of a hematologic cancer may overlap with physiologic changes of pregnancy. A favorable prognosis is contingent upon early diagnosis and treatment. Therefore, a high index of suspicion is required by health care providers. Although timely, accurate diagnosis followed by appropriate staging is essential and should not be delayed due to pregnancy, management guidelines are lacking due to insufficient evidence-based research. Consequently, treatment is delayed, posing significant risks to maternal and fetal health, and potential pregnancy termination. This report provides guidelines for clinical management of hematologic cancers during the perinatal period, which were developed by a multidisciplinary team including an experienced hematologist/oncologist, a high-risk obstetrics specialist, a neonatologist, and experienced nurses, social workers, and psychologists.

Methods: These guidelines were developed by experts in the field during the first International Consensus Meeting of Prenatal Hematologic Malignancies, which took place in Leuven, Belgium, on May 23, 2014.

Results And Conclusion: This consensus summary equips health care professionals with novel diagnostic and treatment methodologies that aim for optimal treatment of the mother, while protecting fetal and pediatric health.
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http://dx.doi.org/10.1200/JCO.2015.62.4445DOI Listing
February 2016

Pediatric Outcome after Maternal Cancer Diagnosed during Pregnancy.

N Engl J Med 2015 Nov 28;373(19):1824-34. Epub 2015 Sep 28.

From the Department of Gynecologic Oncology, University Hospitals Leuven and Department of Oncology, Katholieke Universiteit Leuven (F.A., T.V., M.V., S.H.), Departments of Cardiology (J.-U. V.), Pediatrics (G.N., L.V., L.L.), and Obstetrics (K.V.C.), University Hospitals Leuven, and the Department of Growth and Regeneration (G.N., L.L., K.V.C.) and the Faculty of Psychology and Educational Sciences (L.C.), Katholieke Universiteit Leuven, Leuven, and the Department of Obstetrics, Cliniques Universitaires St. Luc, Brussels (M.M.G.) - all in Belgium; Neonatal Intensive Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Università degli Studi di Milano (M.F.) and Fertility and Reproduction Unit, European Institute of Oncology (F.P.) - both in Milan; the Department of Obstetrics and Gynecology, Charles University, Prague, Czech Republic (M.J.H., L.R.); the Department of Medical Oncology, Erasmus Medical Center Cancer Institute, Rotterdam (I.B.), Center for Gynecologic Oncology Amsterdam, Antoni van Leeuwenhoek-Netherlands Cancer Institute, Amsterdam (F.A., C.L.), and the Department of Medical Oncology, University Medical Center Utrecht Cancer Center, Utrecht (P.W.) - all in the Netherlands; the Departments of Physics, Nuclear Physics, and Medical Physics, University of Oxford, Oxford, United Kingdom (F.V.H.); and the Department of Cardiology, Hospital for Sick Children, University of Toronto, Toronto (L.M.).

Background: Data on the long-term outcome of children who are exposed to maternal cancer with or without treatment during pregnancy are lacking.

Methods: In this multicenter case-control study, we compared children whose mothers received a diagnosis of cancer during the pregnancy with matched children of women without a cancer diagnosis. We used a health questionnaire and medical files to collect data regarding neonatal and general health. All children were prospectively assessed (by means of a neurologic examination and the Bayley Scales of Infant Development) at 18 months, 36 months, or both. A cardiac assessment was performed at 36 months.

Results: A total of 129 children (median age, 22 months; range, 12 to 42) were included in the group whose mother had cancer (prenatal-exposure group) with a matching number in the control group. During pregnancy, 96 children (74.4%) were exposed to chemotherapy (alone or in combination with other treatments), 11 (8.5%) to radiotherapy (alone or in combination), 13 (10.1%) to surgery alone, 2 (1.6%) to other drug treatments, and 14 (10.9%) to no treatment. Birth weight was below the 10th percentile in 28 of 127 children (22.0%) in the prenatal-exposure group and in 19 of 125 children (15.2%) in the control group (P=0.16). There was no significant between-group difference in cognitive development on the basis of the Bayley score (P=0.08) or in subgroup analyses. The gestational age at birth was correlated with the cognitive outcome in the two study groups. Cardiologic evaluation among 47 children at 36 months of age showed normal cardiac findings.

Conclusions: Prenatal exposure to maternal cancer with or without treatment did not impair the cognitive, cardiac, or general development of children in early childhood. Prematurity was correlated with a worse cognitive outcome, but this effect was independent of cancer treatment. (Funded by Research Foundation-Flanders and others; ClinicalTrials.gov number, NCT00330447.).
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http://dx.doi.org/10.1056/NEJMoa1508913DOI Listing
November 2015

Modeling early haematologic adverse events in conformal and intensity-modulated pelvic radiotherapy in anal cancer.

Radiother Oncol 2015 Nov 22;117(2):246-51. Epub 2015 Sep 22.

Department of Oncology, University of Oxford, UK.

Background And Purpose: To determine if there are differences between dose to pelvic bone marrow (PBM) using intensity modulated radiotherapy (IMRT) under UK guidance versus conformal radiotherapy (CRT) per ACT II protocol and if differences translate to rates of early haematological adverse events grade 3 or greater (HT3+).

Methods And Materials: Two groups of 20+ patients, treated under IMRT and CRT regimes respectively, were identified. All patients underwent weekly blood cell count: haemoglobin (HgB), white cell count (WCC), absolute neutrophil count (ANC) and platelets (plats). Percent volume of PBM and sub structures receiving 5-25 Gy were tested for statistical significance. Regression models were used to test for correlation to blood counts. NTCP modeling was also performed.

Results: PMB dose metrics showed a significant increase in the IMRT group. Regression analysis showed iliac and lumbosacral PBM dose metrics to associate with reduced nadir ANC and WCC. NTCP at HT3+ was 0.13 using IMRT relative to 0.07 using CRT (p<0.05).

Conclusion: Whilst this is a relatively small retrospective study and lacks information on the distribution of active PBM, IMRT treatment has been shown to significantly increase PMB irradiation. PBM dose metrics have been shown to be predictive of WCC and ANC suppression. NTCP modeling predicts much high risk of HT3+. Paradoxically, actual rates of HT3+ were comparable suggesting that differences in the distributions of dose metrics maybe a significant factor and/or that there are insufficiency in the NTCP modeling.
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http://dx.doi.org/10.1016/j.radonc.2015.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678285PMC
November 2015

Online adaptation and verification of VMAT.

Med Phys 2015 Jul;42(7):3877-91

Department of Oncology, MRC-CR-UK Gray Institute of Radiation Oncology and Biology, University of Oxford, Oxford OX1 2JD, United Kingdom.

Purpose: This work presents a method for fast volumetric modulated arc therapy (VMAT) adaptation in response to interfraction anatomical variations. Additionally, plan parameters extracted from the adapted plans are used to verify the quality of these plans. The methods were tested as a prostate class solution and compared to replanning and to their current clinical practice.

Methods: The proposed VMAT adaptation is an extension of their previous intensity modulated radiotherapy (IMRT) adaptation. It follows a direct (forward) planning approach: the multileaf collimator (MLC) apertures are corrected in the beam's eye view (BEV) and the monitor units (MUs) are corrected using point dose calculations. All MLC and MU corrections are driven by the positions of four fiducial points only, without need for a full contour set. Quality assurance (QA) of the adapted plans is performed using plan parameters that can be calculated online and that have a relation to the delivered dose or the plan quality. Five potential parameters are studied for this purpose: the number of MU, the equivalent field size (EqFS), the modulation complexity score (MCS), and the components of the

Mcs: the aperture area variability (AAV) and the leaf sequence variability (LSV). The full adaptation and its separate steps were evaluated in simulation experiments involving a prostate phantom subjected to various interfraction transformations. The efficacy of the current VMAT adaptation was scored by target mean dose (CTVmean), conformity (CI95%), tumor control probability (TCP), and normal tissue complication probability (NTCP). The impact of the adaptation on the plan parameters (QA) was assessed by comparison with prediction intervals (PI) derived from a statistical model of the typical variation of these parameters in a population of VMAT prostate plans (n = 63). These prediction intervals are the adaptation equivalent of the tolerance tables for couch shifts in the current clinical practice.

Results: The proposed adaptation of a two-arc VMAT plan resulted in the intended CTVmean (Δ ≤ 3%) and TCP (ΔTCP ≤ 0.001). Moreover, the method assures the intended CI95% (Δ ≤ 11%) resulting in lowered rectal NTCP for all cases. Compared to replanning, their adaptation is faster (13 s vs 10 min) and more intuitive. Compared to the current clinical practice, it has a better protection of the healthy tissue. Compared to IMRT, VMAT is more robust to anatomical variations, but it is also less sensitive to the different correction steps. The observed variations of the plan parameters in their database included a linear dependence on the date of treatment planning and on the target radius. The MCS is not retained as QA metric due to a contrasting behavior of its components (LSV and AAV). If three out of four plan parameters (MU, EqFS, AAV, and LSV) need to lie inside a 50% prediction interval (3/4-50%PI), all adapted plans will be accepted. In contrast, all replanned plans do not meet this loose criterion, mainly because they have no connection to the initially optimized and verified plan.

Conclusions: A direct (forward) VMAT adaptation performs equally well as (inverse) replanning but is faster and can be extended to real-time adaptation. The prediction intervals for the machine parameters are equivalent to the tolerance tables for couch shifts in the current clinical practice. A 3/4-50%PI QA criterion accepts all the adapted plans but rejects all the replanned plans.
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http://dx.doi.org/10.1118/1.4921615DOI Listing
July 2015

Efficacy and workload analysis of a fixed vertical couch position technique and a fixed-action-level protocol in whole-breast radiotherapy.

J Appl Clin Med Phys 2015 Mar 8;16(2):5265. Epub 2015 Mar 8.

University Hospitals of Leuven, KU Leuven.

Quantification of the setup errors is vital to define appropriate setup margins preventing geographical misses. The no-action-level (NAL) correction protocol reduces the systematic setup errors and, hence, the setup margins. The manual entry of the setup corrections in the record-and-verify software, however, increases the susceptibility of the NAL protocol to human errors. Moreover, the impact of the skin mobility on the anteroposterior patient setup reproducibility in whole-breast radiotherapy (WBRT) is unknown. In this study, we therefore investigated the potential of fixed vertical couch position-based patient setup in WBRT. The possibility to introduce a threshold for correction of the systematic setup errors was also explored. We measured the anteroposterior, mediolateral, and superior-inferior setup errors during fractions 1-12 and weekly thereafter with tangential angled single modality paired imaging. These setup data were used to simulate the residual setup errors of the NAL protocol, the fixed vertical couch position protocol, and the fixed-action-level protocol with different correction thresholds. Population statistics of the setup errors of 20 breast cancer patients and 20 breast cancer patients with additional regional lymph node (LN) irradiation were calculated to determine the setup margins of each off-line correction protocol. Our data showed the potential of the fixed vertical couch position protocol to restrict the systematic and random anteroposterior residual setup errors to 1.8 mm and 2.2 mm, respectively. Compared to the NAL protocol, a correction threshold of 2.5mm reduced the frequency of mediolateral and superior-inferior setup corrections with 40% and 63%, respectively. The implementation of the correction threshold did not deteriorate the accuracy of the off-line setup correction compared to the NAL protocol. The combination of the fixed vertical couch position protocol, for correction of the anteroposterior setup error, and the fixed-action-level protocol with 2.5 mm correction threshold, for correction of the mediolateral and the superior-inferior setup errors, was proved to provide adequate and comparable patient setup accuracy in WBRT and WBRT with additional LN irradiation.
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http://dx.doi.org/10.1120/jacmp.v16i2.5265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5690085PMC
March 2015

Accuracy of a new paired imaging technique for position correction in whole breast radiotherapy.

J Appl Clin Med Phys 2015 Jan 8;16(1):4796. Epub 2015 Jan 8.

University Hospitals of Leuven.

Image-guided position verification in breast radiotherapy is accurately performed with kilovoltage cone beam CT (kV-CBCT). The technique is, however, time-consuming and there is a risk for patient collision. Online position verification performed with orthogonal-angled mixed modality paired imaging is less time-consuming at the expense of inferior accuracy compared to kV-CBCT. We therefore investigated whether a new tangential-angled single modality paired imaging technique can reduce the residual error (RE) of orthogonal-angled mixed modality paired imaging. The latter was applied to 20 breast cancer patients. Tangential-angled single modality paired imaging was investigated in 20 breast and 20 breast cancer patients with locoregional lymph node irradiation. The central lung distance (CLD) residual error and the longitudinal residual error were determined during the first 5 treatment fractions. Off-line matching of the tangential breast field images, acquired after online position correction, was used. The mean, systematic, and random REs of each patient group were calculated. The systematic REs were checked for significant differences using the F-test. Tangential-angled single modality paired imaging significantly reduced the systematic CLD residual error of orthogonal-angled mixed modality paired imaging for the breast cancer patients, from 2.3 mm to 1.0 mm, and also significantly decreased the systematic longitudinal RE from 2.4 mm to 1.3 mm. PTV margins, which account for the residual error (PTVRE), were also calculated. The PTVRE margin needed to account for the RE of orthogonal-angled mixed modality paired imaging (i.e., 8 mm) was halved by tangential-angled single modality paired imaging. The differences between the systematic REs of tangential-angled single modality paired imaging of the breast cancer patients and the breast cancer patients with locoregional lymph node irradiation were not significant, yielding comparable PTVRE margins. In this study, we showed that tangential-angled single modality paired imaging is superior to orthogonal-angled mixed modality paired imaging to correct the position errors in whole breast radiotherapy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5689991PMC
http://dx.doi.org/10.1120/jacmp.v16i1.4796DOI Listing
January 2015

A closed parameterization of DNA-damage by charged particles, as a function of energy - a geometrical approach.

PLoS One 2014 23;9(10):e110333. Epub 2014 Oct 23.

CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, United Kingdom; Laboratory for experimental radiotherapy, Department of Oncology, University of Leuven, Leuven, Belgium.

Purpose: To present a closed formalism calculating charged particle radiation damage induced in DNA. The formalism is valid for all types of charged particles and due to its closed nature is suited to provide fast conversion of dose to DNA-damage.

Methods: The induction of double strand breaks in DNA-strings residing in irradiated cells is quantified using a single particle model. This leads to a proposal to use the cumulative Cauchy distribution to express the mix of high and low LET type damage probability generated by a single particle. A microscopic phenomenological Monte Carlo code is used to fit the parameters of the model as a function of kinetic energy related to the damage to a DNA molecule embedded in a cell. The model is applied for four particles: electrons, protons, alpha-particles, and carbon ions. A geometric interpretation of this observation using the impact ionization mean free path as a quantifier, allows extension of the model to very low energies.

Results: The mathematical expression describes the model adequately using a chi-square test ([Formula: see text]). This applies to all particle types with an almost perfect fit for protons, while the other particles seem to result in some discrepancies at very low energies. The implementation calculating a strict version of the RBE based on complex damage alone is corroborated by experimental data from the measured RBE. The geometric interpretation generates a unique dimensionless parameter [Formula: see text] for each type of charged particle. In addition, it predicts a distribution of DNA damage which is different from the current models.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0110333PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207739PMC
June 2015

The photon dose calculation algorithm used in breast radiotherapy has significant impact on the parameters of radiobiological models.

J Appl Clin Med Phys 2014 07 8;15(4):259–269. Epub 2014 Jul 8.

University Hospitals of Leuven, KU Leuven.

The comparison of the pencil beam dose calculation algorithm with modified Batho heterogeneity correction (PBC-MB) and the analytical anisotropic algorithm (AAA) and the mutual comparison of advanced dose calculation algorithms used in breast radiotherapy have focused on the differences between the physical dose distributions. Studies on the radiobiological impact of the algorithm (both on the tumor control and the moderate breast fibrosis prediction) are lacking. We, therefore, investigated the radiobiological impact of the dose calculation algorithm in whole breast radiotherapy. The clinical dose distributions of 30 breast cancer patients, calculated with PBC-MB, were recalculated with fixed monitor units using more advanced algorithms: AAA and Acuros XB. For the latter, both dose reporting modes were used (i.e., dose-to-medium and dose-to-water). Next, the tumor control probability (TCP) and the normal tissue complication probability (NTCP) of each dose distribution were calculated with the Poisson model and with the relative seriality model, respectively. The endpoint for the NTCP calculation was moderate breast fibrosis five years post treatment. The differences were checked for significance with the paired t-test. The more advanced algorithms predicted a significantly lower TCP and NTCP of moderate breast fibrosis then found during the corresponding clinical follow-up study based on PBC calculations. The differences varied between 1% and 2.1% for the TCP and between 2.9% and 5.5% for the NTCP of moderate breast fibrosis. The significant differences were eliminated by determination of algorithm-specific model parameters using least square fitting. Application of the new parameters on a second group of 30 breast cancer patients proved their appropriateness. In this study, we assessed the impact of the dose calculation algorithms used in whole breast radiotherapy on the parameters of the radiobiological models. The radiobiological impact was eliminated by determination of algorithm specific model parameters.
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http://dx.doi.org/10.1120/jacmp.v15i4.4853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5875495PMC
July 2014

Dosimetric adaptive IMRT driven by fiducial points.

Med Phys 2014 Jun;41(6):061716

Department of Oncology, Laboratory of Experimental Radiotherapy, KU Leuven, Herestraat 49, 3000 Leuven, Belgium and Department of Oncology, MRC-CR-UK Gray Institute of Radiation Oncology and Biology, University of Oxford, Oxford OX1 2JD, United Kingdom.

Purpose: Intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy have become standard treatments but are more sensitive to anatomical variations than 3D conformal techniques. To correct for inter- and intrafraction anatomical variations, fast and easy to implement methods are needed. Here, the authors propose a full dosimetric IMRT correction that finds a compromise in-between basic repositioning (the current clinical practice) and full replanning. It simplifies replanning by avoiding a recontouring step and a full dose calculation. It surpasses repositioning by updating the preoptimized fluence and monitor units (MU) using a limited number of fiducial points and a pretreatment (CB)CT. To adapt the fluence the fiducial points were projected in the beam's eye view (BEV). To adapt the MUs, point dose calculation towards the same fiducial points were performed. The proposed method is intrinsically fast and robust, and simple to understand for operators, because of the use of only four fiducial points and the beam data based point dose calculations.

Methods: To perform our dosimetric adaptation, two fluence corrections in the BEV are combined with two MU correction steps along the beam's path. (1) A transformation of the fluence map such that it is realigned with the current target geometry. (2) A correction for an unintended scaling of the penumbra margin when the treatment beams scale to the current target size. (3) A correction for the target depth relative to the body contour and (4) a correction for the target distance to the source. The impact of the correction strategy and its individual components was evaluated by simulations on a virtual prostate phantom. This heterogeneous reference phantom was systematically subjected to population based prostate transformations to simulate interfraction variations. Additionally, a patient example illustrated the clinical practice. The correction strategy was evaluated using both dosimetric (CTV mean dose, conformity index) and clinical (tumor control probability, and normal tissue complication probability) measures.

Results: Based on the current experiments, the intended target dose and tumor control probability could be assured by the proposed method (TCP ≥ TCP(intended)). Additionally, the conformity index error was more than halved compared to the current clinical practice (ΔCI(95%) from 40% to 16%) resulting in improved organ at risk protection. All the individual correction steps had an added value to the full correction.

Conclusions: A limited number of fiducial points (no organ contours required) and an in-room (CB)CT are sufficient to perform a full dosimetric correction for IMRT plans. In the presence of interfraction variation, the corrected plans show superior dose distributions compared to our current clinical practice.
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http://dx.doi.org/10.1118/1.4876378DOI Listing
June 2014

Primary brain tumours, meningiomas and brain metastases in pregnancy: report on 27 cases and review of literature.

Eur J Cancer 2014 May 14;50(8):1462-71. Epub 2014 Mar 14.

Gynecologic Oncology, University Hospitals Leuven, Herestraat, 49, 3000 Leuven, Belgium; Division of Oncology, KULeuven, Herestraat, 49, 3000 Leuven, Belgium. Electronic address:

Background: The concurrence of intracranial tumours with pregnancy is rare. The purpose of this study was to describe all reported patients registered in the international Cancer in Pregnancy registration study (CIP study; http://www.cancerinpregnancy.org), and to review the literature in order to obtain better insight into outcome and possibilities of treatment in pregnancy.

Methods: We collected all intracranial tumours (primary brain tumour, cerebral metastasis, or meningioma) diagnosed during pregnancy, registered prospectively and retrospectively by international collaboration since 1973. Patients diagnosed postpartum were excluded. We summarised the demographic features, treatment decisions, obstetrical and neonatal outcomes.

Results: The mean age of the 27 eligible patients was 31years (range 23-41years), of which 13 and 12 patients were diagnosed in the second and third trimesters, respectively. Eight patients (30%) underwent brain surgery, seven patients (26%) had radiotherapy and in three patients (11%) chemotherapy was administered during gestation. Two patients died during pregnancy and four pregnancies were terminated. In 16 (59%) patients elective caesarean section was performed of which 14 (52%) were still preterm (range 30-36weeks, mean 33weeks). Five patients had a vaginal delivery (range 36-40weeks). Of the 21 ongoing pregnancies all children were born alive without visible congenital malformations and the available long-term follow-up data (range 2-25years) of six children were reassuring.

Conclusion: Adherence to standard protocol for the treatment of brain tumours during pregnancy appears to allow a term delivery and a higher probability of a vaginal delivery.
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http://dx.doi.org/10.1016/j.ejca.2014.02.018DOI Listing
May 2014

Gynecologic cancers in pregnancy: guidelines of a second international consensus meeting.

Int J Gynecol Cancer 2014 Mar;24(3):394-403

*Department of Oncology, Katholieke Universiteit Leuven and Gynecologic Oncology, University Hospitals Leuven, Belgium; †Gynecologic Oncology, 2nd Medical Faculty, Charles University, Prague, Czech Republic; ‡Neonatal Intensive Care, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; §Radiotherapy and Clinical Oncology, Vejle Hospital, Vejle, Denmark; ∥Gynecological Oncology, Center for Gynecological Oncology Amsterdam, Amsterdam, The Netherlands; ¶Obstetrics, University Hospitals Leuven, Katholieke Universiteit Leuven, Belgium; #Medical Oncology, Cochin Teaching Hospital, Paris Descartes University, Paris, France; **Obstetrics and Gynecology, Ospedale San Gerardo, Monza, Italy; ††Gynecologic Surgery, Institute de Cancérologie Gustave Roussy, Villejuif, France; ‡‡Maternal Fetal Medicine Unit, Mt Sinai Hospital, Toronto, Ontario, Canada; §§Obstetrics and Gynecology, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Belgrade, Serbia; ∥∥Department of Gynecology and Obstetrics, Hôpital Trousseau, Assistance-Publique Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France; ¶¶Radiation Oncology, University Hospitals Leuven, Katholieke Universiteit Leuven, Belgium; ##Medical Oncology, Radboudziekenhuis, Nijmegen, The Netherlands; ***Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel; and †††Clinical Pharmacology and Toxicology, Motherisk Program, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

Objectives: This study aimed to provide timely and effective guidance for pregnant women and health care providers to optimize maternal treatment and fetal protection and to promote effective management of the mother, fetus, and neonate when administering potentially teratogenic medications. New insights and more experience were gained since the first consensus meeting 5 years ago.

Methods: Members of the European Society of Gynecological Oncology task force "Cancer in Pregnancy" in concert with other international experts reviewed the existing literature on their respective areas of expertise. The summaries were subsequently merged into a complete article that served as a basis for discussion during the consensus meeting. All participants approved the final article.

Results: In the experts' view, cancer can be successfully treated during pregnancy in collaboration with a multidisciplinary team, optimizing maternal treatment while considering fetal safety. To maximize the maternal outcome, cancer treatment should follow a standard treatment protocol as for nonpregnant patients. Iatrogenic prematurity should be avoided. Individualization of treatment and effective psychologic support is imperative to provide throughout the pregnancy period. Diagnostic procedures, including staging examinations and imaging, such as magnetic resonance imaging and sonography, are preferable. Pelvic surgery, either open or laparoscopic, as part of a treatment protocol, may reveal beneficial outcomes and is preferably performed by experts. Most standard regimens of chemotherapy can be administered from 14 weeks gestational age onward. Apart from cervical and vulvar cancer, as well as important vulvar scarring, the mode of delivery is determined by the obstetrician. Term delivery is aimed for. Breast-feeding should be considered based on individual drug safety and neonatologist-breast-feeding expert's consult.

Conclusions: Despite limited evidence-based information, cancer treatment during pregnancy can succeed. State-of-the-art treatment should be provided for this vulnerable population to preserve maternal and fetal prognosis.

Supplementary Information: Supplementary data on teratogenic effects, ionizing examinations, sentinel lymph node biopsy, tumor markers during pregnancy, as well as additional references and tables are available at the extended online version of this consensus article, go to http://links.lww.com/IGC/A197.
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http://dx.doi.org/10.1097/IGC.0000000000000062DOI Listing
March 2014

Quantification of radiation-induced lung damage with CT scans: the possible benefit for radiogenomics.

Acta Oncol 2013 Oct 19;52(7):1405-10. Epub 2013 Aug 19.

Radiation Oncology, University Hospitals Leuven/KU Leuven , Leuven , Belgium.

Background: Radiation-induced lung damage (RILD) is an important problem. Although physical parameters such as the mean lung dose are used in clinical practice, they are not suited for individualised radiotherapy. Objective, quantitative measurements of RILD on a continuous instead of on an ordinal, semi-quantitative, semi-subjective scale, are needed.

Methods: Hounsfield unit (HU) changes before versus three months post-radiotherapy were correlated per voxel with the radiotherapy dose in 95 lung cancer patients. Deformable registration was used to register pre- and post-CT scans and the density increase was quantified for various dose bins. The dose-response curve for increased HU was quantified using the slope of a linear regression (HU/Gy). The end-point for the toxicity analysis was dyspnoea ≥ grade 2.

Results: Radiation dose was linearly correlated with the change in HU (mean R(2) = 0.74 ± 0.28). No differences in HU/Gy between groups treated with stereotactic radiotherapy, conventional radiotherapy alone, sequential or concurrent chemo- radiotherapy were observed. In the whole patient group, 33/95 (34.7%) had dyspnoea ≥ G2. Of the 48 patients with a HU/Gy below the median, 16 (33.3%) developed dyspnoea ≥ G2, while in the 47 patients with a HU/Gy above the median, 17 (36.1%) had dyspnoea ≥ G2 (not significant). Individual patients showed a nearly 21-fold difference in radiosensitivity, with HU/Gy ranging from 0 to 10 HU/Gy.

Conclusions: HU changes identify objectively the whole range of individual radiosensitivity on a continuous, quantitative scale. CT density changes may allow more robust and accurate radiogenomics studies.
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http://dx.doi.org/10.3109/0284186X.2013.813074DOI Listing
October 2013

CT- and MRI-based seed localization in postimplant evaluation after prostate brachytherapy.

Brachytherapy 2013 Nov-Dec;12(6):580-8. Epub 2013 Jul 19.

Department of Radiation Oncology, University Hospital Gasthuisberg, Leuven, Belgium. Electronic address:

Purpose: To compare the uncertainties in CT- and MRI-based seed reconstruction in postimplant evaluation after prostate seed brachytherapy in terms of interobserver variability and quantify the impact of seed detection variability on a selection of dosimetric parameters for three postplan techniques: (1) CT, (2) MRI-T1 weighted fused with MRI-T2 weighted, and (3) CT fused with MRI-T2 weighted.

Methods And Materials: Seven physicists reconstructed the seed positions on postimplant CT and MRI-T1 images of three patients. For each patient and imaging modality, the interobserver variability was calculated with respect to a reference seed set. The effect of this variability on dosimetry was calculated for CT and CT + MRI-T2 (CT-based seed reconstruction), as well as for MRI-T1 + MRI-T2 (MRI-T1-based seed reconstruction), using fixed CT and MRI-T2 prostate contours.

Results: Averaged over three patients, the interobserver variability in CT-based seed reconstruction was 1.1 mm (1 SDref, i.e., standard deviation with respect to the reference value). The D90 (dose delivered to 90% of the target) variability was 1.5% and 1.3% (1 SDref) for CT and CT + MRI-T2, respectively. The mean interobserver variability in MRI-based seed reconstruction was 3.0 mm (1 SDref), and the impact of this variability on D90 was 6.6% for MRI-T1 + MRI-T2.

Conclusions: Seed reconstruction on MRI-T1-weighted images was less accurate than on CT. This difference in uncertainties should be weighted against uncertainties due to contouring and image fusion when comparing the overall reliability of postplan techniques.
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http://dx.doi.org/10.1016/j.brachy.2013.06.003DOI Listing
May 2014

RapidArc, SmartArc and TomoHD compared with classical step and shoot and sliding window intensity modulated radiotherapy in an oropharyngeal cancer treatment plan comparison.

Radiat Oncol 2013 Feb 20;8:37. Epub 2013 Feb 20.

Department of Radiotherapy, University Radiotherapy department Antwerp - UZA / ZNA, Lindendreef 1, 2020 Antwerp, Belgium.

Background: Radiotherapy techniques have evolved rapidly over the last decade with the introduction of Intensity Modulated RadioTherapy (IMRT) in different forms. It is not clear which of the IMRT techniques is superior in the treatment of head and neck cancer patients in terms of coverage of the planning target volumes (PTVs), sparing the organs at risk (OARs), dose to the normal tissue, number of monitor units needed and delivery time.The present paper aims to compare Step and Shoot (SS) IMRT, Sliding Window (SW) IMRT, RapidArc (RA) planned with Eclipse, Elekta VMAT planned with SmartArc (SA) and helical TomoHD™ (HT).

Methods: Target volumes and organs at risk (OARs) of five patients with oropharyngeal cancer were delineated on contrast enhanced CT-scans, then treatment plans were generated on five different IMRT systems. In 32 fractions, 69.12 Gy and 56 Gy were planned to the therapeutic and prophylactic PTVs, respectively. For the PTVs and 26 OARs ICRU 83 reporting guidelines were followed. Differences in the studied parameters between treatment planning systems were analysed using repeated measures ANOVA.

Results: Mean Homogeneity Index of PTV(therapeutic) is better with HT(.06) followed by SA(.08), RA(.10), SW(.10) and SS(.11). PTV(prophylactic) is most homogeneous with RA. Parotid glands prescribed mean doses are only obtained by SA and HT, 20.6 Gy and 21.7 Gy for the contralateral and 25.6 Gy and 24.1 Gy for the ipsilateral, against 25.6 Gy and 32.0 Gy for RA, 26.4 Gy and 34.6 Gy for SW, and 28.2 Gy and 34.0 Gy for SS. RA uses the least monitor units, HT the most. Treatment times are 3.05 min for RA, and 5.9 min for SA and HT.

Conclusions: In the treatment of oropharyngeal cancer, we consider rotational IMRT techniques preferable to fixed gantry techniques due to faster fraction delivery and better sparing of OARs without a higher integral dose. TomoHD gives most homogeneous target coverage with more sparing of spinal cord, brainstem, parotids and the lower swallowing apparatus than most of the other systems. Between RA and SA, SA gives a more homogeneous PTV(therapeutic) while sparing the parotids more, but the delivery of RA is twice as fast with less overdose to the PTV(elective).
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http://dx.doi.org/10.1186/1748-717X-8-37DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3599972PMC
February 2013

Prostate post-implant dosimetry: interobserver variability in seed localisation, contouring and fusion.

Radiother Oncol 2012 Aug 31;104(2):192-8. Epub 2012 Jul 31.

University Hospital Gasthuisberg, Leuven, Belgium.

Aim: Reliable post-implant evaluation of prostate seed implants requires optimal seed identification and accurate delineation of anatomical structures. In this study the GEC-ESTRO groups BRAPHYQS and PROBATE investigated the interobserver variability in post-implant prostate contouring, seed reconstruction and image fusion and its impact on the dose-volume parameters.

Materials: Post-implant T2-TSE, T1-GE and CT images were acquired for three patients, in order to evaluate four post-plan techniques: (a) CT, (b) T1+T2, (c) CT+T2, (d) CT+T1(int)+T2. Three interobserver studies were set up. (1) Contouring: the CTV-prostate was delineated on CT and T2 by eight physicians. Additionally one reference contour was defined on both image modalities for each patient. (2) Seed reconstruction: seven physicists localised the seeds on T1 and CT, manually and with CT seed finder tools. A reference seed geometry was defined on CT and T1. (3) Fusion: six physicists registered the image sets for technique (b)-(d), using seeds (if visible) and anatomical landmarks. A reference fusion was determined for each combined technique.

Results: (1) The SD(ref) for contouring (1 SD with respect to the reference volume) was largest for CT (23%), but also surprisingly large for MRI (17%). This resulted in large SD(ref) values for D90 for all techniques (17-23%). The surprisingly large SD(ref) for MRI was partly due to variations in interpretation of what to include in the prostate contour. (2) The SD(ref) in D90 for seed reconstruction was small (2%) for all techniques, except for T1+T2 (7%). (3) The SD(ref) in D90 due to image fusion was quite large, especially for direct fusion of CT+T2 (16%) where clearly corresponding landmarks were missing (seeds hardly visible on T2). In general, we observed large differences in D90 depending on the technique used.

Conclusions: The dosimetric parameters for prostate post-implant evaluation showed large technique-dependent interobserver variabilities. Contouring and image fusion are the 'weak links' in the procedure. Guidelines and training in contouring together with incorporation of automated fusion software need to be implemented.
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http://dx.doi.org/10.1016/j.radonc.2012.06.014DOI Listing
August 2012

Out-of-field contributions for IMRT and volumetric modulated arc therapy measured using gafchromic films and compared to calculations using a superposition/convolution based treatment planning system.

Radiother Oncol 2012 Oct 31;105(1):127-32. Epub 2012 Jan 31.

Department of Oncology, University of Leuven, Belgium.

Purpose: To quantify the whole-body-dose delivered during the application of new techniques and compare them to the results obtained by treatment planning systems. The ultimate goal being the use of planning data in combination with complication data to assess the impact of low doses of ionizing radiation.

Methods: A film technique using gafchromic films to assess low doses was used on simplified phantoms and compared to data from treatment planning systems as well as a simplified whole body dose calculation system (Peridose). The types of treatment include open fields, intensity modulated radiation therapy (IMRT) and volumetric arc treatments. The film measurements were confirmed using TLDs in Alderson phantoms. In addition neutron contributions were measured as these are not taken into account in the current modern treatment planning systems, but can add significantly to the patient's whole body dose.

Results: Dose outside of the treatment plane diminished to 1% of the prescribed dose, this for open fields, IMRT and rotational treatments alike. Noteworthy was an increase at about 20cm from the central plane in IMRT, and in a more limited fashion for volumetric modulated arc treatment. In open fields this was not observed. Treatment planning systems were good at determining the out-of-field doses of single field treatments. In complex plans the TPS underestimated the dose to the patient. At distances greater than 20cm from the field edge, these systems did not predict any dose. The Peridose program performed well in the case of classical treatments. In the case of IMRT treatments, the overall evolution of the dose as a function of the distance to the field was well-modeled. However, an over estimation of the order of 60-80% was observed, leaving the possibility for a corrective factor based on a point measurement. Dose levels over the whole body were of the order 100mGy or higher over a complete treatment for the more complex treatments. Neutron dose levels were of the order single digit mSv for 10MV treatments. For 18MV the level of neutron contribution was in agreement with recent publications, corroborating reports that the dose from neutrons is lower than previously reported.
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http://dx.doi.org/10.1016/j.radonc.2011.12.030DOI Listing
October 2012
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