Bram van Asselen

An improved breast irradiation technique using three-dimensional geometrical information and intensity modulation

BACKGROUND AND PURPOSE In spite of the complex geometry of the breast, treatment planning for tangential breast irradiation is conventionally performed using two-dimensional patient anatomy information. The purpose of this work was to develop a new technique which takes the three-dimensional (3D) patient geometry into account. MATERIALS AND METHODS An intensity-modulated radiotherapy (IMRT) technique was developed based on the division of the tangential fields in four multi-leaf collimator (MLC) shaped segments. The shape of these segments was obtained from an equivalent path length map of the irradiated volume. Approximately 88% of the dose was delivered by two open fields covering the whole treated volume. Dose calculations for the IMRT technique and the conventional technique were performed for five patients, using computer tomography (CT) data and a 3D calculation algorithm. A planning target volume (PTV) and ipsilateral lung volume were delineated in these CT data. RESULTS All patients showed similar equivalent path length patterns. Analysis of the dose distribution showed an improved dose distribution using the IMRT technique. The dose inhomogeneity in the PTV was 9.0% (range 6.4-11.4%) for the conventional and 7.6% (range 6.5-10.3%) for the IMRT technique. The mean lung dose was reduced for the IMRT technique by approximately 10% compared with the conventional technique. CONCLUSION A new breast irradiation technique has been developed which improves the dose homogeneity within the planning target volume and reduces the dose to the lung. Furthermore, the IMRT technique creates the possibility to improve the field matching in case of multiple field irradiations of the breast and lymph nodes.

The dose to the parotid glands with IMRT for oropharyngeal tumors: the effect of reduction of positioning margins.

PURPOSE The aim of this paper is to quantify the importance of the reduction of positioning margins applied to the clinical target volume (CTV) on the dose distribution of the parotid gland for different intensity-modulated radiotherapy (IMRT) strategies for the treatment of oropharyngeal cancer. METHODS AND MATERIALS CTVs and organs at risk were delineated in the planning computed tomographic (CT) scans of three patients. Margins of 0, 3, 6 and 9mm were applied to the CTVs in order to obtain the planning target volumes (PTVs). Three IMRT strategies were used to optimize the dose distribution. RESULTS The analysis of the three IMRT strategies resulted in: (1) an optimal dose distribution in the PTV; (2) optimal dose distribution in the PTV while sparing the parotid gland and (3) more parotid gland sparing but at expense of the dose homogeneity in the PTV. The mean parotid dose increased linearly with increasing margin by approximately 1.3Gy per mm. As a result, the normal complication probability (NTCP) for xerostomia decreased when smaller margins were applied. Reducing the margin from 6 to 3mm resulted in an NTCP reduction of approximately 20%. CONCLUSION Reducing the CTV-PTV margin by improving the patient position accuracy may lead to a significant reduction of NTCP for the IMRT treatment of the oropharyngeal tumors and lymph nodes level II.

Intrafraction motions of the larynx during radiotherapy

PURPOSE To quantify the intrafraction motions of the larynx during radiotherapy of laryngeal cancer. Depending on the magnitude, duration, and incidence, these motions may have clinical consequences for the choice of margins around the clinical target volume. METHODS AND MATERIALS The intrafraction motions were analyzed for 10 patients, treated in 33 or 35 fractions. The intrafraction motions of the larynx were visualized using an a-Si flat panel imager. Images were obtained every 200 ms, resulting in a movie of images for each beam. In addition to visual analysis of all movies, the tip of the epiglottis was delineated and used as a landmark, the coordinates of which were followed in time. RESULTS Movies were obtained during 79% of the total number of radiotherapy fractions. The total duration of swallowing was on average 0.45% (range 0.0-1.5) of the total irradiation time. Deviations of motions other than swallowing ranged between 0.3 and 11.5 mm. Some of these motions were more sudden, and others were probably related to breathing, because the frequency of these motions was 8-20/min. CONCLUSION The incidence and total duration of swallowing is low. Therefore, it is not necessary to apply an internal margin to take into account these displacements. Other motions, however, occur more often. In 95% of the irradiation time, the tip of the epiglottis moves within a range of 7.1 mm. A margin should be applied to the clinical target volume to take into account these motions.

Changes in Excision Cavity Volume: Prediction of the Reduction in Absolute Volume During Breast Irradiation

PURPOSE The aim of this study was to determine the changes in the excision cavity volume due to the resolution of the surgical effects during the whole breast treatment. MATERIALS AND METHODS Seventy-seven patients with early-stage (T1-2 N0) breast cancer treated with breast-conserving therapy were included for this study. All patients underwent a standard planning computed tomography (CT) scan before irradiation treatment. A second CT scan was performed in the week before the start of the boost. Excision cavity volumes were delineated based on the surgical clips and the (surrounding) seroma or hematoma or other surgical changes on both scans by an experienced physician. This resulted in the gross tumor volumes GTV1 and GTV2. RESULTS The delineated volumes of the GTVs were on average 78.7 cm(3) (range, 1.1-236.0 cm(3)) and 29.7 cm(3) (range, 1.3-123.6 cm(3)) for, respectively, GTV1 and GTV2. The time between the CT scans was on average 37 days (range, 29-74 days). This resulted in a reduction of on average 62%. The absolute reduction per day of the GTV1 was -1.3 cm(3)/day (range, 0.3 to -5.4 cm(3)/day). A linear correlation (correlation coefficient r(2) = 0.81) was observed between the absolute volume of GTV1 and the absolute reduction per day. CONCLUSION A significant reduction in excision cavity volume during whole breast irradiation was shown. The observed correlation might be helpful in the decision to perform a second CT scan to adapt the treatment plan.

RandomizEd controlled trial for pre-operAtive dose-escaLation BOOST in locally advanced rectal cancer (RECTAL BOOST study) : study protocol for a randomized controlled trial

BackgroundTreatment for locally advanced rectal cancer (LARC) consists of chemoradiation therapy (CRT) and surgery. Approximately 15% of patients show a pathological complete response (pCR). Increased pCR-rates can be achieved through dose escalation, thereby increasing the number patients eligible for organ-preservation to improve quality of life (QoL). A randomized comparison of 65 versus 50Gy with external-beam radiation alone has not yet been performed. This trial investigates pCR rate, clinical response, toxicity, QoL and (disease-free) survival in LARC patients treated with 65Gy (boost + chemoradiation) compared with 50Gy standard chemoradiation (sCRT).Methods/designThis study follows the ‘cohort multiple randomized controlled trial’ (cmRCT) design: rectal cancer patients are included in a prospective cohort that registers clinical baseline, follow-up, survival and QoL data. At enrollment, patients are asked consent to offer them experimental interventions in the future. Eligible patients—histologically confirmed LARC (T3NxM0 <1 mm from mesorectal fascia, T4NxM0 or TxN2M0) located ≤10 cm from the anorectal transition who provided consent for experimental intervention offers—form a subcohort (n = 120). From this subcohort, a random sample is offered the boost prior to sCRT (n = 60), which they may accept or refuse. Informed consent is signed only after acceptance of the boost. Non-selected patients in the subcohort (n = 60) undergo sCRT alone and are not notified that they participate in the control arm until the trial is completed.sCRT consists of 50Gy (25 × 2Gy) with concomitant capecitabine. The boost (without chemotherapy) is given prior to sCRT and consists of 15 Gy (5 × 3Gy) delivered to the gross tumor volume (GTV). The primary endpoint is pCR (TRG 1). Secondary endpoints include acute grade 3–4 toxicity, good pathologic response (TRG 1-2), clinical response, surgical complications, QoL and (disease-free) survival. Data is analyzed by intention to treat.DiscussionThe boost is delivered prior to sCRT so that GTV adjustment for tumor shrinkage during sCRT is not necessary. Small margins also aim to limit irradiation of healthy tissue. The cmRCT design provides opportunity to overcome common shortcomings of classic RCTs, such as slow recruitment, disappointment-bias in control arm patients and poor generalizability.Trial registrationThe Netherlands Trials Register NL46051.041.13. Registered 22 August 2013. ClinicalTrials.gov NCT01951521. Registered 18 September 2013.

Quantification of intra-fraction motion in breast radiotherapy using supine magnetic resonance imaging

In early-stage breast-cancer patients, accelerated partial-breast irradiation techniques (APBI) and hypofractionation are increasingly implemented after breast-conserving surgery (BCS). For a safe and effective radiation therapy (RT), the influence of intra-fraction motion during dose delivery becomes more important as associated fraction durations increase and targets become smaller. Current image-guidance techniques are insufficient to characterize local target movement in high temporal and spatial resolution for extended durations. Magnetic resonance imaging (MRI) can provide high soft-tissue contrast, allow fast imaging, and acquire images during longer periods. The goal of this study was to quantify intra-fraction motion using MRI scans from 21 breast-cancer patients, before and after BCS, in supine RT position, on two time scales. High-temporal 2-dimensional (2D) MRI scans (cine-MRI), acquired every 0.3 s during 2 min, and three 3D MRI scans, acquired over 20 min, were performed. The tumor (bed) and whole breast were delineated on 3D scans and delineations were transferred to the cine-MRI series. Consecutive scans were rigidly registered and delineations were transformed accordingly. Motion in sub-second time-scale (derived from cine-MRI) was generally regular and limited to a median of 2 mm. Infrequently, large deviations were observed, induced by deep inspiration, but these were temporary. Movement on multi-minute scale (derived from 3D MRI) varied more, although medians were restricted to 2.2 mm or lower. Large whole-body displacements (up to 14 mm over 19 min) were sparsely observed. The impact of motion on standard RT techniques is likely small. However, in novel hypofractionated APBI techniques, whole-body shifts may affect adequate RT delivery, given the increasing fraction durations and smaller targets. Motion management may thus be required. For this, on-line MRI guidance could be provided by a hybrid MRI/RT modality, such as the University Medical Center Utrecht MRI linear accelerator.

MRI-guided single fraction ablative radiotherapy for early-stage breast cancer: a brachytherapy versus volumetric modulated arc therapy dosimetry study

BACKGROUND AND PURPOSE A radiosurgical treatment approach for early-stage breast cancer has the potential to minimize the patients treatment burden. The dosimetric feasibility for single fraction ablative radiotherapy was evaluated by comparing volumetric modulated arc therapy (VMAT) with an interstitial multicatheter brachytherapy (IMB) approach. METHODS AND MATERIALS The tumors of 20 patients with early-stage breast cancer were delineated on a preoperative contrast-enhanced planning CT-scan, co-registered with a contrast-enhanced magnetic resonance imaging (MRI), both in radiotherapy supine position. A dose of 15 Gy was prescribed to the planned target volume of the clinical target volume (PTVCTV), and 20 Gy integrated boost to the PTV of the gross tumor volume (PTVGTV). Treatment plans for IMB and VMAT were optimized for adequate target volume coverage and minimal organs at risk (OAR) dose. RESULTS The median PTVGTV/CTV receiving at least 95% of the prescribed dose was ⩾99% with both techniques. The median PTVCTV unintentionally receiving 95% of the prescribed PTVGTV dose was 65.4% and 4.3% with IMB and VMAT, respectively. OAR doses were comparable with both techniques. CONCLUSION MRI-guided single fraction radiotherapy with an integrated ablative boost to the GTV is dosimetrically feasible with both techniques. We perceive IMB less suitable for clinical implementation due to PTVCTV overdosage. Future studies have to confirm the clinical feasibility of the single fraction ablative approach.

Quantification of confounding factors in MRI-based dose calculations as applied to prostate IMRT

Magnetic resonance (MR)-only radiotherapy treatment planning requires pseudo-CT (pCT) images to enable MR-based dose calculations. To verify the accuracy of MR-based dose calculations, institutions interested in introducing MR-only planning will have to compare pCT-based and computer tomography (CT)-based dose calculations. However, interpreting such comparison studies may be challenging, since potential differences arise from a range of confounding factors which are not necessarily specific to MR-only planning. Therefore, the aim of this study is to identify and quantify the contribution of factors confounding dosimetric accuracy estimation in comparison studies between CT and pCT. The following factors were distinguished: set-up and positioning differences between imaging sessions, MR-related geometric inaccuracy, pCT generation, use of specific calibration curves to convert pCT into electron density information, and registration errors. The study comprised fourteen prostate cancer patients who underwent CT/MRI-based treatment planning. To enable pCT generation, a commercial solution (MRCAT, Philips Healthcare, Vantaa, Finland) was adopted. IMRT plans were calculated on CT (gold standard) and pCTs. Dose difference maps in a high dose region (CTV) and in the body volume were evaluated, and the contribution to dose errors of possible confounding factors was individually quantified. We found that the largest confounding factor leading to dose difference was the use of different calibration curves to convert pCT and CT into electron density (0.7%). The second largest factor was the pCT generation which resulted in pCT stratified into a fixed number of tissue classes (0.16%). Inter-scan differences due to patient repositioning, MR-related geometric inaccuracy, and registration errors did not significantly contribute to dose differences (0.01%). The proposed approach successfully identified and quantified the factors confounding accurate MRI-based dose calculation in the prostate. This study will be valuable for institutions interested in introducing MR-only dose planning in their clinical practice.

Inter-observer agreement of MRI-based tumor delineation for preoperative radiotherapy boost in locally advanced rectal cancer

BACKGROUND While surgery remains the cornerstone of rectal cancer treatment, organ-preservation is upcoming. Therefore, neo-adjuvant treatment should be optimized. By escalating doses, response can be increased. To limit toxicity of boost, accurate gross tumor volume (GTV) definition is required. MRI, especially undeformed fast spin echo diffusion-weighted MRI (DWI), looks promising for delineation. However, inconsistencies between observers should be quantified before clinical implementation. We aim to find which MRI sequence (T2w, DWI or combination) is optimal and clinically useful for GTV definition by evaluating inter-observer agreement. METHODS Locally advanced rectal cancer patients (tumors <10 cm from anal verge) were scanned on 3T MRI transverse T2w and DWI (b=800 s/mm(2)). Three independent observers delineated T2w, DWI and combination (Combi) after training-set. Volumes, conformity index (CI), and maximum Hausdorff distance (HD) were calculated between any observer-pair per patient per modality. RESULTS Twenty-four consecutive patients were included. One patient had cT2 (4.2%), 19 cT3 (79.1%) and 4 cT4 (16.7%), with 2 clinical node negative (8.3%), 4 cN1 (16.7%), and 18 cN2 (75.0%) on MRI. From 24 patients, 70 sequences were available (24x T2, 23x DWI, and 23x Combi). Between observers, no significant volume differences were observed per modality. T2 showed significantly largest volumes compared to DWI (mean difference 19.85 ml, SD 17.42, p<0.0001) and Combi (mean difference 7.16 ml, SD 11.58, p<0.0001). Mean CI was 0.70, 0.71 and 0.69 for T2, DWI and Combi respectively (p>0.61). Average HD was largest on T2 (18.60mm, max 31.40 mm, min 9.20mm). DISCUSSION Delineation on DWI resulted in delineation of the smallest volumes with similar consistency and mean distances, but with slightly lower Hausdorff distances compared to T2 and Combi. However, with lack of a gold standard it remains difficult to establish if delineations also represent true tumor. Study strengths were DWI adaptation to exclude geometrical distortions and training-set. DWI shows great potential for delineation purposes as long as sufficient experience exists and geometrical distortions are eliminated.

Statistical Modeling of CTV Motion and Deformation for IMRT of Early-Stage Rectal Cancer

PURPOSE To derive and validate a statistical model of motion and deformation for the clinical target volume (CTV) of early-stage rectal cancer patients. METHODS AND MATERIALS For 16 patients, 4 to 5 magnetic resonance images (MRI) were acquired before each fraction was administered. The CTV was delineated on each MRI. Using a leave-one-out methodology, we constructed a population-based principal component analysis (PCA) model of the CTV motion and deformation of 15 patients, and we tested the model on the left-out patient. The modeling error was calculated as the amount of the CTV motion-deformation of the left-out-patient that could not be explained by the PCA model. Next, the PCA model was used to construct a PCA target volume (PCA-TV) by accumulating motion-deformations simulated by the model. A PCA planning target volume (PTV) was generated by expanding the PCA-TV by uniform margins. The PCA-PTV was compared with uniform and nonuniform CTV-to-PTV margins. To allow comparison, geometric margins were determined to ensure adequate coverage, and the volume difference between the PTV and the daily CTV (CTV-to-PTV volume) was calculated. RESULTS The modeling error ranged from 0.9 ± 0.5 to 2.9 ± 2.1 mm, corresponding to a reduction of the CTV motion-deformation between 6% and 60% (average, 23% ± 11%). The reduction correlated with the magnitude of the CTV motion-deformation (P<.001, R=0.66). The PCA-TV and the CTV required 2-mm and 7-mm uniform margins, respectively. The nonuniform CTV-to-PTV margins were 4 mm in the left, right, inferior, superior, and posterior directions and 8 mm in the anterior direction. Compared to uniform and nonuniform CTV-to-PTV margins, the PCA-based PTV significantly decreased (P<.001) the average CTV-to-PTV volume by 128 ± 20 mL (49% ± 4%) and by 35 ± 6 mL (20% ± 3.5%), respectively. CONCLUSIONS The CTV motion-deformation of a new patient can be explained by a population-based PCA model. A PCA model-generated PTV significantly improved sparing of organs at risk compared to uniform and nonuniform CTV-to-PTV margins.