Marco van Vulpen

The Magnetic Resonance Imaging–Linac System

The current image-guided radiotherapy systems are suboptimal in the esophagus, pancreas, kidney, rectum, lymph node, etc. These locations in the body are not easily accessible for fiducials and cannot be visualized sufficiently on cone-beam computed tomographies, making daily patient set-up prone to geometrical uncertainties and hinder dose optimization. Additional interfraction and intrafraction uncertainties for those locations arise from motion with breathing and organ filling. To allow real-time imaging of all patient tumor locations at the actual treatment position a fully integrated 1.5-T, diagnostic quality, magnetic resonance imaging with a 6-MV linear accelerator is presented. This system must enable detailed dose painting at all body locations.

Long-term biochemical and survival outcome of 921 patients treated with I-125 permanent prostate brachytherapy.

PURPOSE To assess long-term biochemical and survival outcome after permanent prostate brachytherapy (BT). METHODS AND MATERIALS Data on 921 patients, treated with permanent interstitial BT monotherapy between 1989 and 2004 for <or=T2c Nx/0 Mx/0 prostate cancer were evaluated. All patients were treated with I-125 seeds (prescription dose 144 Gy). Eighty-five patients with a gland volume >or=50cc received 6 months of antiandrogen therapy before treatment. Patients were classified into risk groups with 232 defined as low-, 369 intermediate-, and 320 high-risk disease. The median follow-up was 69 months (range, 4-186 months); mean age was 67 years. RESULTS Average 5- and 10-year biochemical no evidence of disease (bNED) rates were 79% and 57%. Average 10-year bNED rates by risk group were 88% for low-risk, 61% for intermediate-risk, and 30% for high-risk disease. The average 10-year overall and disease-specific survival rates were 59% and 82%. Ten-year overall and disease-specific survival rates by risk group were, respectively, 68% and 96% for low-risk, and 64% 87% for intermediate-risk, and 49% and 69% for high-risk disease. In multivariate Cox regression analysis, both risk group and treatment era were independent predictors of bNED and survival. CONCLUSIONS These data on long-term survival continue to support the use of I-125 monotherapy for prostate cancer in low-risk patients and, in particular, demonstrate its efficacy in intermediate-risk patients.

Single blind randomized Phase III trial to investigate the benefit of a focal lesion ablative microboost in prostate cancer (FLAME-trial): study protocol for a randomized controlled trial

BackgroundThe treatment results of external beam radiotherapy for intermediate and high risk prostate cancer patients are insufficient with five-year biochemical relapse rates of approximately 35%. Several randomized trials have shown that dose escalation to the entire prostate improves biochemical disease free survival. However, further dose escalation to the whole gland is limited due to an unacceptable high risk of acute and late toxicity. Moreover, local recurrences often originate at the location of the macroscopic tumor, so boosting the radiation dose at the macroscopic tumor within the prostate might increase local control. A reduction of distant metastases and improved survival can be expected by reducing local failure. The aim of this study is to investigate the benefit of an ablative microboost to the macroscopic tumor within the prostate in patients treated with external beam radiotherapy for prostate cancer.Methods/DesignThe FLAME-trial (F ocal L esion A blative M icroboost in prostatE cancer) is a single blind randomized controlled phase III trial. We aim to include 566 patients (283 per treatment arm) with intermediate or high risk adenocarcinoma of the prostate who are scheduled for external beam radiotherapy using fiducial markers for position verification. With this number of patients, the expected increase in five-year freedom from biochemical failure rate of 10% can be detected with a power of 80%. Patients allocated to the standard arm receive a dose of 77 Gy in 35 fractions to the entire prostate and patients in the experimental arm receive 77 Gy to the entire prostate and an additional integrated microboost to the macroscopic tumor of 95 Gy in 35 fractions. The secondary outcome measures include treatment-related toxicity, quality of life and disease-specific survival. Furthermore, by localizing the recurrent tumors within the prostate during follow-up and correlating this with the delivered dose, we can obtain accurate dose-effect information for both the macroscopic tumor and subclinical disease in prostate cancer. The rationale, study design and the first 50 patients included are described.Trial registrationThis study is registered at ClinicalTrials.gov: NCT01168479

Effectiveness of Reirradiation for Painful Bone Metastases: A Systematic Review and Meta-Analysis

PURPOSE Reirradiation of painful bone metastases in nonresponders or patients with recurrent pain after initial response is performed in up to 42% of patients initially treated with radiotherapy. Literature on the effect of reirradiation for pain control in those patients is scarce. In this systematic review and meta-analysis, we quantify the effectiveness of reirradiation for achieving pain control in patients with painful bone metastases. METHODS AND MATERIALS A free text search was performed to identify eligible studies using the MEDLINE, EMBASE, and the Cochrane Collaboration library electronic databases. After study selection and quality assessment, a pooled estimate was calculated for overall pain response for reirradiation of metastatic bone pain. RESULTS Our literature search identified 707 titles, of which 10 articles were selected for systematic review and seven entered the meta-analysis. Overall study quality was mediocre. Of the 2,694 patients initially treated for metastatic bone pain, 527 (20%) patients underwent reirradiation. Overall, a pain response after reirradiation was achieved in 58% of patients (pooled overall response rate 0.58, 95% confidence interval = 0.49-0.67). There was a substantial between-study heterogeneity (I² = 63.3%, p = 0.01) because of clinical and methodological differences between studies. CONCLUSIONS Reirradiation of painful bone metastases is effective in terms of pain relief for a small majority of patients; approximately 40% of patients do not benefit from reirradiation. Although the validity of results is limited, this meta-analysis provides a comprehensive overview and the most quantitative estimate of reirradiation effectiveness to date.

Validation of functional imaging with pathology for tumor delineation in the prostate

INTRODUCTION A study was performed to validate magnetic resonance (MR) based prostate tumor delineations with pathology. MATERIAL AND METHODS Five patients with biopsy proven prostate cancer underwent a T2 weighted (T2w), diffusion weighted MRI (DW-MRI) and dynamic contrast-enhanced MRI (DCE-MRI) scan before prostatectomy. Suspicious regions were delineated based on all available MR information. After prostatectomy whole-mount hematoxylin-eosin stained (H&E) sections were made. Tumor tissue was delineated on the H&E stained sections and compared with the MR based delineations. The registration accuracy between the MR images and H&E stained sections was estimated. RESULTS A tumor coverage of 44-89% was reached by the MR based tumor delineations. The application of a margin of approximately 5mm to the MR based tumor delineations yielded a tumor coverage of 85-100% in all patients. Errors created during the registration procedure were 2-3mm, which cannot completely explain the limited tumor coverage. CONCLUSIONS An accurate tissue processing and registration method was presented (registration error 2-3mm), which enables the validation of MR based tumor delineations with pathology. Reasonable tumor coverage of about 85% and larger was found when applying a margin of approximately 5 mm to the MR based tumor delineations.

MRI-guided robotic system for transperineal prostate interventions: proof of principle

In this study, we demonstrate the proof of principle of the University Medical Center Utrecht (UMCU) robot dedicated to magnetic resonance imaging (MRI)-guided interventions in patients. The UMCU robot consists of polymers and non-ferromagnetic materials. For transperineal prostate interventions, it can be placed between the patients legs inside a closed bore 1.5T MR scanner. The robot can manually be translated and rotated resulting in five degrees of freedom. It contains a pneumatically driven tapping device to automatically insert a needle stepwise into the prostate using a controller unit outside the scanning room. To define the target positions and to verify the needle insertion point and the needle trajectory, a high-resolution 3D balanced steady state free precession (bSSFP) scan that provides a T2/T1-weighted contrast is acquired. During the needle insertion fast 2D bSSFP images are generated to track the needle on-line. When the target position is reached, the radiation oncologist manually places a fiducial gold marker (small seed) at this location. In total two needle trajectories are used to place all markers. Afterwards, a high-resolution 3D bSSFP scan is acquired to visualize the fiducial gold markers. Four fiducial gold markers were placed transperineally into the prostate of a patient with a clinical stage T3 prostate cancer. In the generated scans, it was possible to discriminate the patients anatomy, the needle and the markers. All markers were delivered inside the prostate. The procedure time was 1.5 h. This study proves that MRI-guided needle placement and seed delivery in the prostate with the UMCU robot are feasible.

High-dose intensity-modulated radiotherapy for prostate cancer using daily fiducial marker-based position verification: acute and late toxicity in 331 patients.

We evaluated the acute and late toxicity after high-dose intensity-modulated radiotherapy (IMRT) with fiducial marker-based position verification for prostate cancer. Between 2001 and 2004, 331 patients with prostate cancer received 76 Gy in 35 fractions using IMRT combined with fiducial marker-based position verification. The symptoms before treatment (pre-treatment) and weekly during treatment (acute toxicity) were scored using the Common Toxicity Criteria (CTC). The goal was to score late toxicity according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) scale with a follow-up time of at least three years. Twenty-two percent of the patients experienced pre-treatment grade ≥ 2 genitourinary (GU) complaints and 2% experienced grade 2 gastrointestinal (GI) complaints. Acute grade 2 GU and GI toxicity occurred in 47% and 30%, respectively. Only 3% of the patients developed acute grade 3 GU and no grade ≥ 3 GI toxicity occurred. After a mean follow-up time of 47 months with a minimum of 31 months for all patients, the incidence of late grade 2 GU and GI toxicity was 21% and 9%, respectively. Grade ≥ 3 GU and GI toxicity rates were 4% and 1%, respectively, including one patient with a rectal fistula and one patient with a severe hemorrhagic cystitis (both grade 4). In conclusion, high-dose intensity-modulated radiotherapy with fiducial marker-based position verification is well tolerated. The low grade ≥ 3 toxicity allows further dose escalation if the same dose constraints for the organs at risk will be used.

Pathologic Validation of a Model Based on Diffusion-Weighted Imaging and Dynamic Contrast-Enhanced Magnetic Resonance Imaging for Tumor Delineation in the Prostate Peripheral Zone

PURPOSE For focal boost strategies in the prostate, the robustness of magnetic resonance imaging-based tumor delineations needs to be improved. To this end we developed a statistical model that predicts tumor presence on a voxel level (2.5×2.5×2.5 mm3) inside the peripheral zone. Furthermore, we show how this model can be used to derive a valuable input for radiotherapy treatment planning. METHODS AND MATERIALS The model was created on 87 radiotherapy patients. For the validation of the voxelwise performance of the model, an independent group of 12 prostatectomy patients was used. After model validation, the model was stratified to create three different risk levels for tumor presence: gross tumor volume (GTV), high-risk clinical target volume (CTV), and low-risk CTV. RESULTS The model gave an area under the receiver operating characteristic curve of 0.70 for the prediction of tumor presence in the prostatectomy group. When the registration error between magnetic resonance images and pathologic delineation was taken into account, the area under the curve further improved to 0.89. We propose that model outcome values with a high positive predictive value can be used to define the GTV. Model outcome values with a high negative predictive value can be used to define low-risk CTV regions. The intermediate outcome values can be used to define a high-risk CTV. CONCLUSIONS We developed a logistic regression with a high diagnostic performance for voxelwise prediction of tumor presence. The model output can be used to define different risk levels for tumor presence, which in turn could serve as an input for dose planning. In this way the robustness of tumor delineations for focal boost therapy can be greatly improved.

Simultaneous MRI diffusion and perfusion imaging for tumor delineation in prostate cancer patients

BACKGROUND AND PURPOSE A study was performed to investigate if we can quantify if the two imaging modalities diffusion weighted imaging (DWI) and dynamic contrast-enhanced (DCE)-MRI are consistent in what voxels they determine as being suspicious of tumor tissue. MATERIAL AND METHODS Twenty-one patients with biopsy proven prostate cancer underwent a DWI and a DCE-MRI scan. These scans were compared using a receiver operating curve (ROC) analysis, where either one of the two imaging modalities was thresholded and taken as a reference. The resulting area under the curve (AUC) reflects the consistency between target delineations based on the two imaging techniques. This analysis was performed for the complete prostate and the peripheral zone (PZ). RESULTS Consistency between DWI and DCE-MRI parameter maps varied greatly between patients. Values of the AUC up to 0.90 were found. However, on average AUC values were 0.60. The AUC values were related to the patients PSA and clinical stage. CONCLUSIONS Large variation in consistency between the two imaging modalities was found. This did not depend on the precise thresholds used. For making decisions on dose painting in the prostate, the knowledge about the inconsistency must be taken into account.

Periprostatic fat correlates with tumour aggressiveness in prostate cancer patients

Study Type – Prognostic (case series)
Level of Evidence 4