E. Seravalli

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.

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.

Comparing conVEntional RadioTherapy with stereotactIC body radiotherapy in patients with spinAL metastases : study protocol for an randomized controlled trial following the cohort multiple randomized controlled trial design

BackgroundStandard radiotherapy is the treatment of first choice in patients with symptomatic spinal metastases, but is only moderately effective. Stereotactic body radiation therapy is increasingly used to treat spinal metastases, without randomized evidence of superiority over standard radiotherapy. The VERTICAL study aims to quantify the effect of stereotactic radiation therapy in patients with metastatic spinal disease.Methods/designThis study follows the ‘cohort multiple Randomized Controlled Trial’ design. The VERTICAL study is conducted within the PRESENT cohort. In PRESENT, all patients with bone metastases referred for radiation therapy are enrolled. For each patient, clinical and patient-reported outcomes are captured at baseline and at regular intervals during follow-up. In addition, patients give informed consent to be offered experimental interventions. Within PRESENT, 110 patients are identified as a sub cohort of eligible patients (i.e. patients with unirradiated painful, mechanically stable spinal metastases who are able to undergo stereotactic radiation therapy). After a protocol amendment, also patients with non-spinal bony metastases are eligible. From the sub cohort, a random selection of patients is offered stereotactic radiation therapy (n = 55), which patients may accept or refuse. Only patients accepting stereotactic radiation therapy sign informed consent for the VERTICAL trial. Non-selected patients (n = 55) receive standard radiotherapy, and are not aware of them serving as controls. Primary endpoint is pain response after three months. Data will be analyzed by intention to treat, complemented by instrumental variable analysis in case of substantial refusal of the stereotactic radiation therapy in the intervention arm.DiscussionThis study is designed to quantify the treatment response after (stereotactic) radiation therapy in patients with symptomatic spinal metastases. This is the first randomized study in palliative care following the cohort multiple Randomized Controlled Trial design. This design addresses common difficulties associated with classic pragmatic randomized controlled trials, such as disappointment bias in patients allocated to the control arm, slow recruitment, and poor generalizability.Trial registrationThe Netherlands Trials Register number NL49316.041.14. ClinicalTrials.gov registration number NCT02364115. Date of trial registration February 1, 2015.

First Results of a Scintillating GEM Detector for 2-D Dosimetry in an Alpha Beam

The characterization of a scintillating GEM based gas detector for quality control of clinical radio-therapeutic beams is presented. Photons emitted by the Ar/CF4 gas mixture are detected by means of a CCD camera; in addition, the charge is measured. The detector response has been studied as a function of alpha particle energy and dose rate. The measured signal underestimation, at the Bragg peak depth, is only few percent with respect to an air filled ionization chamber.

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.

A scintillating triple GEM beam monitor for radiation therapy

We report on the characterization of a gas detector, based on gas electron multipliers (GEMs), for use in intensity modulated radiation therapy (IMRT). The light emitted during the gas multiplication process in 1 atm Ar-CF4 (96-4) scintillating gas mixture has been studied as a function of applied voltages and treatment conditions such as beam time and photon energy

Dosimetric feasibility of the hybrid Magnetic Resonance Imaging (MRI)-linac System (MRL) for brain metastases: The impact of the magnetic field

BACKGROUND AND PURPOSE We aimed to investigate the suitability of treating patients with single brain metastases using stereotactic radiosurgery (SRS) with the MRL and to characterize the dosimetric impact at tissue-air interfaces resulting primarily from the electron return effect (ERE). MATERIAL AND METHODS 24 patients treated for intact single brain metastases were analyzed. Three radiotherapy plans with the same prescribed dose were generated for each case: (1) noncoplanar volumetric modulated arc therapy (VMAT), (2) coplanar step-and-shoot intensity modulated radiotherapy (IMRT) on the MRL in the absence (MRLB=0), and (3) in the presence of the transverse magnetic field (MRLB=1.5). The plans were evaluated using cumulative dose-volume histograms and by calculation of Paddick conformity index (CI), V100%, V12Gy minus gross tumor volume (V12Gy - GTV), and V2Gy. At tissue-air boundaries, the dosimetric impact of the magnetic field was quantified using a 5 mm rim of tissue. RESULTS All plans met the target coverage and organs-at-risk planning objectives. Differences between all investigated dosimetric parameters significantly favored the VMAT plans as compared to the MRLB=0 and MRLB=1.5 plans, except for V2Gy. The mean V12Gy - GTV and V2Gy marginally favored the MRLB=0 plans compared to the MRLB=1.5 plans (mean difference: 0.45 cm3, p = 0.0019 and 16.46 cm3, p < 0.0001, respectively). The presence of the magnetic field resulted in a statistically significant but small increase in mean dose and D2cc in the skin (0.08 Gy, p < 0.0001 and 0.6 Gy, p < 0.0001, respectively) and around air cavities (0.07 Gy, p = 0.0092 and 0.3 Gy, p = 0.0004, respectively). CONCLUSIONS It is feasible to generate stereotactic radiation plans that satisfy clinical requirements using the MRL in the setting of single brain metastases. The dosimetric impact of the magnetic field including the ERE at tissue-air boundaries is minor and does not negatively impact target conformity or dose gradient.

The TRENDY multi-center randomized trial on hepatocellular carcinoma – Trial QA including automated treatment planning and benchmark-case results

BACKGROUND AND PURPOSE The TRENDY trial is an international multi-center phase-II study, randomizing hepatocellular carcinoma (HCC) patients between transarterial chemoembolization (TACE) and stereotactic body radiation therapy (SBRT) with a target dose of 48-54 Gy in six fractions. The radiotherapy quality assurance (QA) program, including prospective plan feedback based on automated treatment planning, is described and results are reported. MATERIALS AND METHODS Scans of a single patient were used as a benchmark case. Contours submitted by nine participating centers were compared with reference contours. The subsequent planning round was based on a single set of contours. A total of 20 plans from participating centers, including 12 from the benchmark case, 5 from a clinical pilot and 3 from the first study patients, were compared to automatically generated VMAT plans. RESULTS For the submitted liver contours, Dice Similarity Coefficients (DSC) with the reference delineation ranged from 0.925 to 0.954. For the GTV, the DSC varied between 0.721 and 0.876. For the 12 plans on the benchmark case, healthy liver normal-tissue complication probabilities (NTCPs) ranged from 0.2% to 22.2% with little correlation between NCTP and PTV-D95% (R2 < 0.3). Four protocol deviations were detected in the set of 20 treatment plans. Comparison with co-planar autoVMAT QA plans revealed these were due to too high target dose and suboptimal planning. Overall, autoVMAT resulted in an average liver NTCP reduction of 2.2 percent point (range: 16.2 percent point to -1.8 percent point, p = 0.03), and lower doses to the healthy liver (p < 0.01) and gastrointestinal organs at risk (p < 0.001). CONCLUSIONS Delineation variation resulted in feedback to participating centers. Automated treatment planning can play an important role in clinical trials for prospective plan QA as suboptimal plans were detected.

Auditing local methods for quality assurance in radiotherapy using the same set of predefined treatment plans

Background and purpose Local implementation of plan-specific quality assurance (QA) methods for intensity-modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) treatment plans may vary because of dissimilarities in procedures, equipment and software. The purpose of this work is detecting possible differences between local QA findings and those of an audit, using the same set of treatment plans. Methods A pre-defined set of clinical plans was devised and imported in the participating institute’s treatment planning system for dose computation. The dose distribution was measured using an ionisation chamber, radiochromic film and an ionisation chamber array. The centres performed their own QA, which was compared to the audit findings. The agreement/disagreement between the audit and the institute QA results were assessed along with the differences between the dose distributions measured by the audit team and computed by the institute. Results For the majority of the cases the results of the audit were in agreement with the institute QA findings: ionisation chamber: 92%, array: 88%, film: 76% of the total measurements. In only a few of these cases the evaluated measurements failed for both: ionisation chamber: 2%, array: 4%, film: 0% of the total measurements. Conclusion Using predefined treatment plans, we found that in approximately 80% of the evaluated measurements the results of local QA of IMRT and VMAT plans were in line with the findings of the audit. However, the percentage of agreement/disagreement depended on the characteristics of the measurement equipment used and on the analysis metric.

Intra- and inter-fraction uncertainties during IGRT for Wilms’ tumor

Abstract Background and purpose: To assess intra- and inter-fraction motion uncertainties, due to displacements of the tumor bed (TB) and organs at risk (OAR), as well as intra- and inter-fraction patient set-up uncertainties, due to positioning variations, during image-guided radiation therapy (IGRT) in children with Wilms’ tumor. Material and methods: Four-dimensional computed tomography (4D-CT) and daily pre- and post-treatment cone-beam CT (CBCT)-scans of 15 patients (average 4, range 1–8 years) undergoing flank irradiation after nephrectomy were analyzed. TB (marked by four surgical clips) and OAR motion uncertainties were quantified by displacements of the center of mass in all orthogonal directions. Translational and rotational bone off-sets were recorded for patient set-up uncertainties assessment in all orthogonal directions. The average results, systematic and random errors were computed. Results: Average intra- and inter-fraction motion uncertainties were ≤1.1 mm (range: [−6.9;7.9] mm) for the TB and ≤3.2 mm (range: [−9.1;9.6] mm) for the OAR. Average intra- and inter-fraction patient set-up uncertainties were ≤0.1 mm (range: [−3.3;4.8] mm) and ≤0.9° (range: [0.0;2.8°]). Both motion and patient set-up uncertainties were larger for the cranio-caudal direction. Calculated systematic and random errors were ≤2.4 mm for the motion uncertainties and ≤0.8 mm/0.7° for the patient set-up uncertainties. Conclusions: Average motion and patient set-up uncertainties during radiotherapy treatment were found to be limited. However, uncertainties were larger for the cranio-caudal direction and outliers were found in all orthogonal directions. When having available 4D-CT and CBCT information, the use of patient-specific and anisotropic safety margin expansions is advised for both target volume and OAR.