J.J.E. Kleijnen

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.

Evolution of motion uncertainty in rectal cancer: implications for adaptive radiotherapy.

Reduction of motion uncertainty by applying adaptive radiotherapy strategies depends largely on the temporal behavior of this motion. To fully optimize adaptive strategies, insight into target motion is needed. The purpose of this study was to analyze stability and evolution in time of motion uncertainty of both the gross tumor volume (GTV) and clinical target volume (CTV) for patients with rectal cancer. We scanned 16 patients daily during one week, on a 1.5 T MRI scanner in treatment position, prior to each radiotherapy fraction. Single slice sagittal cine MRIs were made at the beginning, middle, and end of each scan session, for one minute at 2 Hz temporal resolution. GTV and CTV motion were determined by registering a delineated reference frame to time-points later in time. The 95th percentile of observed motion (dist95%) was taken as a measure of motion. The stability of motion in time was evaluated within each cine-MRI separately. The evolution of motion was investigated between the reference frame and the cine-MRIs of a single scan session and between the reference frame and the cine-MRIs of several days later in the course of treatment. This observed motion was then converted into a PTV-margin estimate. Within a one minute cine-MRI scan, motion was found to be stable and small. Independent of the time-point within the scan session, the average dist95% remains below 3.6 mm and 2.3 mm for CTV and GTV, respectively 90% of the time. We found similar motion over time intervals from 18 min to 4 days. When reducing the time interval from 18 min to 1 min, a large reduction in motion uncertainty is observed. A reduction in motion uncertainty, and thus the PTV-margin estimate, of 71% and 75% for CTV and tumor was observed, respectively. Time intervals of 15 and 30 s yield no further reduction in motion uncertainty compared to a 1 min time interval.

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.

WE-G-BRD-08: Motion Analysis for Rectal Cancer: Implications for Adaptive Radiotherapy On the MR-Linac

Purpose: Purpose of this study is to find the optimal trade-off between adaptation interval and margin reduction and to define the implications of motion for rectal cancer boost radiotherapy on a MR-linac. Methods: Daily MRI scans were acquired of 16 patients, diagnosed with rectal cancer, prior to each radiotherapy fraction in one week (N=76). Each scan session consisted of T2-weighted and three 2D sagittal cine-MRI, at begin (t=0 min), middle (t=9:30 min) and end (t=18:00 min) of scan session, for 1 minute at 2 Hz temporal resolution. Tumor and clinical target volume (CTV) were delineated on each T2-weighted scan and transferred to each cine-MRI. The start frame of the begin scan was used as reference and registered to frames at time-points 15, 30 and 60 seconds, 9:30 and 18:00 minutes and 1, 2, 3 and 4 days later. Per time-point, motion of delineated voxels was evaluated using the deformation vector fields of the registrations and the 95th percentile distance (dist95%) was calculated as measure of motion. Per time-point, the distance that includes 90% of all cases was taken as estimate of required planning target volume (PTV)-margin. Results: Highest motion reduction is observed going from 9:30 minutes to 60 seconds. We observe a reduction in margin estimates from 10.6 to 2.7 mm and 16.1 to 4.6 mm for tumor and CTV, respectively, when adapting every 60 seconds compared to not adapting treatment. A 75% and 71% reduction, respectively. Further reduction in adaptation time-interval yields only marginal motion reduction. For adaptation intervals longer than 18:00 minutes only small motion reductions are observed. Conclusion: The optimal adaptation interval for adaptive rectal cancer (boost) treatments on a MR-linac is 60 seconds. This results in substantial smaller PTV-margin estimates. Adaptation intervals of 18:00 minutes and higher, show little improvement in motion reduction.

Tumor volume regression during preoperative chemoradiotherapy for rectal cancer: a prospective observational study with weekly MRI

Abstract Purpose: Few data is available on rectal tumor shrinkage during preoperative chemoradiotherapy (CRT). This regression pattern is interesting to optimize timing of dose escalation on the tumor. Methods: Gross tumor volumes (GTV) were contoured by two observers on magnetic resonance imaging (MRI) obtained before, weekly during, 2–4 weeks after, and 7–8 weeks after a 5-week course of concomitant CRT for rectal cancer. Results: Overall, 120 MRIs were acquired in 15 patients. A statistically significant tumor volume reduction is seen from the first week, and between any two time points (p < .007). At the end of CRT, 46.3% of the initial tumor volume remained, and 32.4% at time of surgery. PTV measured 61.2% at the end of treatment. Tumor shrinkage is the fastest in the beginning of treatment (26%/week), slows down to 7%/week in the last 2 weeks of CRT, and finally to 1.3%/week in the last 5 weeks before surgery. Conclusions: The main rectal tumor regression occurs during CRT course itself, and mostly in the first half, with shrinking speed decreasing over the course. This suggests that a sequential boost is preferably done after the elective fields, yielding an average PTV-reduction of 39%. A simultaneous integrated boost strategy could benefit from adaptive planning during the course.

SU-F-J-145: MRI-Guided Interventional Boost Radiotherapy for Rectal Cancer: Investigating the Feasibility of Adapting the Anatomy

PURPOSE The recent development of an MRI-linac allows adaptation of treatments to the anatomy of the moment. This anatomy, in turn, could be altered into a more favorable situation for radiotherapy purposes. The purpose of this study is to investigate the potential dosimetric benefits of manipulating rectal anatomy in MRI-guided interventional external-beam radiotherapy for rectal cancer. METHODS For this retrospective analysis, four patients (1M/3F) diagnosed with rectal cancer were included. These underwent MR-imaging using sonography transmission gel as endorectal contrast at time of diagnosis and standard, non-contrast, MR-imaging prior to radiotherapy planning. In the contrast scan, the rectum is inflated by the inserted contrast gel, thereby potentially increasing the distance between tumor and the organs-at-risk (OAR). Both anatomies were delineated and 7- beam IMRT-plans were calculated for both situations (RT-standard and RT-inflated), using in-house developed treatment planning software. Each plan was aimed to deliver 15Gy to the planning target volume (PTV; tumor+3mm margin) with a D99>95% and Dmax<120% of the planned dose. The D2cc dose to the OAR were then compared for both situations. RESULTS At equal (or better) target coverage, we found a mean reduction in D2cc of 4.1Gy/237% [range 2.6Gy-6.3Gy/70%-621%] for the bladder and of 2.0Gy/145% [range -0.7Gy-7.9Gy/-73%-442%] for the small-bowel, for the RT-inflated compared to the RT-standard plans. For the three female patients, a reduction in D2cc of 5.2Gy/191% [range 3.2Gy-9.2Gy/44%-475%] for the gynecological organs was found. We found all D2cc doses to be better for the RT-inflated plans, except for one patient for whom the bladder D2cc dose was slightly increased. CONCLUSION Reduction of OAR dose by manipulation of anatomy is feasible. Inflation of the rectum results in more distance between OAR and PTV. This leads to a substantial reduction in dose to OAR at equal or better target coverage.

Poster: Clinical track: Early phase trialsPO-0813: Feasibility of using the 'cohort multiple Randomized Controlled Trial' design to conduct the RECTAL BOOST* study

any treatment was 23 weeks vs. 9 weeks in pts with BSC, p<0.0001. In pts who received local treatment (8: surgery + 3: RT) median PPS was 51 vs. 21 weeks for CHT, p = 0.36. Median PPS for surgery was 51 weeks vs. 17 weeks for RT, p = 0.62. Pts with poor KPS (<60) at relapse did not benefit from local treatment as compared with CHT: median PPS for local treatment vs. CHT was 14 vs. 18 weeks, p = 0.81. Median PPS for poor KPS pts with BSC was 7 weeks. For the whole group of 84 pts, median OS from randomization was 35 weeks: 55 vs. 30 weeks in pts who received any treatment vs. BSC only, p < 0.0001.

TH‐A‐BRF‐04: Intra‐Fraction Motion Characterization for Early Stage Rectal Cancer Using Cine‐MRI

PURPOSE To investigate the intra-fraction motion in patients with early stage rectal cancer using cine-MRI. METHODS Sixteen patient diagnosed with early stage rectal cancer underwent 1.5 T MR imaging prior to each treatment fraction of their short course radiotherapy (n=76). During each scan session, three 2D sagittal cine-MRIs were performed: at the beginning (Start), after 9:30 minutes (Mid), and after 18 minutes (End). Each cine-MRI has a duration of one minute at 2Hz temporal resolution, resulting in a total of 3:48 hours of cine-MRI. Additionally, standard T2-weighted (T2w) imaging was performed. Clinical target volume (CTV) an tumor (GTV) were delineated on the T2w scan and transferred to the first time-point of each cine-MRI scan. Within each cine-MRI, the first frame was registered to the remaining frames of the scan, using a non-rigid B-spline registration. To investigate potential drifts, a similar registration was performed between the first frame of the Start and End scans. To evaluate the motion, the distances by which the edge pixels of the delineations move in anterior-posterior (AP) and cranial-caudal (CC) direction, were determined using the deformation field of the registrations. The distance which incorporated 95% of these edge pixels (dist95%) was determined within each cine-MRI, and between Start- End scans, respectively. RESULTS Within a cine-MRI, we observed an average dist95% for the CTV of 1.3mm/1.5mm (SD=0.7mm/0.6mm) and for the GTV of 1.2mm/1.5mm (SD=0.8mm/0.9mm), in respectively AP/CC. For the CTV motion between the Start and End scan, an average dist95% of 5.5mm/5.3mm (SD=3.1mm/2.5mm) was found, in respectively AP/CC. For the GTV motion, an average dist95% of 3.6mm/3.9mm (SD=2.2mm/2.5mm) was found in AP/CC, respectively. CONCLUSION Although intra-fraction motion within a one minute cine-MRI is limited, substantial intra-fraction motion was observed within the 18 minute time period between the Start and End cine-MRI.

SU-C-17A-05: Quantification of Intra-Fraction Motion of Breast Tumors Using Cine-MRI

PURPOSE Magnetic resonance imaging (MRI) enables direct characterization of intra-fraction motion ofbreast tumors, due to high softtissue contrast and geometric accuracy. The purpose is to analyzethis motion in early-stage breast-cancer patients using pre-operative supine cine-MRI. METHODS MRI was performed in 12 female early-stage breast-cancer patients on a 1.5-T Ingenia (Philips)wide-bore scanner in supine radiotherapy (RT) position, prior to breast-conserving surgery. Twotwodimensional (2D) T2-weighted balanced fast-field echo (cine-MRI) sequences were added tothe RT protocol, oriented through the tumor. They were alternately acquired in the transverse andsagittal planes, every 0.3 s during 1 min. A radiation oncologist delineated gross target volumes(GTVs) on 3D contrast-enhanced MRI. Clinical target volumes (CTV = GTV + 15 mm isotropic)were generated and transferred onto the fifth time-slice of the time-series, to which subsequents lices were registered using a non-rigid Bspline algorithm; delineations were transformed accordingly. To evaluate intra-fraction CTV motion, deformation fields between the transformed delineations were derived to acquire the distance ensuring 95% surface coverage during scanning(P95%), for all in-plane directions: anteriorposterior (AP), left-right (LR), and caudal-cranial(CC). Information on LR was derived from transverse scans, CC from sagittal scans, AP fromboth sets. RESULTS Time-series with registration errors - induced by motion artifacts - were excluded by visual inspection. For our analysis, 11 transverse, and 8 sagittal time-series were taken into account. Themedian P95% calculated in AP (19 series), CC (8), and LR (11) was 1.8 mm (range: 0.9-4.8), 1.7mm (0.8-3.6), and 1.0 mm (0.6-3.5), respectively. CONCLUSION Intra-fraction motion analysis of breast tumors was achieved using cine-MRI. These first results show that in supine RT position, motion amplitudes are limited. This information can be used for adaptive RT planning, and to develop preoperative partial-breast RT strategies, such asablative RT for early-stage breast-cancer patients.