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Purpose: Dose-escalated chemoradiation (CRT) for locally advanced rectal cancer did not result in higher complete response rates but initiated more tumor regression in the randomized RECTAL-BOOST trial (Clinicaltrials.gov NCT01951521). This study compared patient reported outcomes between patients who received dose-escalated CRT (5 × 3 gray boost + CRT) or standard CRT for 2 years after randomization.Methods and Materials: Patients with locally advanced rectal cancer who were participating in the RECTAL-BOOST trial filled out European Organisation for Research and Treatment of Cancer QLQ-C30 and CR29 questionnaires on quality of life (QoL) and symptoms at baseline, 3, 6, 12, 18, and 24 months after start of treatment. Between-group differences in functional QoL domains were estimated using a linear mixed-effects model and expressed as effect size (ES). Symptom scores were compared using Mann-Whitney U test.Results: Patients treated with dose–escalated CRT (boost group, n = 51) experienced a significantly stronger decline in global health at 3 and 6 months (ES –0.4 and ES –0.4), physical functioning at 6 months (ES –1.1), role functioning at 3 and 6 months (ES –0.8 and ES –0.6), and social functioning at 6 months (ES –0.6), compared with patients treated with standard CRT (control group, n = 64). The boost group reported significantly more fatigue at 3 and 6 months (83% vs 66% respectively 89% vs 76%), pain at 3 and 6 months (67% vs 36% respectively 80% vs 44%), and diarrhea at 3 months (45% vs 29%) compared with the control group. From 12 months onwards, QoL and symptoms were similar between groups, apart from more blood/mucus in stool in the boost group.Conclusions: In patients with locally advanced rectal cancer, dose-escalated CRT resulted in a transient deterioration in global health, physical, role, and social functioning and more pain, fatigue and diarrhea at 3 and 6 months after start of treatment compared with standard CRT. From 12 months onwards, the effect of dose-escalated CRT on QoL largely resolved.

Purpose: Worldwide, colorectal carcinoma (CRC) has a high incidence and a substantial cancer-related mortality. The recurrence risk is 30–50% and lung metastases are common. Treatment of lung metastases with stereotactic ablative radiotherapy (SABR) or metastasectomy may increase survival. The best modality for thoracic screening in the follow-up, however, remains controversial. In this study, we aimed to unravel the additional value of routine chest X-ray (CXR) for detecting lung metastases during the follow-up of CRC patients treated with curative surgery. Methods: Between 2013 and 2017, 668 CRC patients were treated with curative intent, of whom 633 patients were included in follow-up, which consisted of CXR, serum Carcino-Embryonic Antigen (CEA) and ultrasound of the liver. Patients who developed lung metastases, diagnosed with CXR and characterised by a normal concomitant serum CEA level, were identified. Number, size and treatment of lung metastases were described. Results: Thirty-four (5.4%) patients developed lung metastases. Seventeen (50%) were detected by CXR without pathological CEA levels. Eleven (65%) of these patients were treated with curative intent, whereas 21% of patients with lung metastases and elevated CEA levels were treated with curative intent (p = 0.049). Higher numbers of lung metastases were associated with a lower chance of curative treatment. Conclusions: More than 50% of patients with lung metastases on CXR in the follow-up would not have been detected with CEA-triggered imaging only. In addition, patients with colorectal lung metastases without elevated CEA levels were often suitable for curative treatment and, therefore, CXR seems to have additional value within the follow-up of CRC.

Background: In patients diagnosed with rectal cancer, dose escalation is currently being investigated in a large number of studies. Since there is little known on gross tumor volume (GTV) inter-fraction motion for rectal cancer, a wide variety in margins is used. Purpose of this study is to quantify GTV inter-fraction motion statistics on different timescales and to give estimates of planning target volume (PTV) margins. Material and methods: Thirty-two patients, diagnosed with rectal cancer, were included. To investigate motion from week-to-week, 16 patients underwent a pretreatment and five weekly MRIs, prior to a radiotherapy (RT) fraction of the chemoradiotherapy treatment. To investigate motion from day-to-day, the remaining 16 patients underwent five daily MRIs before each fraction in one week of RT. GTV was delineated on all scans according to guidelines. Scans were aligned on bony anatomy with the first MRI. For both datasets separately, GTV inter-fraction motion was determined based on center-of-gravity displacement. Therefrom, systematic and random errors were determined in left/right (LR), anterior/posterior and cranial/caudal (CC) direction. PTV margin estimates were calculated and evaluated on GTV coverage. Results: Systematic and random errors were found in the range of 2.3–4.8 mm and 1.5–3.3 mm from week-to-week, and 1.8–4.5 mm and 1.8–4.0 mm from day-to-day, respectively. On both timescales, similar motion patterns were found; the most motion was observed in CC whilst the least motion was observed in LR. On the week-to-week data more systematic and less random motion was observed compared to the day-to-day data. Overall, only slight differences in margin estimates were found. Derived PTV margin estimates were found to give adequate GTV coverage. Conclusion: GTV inter-fraction motion, on a week-to-week and day-to-day timescale, can be accounted for using motion statistics presented in this study.

Contains fulltext : 232797.pdf (Publisher’s version ) (Open Access) PURPOSE: Although various studies have reported that stereotactic body radiation therapy (SBRT) for liver metastases has high local control rates and relatively low toxicity, most series included a small number of patients. We aimed to validate these outcomes in a large multi-institution patient cohort treated in accordance with a common protocol. METHODS AND MATERIALS: A shared web-based registry of patients with liver metastases treated with SBRT was developed by 13 centers (12 in the Netherlands and 1 in Belgium). All the centers had previously agreed on the items to be collected, the fractionation schemes, and the organs-at-risk constraints to be applied. Follow-up was performed at the discretion of the centers. Patient, tumor, and treatment characteristics were entered in the registry. Only liver metastases treated individually as independent targets and with at least 1 radiologic follow-up examination were considered for local control analysis. Toxicity of grade 3 or greater was scored according to the Common Terminology Criteria of Adverse Events (v4.03). RESULTS: Between January 1, 2013, and July 31, 2019, a total of 515 patients were entered in the web-based registry. The median age was 71 years. In total, 668 liver metastases were registered, and 447 were included for local control analysis. The most common primary tumor origin was colorectal cancer (80.3%), followed by lung cancer (8.9%) and breast cancer (4%). The most-used fractionation scheme was 3x18-20 Gy (36.0%), followed by 8x7.5 Gy (31.8%), 5x11-12 Gy (25.5%), and 12x5 Gy (6.7%). The median follow-up time was 1.1 years for local control and 2.3 years for survival. Actuarial 1-year local control was 87%; 1-year overall survival was 84%. Toxicity of grade 3 or greater was found in 3.9% of the patients. CONCLUSIONS: This multi-institutional study confirms the high rates of local control and limited toxicity in a large patient cohort. Stereotactic body radiation therapy should be considered a valuable part of the multidisciplinary approach to treating liver metastases.

Purpose: Pathologic complete tumor response after chemoradiation in patients with locally advanced rectal cancer (LARC) is associated with a favorable prognosis and allows organ-sparing treatment strategies. In the RECTAL-BOOST trial, we aimed to investigate the effect of an external radiation boost to the tumor before chemoradiation on pathologic or sustained clinical complete tumor response in LARC.Methods and Materials: This multicenter, nonblinded, phase 2 randomized controlled trial followed the trials-within-cohorts design, which is a pragmatic trial design allowing cohort participants to be randomized for an experimental intervention. Patients in the intervention group are offered the intervention (and can either accept or refuse this), whereas patients in the control group are not notified about the randomization. Participants of a colorectal cancer cohort referred for chemoradiation of LARC to either of 2 radiation therapy centers were eligible. Patients were randomized to no boost or an external radiation boost (5 x 3 Gy) without concurrent chemotherapy, directly followed by standard pelvic chemoradiation (25 x 2 Gy with concurrent capecitabine). The primary outcome was pathologic complete response (ie, ypT0N0) in patients with planned surgery at 12 weeks, or, as surrogate for pathologic complete response, a 2-year sustained clinical complete response for patients treated with an organ preservation strategy. Analyses were intention to treat. The study was registered with ClinicalTrials.gov, number NCT01951521.Results: Between September 2014 and July 2018, 128 patients were randomized. Fifty-one of the 64 (79.7%) patients in the intervention group accepted and received a boost. Compared with the control group, fewer patients in the intervention group had a cT4 stage and a low rectal tumor (31.3% vs 17.2% and 56.3% vs 45.3%, respectively), and more patients had a cN2 stage (59.4% vs 70.3%, respectively). Rate of pathologic or sustained clinical complete tumor response was similar between the groups: 23 of 64 (35.9%; 95% confidence interval [CI], 24.3-48.9) in the intervention group versus 24 of 64 (37.5%; 95% CI, 25.7-50.5) in the control group (odds ratio [OR] = 0.94; 95% CI, 0.46-1.92). Near-complete or complete tumor regression was more common in the intervention group (34 of 49; 69.4%) than in the control group (24 of 53; 45.3%; (OR = 2.74, 95% CI 1.21-6.18). Grade >= 3 acute toxicity was comparable: 6 of 64 (9.4%) in the intervention group versus 5 of 64 (7.8%) in the control group (OR Z 1.22; 95% CI, 0.35-4.22).Conclusions: Dose escalation with an external radiation therapy boost to the tumor before neoadjuvant chemoradiation did not increase the pathologic or sustained clinical complete tumor response rate in LARC. (C) 2020 The Authors. Published by Elsevier Inc.

We studied the influence of a custom abdominal corset on cine MRI based pancreatic tumor motion. All patients were imaged twice; once without the corset, and once with the corset in place. Craniocaudal motion decreased on average by 4.1 mm, from 11.3 to 7.2 mm. No effects of the corset were observed in anteroposterior and lateral directions. The efficacy of the abdominal corset in combination with its simplicity, the low manufacturing costs and the good tolerance makes this an easy way to decrease motion. This might open the way to safer dose escalation when treating patients under free breathing conditions. Keywords: Pancreatic cancer, Motion management, MRI

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% (R-2 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. (c) 2017 Elsevier B.V. All rights reserved.

Purpose: To explore and evaluate the potential value of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) for the prediction of pathologic response to neoadjuvant chemoradiotherapy (nCRT) in oesophageal cancer.Material and methods: Twenty-six patients underwent DCE-MRI before, during (week 2-3) and after nCRT, but before surgery (pre/per/post, respectively). Histopathologic tumour regression grade (TRG) was assessed after oesophagectomy. Tumour area-under-the-concentration time curve (AUC), time-to peak (TTP) and slope were calculated. The ability of these DCE-parameters to distinguish good responders (GR, TRG 1-2) from poor responders (noGR, TRG >= 3), and pathologic complete responders (pCR) from no-pCR was assessed.Results: Twelve patients (48%) showed GR of which 8 patients (32%) pCR. Analysis of AUC change throughout treatment, AUC(per-pre), was most predictive for GR, at a threshold of 22.7% resulting in a sensitivity of 92%, specificity of 77%, PPV of 79%, and a NPV of .91%. AUC(post-pre) was most predictive for pCR, at a threshold of -24.6% resulting in a sensitivity of 83%, specificity of 88%, PPV of 71%, and a NPV of 93%. TTP and slope were not associated with pathologic response.Conclusions: This study demonstrates that changes in AUC throughout treatment are promising for prediction of histopathologic response to nCRT for oesophageal cancer. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

BACKGROUND: Patient selection for organ sparing treatment after good response to neo-adjuvant chemoradiation (CRT) for locally advanced rectal cancer is challenging as no optimal restaging modality is available after CRT. In this study, we assessed the value of dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) for rectal cancer pathological response prediction. METHODS: In 51 patients with locally advanced rectal cancer, the tumor volume and volume transfer constant (Ktrans) were obtained at 3 Tesla before CRT and surgery. The predictive potential for pathological complete response (pCR) and good response (GR) was assessed. GR was defined as pCR and near-pCR based on the tumor regression grade. RESULTS: The GR group consisted of 10 patients (19.6%) with six pCR (11.8%). Both the post-CRT tumor volume and post-CRT Ktrans values and the relative change in volume (ΔVolume) and Ktrans (ΔKtrans) were predictive for pathological response. ΔKtrans showed the best predictive potential with a positive predictive value (PPV) of 100% for GR using a cutoff value of 32% reduction in Ktrans. For pCR the best PPV was 80% with a multiparameter model containing ΔVolume and ΔKtrans. CONCLUSION: DCE-MRI has predictive potential for pathological response after CRT in rectal cancer with the relative ΔKtrans being the most predictive parameter.

OBJECTIVE: We want to explore the safety and technical feasibility of MRI-guided stereotactic radiotherapy for locally advanced pancreatic cancer. METHODS: A custom-made abdominal corset was manufactured to reduce breathing induced tumour motion. Delineation of the tumour and organs at risk (OARs) was performed on CT and multiparametric MRI. Tumour motion was quantified with cine MRI. After treatment planning, the static dose distribution was convolved with the cine MRI-based motion trajectory to simulate the delivered dose to the tumour and OARs. Stereotactic body radiation therapy (SBRT) was carried out up to a dose of 24 G in three fractions in 1 week. RESULTS: From July 2013 to January 2016, 20 patients were included. Tumours and OARs were clearly visible with contrast-enhanced CT and MRI. After simulation of the delivered dose taking the motion into account, an adequate target coverage was achieved with acceptable dose in the OARs. No Grade3 or higher treatment related toxicity was observed. CONCLUSION: MRI-guided SBRT for pancreatic cancer is technical feasible and safe, with no treatment related grade ≥3 toxicity. New strategies are applied, including an individual corset to reduce breathing motion, MRI-based delineation and simulation of motion-integrated dose distributions. ADVANCES IN KNOWLEDGE: This article is the first to describe an MRI-integrated workflow in SBRT for locally advanced pancreatic cancer. In addition, it demonstrated that SBRT with an abdominal corset to reduce tumour motion is feasible and safe. TRIAL REGISTRATION: This trial was registered at www.clinicaltrials.gov (NCT01898741) on July 9, 2013.

Purpose Serial diffusion-weighted MRI (DW-MRI) measurements of the apparent diffusion coefficient (ADC) of rectal tumors are used for rectal cancer response evaluation after neo-adjuvant treatment. In this study, we determined the repeatability of DW-MRI to distinguish therapy-related response from measurement variations. Materials and Methods In 18 patients with rectal cancer on five consecutive days, 1.5 Tesla (T) MR imaging was performed including two identical DW-MRI sequences. The repeatability of the tumor ADC measurements and the intraobserver ADC variation were depicted in a Bland-Altman plot. The repeatability coefficient was calculated as the range of ADC values of two identical DWI measurements for 95% of subjects. It was expressed as percentage of the mean ADC value. Results Three females and 15 males were included. The mean tumor ADC value was 1.15 × 10−3 mm2/s (SD 0.07 × 10−3 mm2). The repeatability coefficient of the ADC value was 9.8% and for the intraobserver repeatability 4.7%. Conclusion In serial DW-MRI for rectal cancer treatment response evaluation, a repeatability coefficient of 9.8% has to be considered to account for measurement variations in rectal tumor ADC. These variations represent observer judgement and patient and MR spectrometer induced variations. J. Magn. Reson. Imaging 2014;40:146–150. © 2013 Wiley Periodicals, Inc.

The aim of this study was to assess the predictive potential of diffusion-weighted magnetic resonance imaging (MRI) for the selection of favorable pathological responders after radiochemotherapy for locally advanced rectal cancer.In 59 patients with locally advanced rectal cancer, the apparent diffusion coefficient (ADC) in the tumor was obtained at 3 Tesla before radiochemotherapy and surgery. The predictive potential for pathological complete response (pCR) and good response (GR) was assessed. GR was defined as pCR and near-pCR based on the tumor regression grade.The GR group consisted of 13 patients (22%) with 9 complete responders. Both the preradiochemotherapy ADC values and relative change in ADC (ΔADC) were predictive for pathological response. Preradiochemotherapy ADC values showed a positive predictive value of 42% for pCR and 67% for GR using a similar cut-off value of 0.97(*)10(-3) mm(2)/s. For ΔADC, the optimal threshold for predicting GR or pCR was a 41% increase of the ADC. With this threshold, positive predictive values of 64% and 91% were found for pCR and GR, respectively.Low preradiochemotherapy ADC values and high ΔADC correspond to pathological good response. Diffusion-weighted MRI may be used as an additional tool for selecting good treatment responders after radiochemotherapy.

This study investigates the predictive value of diffusion-weighted magnetic resonance imaging (DW-MRI) for good pathological response at different time points during and after preoperative chemoradiotherapy (CRT) in locally advanced rectal cancer.Preoperative CRT followed by total mesorectal excision (TME) is the standard of care for locally advanced rectal cancer. The use of standard radical surgery in good treatment responders after CRT is being questioned.Patients with locally advanced rectal adenocarcinoma were treated with preoperative CRT followed by surgery. DW-MRI scans were performed before CRT, during the third week of CRT, 4 weeks post-CRT and presurgery. Tumor apparent diffusion coefficient (ADC) values were acquired from the DW-MRI scans. After surgery the pathological tumor regression grade was assessed according to the classification by Mandard et al [Cancer. 1994;73:2680-2686]. Patients with pathological complete or near-complete response (tumor regression grade 1-2) were classified as good responders (GRs).Twenty-two patients participated of which 9 were GRs (41%). Pre-CRT ADC values were lower in good versus moderate/poor responders (P = 0.04). ADC values during CRT and four weeks post-CRT were higher in GR. ADC values presurgery did not differ between response groups. For all time points the relative ADC increase (ΔADC) compared to the ADC pre-CRT was higher in GR (P0.001). The ΔADC during CRT and four weeks post-CRT were the best predictive parameters for pathological good response.This study shows that DW-MRI is feasible to select good treatment responders during preoperative CRT for locally advanced rectal cancer.

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.

Background. To assess the value of combined T2-weighted magnetic resonance imaging (MRI) (T2w) volumetry, diffusion-weighted (DW)-MRI and dynamic contrast enhanced (DCE)-MRI for pathological response prediction after neo-adjuvant chemoradiation (CRT) in locally advanced rectal cancer (LARC).Material and methods. MRI with DW-MRI and DCE-MRI sequences was performed before start of CRT and before surgery. After surgery, the tumor regression grade (TRG) was obtained based on the score by Mandard et al. Pathological complete responders (pCR, TRG 1), and pathological good responders (GR, TRG 1 + 2) were compared to non-pCR and non-GR patients, respectively.Results. In total 55 patients were analyzed, six had a pCR (10.9%) and 10 a GR (18.2%). Favorable responders had a larger decrease in tumor volume and Ktrans and a larger increase in apparent diffusion coefficient (ADC) values compared to non-responders. ADC change showed the best diagnostic accuracy for pCR. For GR, the model including ADC change and volume change showed the best diagnostic performance. However, this performance was not statistically better compared to the model with ADC change alone. Inclusion of Ktrans change did not increase the diagnostic accuracy for pathological favorable response.Conclusions. This explorative study showed that ADC change is a promising diagnostic tool for pCR and GR. Volume decrease showed potential limited additional diagnostic value for GR while Ktrans change showed no additional diagnostic value for pCR and GR.

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

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.Locally advanced rectal cancer patients (tumors10 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.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, p0.0001) and Combi (mean difference 7.16 ml, SD 11.58, p0.0001). Mean CI was 0.70, 0.71 and 0.69 for T2, DWI and Combi respectively (p0.61). Average HD was largest on T2 (18.60mm, max 31.40 mm, min 9.20mm).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.

Contains fulltext : 155026.pdf (Publisher’s version ) (Closed access) PURPOSE: To explore the value of diffusion-weighted magnetic resonance imaging (DW-MRI) for the prediction of pathologic response to neoadjuvant chemoradiotherapy (nCRT) in esophageal cancer. MATERIAL AND METHODS: In 20 patients receiving nCRT for esophageal cancer DW-MRI scanning was performed before nCRT, after 8-13 fractions, and before surgery. The median tumor apparent diffusion coefficient (ADC) was determined at these three time points. The predictive potential of initial tumor ADC, and change in ADC (DeltaADC) during and after treatment for pathologic complete response (pathCR) and good response were assessed. Good response was defined as pathCR or near-pathCR (tumor regression grade [TRG] 1 or 2). RESULTS: A pathCR after nCRT was found in 4 of 20 patients (20%), and 8 patients (40%) showed a good response to nCRT. The DeltaADCduring was significantly higher in pathCR vs. non-pathCR patients (34.6%+/-10.7% [mean+/-SD] vs. 14.0%+/-13.1%, p=0.016), as well as in good vs. poor responders (30.5%+/-8.3% vs. 9.5%+/-12.5%, p=0.002). The DeltaADCduring was predictive of residual cancer at a threshold of 29% (sensitivity of 100%, specificity of 75%, PPV of 94%, and NPV of 100%), and for poor pathologic response at a threshold of 21% (sensitivity of 82%, specificity of 100%, PPV of 100%, and NPV of 80%). CONCLUSIONS: In this exploratory study, the treatment-induced change in ADC during the first 2-3weeks of nCRT for esophageal cancer seemed highly predictive of histopathologic response. Larger series are warranted to verify these results. 01 mei 2015

Integrated 2-[F-18]-fluoro-2-deoxy-D-glucose (FOG) PET/CT and magnetic resonance imaging (MRI) with functional features of diffusion-weighted imaging (DWI) are advancing imaging technologies that have current and future potential to overcome important limitations of conventional staging methods in the management of patients with oesophageal cancer. PET/CT has emerged as an important part of the standard work-up of patients with oesophageal cancer. Besides its important ability to detect unsuspected metastatic disease, PET/CT may be useful in the assessment of treatment response, radiation treatment planning, and detection of recurrent disease. In addition, high-resolution T2-weighted MRI and DWI have potential complementary roles. Recent improvements in MRI protocols and techniques have resulted in better imaging quality with the potential to bring improvement in staging, radiation treatment planning, and the assessment of treatment response. Optimal use and understanding of PET/CT and MRI in oesophageal cancer will contribute to the impact of these advancing technologies in tailoring treatment to the individual patient and achieving best possible outcomes. In this article, we graphically outline the current and potential future roles of PET/CT and MRI in the multidisciplinary management of oesophageal cancer. (C) 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

To derive and validate a statistical model of motion and deformation for the clinical target volume (CTV) of early-stage rectal cancer patients.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.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.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.

Contains fulltext : 136634.pdf (Publisher’s version ) (Closed access) PURPOSE: To quantify the movement of esophageal tumors noninvasively on cine-magnetic resonance imaging (MRI) by use of a semiautomatic method to visualize tumor movement directly throughout multiple breathing cycles. METHODS AND MATERIALS: Thirty-six patients with esophageal tumors underwent MRI. Tumors were located in the upper (8), middle (7), and lower (21) esophagus. Cine-MR images were collected in the coronal and sagittal plane during 60 seconds at a rate of 2 Hz. An adaptive correlation filter was used to automatically track a previously marked reference point. Tumor movement was measured in the craniocaudal (CC), left-right (LR), and anteroposterior (AP) directions and its relationship along the longitudinal axis of the esophagus was investigated. RESULTS: Tumor registration within the individual images was typically done at a millisecond time scale. The mean (SD) peak-to-peak displacements in the CC, AP, and LR directions were 13.3 (5.2) mm, 4.9 (2.5) mm, and 2.7 (1.2) mm, respectively. The bandwidth to cover 95% of excursions from the mean position (c95) was also calculated to exclude outliers caused by sporadic movements. The mean (SD) c95 values were 10.1 (3.8) mm, 3.7 (1.9) mm, and 2.0 (0.9) mm in the CC, AP, and LR dimensions. The end-exhale phase provided a stable position in the respiratory cycle, compared with more variety in the end-inhale phase. Furthermore, lower tumors showed more movement than did higher tumors in the CC and AP directions. CONCLUSIONS: Intrafraction tumor movement was highly variable between patients. Tumor position proved the most stable during the respiratory cycle in the end-exhale phase. A better understanding of tumor motion makes it possible to individualize radiation delivery strategies accordingly. Cine-MRI is a successful noninvasive modality to analyze motion for this purpose in the future.

Background. Local and systemic recurrence are important sources of treatment failure following surgical resection of esophageal adenocarcinoma. We hypothesized that adding preoperative cetuximab and radiotherapy (cetux-RT) to perioperative chemotherapy would increase treatment efficacy with acceptable toxicity. Methods. In this prospective phase II trial, patients were treated with three cycles of epirubicin, cisplatin, and capecitabine (ECX), followed by cetux-RT. After surgery with curative intent, patients received three more cycles of ECX. Primary endpoints were efficacy, determined by histopathological complete response (pCR) rate, and safety, which was assessed with resectability rate. Results. Of the 12 patients enrolled in this trial, six received at least one dose of cetux-RT. In five patients, cetux-RT was not started because of adverse events (AEs) related to preoperative chemotherapy; one patient had progressive disease. Addition of cetux-RT was well tolerated and did not interfere with the resectability rate (100%). However, the pCR rate was 0, and 50% of patients experienced serious adverse events (SAEs) postoperatively. Conclusion. With 12 patients enrolled, the lack of initial signs of efficacy and a high incidence of postoperative SAEs prompted us to end this study prematurely. Perioperative ECX was associated with considerable toxicity, and further treatment intensification is problematic.

Background and purpose To characterize pancreatic tumor motion and to develop a gating scheme for radiotherapy in pancreatic cancer. Materials and methods Two cine MRIs of 60 s each were performed in fifteen pancreatic cancer patients, one in sagittal direction and one in coronal direction. A Minimum Output Sum of Squared Error (MOSSE) adaptive correlation filter was used to quantify tumor motion in craniocaudal, lateral and anteroposterior directions. To develop a gating scheme, stability of the breathing phases was examined and a gating window assessment was created, incorporating tumor motion, treatment time and motion margins. Results The largest tumor motion was found in craniocaudal direction, with an average peak-to-peak amplitude of 15 mm (range 6–34 mm). Amplitude of the tumor in the anteroposterior direction was on average 5 mm (range 1–13 mm). The least motion was seen in lateral direction (average 3 mm, range 2–5 mm). The end exhale position was the most stable position in the breathing cycle and tumors spent more time closer to the end exhale position than to the end inhale position. On average, a margin of 25% of the maximum craniocaudal breathing amplitude was needed to achieve full target coverage with a duty cycle of 50%. When reducing the duty cycle to 50%, a margin of 5 mm was sufficient to cover the target in 11 out of 15 patients. Conclusion Gated delivery for radiotherapy of pancreatic cancer is best performed around the end exhale position as this is the most stable position in the breathing cycle. Considerable margin reduction can be established at moderate duty cycles, yielding acceptable treatment efficiency. However, motion patterns and amplitude do substantially differ between individual patients. Therefore, individual treatment strategies should be considered for radiotherapy in pancreatic cancer.

Serial diffusion-weighted MRI (DW-MRI) measurements of the apparent diffusion coefficient (ADC) of rectal tumors are used for rectal cancer response evaluation after neo-adjuvant treatment. In this study, we determined the repeatability of DW-MRI to distinguish therapy-related response from measurement variations.In 18 patients with rectal cancer on five consecutive days, 1.5 Tesla (T) MR imaging was performed including two identical DW-MRI sequences. The repeatability of the tumor ADC measurements and the intraobserver ADC variation were depicted in a Bland-Altman plot. The repeatability coefficient was calculated as the range of ADC values of two identical DWI measurements for 95% of subjects. It was expressed as percentage of the mean ADC value.Three females and 15 males were included. The mean tumor ADC value was 1.15 × 10(-3) mm(2)/s (SD 0.07 × 10(-3) mm(2)). The repeatability coefficient of the ADC value was 9.8% and for the intraobserver repeatability 4.7%.In serial DW-MRI for rectal cancer treatment response evaluation, a repeatability coefficient of 9.8% has to be considered to account for measurement variations in rectal tumor ADC. These variations represent observer judgement and patient and MR spectrometer induced variations.

Background: For the palliative treatment of dysphagia, esophageal stent placement provides immediate improvement, whereas brachytherapy offers better long-term relief. Objective: To evaluate safety and efficacy of concurrent brachytherapy and biodegradable stent placement. Design: Prospective, single-arm study. Setting: Two tertiary-care referral centers. Patients: Nineteen consecutive patients with significant dysphagia resulting from unresectable esophageal cancer, with a life expectancy of more than 3 months. Intervention: Single-dose brachytherapy (12 Gy) on day 1 followed by biodegradable stent placement on day 2. Main Outcome Measurements: Intervention-related major complications (determined by an expert panel) and dysphagia. Results: Nineteen patients (13 men, median age 66 years [interquartile range (IQR) 59-71] years) were included; 7 patients (37%) also received palliative chemotherapy. After inclusion of 19 patients, the study was ended prematurely because the safety threshold was exceeded. In total, 28 major complications occurred in 17 patients (89%). In 9 patients (47%), major complications were determined intervention-related (severe retrosternal pain with or without vomiting [n = 6], hematemesis [n = 1], recurrent dysphagia [n = 2]. Dysphagia scores decreased significantly from a median of 3 (IQR 3-4) to a median of 1 (IQR 0-3) after 1 month (P

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.

The aim was to determine the maximum tolerable dose of oxaliplatin added to (oral) 5FU in irresectable rectal cancer.Nineteen patients were treated; 13 patients received 5FU/LV and 6 patients capecitabine. Oxaliplatin was administered on days 1 and 29 at dose levels 85 and 130 mg/m2. Four to seven weeks thereafter, surgery was performed.In 6 patients treated with 85 mg/m2, one grade 3 elevation of liver transaminases occurred. Of 7 patients who received 130 mg/m2, 1 patient experienced a grade III thrombocytopenia and 1 patient died of neutropenic fever, probably due to an urosepsis. Six patients were treated with capecitabine, of whom 3 developed a grade III gastrointestinal toxicity. An R0 resection could be performed in 93%, a pT0-2N0 in 39%, with 2 pCR's.The addition of oxaliplatin at 85 mg/m2 on days 1 and 29 to radiotherapy and 5FU/LV or capecitabine in irresectable rectal cancer is feasible.

The aim of this study was to determine the relationship between survival and value of molecular markers in the primary tumour in a group of patients with irresectable rectal cancer, treated with preoperative chemo-radiotherapy.Immunohistochemistry for p53, p21, bcl-2 and Ki-67 was performed on pre-treatment biopsy specimens of 34 patients with irresectable rectal cancer. Preoperative treatment consisted of pelvic irradiation of 45-56 Gy, combined with 5FU and leucovorin (350/20 mg/m2 x 5 d; in weeks 1 and 5 during radiotherapy). The median follow-up was 38 months. Endpoints were pathological T-stage and survival after surgery.Expression of p21 correlated significantly with survival (p=0.005). Survival and p21 expression also correlated significantly, when adjusted for tumour response (p=0.005, RR=4.8 (1.6-14.7)).Expression of p21 predicts a worse survival in irresectable rectal cancer treated with preoperative chemo-radiotherapy. No relationship was found between tumour response in chemo-radiotherapy and p53, bcl-2 or Ki-67.

Purpose: A major hurdle in adaptive radiotherapy is the adaptation of the planning MRI's delineations to the daily anatomy. We therefore investigate the accuracy and time needed for online clinical target volume (CTV) adaptation by radiation therapists (RTT), to be used in MRI-guided adaptive treatments on a MRI-Linac (MRL). Methods: Sixteen patients, diagnosed with early stage rectal cancer, underwent a T2-weighted MRI prior to each fraction of short-course radiotherapy, resulting in 4–5 scans per patient. On these scans, the CTV was delineated according to guidelines by an experienced radiation oncologist (RO) and considered to be the gold standard. For each patient, the first MRI was considered as the planning MRI and matched on bony anatomy to the 3–4 daily MRIs. The planning MRI's CTV delineation was rigidly propagated to the daily MRI scans as a proposal for adaptation. Three RTTs in training started the adaptation of the CTV conform guidelines, after a two hour training lecture and a two patient (n=7) training set. To assess the inter-therapist variation, all three RTTs altered delineations of 3 patients (n=12). One RTT altered the CTV delineations (n=53) of the remaining 11 patients. Time needed for adaptation of the CTV to guidelines was registered.As a measure of agreement, the conformity index (CI) was determined between the RTTs' delineations as a group. Dice similarity coefficients were determined between delineations of the RTT and the RO. Results: We found good agreement between RTTs' and RO's delineations (average Dice=0.91, SD=0.03). Furthermore, the inter-observer agreement between the RTTs was high (average CI=0.94, SD=0.02). Adaptation time reduced from 10:33 min (SD= 3:46) to 2:56 min (SD=1:06) between the first and last ten delineations, respectively. Conclusion: Daily CTV adaptation by RTTs, seems a feasible and safe way to introduce daily, online MRI-based plan adaptation for a MRL.

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 betweenmore » 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.« less