Multimodal treatment strategies for patients with rectal cancer are increasingly including the possibility of organ preservation, through nonoperative management or local excision. Organ preservation ...strategies can enable patients with a complete response or near-complete clinical responses after radiotherapy with or without concomitant chemotherapy to safely avoid the morbidities associated with radical surgery, and thus to maintain anorectal function and quality of life. However, standardization of the key outcome measures of organ preservation strategies is currently lacking; this includes a lack of consensus of the optimal definitions and selection of primary end points according to the trial phase and design; the optimal time points for response assessment; response-based decision-making; follow-up schedules; use of specific anorectal function tests; and quality of life and patient-reported outcomes. Thus, a consensus statement on outcome measures is necessary to ensure consistency and facilitate more accurate comparisons of data from ongoing and future trials. Here, we have convened an international group of experts with extensive experience in the management of patients with rectal cancer, including organ preservation approaches, and used a Delphi process to establish the first international consensus recommendations for key outcome measures of organ preservation, in an attempt to standardize the reporting of data from both trials and routine practice in this emerging area.
Background Endoscopic resection (ER) is an important treatment for high-grade intraepithelial neoplasia and early cancer in Barrett's esophagus. ER-cap requires submucosal lifting and positioning of ...a snare in the cap, making it technically demanding and laborious. Multiband mucosectomy (MBM) uses a modified variceal band ligator and requires no submucosal lifting or positioning of a snare. Objective To compare ER-cap and MBM for piecemeal ER of early Barrett's neoplasia. Design Randomized, controlled trial. Setting Tertiary-care and community-care centers. Patients This study involved 84 patients (64 men; median age 70 years) undergoing piecemeal ER of Barrett's neoplasia. Intervention Piecemeal ER was performed by using ER-cap (n = 42) or MBM (n = 42). Main Outcome Measurements Safety, efficacy, procedure time, costs. Results Procedure time (34 vs 50 minutes; P = .02) and costs (€240 vs €322; P < .01) were significantly less with MBM compared with ER-cap. MBM resulted in smaller resection specimens than ER-cap (18 ×13 mm vs 20 × 15 mm; P < .01). Maximum thicknesses of specimens and resected submucosa were not significantly different. There were no clinically relevant bleeding episodes. Four perforations occurred, 3 with ER-cap, 1 with MBM ( P = not significant). Limitations Potential bias because of different levels of experience among participating endoscopists. Conclusion Piecemeal ER with MBM is faster and cheaper than with ER-cap. Despite the lack of submucosal lifting, MBM appears not to be associated with more perforations. Although MBM results in slightly smaller specimens, the clinical relevance of this may be limited because depth of resections does not differ between both techniques. MBM may thus be preferred for piecemeal ER of early Barrett's neoplasia. (Clinical trial registration number: NTR1435.)
Background Video-autofluorescence imaging (AFI) and narrow band imaging (NBI) are new endoscopic techniques that may improve the detection of high-grade intraepithelial neoplasia (HGIN) in Barrett's ...esophagus (BE). AFI improves the detection of lesions but may give false-positive findings. NBI allows for detailed inspection of the mucosal and (micro)vascular patterns, which are related to HGIN. Objective A proof-of-principle study to combine AFI and NBI to improve the detection of HGIN and to reduce false-positive findings. Design Cross-sectional study of consecutive eligible patients. Setting Single-center. Patients Twenty patients with BE with suspected or endoscopically treated HGIN were investigated with 2 prototype imaging systems: AFI (inspection with high-resolution videoendoscopy and autofluorescence imaging for detection of lesions) and NBI (for detailed inspection of mucosal and vascular patterns of identified lesions). Lesions were sampled for histopathologic evaluation. Main Outcome Measurements The positive predictive value of AFI alone and of AFI-NBI for detecting HGIN and the reduction of false-positive findings because of the use of NBI. Results All of the 28 lesions with HGIN were identified with AFI. Seventeen were identified with white light (61%). Forty-seven suspicious lesions were detected with AFI: 28 contained HGIN (60%) and 19 were false positive (40%). With NBI, 25 of the true-positive lesions had definitely suspicious patterns, and 3 had dubiously suspicious patterns. Of the 19 false positives, 14 were not suspicious on NBI. The false-positive rate, therefore, was reduced from 40% to 10%. Low-grade dysplasia was found in 4 of the remaining 5 false positives. All of the 14 patients with HGIN were identified by AFI-NBI (sensitivity 100%). Limitations Uncontrolled study in high-risk patients. Conclusions This proof-of-principle study confirms that AFI can be used as a red-flag technique to detect suspicious lesions. With NBI, detailed inspection of the surface patterns can be performed. This combination may increase the accuracy of detecting HGIN in BE.
This study assessed the margins needed to cover tumor intrafraction motion during an MR-guided radiotherapy (MRgRT) dose-escalation strategy in intermediate risk rectal cancer.
Fifteen patients with ...rectal cancer were treated with neoadjuvant short-course radiotherapy, 5x5 Gy, according to an online adaptive workflow on a 1.5 T MR-linac. Per patient, 26 3D T2 weighted MRIs were made; one reference scan preceding treatment and five scans per treatment fraction. The primary tumor was delineated on each scan as gross tumor volume (GTV). Target coverage margins were assessed by isotropically expanding the reference GTV until more than 95% of the voxels of the sequential GTVs were covered. A margin with a coverage probability threshold of 90% was defined as adequate. Intra- and interfraction margins to cope with the movement of the GTV in the period between scans were calculated to indicate the target volume margins. Furthermore, the margin needed to cover GTV movement was calculated for different time intervals.
The required margins to cover inter- and intrafraction GTV motion were 17 mm and 6 mm, respectively. Analysis based on time intervals between scans showed smaller margins were needed for adequate GTV coverage as time intervals became shorter, with a 4 mm margin required for a procedure of 15 min or less.
The shorter the treatment time, the smaller the margins needed to cover for the GTV movement during an online adaptive MRgRT dose-escalation strategy for intermediate risk rectal cancer. When time intervals between replanning and the end of dose delivery could be reduced to 15 min, a 4 mm margin would allow adequate target coverage.
Abstract
Purpose
To determine PTV margins for intrafraction motion in MRI-guided online adaptive radiotherapy for rectal cancer and the potential benefit of performing a 2nd adaptation prior to ...irradiation.
Methods
Thirty patients with rectal cancer received radiotherapy on a 1.5 T MR-Linac. On T2-weighted images for adaptation (MRI
adapt
), verification prior to (MRI
ver
) and after irradiation (MRI
post
) of 5 treatment fractions per patient, the primary tumor GTV (GTV
prim
) and mesorectum CTV (CTV
meso
) were delineated. The structures on MRI
adapt
were expanded to corresponding PTVs. We determined the required expansion margins such that on average over 5 fractions, 98% of CTV
meso
and 95% of GTV
prim
on MRI
post
was covered in 90% of the patients. Furthermore, we studied the benefit of an additional adaptation, just prior to irradiation, by evaluating the coverage between the structures on MRI
ver
and MRI
post.
A threshold to assess the need for a secondary adaptation was determined by considering the overlap between MRI
adapt
and MRI
ver.
Results
PTV margins for intrafraction motion without 2nd adaptation were 6.4 mm in the anterior direction and 4.0 mm in all other directions for CTV
meso
and 5.0 mm isotropically for GTV
prim
. A 2nd adaptation, applied for all fractions where the motion between MRI
adapt
and MRI
ver
exceeded 1 mm (36% of the fractions) would result in a reduction of the PTV
meso
margin to 3.2 mm/2.0 mm. For PTV
prim
a margin reduction to 3.5 mm is feasible when a 2nd adaptation is performed in fractions where the motion exceeded 4 mm (17% of the fractions).
Conclusion
We studied the potential benefit of intrafraction motion monitoring and a 2nd adaptation to reduce PTV margins in online adaptive MRIgRT in rectal cancer. Performing 2nd adaptations immediately after online replanning when motion exceeded 1 mm and 4 mm for CTV
meso
and GTV
prim
respectively, could result in a 30–50% margin reduction with limited reduction of dose to the bowel.
Background Evidence-based selection criteria for endoscopic resection (ER) of Barrett's neoplasia are scarce. Objective To study the histopathology of ER specimens of Barrett's neoplasia and ...correlate this with endoscopic characteristics to make recommendations for patient management. Design, Setting, Interventions Histology and correlating endoscopy reports of specimens obtained at 293 consecutive ERs performed at a Dutch tertiary referral center between 2000 and 2006 were reviewed. Main Outcome Measurements Histologic findings in ER specimens and their relation with endoscopic characteristics. Results A total of 150 ERs were performed for focal lesions: 16% type 0-I, 23% 0-IIa, 7% 0-IIb, 3% 0-IIc, 9% 0-IIa-IIb, and 42% 0-IIa-IIc; and 143 for flat mucosa. Histology revealed no dysplasia in 57 ERs, low-grade intraepithelial neoplasia in 52, high-grade intraepithelial neoplasia in 104, T1m in 61, and T1sm in 17; in two cancers, infiltration depth was not assessable because of artifacts. Type 0-I and 0-IIc lesions significantly more often penetrated the submucosa ( P = .009): 60% were G1 cancers, 23% were G2 cancers, and 18% were G3 cancers. G2-G3 cancers significantly more often invaded the submucosa ( P < .001) or had positive vertical margins ( P = .015). Histology of ER specimens led to a change in diagnosis in 49% of the focal lesions and a relevant change in treatment policy in 30%. Limitations A retrospective study. Conclusions ER is a valuable diagnostic tool that frequently leads to a change in treatment policy. Most endoscopically resected early Barrett's neoplasia are 0-II type, G1 mucosal neoplasia. Submucosal infiltration is more often encountered in type 0-I and 0-IIc lesions and in G2-G3 cancers.
The purpose of this study was to characterize the motion and define the required treatment margins of the pathological mesorectal lymph nodes (GTV
) for two online adaptive MRI-guided strategies for ...sequential boosting. Secondly, we determine the margins required for the primary gross tumor volume (GTV
). Twenty-eight patients treated on a 1.5T MR-Linac were included in the study. On T2-weighted images for adaptation (MRI
) before and verification after irradiation (MRI
) of five treatment fractions per patient, the GTV
and GTV
were delineated. With online adaptive MRI-guided radiotherapy, daily plan adaptation can be performed through the use of two different strategies. In an adapt-to-shape (ATS) workflow the interfraction motion is effectively corrected by redelineation and the only relevant motion is intrafraction motion, while in an adapt-to-position (ATP) workflow the margin (for GTV
) is dominated by interfraction motion. The margin required for GTV
will be identical to the ATS workflow, assuming each fraction would be perfectly matched on GTV
. The intrafraction motion was calculated between MRI
and MRI
for the GTV
and GTV
separately. The interfraction motion of the GTV
was calculated with respect to the position of GTV
, assuming each fraction would be perfectly matched on GTV
. PTV margins were calculated for each strategy using the Van Herk recipe. For GTV
we randomly sampled the original dataset 20 times, with each subset containing a single randomly selected lymph node for each patient. The resulting margins for ATS ranged between 3 and 4 mm (LR), 3 and 5 mm (CC) and 5 and 6 mm (AP) based on the 20 randomly sampled datasets for GTV
. For ATP, the margins for GTV
were 10-12 mm in LR and AP and 16-19 mm in CC. The margins for ATS for GTV
were 1.7 mm (LR), 4.7 mm (CC) and 3.2 mm anterior and 5.6 mm posterior. Daily delineation using ATS of both target volumes results in the smallest margins and is therefore recommended for safe dose escalation to the primary tumor and lymph nodes.
Pretreatment response prediction is crucial to select those patients with rectal cancer who will benefit from organ preservation strategies following (intensified) neoadjuvant therapy and to avoid ...unnecessary toxicity in those who will not. The combination of individual predictors in multivariable prediction models might improve predictive accuracy. The aim of this systematic review was to summarize and critically appraise validated pretreatment prediction models (other than radiomics-based models or image-based deep learning models) for response to neoadjuvant therapy in patients with rectal cancer and provide evidence-based recommendations for future research. MEDLINE via Ovid, Embase.com, and Scopus were searched for eligible studies published up to November 2022. A total of 5006 studies were screened and 16 were included for data extraction and risk of bias assessment using Prediction model Risk Of Bias Assessment Tool (PROBAST). All selected models were unique and grouped into five predictor categories: clinical, combined, genetics, metabolites, and pathology. Studies generally included patients with intermediate or advanced tumor stages who were treated with neoadjuvant chemoradiotherapy. Evaluated outcomes were pathological complete response and pathological tumor response. All studies were considered to have a high risk of bias and none of the models were externally validated in an independent study. Discriminative performances, estimated with the area under the curve (AUC), ranged per predictor category from 0.60 to 0.70 (clinical), 0.78 to 0.81 (combined), 0.66 to 0.91 (genetics), 0.54 to 0.80 (metabolites), and 0.71 to 0.91 (pathology). Model calibration outcomes were reported in five studies. Two collagen feature-based models showed the best predictive performance (AUCs 0.83-0.91 and good calibration). In conclusion, some pretreatment models for response prediction in rectal cancer show encouraging predictive potential but, given the high risk of bias in these studies, their value should be evaluated in future, well-designed studies.
A watch-and-wait approach for patients with rectal cancer and a clinical complete response after neoadjuvant chemoradiotherapy or radiotherapy is associated with better quality of life and functional ...outcome. Nevertheless, prospective data on both parameters are scarce.
To prospectively evaluate quality of life and functional outcome, including bowel, urinary, and sexual function, of patients following a watch-and-wait approach.
A total of 278 patients with rectal cancer and a clinical complete response or near-complete response after neoadjuvant chemoradiotherapy or radiotherapy were included in 2 prospective cohort studies: a single-center study (March 2014 to October 2017) and an ongoing multicenter study (from September 2017). Patients were observed by a watch-and-wait approach. Additional local excision or total mesorectal excision was performed for residual disease or regrowth. Data were analyzed between April 1, 2021, and August 27, 2021, for patients with a minimum follow-up of 24 months.
Quality of life was evaluated with the European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire-C30 (EORTC-QLQ-C30), EORTC-QLQ-CR38, or EORTC-QLQ-CR29 and 36-Item Short-Form Health Survey. The score for the questionnaires and 36-Item Short-Form Health Survey ranges from 0 to 100. For some scales, a high score indicates a high level of functioning, and for others it indicates a high level of complaints and symptomatology. Functional outcome was assessed by the Low Anterior Resection Syndrome score, Vaizey incontinence score, International Prostate Symptom Score, International Index of Erectile Function, and Female Sexual Function Index.
Of 278 patients included, 187 were male (67%), and the median age was 66 years (range, 34-85 years). In the first 24 months, 221 patients (80%) were observed by a watch-and-wait approach without requiring surgery, 18 patients (6%) underwent additional local excision, and 39 patients (14%) underwent total mesorectal excision. In general, patients observed by a watch-and-wait approach reported good quality of life, with limited variation over time. At 3 months, 56 of 221 patients (25.3%) reported major bowel dysfunction; at 12 months, 53 patients (24.0%) reported it; and at 24 months, 55 patients (24.9%) reported it. At 24 months, 48 of 151 male patients (31.8%) reported severe erectile dysfunction. For female patients, sexual satisfaction and overall sexual function decreased during follow-up. Patients who underwent local excision reported more major bowel dysfunction (10 of 18 patients 55.6%) compared with those without additional surgery. Quality-of-life scores, however, were comparable. After total mesorectal excision, patients scored significantly worse on several quality-of-life subscales.
Results of this study suggest that patients with rectal cancer who were observed by a watch-and-wait approach had good quality of life, with some patients reporting bowel and sexual dysfunction. Quality of life and functional outcome deteriorated when patients required surgery. These data will be useful in daily care to counsel patients on what to expect from a watch-and-wait approach.
IntroductionStandard treatment for patients with intermediate or locally advanced rectal cancer is (chemo)radiotherapy followed by total mesorectal excision (TME) surgery. In recent years, organ ...preservation aiming at improving quality of life has been explored. Patients with a complete clinical response to (chemo)radiotherapy can be managed safely with a watch-and-wait approach. However, the optimal organ-preserving treatment strategy for patients with a good, but not complete clinical response remains unclear. The aim of the OPAXX study is to determine the rate of organ preservation that can be achieved in patients with rectal cancer with a good clinical response after neoadjuvant (chemo)radiotherapy by additional local treatment options.Methods and analysisThe OPAXX study is a Dutch multicentre study that investigates the efficacy of two additional local treatments aiming at organ preservation in patients with a good, but not complete response to neoadjuvant treatment (ie near-complete response or a small residual tumour mass <3 cm). The sample size will be 168 patients in total. Patients will be randomised (1:1) between two parallel single-arm phase II studies: study arm 1 involves additional contact X-ray brachytherapy (an intraluminal radiation boost), while in study arm 2 the observation period is extended followed by a second response evaluation and optional transanal local excision. The primary endpoint of the study is the rate of successful organ preservation at 1 year following randomisation. Secondary endpoints include toxicity, morbidity, oncological and functional outcomes at 1 and 2 years of follow-up. Finally, an observational cohort study for patients who are not eligible for randomisation is conducted.Ethics and disseminationThe trial protocol has been approved by the medical ethics committee of the Netherlands Cancer Institute (METC20.1276/M20PAX). Informed consent will be obtained from all participants. The trial results will be published in an international peer-reviewed journal.Trial registration numberNCT05772923.
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