The purpose of this study was to characterize the motion and define the required treatment margins of the pathological mesorectal lymph nodes (GTVln) for two online adaptive MRI-guided strategies... Show moreThe purpose of this study was to characterize the motion and define the required treatment margins of the pathological mesorectal lymph nodes (GTVln) for two online adaptive MRI-guided strategies for sequential boosting. Secondly, we determine the margins required for the primary gross tumor volume (GTVprim). Twenty-eight patients treated on a 1.5T MR-Linac were included in the study. On T2-weighted images for adaptation (MRIadapt) before and verification after irradiation (MRIpost) of five treatment fractions per patient, the GTVln and GTVprim 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 GTVln) is dominated by interfraction motion. The margin required for GTVprim will be identical to the ATS workflow, assuming each fraction would be perfectly matched on GTVprim. The intrafraction motion was calculated between MRIadapt and MRIpost for the GTVln and GTVprim separately. The interfraction motion of the GTVln was calculated with respect to the position of GTVprim, assuming each fraction would be perfectly matched on GTVprim. PTV margins were calculated for each strategy using the Van Herk recipe. For GTVln 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 GTVln. For ATP, the margins for GTVln were 10–12 mm in LR and AP and 16–19 mm in CC. The margins for ATS for GTVprim 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. Show less
Lynn, P.B.; Valk, M.J.M. van der; Claassen, Y.H.M.; Shi, Q.; Widmar, M.; Bastiaannet, E.; ... ; Garcia-Aguilar, J. 2023
Objective: Compare oncological long-term and short-term outcomes between patients with distal cT2NO rectal cancer treated with chemoradio-therapy and local excision (CRT + LE) and patients treated... Show moreObjective: Compare oncological long-term and short-term outcomes between patients with distal cT2NO rectal cancer treated with chemoradio-therapy and local excision (CRT + LE) and patients treated with total mesorectal excision (TME). Summary Background Data: Previous studies showed that CRT + LE is equivalent to TME in local tumor control and survival for T2N0 rectal cancer. Methods: Seventy-nine patients with cT2N0 rectal adenocarcinoma treated with CRT + LE in the ACOSOG Z6041 trial were compared to a cohort of 79 patients with pT2N0 tumors treated with upfront TME in the Dutch TME trial. Survival, short-term outcomes, and health-related quality of life (HRQOL) were compared between groups. Results:Three patients (4%) in the CRT + LE group required abdominoperineal resection, compared with 31 (40%) in the TME group. Forty TME patients (51%) required a permanent stoma. CRT-related toxicity occurred in 43% of the CRT + LE patients; however, TME patients had a higher rate of complications requiring reoperation (1 vs 9%; P = 0.03). Five-year disease-free survival {88.2% [confidence interval (CI), 77.7%-93.9%] vs 88.3% [CI, 78.7%-93.7%]; P = 0.88} and overall survival [90.3% (CI, 80.8%-95.3%) vs 88.4% (CI, 78.9%-93.8%); P = 0.82] were similar in the 2 groups. Compared to baseline, overall HRQOL decreased in the CRT + LE group and improved in the TME group. In both groups, patients with sphincter preservation had worse HRQOL scores 1 year after surgery. Conclusions: In patients who underwent CRT + LE, oncological outcomes were similar to those of patients who underwent TME, with fewer complications requiring reoperation but significant CRT toxicity. Although overall HRQOL decreased in the CRT + LE group and improved in TME patients, when considering anorectal function, results were worse in both groups. Show less
Custers, P.A.; Maas, M.; Lambregts, D.M.J.; Beets-Tan, R.G.H.; Beets, G.L.; Peters, F.P.; ... ; Triest, B. van 2022
Simple Summary: Contact X-ray brachytherapy (CXB) after neoadjuvant (chemo)radiotherapy for rectal cancer is applied in selected patients aiming at organ preservation. However, limited data exist... Show moreSimple Summary: Contact X-ray brachytherapy (CXB) after neoadjuvant (chemo)radiotherapy for rectal cancer is applied in selected patients aiming at organ preservation. However, limited data exist on features observed on endoscopy and MRI after treatment with CXB. On endoscopy, features observed in most patients 6 months after CXB are a flat, white scar, indicative for a clinical complete response (cCR), or tumor mass. On MRI, features indicative for a residual tumor are a focal tumor signal on T2W-MRI and a mass-like high signal on DWI. Due to treatment-related features observed early in follow-up, an irregular ulcer on endoscopy and a diffuse "reactive" mucosal signal on DWI, the distinction between a cCR and a residual tumor generally can be made at 6 months of follow-up. These results can help clinicians to interpret imaging features following CXB, ultimately, to identify patients with a cCR for Watch-and-Wait and to identify patients with a residual tumor for subsequent total mesorectal excision. After neoadjuvant (chemo)radiotherapy for rectal cancer, contact X-ray brachytherapy (CXB) can be applied aiming at organ preservation. This explorative study describes the early features on endoscopy and MRI after CXB. Patients treated with CXB following (chemo)radiotherapy and a follow-up of >= 12 months were selected. Endoscopy and MRI were performed every 3 months. Expert readers scored all the images according to structured reporting templates. Thirty-six patients were included, 15 of whom obtained a cCR. On endoscopy, the most frequently observed feature early in follow-up was an ulcer, regardless of whether patients developed a cCR. A flat, white scar and tumor mass were common at 6 months. Focal tumor signal on T2W-MRI and mass-like high signal on DWI were generally absent in patients with a cCR. An ulceration on T2W-MRI and "reactive" mucosal signal on DWI were observed early in follow-up regardless of the final tumor response. The distinction between a cCR and a residual tumor generally can be made at 6 months. Features associated with a residual tumor are tumor mass on endoscopy, focal tumor signal on T2W-MRI, and mass-like high signal on DWI. Early recognition of these features is necessary to identify patients who will not develop a cCR as early as possible. Show less
Swets, M.; Martinez, C.G.; Vliet, S. van; Tilburg, A. van; Gelderblom, H.; Marijnen, C.A.M.; ... ; Nagtegaal, I.D. 2022
Aim Currently, compelling evidence illustrates the significance of determining microsatellite instability (MSI) in colorectal cancer (CRC). The association of MSI with proximal CRC is well... Show moreAim Currently, compelling evidence illustrates the significance of determining microsatellite instability (MSI) in colorectal cancer (CRC). The association of MSI with proximal CRC is well established, however, its implications in patients with rectal cancer remain undefined. We therefore aimed to determine the role of MSI with respect to incidence and outcome in patients with rectal cancer. Methods and Results For this we examined patients from two prospective phase III trials: TME trial and PROCTOR-SCRIPT trial (n = 1250). In addition, we performed a literature review to evaluate the overall prevalence, the effect on survival and the response to neo-adjuvant treatment in patients with MSI rectal cancer compared with microsatellite stable (MSS) rectal cancer. Our TME and PROCTOR-SCRIPT cohort showed no differences in terms of overall survival (OS) (hazard ratio [HR] 1.00, 95% confidence interval [CI] 0.69-1.47) and disease-free survival (DFS) (HR 1.00, 95% CI 0.68-1.45) in patients with MSI compared to MSS rectal cancer. The total number of MSI cases in all included studies (including our own) was 1220 (out of 16,526 rectal cancer patients), with an overall prevalence of 6.7% (standard error 1.19%). Both for OS as for DFS there was no impact of MSI status on prognosis (HR 1.00, 95% CI 0.77-1.29 and HR 0.86, 95% CI 0.60-1.22, respectively). The risk ratio (RR) for downstaging and pathological complete response showed also no impact of MSI status (RR 1.15, 95% CI 0.86-1.55 and RR 0.81, 95% CI 0.54-1.22, respectively). Conclusion Rectal cancer patients with MSI form a distinct and rare subcategory, however, there is no prognostic effect of MSI in rectal cancer patients. Show less
Custers, P.A.; Geubels, B.M.; Huibregtse, I.L.; Peters, F.P.; Engelhardt, E.G.; Beets, G.L.; ... ; Triest, B. van 2021
Simple Summary The cornerstone in rectal cancer treatment is total mesorectal excision, a major surgical procedure associated with morbidity and mortality, especially in older rectal cancer... Show moreSimple Summary The cornerstone in rectal cancer treatment is total mesorectal excision, a major surgical procedure associated with morbidity and mortality, especially in older rectal cancer patients. To avoid major surgery, different radiotherapy techniques are being investigated. Studies on contact X-ray brachytherapy reveal promising oncological results. However, there are limited data on functional outcome and quality of life, which are highly important for older or inoperable patients. This study aims to report the oncological and functional outcome, quality of life, and patients' experiences of older or inoperable rectal cancer patients treated with contact X-ray brachytherapy to avoid major surgery. This study shows that contact X-ray brachytherapy can provide a good tumor response and is well tolerated, with minimal impact on functional outcome and quality of life. These data suggest contact X-ray brachytherapy can be considered an option for older or inoperable rectal cancer patients to avoid major rectal surgery. Total mesorectal excision for rectal cancer is a major operation associated with morbidity and mortality. For older or inoperable patients, alternatives are necessary. This prospective study evaluated the oncological and functional outcome and quality of life of older or inoperable rectal cancer patients treated with a contact X-ray brachytherapy boost to avoid major surgery. During follow-up, tumor response and toxicity on endoscopy were scored. Functional outcome and quality of life were assessed with self-administered questionnaires. Additionally, in-depth interviews regarding patients' experiences were conducted. Nineteen patients were included with a median age of 80 years (range 72-91); nine patients achieved a clinical complete response and in another four local control of the tumor was established. The 12 month organ-preservation rate, progression-free survival, and overall survival were 88%, 78%, and 100%, respectively. A transient decrease in quality of life and bowel function was observed at 3 months, which was generally restored at 6 months. In-depth interviews revealed that patients' experience was positive despite the side-effects shortly after treatment. In older or inoperable rectal cancer patients, contact X-ray brachytherapy can be considered an option to avoid total mesorectal excision. Contact X-ray brachytherapy is well-tolerated and can provide good tumor control. Show less
Sande, M.E. van der; Maas, M.; Melenhorst, J.; Breukink, S.O.; Leerdam, M.E. van; Beets, G.L. 2021
Objective and Background: Watch-and-wait approach in rectal cancer relies on the identification of a clinical complete response (CR) after neoadjuvant (chemo)radiotherapy. This is mainly performed... Show moreObjective and Background: Watch-and-wait approach in rectal cancer relies on the identification of a clinical complete response (CR) after neoadjuvant (chemo)radiotherapy. This is mainly performed by rectal examination. magnetic resonance imaging, and endoscopy. Endoscopy has been less well studied, and the objective of the study is to assess the diagnostic value of endoscopy and the predictive value of endoscopic features for the identification of CR.Patients and Methods: A total of 161 patients with primary rectal cancer undergoing flexible sigmoidoscopy for response assessment after neoadjuvant (chemo)radiotherapy between January 2012 and December 2015 at a single institution were evaluated retrospectively. Three independent readers scored endoscopic features and a confidence level score for a CR. Diagnostic performance of endoscopy and positive predictive value (PPV) of endoscopic features for a CR were calculated. If available, biopsy results were revealed to the reader and a change in confidence level was noted. Reference standard was histology after surgery, or long-term outcome in a watch-and-wait policy.Results: Median time to endoscopy was 9 (interquartile range 8 12) weeks. Area under the receiver operator characteristic curve, sensitivity, specificity. PPV, and negative predictive value for a CR were 0.80 to 0.84, 72% to 94%, 61% to 85%, 63% to 78% and 80% to 89%, respectively. A flat scar was the most predictive feature of a CR (PPV 70%-80%). The PPV of small flat ulcers and large flat ulcers were 40% to 50% and 29% to 33%, respectively. The addition of biopsy results led to a significant change in confidence level score in 4% to 13% of patients.Conclusions: More than 70% of the patients with a luminal CR after neoadjuvant treatment for rectal cancer can be identified by endoscopy at +/- 9 weeks. Together with findings on digital rectal examination (DRE) and magnetic resonance imaging, specific endoscopic features can be used to select patients for an extended observation period to select for organ preservation. Show less
Vuijk, F.A.; Water, C. van de; Lent-van Vliet, S.; Valk, M.J.M. van der; Simmer, F.; Velde, C.J.H. van de; ... ; Hilling, D.E. 2021
Simple SummaryA subset of patients with rectal cancer are treated before surgery with chemoradiation. Unfortunately, this neoadjuvant chemoradiotherapy does not have the preferred effect of tumor... Show moreSimple SummaryA subset of patients with rectal cancer are treated before surgery with chemoradiation. Unfortunately, this neoadjuvant chemoradiotherapy does not have the preferred effect of tumor downstaging in all patients, but does bring substantial side effects and possible complications. A pre-treatment prediction based on available parameters might provide a means to better select therapy for individual patients. Genomic mutational status of pre-treatment biopsies may provide prognostic information, however, it also might be influenced by tumor heterogeneity. This study investigates whether pre-treatment biopsy material is a reliable way of defining mutational status in rectal cancer.Neoadjuvant therapy before surgical resection is indicated for patients with locally advanced rectal cancer. However, a significant number of patients show minimal or no response to neoadjuvant therapy. Unfortunately, we are currently unable to predict response and identify non-responding patients before neoadjuvant treatment is given. Genomic mutational status might provide valuable prognostic information. However, it is unclear whether predictions based on genomic mutational status in single preoperative biopsies are reliable due to intra-tumoral heterogeneity. In this study we aim to investigate the reliability of genomic mutations found in single pre-operative biopsies by comparing genomic mutations to four other locations within the same tumor using next generation sequencing. Rectal cancer patients undergoing primary resection without neoadjuvant therapy were included. From each patient, one biopsy, two deep and two superficial samples were obtained and sequenced using a targeted next generation sequencing gene panel. Concordance between these five samples was assessed. In this feasibility study we included 11 patients. In 7 out of 11 (64%) patients, all 5 samples showed concordant mutations. In 4 out of 11 patients (36%) discordant mutations were observed. In conclusion, assessment of mutational status on a single pre-operative biopsy shows discordance with tumor tissue from other locations in 36% of cases. These results warrant careful interpretation of biopsy material analysis, as these might be influenced by tumor heterogeneity. Show less
Linders, D.; Deken, M.; Valk, M. van der; Tummers, W.; Bhairosingh, S.; Schaap, D.; ... ; Hilling, D. 2021
Rectal cancer patients with a complete response after neoadjuvant therapy can be monitored with a watch-and-wait strategy. However, regrowth rates indicate that identification of patients with a... Show moreRectal cancer patients with a complete response after neoadjuvant therapy can be monitored with a watch-and-wait strategy. However, regrowth rates indicate that identification of patients with a pathological complete response (pCR) remains challenging. Targeted near-infrared fluorescence endoscopy is a potential tool to improve response evaluation. Promising tumor targets include carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EpCAM), integrin alpha v beta 6, and urokinase-type plasminogen activator receptor (uPAR). To investigate the applicability of these targets, we analyzed protein expression by immunohistochemistry and quantified these by a total immunostaining score (TIS) in tissue of rectal cancer patients with a pCR. CEA, EpCAM, alpha v beta 6, and uPAR expression in the diagnostic biopsy was high (TIS > 6) in, respectively, 100%, 100%, 33%, and 46% of cases. CEA and EpCAM expressions were significantly higher in the diagnostic biopsy compared with the corresponding tumor bed (p < 0.01). CEA, EpCAM, alpha v beta 6, and uPAR expressions were low (TIS < 6) in the tumor bed in, respectively, 93%, 95%, 85%, and 62.5% of cases. Immunohistochemical evaluation shows that CEA and EpCAM could be suitable targets for response evaluation after neoadjuvant treatment, since expression of these targets in the primary tumor bed is low compared with the diagnostic biopsy and adjacent pre-existent rectal mucosa in more than 90% of patients with a pCR. Show less
Kraima, A.C.; West, N.P.; Roberts, N.; Magee, D.R.; Smit, N.N.; Velde, C.J.H. van de; ... ; Quirke, P. 2019
Intersphincteric resection (ISR) enables radical sphincter-preserving surgery in a subset of low rectal tumors impinging on the anal sphincter complex (ASC). Excellent anatomical knowledge is... Show moreIntersphincteric resection (ISR) enables radical sphincter-preserving surgery in a subset of low rectal tumors impinging on the anal sphincter complex (ASC). Excellent anatomical knowledge is essential for optimal ISR. This study describes the role of the longitudinal muscle (LM) in the ASC and implications for ISR and other low rectal and anal pathologies. Six human adult en bloc cadaveric specimens (three males, three females) were obtained from the University of Leeds GIFT Research Tissue Programme. Paraffin-embedded mega blocks containing the ASC were produced and serially sectioned at 250 mu m intervals. Whole mount microscopic sections were histologically stained and digitally scanned. The intersphincteric plane was shown to be potentially very variable. In some places adipose tissue is located between the external anal sphincter (EAS) and internal anal sphincter (IAS), whereas in others the LM interdigitates to obliterate the plane. Elsewhere the LM is (partly) absent with the intersphincteric plane lying on the IAS. The LM gave rise to the formation of the submucosae and corrugator ani muscles by penetrating the IAS and EAS. In four of six specimens, striated muscle fibers from the EAS curled around the distal IAS reaching the anal submucosa. The ASC formed a complex structure, varying between individuals with an inconstant LM affecting the potential location of the intersphincteric plane as well as a high degree of intermingling striated and smooth muscle fibers potentially further disrupting the plane. The complexity of identifying the correct pathological staging of low rectal cancer is also demonstrated. Clin. Anat., 2019. (c) 2019 Wiley Periodicals, Inc. Show less
Kusters, M.; Uehara, K.; Velde, C.J.H. van de; Moriya, Y. 2017
