Defining near-complete response following (chemo)radiotherapy for rectal cancer: systematic review

This review identified the various terminology, features, and criteria used in the literature to define a near-complete response. This heterogeneity in criteria and features is probably related to the differences in therapeutic aim (watchful waiting versus additional treatment aiming at organ preservation). In the future, more evidence should be gathered that support the use of specific features at response evaluation to define a near-complete response.Background A uniform definition of a clinical near-complete response (near-CR) after neoadjuvant (chemo)radiotherapy for rectal cancer is lacking. A clear definition is necessary for uniformity in clinical practice and trial enrolment for organ-preserving treatments. This review aimed to provide an overview of the terminology, criteria, and features used in the literature to define a near-CR. Methods A systematic review was performed based on the PRISMA statement. PubMed and Embase were searched up to May 2021 to identify the terminology, criteria, and features used to define a near-CR after (chemo)radiotherapy for rectal cancer. Studies with no clear cut-off point between a cCR and near-CR, studies using Response Evaluation Criteria In Solid Tumours, and studies including only complete responders were excluded. Results A total of 1876 articles were found, of which 23 were included. Patients were managed by watchful waiting and/or additional local treatment in 11 and 17 of 23 studies respectively. Response evaluation included digital rectal examination (DRE) and/or endoscopy with MRI in 18 studies. The majority of studies used the term 'near-complete response'. In most studies, minor irregularities or a smooth induration with DRE and a small flat ulcer on endoscopy were considered to indicate a near-CR. On MRI, five studies used features (obvious downstaging with or without heterogeneous/irregular fibrosis on T2-weighted MRI or small spot of high signal on diffusion-weighted imaging), five studies used TNM criteria (ycT2), and four used magnetic resonance tumour regression grade (mrTRG) (mrTRG1-2/mrTRG2) to describe a near-CR. Conclusion The terminology, criteria, and features used to describe a near-CR vary substantially, which can partly be explained by the different treatment strategies patients are selected for (watchful waiting or additional local treatment). A reproducible definition of near-CR is required.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Master protocol trial design for technical feasibility of MR-guided radiotherapy

The master protocol trial design aims to increase efficiency in terms of trial infrastructure and protocol administration which may accelerate development of (technical) innovations in radiation oncology. A master protocol to study feasibility of techniques/software for MR-guided adaptive radiotherapy with the MR-Linac is described and discussed. </p

Feasibility of Gold Fiducial Markers as a Surrogate for Gross Tumor Volume Position in Image-Guided Radiation Therapy of Rectal Cancer

Imaging- and therapeutic targets in neoplastic and musculoskeletal inflammatory diseas

Predictive factors for response and toxicity after brachytherapy for rectal cancer; results from the HERBERT study

Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Features on Endoscopy and MRI after Treatment with Contact X-ray Brachytherapy for Rectal Cancer: Explorative Results

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 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.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Oxygen-consumption based quantification of chemogenetic H2O2 production in live human cells

Reactive Oxygen Species (ROS) in the form of H2O2 can act both as physiological signaling molecules as well as damaging agents, depending on their concentration and localization. The downstream biological effects of H2O2 were often studied making use of exogenously added H2O2, generally as a bolus and at supraphysiological levels. But this does not mimic the continuous, low levels of intracellular H2O2 production by for instance mitochondrial respiration. The enzyme D-Amino Acid Oxidase (DAAO) catalyzes H2O2 formation using D-amino acids, which are absent from culture media, as a substrate. Ectopic expression of DAAO has recently been used in several studies to produce inducible and titratable intracellular H2O2. However, a method to directly quantify the amount of H2O2 produced by DAAO has been lacking, making it difficult to assess whether observed phenotypes are the result of physiological or artificially high levels of H2O2. Here we describe a simple assay to directly quantify DAAO activity by measuring the oxygen consumed during H2O2 production. The oxygen consumption rate (OCR) of DAAO can directly be compared to the basal mitochondrial respiration in the same assay, to estimate whether the ensuing level of H2O2 production is within the range of physiological mitochondrial ROS production. In the tested monoclonal RPE1-hTERT cells, addition of 5 mM D-Ala to the culture media amounts to a DAAO-dependent OCR that surpasses ∼5% of the OCR that stems from basal mitochondrial respiration and hence produces supra-physiological levels of H2O2. We show that the assay can also be used to select clones that express differentially localized DAAO with the same absolute level of H2O2 production to be able to discriminate the effects of H2O2 production at different subcellular locations from differences in total oxidative burden. This method therefore greatly improves the interpretation and applicability of DAAO-based models, thereby moving the redox biology field forward

A polymorphism in the enhancer region of the thymidylate synthase promoter influences the survival of colorectal cancer patients treated with 5-fluorouracil

High levels of thymidylate synthase (TS) expression have been associated with poor survival of colorectal cancer (CRC) patients to 5-fluorouracil (5-FU)-based chemotherapy. Recent evidence suggests that a polymorphism within the enhancer region of the TS gene promoter can influence TS expression, with the triple repeat homozygote (3R/3R) being associated with significantly higher tumour TS levels than either the double repeat homozygote (2R/2R) or heterozygotes (2R/3R). In the present study we investigated whether TS genotype was associated with the degree of survival benefit from chemotherapy in 221 Dukes' C stage CRC patients. Patients with the 3R/3R polymorphism (n = 58, 26%) showed no significant long-term survival benefit from chemotherapy (RR = 0.62, 95% CI: 0.30–1.25, P = 0.18), whereas those with the 2R/2R or 2R/3R genotype (n = 163, 74%) showed significant gains in survival from this treatment (RR = 0.52, 95% CI: 0.52–0.82, P = 0.005). These results demonstrate that a polymorphism within the TS gene, probably through its effect on TS expression levels, can influence the survival benefit obtained by CRC patients from 5-FU-based chemotherapy. © 2001 Cancer Research Campaignhttp://www.bjcancer.co

First system for fully-automated multi-criterial treatment planning for a high-magnetic field MR-Linac applied to rectal cancer

Background and purpose: In this study we developed a workflow for fully-automated generation of deliverable IMRT plans for a 1.5 T MR-Linac (MRL) based on contoured CT scans, and we evaluated automated MRL planning for rectal cancer. Methods: The Monte Carlo dose calculation engine used in the clinical MRL TPS (Monaco, Elekta AB, Stockholm, Sweden), suited for high accuracy dose calculations in a 1.5 T magnetic field, was coupled to our in-house developed Erasmus-iCycle optimizer. Clinically deliverable plans for 23 rectal cancer patients were automatically generated in a two-step process, i.e., multi-criterial fluence map optimization with Erasmus-iCycle followed by a conversion into a deliverable IMRT plan in the clinical TPS. Automatically generated plans (AUTOplans) were compared to plans that were manually generated with the clinical TPS (MANplans). Results: With AUTOplanning large reductions in planning time and workload were obtained; 4–6 h mainly hands-on planning for MANplans vs 1 h of mainly computer computation time for AUTOplans. For equal target coverage, the bladder and bowel bag Dmean was reduced in the AUTOplans by 1.3 Gy (6.9%) on average with a maximum reduction of 4.5 Gy (23.8%). Dosimetric measurements at the MRL demonstrated clinically acceptable delivery accuracy for the AUTOplans. Conclusions: A system for fully automated multi-criterial planning for a 1.5 T MR-Linac was developed and tested for rectal cancer patients. Automated planning resulted in major reductions in planning workload and time, while plan quality improved. Negative impact of the high magnetic field on the dose distributions could be avoided

Changes in the status of p53 affect drug sensitivity to thymidylate synthase (TS) inhibitors by altering TS levels

Colorectal cancer (CRC) resistance to fluoropyrimidines and other inhibitors of thymidylate synthase (TS) is a serious clinical problem often associated with increased intracellular levels of TS. Since the tumour suppressor gene p53, which is mutated in 50% of CRC, regulates the expression of several genes, it may modulate TS activity, and changes in the status of p53 might be responsible for chemoresistance. Therefore, this study was aimed to investigate TS levels and sensitivity to TS inhibitors in wild-type (wt) and mutant (mt) p53 CRC cells, Lovo and WiDr, respectively, transfected with mt and wt p53. Lovo 175X2 cells (transfected with mt p53) were more resistant to 5-fluorouracil (5-FU; 2-fold), nolatrexed (3-fold), raltitrexed (3-fold) and pemetrexed (10-fold) in comparison with the wt p53 parental cells Lovo 92. Resistance was associated with an increase in TS protein expression and catalytic activity, which might be caused by the loss of the inhibitory effect on the activity of TS promoter or by the lack of TS mRNA degradation, as suggested by the reversal of TS expression to the levels of Lovo 92 cells by adding actinomycin. In contrast, Lovo li cells, characterized by functionally inactive p53, were 3-13-fold more sensitive to nolatrexed, raltitrexed and pemetrexed, and had a lower TS mRNA, protein expression and catalytic activity than Lovo 92. However, MDM-2 expression was significantly higher in Lovo li, while no significant differences were observed in Lovo 175X2 cells with respect to Lovo 92. Finally, mt p53 WiDr transfected with wt p53 were not significantly different from mt p53 WiDr cells with respect to sensitivity to TS inhibitors or TS levels. Altogether, these results indicate that changes in the status of p53, can differently alter sensitivity to TS inhibitors by affecting TS levels, depending on activity or cell line, and might explain the lack of clear correlation between mutations in p53 and clinical outcome after chemotherapy with TS inhibitors