RESUMEN
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.
RESUMEN
INTRODUCTION: Organ preservation is associated with superior functional outcome and quality of life (QoL) compared with total mesorectal excision (TME) for rectal cancer. Only 10% of patients are eligible for organ preservation following short-course radiotherapy (SCRT, 25 Gy in five fractions) and a prolonged interval (4-8 weeks) to response evaluation. The organ preservation rate could potentially be increased by dose-escalated radiotherapy. Online adaptive magnetic resonance-guided radiotherapy (MRgRT) is anticipated to reduce radiation-induced toxicity and enable radiotherapy dose escalation. This trial aims to establish the maximum tolerated dose (MTD) of dose-escalated SCRT using online adaptive MRgRT. METHODS AND ANALYSIS: The preRADAR is a multicentre phase I trial with a 6+3 dose-escalation design. Patients with intermediate-risk rectal cancer (cT3c-d(MRF-)N1M0 or cT1-3(MRF-)N1M0) interested in organ preservation are eligible. Patients are treated with a radiotherapy boost of 2×5 Gy (level 0), 3×5 Gy (level 1), 4×5 Gy (level 2) or 5×5 Gy (level 3) on the gross tumour volume in the week following standard SCRT using online adaptive MRgRT. The trial starts on dose level 1. The primary endpoint is the MTD based on the incidence of dose-limiting toxicity (DLT) per dose level. DLT is a composite of maximum one in nine severe radiation-induced toxicities and maximum one in three severe postoperative complications, in patients treated with TME or local excision within 26 weeks following start of treatment. Secondary endpoints include the organ preservation rate, non-DLT, oncological outcomes, patient-reported QoL and functional outcomes up to 2 years following start of treatment. Imaging and laboratory biomarkers are explored for early response prediction. ETHICS AND DISSEMINATION: The trial protocol has been approved by the Medical Ethics Committee of the University Medical Centre Utrecht. The primary and secondary trial results will be published in international peer-reviewed journals. TRIAL REGISTRATION NUMBER: WHO International Clinical Trials Registry (NL8997; https://trialsearch.who.int).
