Response prediction for neoadjuvant treatment in locally advanced rectal cancer patients-improvement in decision-making: A systematic review.

Background: Predicting pathological complete response (pCR) from pre or post-treatment features could be significant in improving the process of making clinical decisions and providing a more personalized treatment approach for better treatment outcomes. However, the lack of external validation of predictive models, missing in several published articles, is a major issue that can potentially limit the reliability and applicability of predictive models in clinical settings. Therefore, this systematic review described different externally validated methods of predicting response to neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC) patients and how they could improve clinical decision-making.

Method: An extensive search for eligible articles was performed on PubMed, Cochrane, and Scopus between 2018 and 2023, using the keywords: (Response OR outcome) prediction AND (neoadjuvant OR chemoradiotherapy) treatment in 'locally advanced Rectal Cancer'.

Inclusion criteria: (i) Studies including patients diagnosed with LARC (T3/4 and N- or any T and N+) by pre-medical imaging and pathological examination or as stated by the author (ii) Standardized nCRT completed. (iii) Treatment with long or short course radiotherapy. (iv) Studies reporting on the prediction of response to nCRT with pathological complete response (pCR) as the primary outcome. (v) Studies reporting external validation results for response prediction. (vi) Regarding language restrictions, only articles in English were accepted.

Exclusion criteria: (i) We excluded case report studies, conference abstracts, reviews, studies reporting patients with distant metastases at diagnosis. (ii) Studies reporting response prediction with only internally validated approaches.

Data collection and quality assessment: Three researchers (DC-D, FB, HT) independently reviewed and screened titles and abstracts of all articles retrieved after de-duplication. Possible disagreements were resolved through discussion among the three researchers. If necessary, three other researchers (LB, GC, MG) were consulted to make the final decision. The extraction of data was performed using the CHecklist for critical Appraisal and data extraction for systematic Reviews of prediction Modelling Studies (CHARMS) template and quality assessment was done using the Prediction model Risk Of Bias Assessment Tool (PROBAST).

Results: A total of 4547 records were identified from the three databases. After excluding 392 duplicate results, 4155 records underwent title and abstract screening. Three thousand and eight hundred articles were excluded after title and abstract screening and 355 articles were retrieved. Out of the 355 retrieved articles, 51 studies were assessed for eligibility. Nineteen reports were then excluded due to lack of reports on external validation, while 4 were excluded due to lack of evaluation of pCR as the primary outcome. Only Twenty-eight articles were eligible and included in this systematic review. In terms of quality assessment, 89 % of the models had low concerns in the participants domain, while 11 % had an unclear rating. 96 % of the models were of low concern in both the predictors and outcome domains. The overall rating showed high applicability potential of the models with 82 % showing low concern, while 18 % were deemed unclear.

Conclusion: Most of the external validated techniques showed promising performances and the potential to be applied in clinical settings, which is a crucial step towards evidence-based medicine. However, more studies focused on the external validations of these models in larger cohorts is necessary to ensure that they can reliably predict outcomes in diverse populations.