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Introduction: The Neoadjuvant rectal (NAR) score is a new surrogate endpoint to be used in clinical trials for early determination of treatment response to different preoperative therapies. The aim is to further validate the NAR-score, primarily developed using chemoradiotherapy (CRT) with a delay to surgery 6-8 weeks, and explore its value using other schedules. Materials and Methods: The study included all 9978 patients diagnosed with non-metastasized RC in 2007-2015 that had undergone surgery and was registered in the Swedish Colorectal Cancer Registry. The patients of interest had either short-course radiotherapy (scRT)/CRT + delayed surgery, longcourse radiotherapy (RT) + delayed surgery, (C)RT + additional chemotherapy, primary surgery, or scRT + immediate surgery. The scRT/CRT + delayed surgery groups were further divided based on time to surgery. Results: Mean NAR-score differed significantly (p < 0.0001) between different treatments. (C) RT + additional chemotherapy had the lowest mean score of 16.3 and CRT + delayed surgery had 17.7. There was a significant difference (p < 0.05) in overall survival (OS) and time to recurrence (TTR) of patients with a Low NAR-score (<8) compared to those with a High score (>16) for both CRT- and scRT, with a stronger correlation for CRT-patients. C-index for the NAR-score model (0.623) was not superior to when only pathological T- and N-stage was used (0.646). Conclusions: The NAR-score is prognostic, but it is not better than pT- and pN-stage. However, the NARscore can still discriminate between two treatments that have different cell killing effect and may still be of value in clinical trials as an easier method than pT- and N-stage.

Simple Summary Preoperative radiotherapy has an established role in the treatment of rectal cancer, alone or with chemotherapy, but the use varies considerably. Many scientists have strived to reduce the use of radiation while maintaining high local control rates, partly counterbalanced by an ambition to preserve the organ. Besides patient-related factors, stage as defined by magnetic resonance imaging (MRI) is most important for the decision at multidisciplinary team (MDT) conferences to recommend direct surgery or any treatment prior to (eventual) surgery. In a large prospective, unselected and properly staged patient cohort, MRI characteristics were most important for treatment selection, but patient-related factors were also relevant. Changes over time, reflecting changed national guidelines that were striving to reduce the use of radiation, were seen; however, they were probably interpreted differently in the two analysed regions. The accuracy of MRI evaluated by specially trained radiologists, during an MDT conference in real life, was poor. When preoperative radiotherapy (RT) is best used in rectal cancer is subject to discussions and guidelines differ. To understand the selection mechanisms, we analysed treatment decisions in all patients diagnosed between 2010-2020 in two Swedish regions (Uppsala with a RT department and Dalarna without). Information on staging and treatment (direct surgery, short-course RT, or combinations of RT/chemotherapy) in the Swedish Colorectal Cancer Registry were used. Staging magnetic resonance imaging (MRI) permitted a division into risk groups, according to national guidelines. Logistic regression explored associations between baseline characteristics and treatment, while Cohen's kappa tested congruence between clinical and pathologic stages. A total of 1150 patients without synchronous metastases were analysed. Patients from Dalarna were older, had less advanced tumours and were pre-treated less often (52% vs. 63%, p < 0.001). All MRI characteristics (T-/N-stage, MRF, EMVI) and tumour levels were important for treatment choice. Age affected if chemotherapy was added. The correlation between clinical and pathological T-stage was fair/moderate and poor for N-stage. The MRI-based risk grouping influenced treatment choice the most. Since the risk grouping was modified to diminish the pre-treated proportion, fewer patients were irradiated with time. MRI staging is far from optimal. A stronger wish to decrease irradiation may explain why fewer patients from Dalarna were irradiated, but inequality in health care cannot be ruled out.