Introduction Postoperative radiotherapy in patients with breast cancer with one to three lymph node metastases, particularly within the pT1–2N1M0 cohort with a low clinical risk of local–regional recurrence (LRR), has incited a discourse surrounding personalised treatment strategies. Multigene testing for Recurrence Index (RecurIndex) model capably differentiates patients based on their level of LRR risk. This research aims to validate whether a more aggressive treatment approach can enhance clinical outcomes in N1 patients who possess a clinically low risk of LRR, yet a high RecurIndex-determined risk of LRR. Specifically, this entails postoperative whole breast irradiation combined with regional lymph node irradiation (RNI) following breast-conserving surgery or chest wall irradiation with RNI after mastectomy. Methods and analysis The RIGAIN (RecurIndex-Guided postoperative radiotherapy with or without Avoidance of Irradiation of regional Nodes in 1–3 node-positive breast cancer) Study is a multicentre, prospective, randomised, open-label, phase III clinical trial that is being conducted in China. In this study, patients with low clinical LRR risk but high RecurIndex-LRR risk are randomly assigned in a 1:1 ratio to the experimental group or the control group. In the experimental group, RNI is performed and the control group omits RNI. Efficacy and safety analyses will be conducted, enrolling a total of 540 patients (270 per group). The primary endpoint is invasive disease-free survival, and secondary endpoints include any first recurrence, LRR-free survival, distant metastasis-free survival, recurrence-free survival, overall survival, disease-free survival, breast cancer-specific mortality and assessment of patient quality of life. The study began in April 2023 and with a follow-up period of 60 months after the last participant completes radiation therapy. Ethics and dissemination The study was approved by the Ethics Committee of Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University (SYSKY-2022-097-02, V.3.1). It adheres to the Helsinki Declaration and Good Clinical Practice. Research findings will be submitted for publication in peer-reviewed journals. Trial registration number NCT04069884.

Background/Objectives: To compare diagnostic performance and cost-effectiveness of [¹⁸F]FDG PET/CT versus MRI for cervical lymph node assessment in nasopharyngeal carcinoma (NPC) and to evaluate their impact on N-staging and upper-neck-only irradiation planning. Materials and Methods: We retrospectively identified treatment-naïve NPC patients who underwent both MRI and FDG PET/CT within 14 days prior to ultrasound-guided biopsy of specific cervical lymph nodes with rigorous one-to-one multimodal matching. Using histopathology as the reference standard (Cohort A, node level), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the curve (AUC) were compared between PET/CT and MRI. In a staging cohort (Cohort B, patient level), we compared imaging-based N-staging accuracy and the pathology-concordant classification of treatment recommendations assuming upper-neck-only irradiation for N0 to N1 disease. In discordant cases (Cohort C), three experienced radiation oncologists designed dose prescriptions and neck irradiation volumes, first using MRI alone and then after reviewing PET/CT to quantify decision impact. A decision tree/Markov model (10-year horizon) evaluated cost-effectiveness of MRI- versus PET/CT-initiated strategies. Results: In total, 694 biopsy-verified lymph nodes from 649 patients were analyzed. PET/CT demonstrated higher sensitivity (96.0% vs. 92.6%, p = 0.001) and NPV (80.2% vs. 66.7%, p < 0.001) than MRI, with comparable specificity (64.0% vs. 59.0%, p = 0.317) and PPV (91.4% vs. 90.0%, p = 0.203); AUCs were 0.864 and 0.841, respectively (p = 0.298). In Cohort B (N = 503), PET/CT provided accurate N-staging for a significantly higher proportion of patients compared to MRI (8.0% vs. 4.2%, p = 0.021) and yielded more accurate recommendations for upper-neck-only irradiation when restricted to N0 to N1 disease (93.8% vs. 88.9%, p = 0.003). In discordant cases (Cohort C, N = 62), PET/CT substantially improved accuracy compared with MRI and prompted clinically meaningful plan adjustments, including dose escalation for metastatic nodes (up to 16.7%) and expansion from upper-neck-only to whole-neck irradiation with rates of 6.4%, 8.0%, and 11.3% for the three radiation oncologists, respectively. In the base case economic analysis, PET/CT achieved higher effectiveness (5.329 vs. 5.305 quality-adjusted life years [QALYs]) at higher cost (US$27,228 vs. US$25,596), with an incremental cost–effectiveness ratio (ICER) of approximately US$68,000 per QALY, remaining below a willingness-to-pay threshold of US$100,000 per QALY; probabilistic sensitivity analysis favored PET/CT in 79.6% of iterations. Conclusions: FDG PET/CT provided superior sensitivity and negative predictive value versus MRI for detecting nodal metastases in NPC, improving pathology-adjudicated N-staging and the accuracy of upper-neck-only irradiation recommendations. PET/CT was cost-effective in the modeled setting, although treatment de-escalation for benign nodes remained conservative in clinical decision-making.