[68Ga]Ga-GZP and [18F]FDG PET for Early Response Prediction in Locally Advanced Rectal Cancer Undergoing Neoadjuvant Immunochemoradiotherapy

Early and accurate assessment of treatment response is crucial for determining therapeutic strategy in patients with locally advanced rectal cancer (LARC), particularly in those desiring organ preservation. By visualizing tumor glycolysis and granzyme B release from cytotoxic immune cells, respectively, [ 18 F]FDG and [ 68 Ga]Ga-GZP PET imaging may provide a promising strategy for precise response evaluation during neoadjuvant immunochemoradiotherapy. This prospective, single-center study enrolled high-risk LARC patients undergoing neoadjuvant short-course radiotherapy (SCRT) and six-cycle immunochemotherapy. Paired imaging with [ 18 F]FDG PET/CT and [ 68 Ga]Ga-GZP PET/MR was performed at baseline and after two treatment cycles. The status of clinical complete response (cCR) or pathological complete response (pCR) after therapy was determined by the combination of digital rectal examination, endoscopic ultrasound, enhanced MRI, or surgery. Changes in PET parameters were analyzed for associations with pCR and cCR. Receiver operating characteristic (ROC) curves were used to assess predictive performance. A total of 20 eligible patients (8 men, 12 women; mean age, 53.10 years) were enrolled and completed the entire trial, and all patients had microsatellite instability-high/deficient mismatch repair LARC. [ 18 F]FDG PET parameters significantly decreased post two-cycle treatment, while [ 68 Ga]Ga-GZP SUV max increased ( P < 0.001). After treatment, pCR and cCR rates were 53.85% (7/13) and 70.0% (14/20), respectively. Patients with pCR/cCR exhibited greater reductions in FDG-MTV than those with non-pCR/cCR ( P < 0.05), whereas GZP-SUV max-2 was significantly higher in the cCR patients ( P < 0.05). The accuracies of ΔFDG-MTV% (cutoff = 73.19%) for predicting pCR ( P = 0.039) and cCR ( P = 0.032) were 84.62% and 80.0%, respectively. GZP-SUV max-2 (cutoff = 2.85) held the accuracies of 76.92% and 80.0% for pCR ( P = 0.116) and cCR ( P = 0.058), respectively. [ 18 F]FDG PET/CT is a valuable tool for early prediction of treatment response in LARC, with ΔFDG-MTV% significantly associated with pCR and cCR. Though post-treatment GZP-SUV max reflects interpatient differences in immune response, [ 68 Ga]Ga-GZP PET fails to predict pCR and cCR. These findings support ΔFDG-MTV% as a reliable early imaging biomarker for identifying candidates who are likely to benefit from organ-preserving management. • Early response prediction is crucial to determine therapeutic strategies, especially organ preservation in patients with LARC • ΔFDG-MTV% on [ 18 F]FDG PET predicted both pCR and cCR in high-risk LARC patients who are undergoing neoadjuvant immunotherapy • [ 68 Ga]Ga-GZP PET did not predict pCR/cCR but post-treatment GZP-SUVmax reflected interpatient variability in immune activation.