A More Stringent Hematologic Toxicity Control for Hypofractionated Cervical Cancer Concurrent Chemoradiation via CT- and MRI-based Bone Marrow Dosimetry: Pooled Analysis from HYPOCx-iRex and Single-Institute EMBRACE-II Studies

Purpose To compare CT- and MRI-based bone marrow (BM_CT and BM_MRI) dose-hematologic toxicity (HemTox) correlations and identify dosimetric constraints for HemTox mitigation, including hypofractionated 44Gy/20F. Methods Pooled data of IMRT/VMAT planning were analysed from 45Gy/25F (single-institute EMBRACE-II cohort without BM-sparing and conventional fractionation (CVRT) arm of HYPOCx-iRex trial with BM-sparing) and hypofractionated 44Gy/20F from HYPO arm of HYPOCx-iRex trial. BM volumes included pelvic and lumbosacral bones within PTV level (femora excluded). BM_CT covered whole bone with cortices; BM_MRI covered iso-to-hyposignal T1/T2 as active marrow surrogate. BM dose parameters were correlated with CTCAEv5.0 grade (Gr) ≥2 and Gr≥3 HemTox by Mann-Whitney U-test and Probit analysis to identify effective dose associated with 10% toxicity probability (ED10). Results 68 patients analysed from EMBRACE-II (n=28), CVRT (n=19, 45Gy/25F), HYPO (n=21, 44Gy/20F). BM dose reduction was achieved in both HYPOCx-iRex arms. Gr≥2 HemTox were CVRT 68%, HYPO 67%, vs EMBRACE-II 79% (P=0.62). Gr≥3 HemTox: HYPO 24% vs. CVRT 11% and EMBRACE-II 18% (P=0.61). Significant BM_CT and Gr≥3 HemTox correlations were with ED10s of V20Gy 74%, V25Gy 480 cc, V30Gy 360 cc, and V35Gy 235 cc. BM_MRI and Gr≥2 HemTox correlations were identified exclusively in HYPO with ED10s of V25Gy 39% and Dmean 24 Gy. Conclusion Both CT- and MRI-based BM sparing showed potential for reducing HemTox. Proposed constraints with significant dose-response correlation with practical adaptation for both 45Gy/20F and 44Gy/20F were BM_CT V20Gy <70%, V25Gy <450 cc, V30Gy <300 cc, V35Gy <200 cc; and the more stringent constraints for hypofractionation 44Gy/20F were BM_MRI V25Gy <45% and Dmean <25 Gy. The trade-off PTV strategy may create the low-dose fall-off space enabling these stricter constraints and warrants prospective Phase III validation.