RapidPlan Knowledge-Based Radiotherapy Planning Compared to Manual Planning in Locally Advanced Non-Small-Cell Lung Cancer

<b>Background/Objectives:</b> Treatment planning for stage III non-small cell lung cancer (NSCLC) presents dosimetric challenges due to the proximity of critical structures. RapidPlan (RP), a knowledge-based planning (KBP) system, offers the potential for improved plan consistency and organ-at-risk (OAR) sparing. The objective of this study was to compare dosimetric and clinical outcomes of RP-generated plans versus manually optimized plans in patients with stage III NSCLC undergoing IMRT or VMAT. <b>Methods:</b> In this retrospective analysis, 50 patients treated with concurrent chemoradiation for stage III NSCLC at Hadassah Medical Center (2015-2021) were analyzed. RP plans were generated using a lung-specific model in the Eclipse treatment planning system and compared with the original clinical manual plans. Dosimetric parameters for target volumes and OARs were evaluated, and subgroup analyses were performed by technique (IMRT vs. VMAT). Toxicity and survival outcomes were analyzed, and Normal Tissue Complication Probability (NTCP) modeling was conducted. <b>Results:</b> RP significantly reduced mean heart dose (Δ = -2.54 Gy, <i>p</i> < 0.001), spinal cord maximum dose (Δ = -4.08 Gy, <i>p</i> < 0.001), and esophageal mean dose (Δ = -3.89 Gy, <i>p</i> < 0.001) compared with manual plans. Lung doses were slightly higher in RP plans (V20 Δ = +2.12%, <i>p</i> < 0.001). VMAT-RP plans demonstrated greater cardiac and esophageal sparing than VMAT-manual plans. RP yielded significant NTCP reductions for the heart (0.34% → 0.20%) and esophagus (16.6% → 11.5%), but no improvement for lung or spinal cord. Lung toxicity ≥ grade 2 was associated with reduced overall survival (16.2 vs. 51.8 months, <i>p</i> < 0.001). <b>Conclusions:</b> RapidPlan-based knowledge-based planning enhances OAR sparing while maintaining target coverage in locally advanced NSCLC. Slight increases in lung dose highlight the need for ongoing model refinement. An association between lung toxicity and reduced survival was observed, underscoring the impact of treatment-related morbidity on outcomes.