The First Multi-Ion Therapy for Head and Neck Cancers: Planning Protocol, Plan Robustness, and Biological Rationale for a Phase I Clinical Trial
Abstract
Purpose
To establish the treatment planning protocol and evaluate the biological rationale for the world’s first dose-averaged LET (LETd)-optimized multi-ion therapy program for head and neck cancers. This study characterizes the plan robustness and potential therapeutic efficacy to support a phase I trial aiming to systematically escalate target LETd within the gross tumor volume (GTV) from 70 to 90 keV/μm.
Methods
Plans for 16 patients were retrospectively optimized using carbon (C), oxygen (O), and neon (Ne) ions. A two-port configuration was employed to escalate optimized LETd while maintaining clinical dose constraints equivalent to conventional carbon-ion therapy. Plan robustness was evaluated against systematic range uncertainty (±2.5%) and random daily setup variations across 16 fractions to address the LET trilemma―an inherent conflict between dose homogeneity, robustness, and high LETd. Efficacy against tumor hypoxia was estimated using the oxygen effect-incorporated stochastic microdosimetric kinetic model.
Results
Specific target LETd levels were achieved by selecting optimal ion combinations based on the GTV size. For the final target LETd level (90 keV/μm), small (~20 cm3), medium (~50 cm3), and large (~100 cm3) tumors typically required C+O, O-only, and C+Ne combinations, respectively. Robustness analysis revealed that range uncertainty was the dominant factor. Small, deep-seated tumors were most susceptible to dose degradation (>10% inhomogeneity) due to steep physical dose gradients at field junctions when using lightest feasible ion combinations. Strategic heavier-ion selection mitigated uncertainties through shallower gradients, which reduced dose inhomogeneity by >7% while maintaining target LETd and normal tissue sparing. The 90 keV/μm target yielded a ~30% effective dose improvement for anoxic cancer cells compared to conventional carbon-ion therapy.
Conclusion
The proposed protocol demonstrates the feasibility of staged LETd escalation to 90 keV/μm. Strategic ion selection is essential to overcome the LET trilemma, ensuring both plan robustness and therapeutic efficacy in the first multi-ion therapy program.