Toward Optimal Fractionation Schemes in Nonuniform Radiation Therapy: Exploiting Helical Tomotherapy's Thread Effect for Gynecological Cancer Treatment.

Abstract

This study aimed to optimize dose fractionation for helical tomotherapy-based spatially fractionated radiation therapy (HT-SFRT) in gynecologic cancers by exploiting the "thread effect" to induce cohort effects. HT-SFRT plans with varying parameters (pitch: 0.3-0.5; field width: 2.512 and 5.048 cm; modulation factor: 1.0-4.0) were applied to HeLa cells to identify the optimal configuration maximizing the peak-to-valley dose ratio. The cohort effect threshold was determined through quantification of DNA damage (γ-H2AX) and cell viability. Clinical validation involved 45 patients with gynecologic cancer, comparing 3 treatment approaches: conventional HT, stereotactic body radiation therapy, and SFRT (3 and 4 fractions). Comprehensive dosimetric analysis included evaluation of physical doses, biologically effective doses, tumor control probability, and normal tissue complication probability (NTCP) using the universal survival curve and Lyman-Kutcher-Burman models. Optimized HT-SFRT parameters (field width = 5.048 cm; pitch = 0.5; modulation factor = 2.0) achieved a peak-to-valley dose ratio of 1.15 at 10 cm off-axis. The 8 Gy/fraction dose threshold induced significant γ-H2AX expression and reduced cell viability by 15.41% (P < .05), establishing the cohort effect criterion. Clinically, the 32 Gy/4 fractions SFRT regimen demonstrated approximate tumor control (tumor control probability: 99.34% vs 100%) to conventional HT (50 Gy/25 fractions), whereas offering superior therapeutic advantages: (1) 84% reduction in treatment duration (4 vs 25 days); (2) significantly lower NTCP for bladder (6.5 × 10^-⁶ % vs 3.6 × 10^-⁴ %, P = .05); and (3) 42.9% faster fractional delivery than stereotactic body radiation therapy. Notably, SFRT exhibited elevated NTCP for rectum (3.99% vs 0.10%) and femoral head (0.16%-0.22% vs 2.9 × 10^-⁷ %-4.8 × 10^-⁷ %) structures. The thread effect in HT can be harnessed for SFRT, avoiding traditional mitigation strategies. The optimized HT-SFRT scheme (32 Gy/4 fractions) offers equivalent tumor control, shorter treatment duration, and acceptable normal tissue toxicity, providing a promising alternative for gynecologic cancer radiation therapy. Prospective clinical trials are warranted to validate these findings.