Treatment of fast-growing, human papillomavirus-negative, head and neck cancers (HNCs) remains challenging from the perspectives of both tumor control and late sequelae. In this study, we use systematic radiobiological optimization to identify fractionation schemes that markedly improve the radiotherapeutic effectiveness balance between tumor control probability (TCP) and late normal tissue complication probability (LNTCP), as compared with standard fractionation.

We track the development after each treatment fraction of both tumor control and late sequelae. Toward the end of the treatment, accelerated repopulation of fast-growing HNC tumors means that further fractions minimally improve TCP but result in major LNTCP increases, providing the potential for optimization of the TCP-LNTCP balance. We used a recent improved model of accelerated repopulation, calibrated with extensive HNC clinical trials data, to identify optimally effective treatment regimens that both increase TCP and significantly decrease LNTCP. For comparison, we also used standard repopulation models.

An optimized hypofractionated schedule of 18 × 3.0 Gy is predicted to substantially increase TCP, particularly for late-stage HNC tumors (eg, ∼35% to 49% for late-stage tumors) while decreasing high-grade LNTCP (eg, ∼13% to <2%), as compared with a standard 35 × 2.0 Gy protocol. In addition, the treatment time is reduced from 47 to 24 days. Twice-daily treatments of 1.8 Gy per fraction provide still better outcomes. The hypofractionation predictions are robust, being almost independent of the details of the repopulation model.

Hypofractionation or its close variant, accelerated hyperfractionation, efficiently overcomes tumor repopulation in fast-growing tumors and can be optimized toward the end of treatment when repopulation causes the TCP to increase only very slowly while LNTCP increases rapidly. Radiobiological modeling suggests that optimized 3.0 Gy per fraction hypofractionation (or 1.8 Gy per fraction, 2 fractions per weekday, accelerated hyperfractionation) is considerably more effective for HNC tumor control and for reduction of late effects than standard 2.0-Gy fractionation.