Temporally feathered intensity-modulated radiation therapy: A planning technique to reduce normal tissue toxicity

Abstract

Purpose: Intensity-modulated radiation therapy (IMRT) has allowed optimization of three-dimensional spatial radiation dose distributions permitting target coverage while reducing normal tissue toxicity. However, radiation-induced normal tissue toxicity is a major contributor to patients' quality of life and often a dose-limiting factor in the definitive treatment of cancer with radiation therapy. We propose the next logical step in the evolution of IMRT using canonical radiobiological principles, optimizing the temporal dimension through which radiation therapy is delivered to further reduce radiation-induced toxicity by increased time for normal tissue recovery. We term this novel treatment planning strategy "temporally feathered radiation therapy" (TFRT).

Methods: Temporally feathered radiotherapy plans were generated as a composite of five simulated treatment plans each with altered constraints on particular hypothetical organs at risk (OARs) to be delivered sequentially. For each of these TFRT plans, OARs chosen for feathering receive higher doses while the remaining OARs receive lower doses than the standard fractional dose delivered in a conventional fractionated IMRT plan. Each TFRT plan is delivered a specific weekday, which in effect leads to a higher dose once weekly followed by four lower fractional doses to each temporally feathered OAR. We compared normal tissue toxicity between TFRT and conventional fractionated IMRT plans by using a dynamical mathematical model to describe radiation-induced tissue damage and repair over time.

Results: Model-based simulations of TFRT demonstrated potential for reduced normal tissue toxicity compared to conventionally planned IMRT. The sequencing of high and low fractional doses delivered to OARs by TFRT plans suggested increased normal tissue recovery, and hence less overall radiation-induced toxicity, despite higher total doses delivered to OARs compared to conventional fractionated IMRT plans. The magnitude of toxicity reduction by TFRT planning was found to depend on the corresponding standard fractional dose of IMRT and organ-specific recovery rate of sublethal radiation-induced damage.

Conclusions: TFRT is a novel technique for treatment planning and optimization of therapeutic radiotherapy that considers the nonlinear aspects of normal tissue repair to optimize toxicity profiles. Model-based simulations of TFRT to carefully conceptualized clinical cases have demonstrated potential for radiation-induced toxicity reduction in a previously described dynamical model of normal tissue complication probability (NTCP).

Keywords: dosimetry planning; normal tissue complication probability; normal tissue toxicity reduction; temporally feathered radiation therapy; therapeutic ratio.

Figure 1

Schematic representation of treatment planning in temporally feathered radiation therapy (TFRT). The planning target volume (PTV) is in close proximity to five organs at risk (OARs). Each OAR i receives a higher fractional dose once weekly (d_{H i}), followed by lower fractional doses for the remaining 4 weekdays (d_{L i}), 1 ≤ i ≤ 5. The PTV is represented as a pentagon, and circles represent the surrounding OARs. For each weekday and treatment plan a single and different OAR is unconstrained, where the remaining are constrained. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2

Comparison of conventionally fractionated IMRT and TFRT based on the biologically effective dose (BED) model. From left to right, ∆BED is represented in the divergent colormap for increasing doses d_S . The x‐ and y‐axes represent ∆L = d_S −d_L and ∆H = d_H −d_S , respectively. The regions below and above the dashed lines represent combinations of d_L and d_H in which TFRT plans deliver lower and higher total doses compared to the corresponding IMRT plan delivering a fractional dose d_S , respectively. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 3

Comparison and representation of NTCP and radiation‐induced OAR toxicity between conventionally fractionated IMRT and TFRT with varying organ‐specific recovery rates (μ). Bottom panels, from left to right, ∆NTCP (colorbar: positive values are beneficial, negative values are detrimental) are represented for d_S  = 1.2 Gy and increasing values of μ. The x‐ and y‐axes represent ∆L = d_S −d_L and ∆H = d_H −d_S , respectively. The regions below and above the dashed lines represent combinations of d_L and d_H in which TFRT plans deliver lower and higher total composite doses compared to the corresponding IMRT plan delivering a fractional dose d_S , respectively. Top panels show the time‐evolution of OAR toxicity induced by the IMRT and TFRT plans corresponding to the location marked by stars in bottom panels. Dashed lines represent the time points at which NTCP of IMRT (higher OAR toxicity) and TFRT (lower OAR toxicity) plans are compared. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 4

Comparison and representation of NTCP and radiation‐induced OAR toxicity between conventionally fractionated IMRT and TFRT with varying standard fractional doses (d_S ). Bottom panels, from left to right, ∆NTCP (colorbar: positive values are beneficial, negative values are detrimental) are represented for μ = 0.15 day⁻¹ and increasing fractional doses d_S IMRT plans. The x‐ and y‐axes represent ∆L = d_S −d_L and ∆H = d_H −d_S , respectively. The regions below and above the dashed lines represent combinations of d_L and d_H in which TFRT plans deliver lower and higher total composite doses compared to the corresponding IMRT plan delivering a fractional dose d_S , respectively. Top panels show the time‐evolution of OAR toxicity induced by the IMRT and TFRT plans corresponding to the location marked by stars in bottom panels. Dashed lines represent the time points at which NTCP of IMRT (higher OAR toxicity) and TFRT (lower OAR toxicity) plans are compared. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 5

Comparison of conventionally fractionated IMRT and TFRT with respect to the standard fractional dose (d_S ) and organ‐specific recovery rate (μ). (a) Overall potential benefit (OPB_TF ) and (b) maximum potential benefit (MAX_TF ) of TFRT over conventional planned IMRT. (I‐III) Top panels represent the single cases marked by stars in (a). The x‐ and y‐axes represent ∆L = d_S −d_L and ∆H = d_H −d_S , respectively. Bottom panels show time‐evolution of OAR toxicity induced by the IMRT and TFRT plans corresponding to the location marked by diamonds in the top panels. [Color figure can be viewed at wileyonlinelibrary.com]