Improved tumour response prediction with equivalent uniform dose in pre-clinical study using direct intratumoural infusion of liposome-encapsulated ¹⁸⁶Re radionuclides

Abstract

Crucial to all cancer therapy modalities is a strong correlation between treatment and effect. Predictability of therapy success/failure allows for the optimization of treatment protocol and aids in the decision of whether additional treatment is necessary to prevent tumour progression. This work evaluated the relationship between cancer treatment and effect for intratumoural infusions of liposome-encapsulated ¹⁸⁶Re to head and neck squamous cell carcinoma xenografts of nude rats. Absorbed dose calculations using a dose-point kernel convolution technique showed significant intratumoural dose heterogeneity due to the short range of the beta-particle emissions. The use of three separate tumour infusion locations improved dose homogeneity compared to a single infusion location as a result of a more uniform radioactivity distribution. An improved dose-response correlation was obtained when using effective uniform dose (EUD) calculations based on a generic set of radiobiological parameters (R² = 0.84) than when using average tumour absorbed dose (R² = 0.22). Varying radiobiological parameter values over ranges commonly used for all types of tumours showed little effect on EUD calculations, which suggests that individualized parameter use is of little significance as long as the intratumoural dose heterogeneity is taken into consideration in the dose-response relationship. The improved predictability achieved when using EUD calculations for this cancer therapy modality may be useful for treatment planning and evaluation.

Figure 1

Ratio of day 43 tumour volume to that of day 0 tumour volume versus average tumour absorbed dose for individual rats. ● represents rats receiving one tumour infusion location of ¹⁸⁶Re-liposomes, ▲ represents rats receiving three tumour infusion locations of ¹⁸⁶Re-liposomes, and ■ represents rats receiving neoadjuvant bevacizumab treatment in addition to three tumour infusion locations of ¹⁸⁶Re-liposomes.

Figure 2

Average DVHs for the three therapy groups. (a) Linear plot used to show significant tumour absorbed dose heterogeneity; (b) Semilogarithmic plot used to better illustrate low dose regions.

Figure 3

Ratio of day 43 tumour volume to that of day 0 tumour volume versus EUD for individual rats. ● represents rats receiving one tumour infusion location of ¹⁸⁶Re-liposomes, ▲ represents rats receiving three tumour infusion locations of ¹⁸⁶Re-liposomes, and ■ represents rats receiving neoadjuvant bevacizumab treatment in addition to three tumour infusion locations of ¹⁸⁶Re-liposomes. The dotted line represents an exponential decay fit (R² = 0.84) to all data points.

Figure 4

Variation in average group EUD values with α/β for different α values. ◆ represents rats receiving one tumour infusion location of ¹⁸⁶Re-liposomes, ■ represents rats receiving three tumour infusion locations of ¹⁸⁶Re-liposomes, ▲ represents rats receiving neoadjuvant bevacizumab treatment in addition to three tumour infusion locations of ¹⁸⁶Re-liposomes, and ⨯ represents α/β and α values for each group used for EUD calculations in figure 3.

Figure 5

Variation in individual rat EUD values with T_pot. Numbers in parenthesis of legend represent relative tumour volume changes from table 1. Solid lines represent rats receiving one tumour infusion location of ¹⁸⁶Re-liposomes, dotted lines represent rats receiving three tumour infusion locations of ¹⁸⁶Re-liposomes, and dashed lines represent rats receiving neoadjuvant bevacizumab treatment in addition to three tumour infusion locations of ¹⁸⁶Re-liposomes, and ⨯ represents T_pot values for each rat used for EUD calculations in figure 3.

Figure 6

Variation in individual rat EUD values with T_rep. Numbers in parenthesis of legend represent relative tumour volume changes from table 1. Solid lines represent rats receiving one tumour infusion location of ¹⁸⁶Re-liposomes, dotted lines represent rats receiving three tumour infusion locations of ¹⁸⁶Re-liposomes, and dashed lines represent rats receiving neoadjuvant bevacizumab treatment in addition to three tumour infusion locations of ¹⁸⁶Re-liposomes, and ⨯ represents T_rep values for each group used for EUD calculations in figure 3.