Radiobiological restrictions and tolerance doses of repeated single-fraction hdr-irradiation of intersecting small liver volumes for recurrent hepatic metastases

Abstract

Background: To assess radiobiological restrictions and tolerance doses as well as other toxic effects derived from repeated applications of single-fraction high dose rate irradiation of small liver volumes in clinical practice.

Methods: Twenty patients with liver metastases were treated repeatedly (2 - 4 times) at identical or intersecting locations by CT-guided interstitial brachytherapy with varying time intervals. Magnetic resonance imaging using the hepatocyte selective contrast media Gd-BOPTA was performed before and after treatment to determine the volume of hepatocyte function loss (called pseudolesion), and the last acquired MRI data set was merged with the dose distributions of all administered brachytherapies. We calculated the BED (biologically equivalent dose for a single dose d = 2 Gy) for different alpha/beta values (2, 3, 10, 20, 100) based on the linear-quadratic model and estimated the tolerance dose for liver parenchyma D90 as the BED exposing 90% of the pseudolesion in MRI.

Results: The tolerance doses D90 after repeated brachytherapy sessions were found between 22 - 24 Gy and proved only slightly dependent on alpha/beta in the clinically relevant range of alpha/beta = 2 - 10 Gy. Variance analysis showed a significant dependency of D90 with respect to the intervals between the first irradiation and the MRI control (p < 0.05), and to the number of interventions. In addition, we observed a significant inverse correlation (p = 0.037) between D90 and the pseudolesion's volume. No symptoms of liver dysfunction or other toxic effects such as abscess formation occurred during the follow-up time, neither acute nor on the long-term.

Conclusions: Inactivation of liver parenchyma occurs at a BED of approx. 22 - 24 Gy corresponding to a single dose of ~10 Gy (alpha/beta ~ 5 Gy). This tolerance dose is consistent with the large potential to treat oligotopic and/or recurrent liver metastases by CT-guided HDR brachytherapy without radiation-induced liver disease (RILD). Repeated small volume irradiation may be applied safely within the limits of this study.

Figure 1

Image-fusion: Contrast-enhanced computed tomography (CT) after CT-guided positioning of brachytherapy catheters (arrows) in a liver metastasis of a colorectal carcinoma, merged with the last magnetic resonance imaging of the liver acquired after all interventions (grey delineation). The hypointensity area shows the impairment of hepatocyte function in the left liver lobe.

Figure 2

Image fusion of CT-data set with the accumulated 3-D dosimetry of three different irradiation sessions. (a) Contrast-enhanced CT after first (No.1) CT-guided positioning of brachytherapy catheters (long arrow) in metastases of a colorectal carcinoma. The short arrow shows the 3-D dosimetry of another lesion, irradiated in session No.2. (b) Contrast-enhanced CT after third intervention (No.3) in the same patient. The arrow shows the upper boundary of the 3-D dosimetry of the lesion irradiated in session No.2. Physical doses are shown in the colour map.

Figure 3

Development of radiation injury of the liver after HDR brachytherapy: (a) Colorectal metastasis in liver segment IV (arrow), T1w-GRE 20 minutes after application of Gd-BOPTA. (b) Contrast-enhanced planning-CT and dosimetry after insertion of brachytherapy catheters (arrow) in the metastasis. The coloured lines indicate different isodoses. Applicated dose at the tumor margin was 20 Gy. (c) MRI after 3 months with a decreased uptake (arrow) of Gd-BOPTA around the irradiated and shrunken metastasis (T1w-GRE 20 minutes after application of Gd-BOPTA).

Figure 4

Liver biopsy. Biopsy was performed to rule out a suspected local recurrence. Tissue had been exposed to approximately 20 Gy two months ago. Heterogenous congestion of the sinusoids with beginning atrophy of liver cells. Hematoxylin-eosin, original magnification: ȕ100.

Figure 5

Based on the total 3D-D_tot-data set, Amira software calculated dose-volume histograms for all different α/β-values.

Figure 6

Mean D₉₀ for different α/β-values (2, 3, 10, 20, 100) of all patients. Statistically there was a significant difference in the D₉₀ results but the differences for clinical α/β-values were less than 1 Gy and therefore of no clinical. The star (*) represents one outlier in the series of calculation.