Safety margin in irradiation of colorectal liver metastases: assessment of the control dose of micrometastases

Abstract

Background: Micrometastases of colorectal liver metastases are present in up to 50% of lesions. In this study we sought to determine the threshold dose for local control of occult micrometastases in patients undergoing CT (computed tomography)-guided brachytherapy of colorectal liver metastases.

Materials and methods: Nineteen patients demonstrated 34 local tumor recurrences originating from micrometastases after CT-guided brachytherapy of 27 colorectal liver metastases. We considered a local tumor recurrence as originating from a micrometastasis if tumor regrowth occurred adjacent to a formerly irradiated lesion and the distance of the 3D isocenter of the new lesion was <or= 23.5 mm from the previous tumor margin. Follow-up MRI was fused with the planning-CT and dosimetry data. Two reviewers independently indicated the dose exposure at the isocenter of the micrometastases. Statistical analysis included an analysis of variance (ANOVA) using backward selection. 95% tolerance intervals with coverage of 87.5 and 75% of the data of the normal distribution were calculated.

Results: The median distance of the micrometastases to the margin of the originating colorectal metastases was 8.75 mm (1-21 mm). Dose exposure at the isocenter was 12.25 Gy (7-19.8) in median. We stratified according to the distance from the isocenter to the initial tumor margin: <or= 9 mm, > 9-15 mm and > 15 mm. The median dose in the according isocenters was 13.18, 11.6 and 11.85 Gy. The threshold dose failing to prevent micrometastasis growth was sigificantly higher in a subgroup of lesions with <or= 9 mm distance as compared to > 15 mm (13.18 vs 11.85 Gy). Adjuvant chemotherapy correlated with greater distance of micrometastasis growth to the tumor but not with the threshold dose.

Conclusion: To prevent loss of local tumor control by continuous growth of micrometastases a threshold dose of 15,4 Gy (single fraction) should be delivered at a distance of 21 mm to the gross tumor margin.

Figure 1

Scheme of a follow-up MRI merged with the initial dosimetry displaying a tumor recurrence of a micrometastasis (LR). The black cross in LR marks the 3D isocenter. The dashed line describes the CTV around the colorectal liver metastasis which had been treated initially. The bold dashed line outlines 23.5 mm distance from the initial tumor margin.

Figure 2

A: planning CT with overlayed dosimetry (BrachyVision^®) showing a colorectal liver metastasis in segment 8. One catheter tip is displayed directly (black arrow), more catheters in other levels of the liver are indicated by green arrows. Verification of correct definition of the CTV was performed by image fusion of the planning CT with a MR scan (T1 GRE without contrast media) obtained 3 days prior to treatment (B). Local recurrence (white arrow) 6 months after treatment (MR, T1 GRE without contrast media, C). The distance of the 3D isocenter of the local recurrence from the initial tumor margin is 9 mm. Thus, the local tumor recurrence meets the criteria for micrometastasis growth (D). The dose initially applied in the center of the micrometastasis was 10.9 Gy.

Figure 3

Boxplot of the point dose at the center of each micrometastasis as indicated by both readers.

Figure 4

Intra-class correlation for comparison of the readers demonstrating a very high interobserver correlation (0.86).

Figure 5

Boxplot of the dose at the 3D isocenter of each micrometastasis grouped according to the distance to the margin of the originating metastases across readers. The difference between the doses measured in the group ≤ 9 mm (in median 13.18 Gy) and > 15 mm (in median 11.85 Gy) was significant (p = 0.0442).

Figure 6

Distance of the micrometastases to the former tumor margin stratified by history of adjuvant chemotherapy (yes: figure 6 A, no: figure 6 B), whereas tumor growth occurred in significantly greater distance from the originating metastasis when adjuvant chemotherapy was applied (p = 0.0038)— related lower dose levels failed to reach statistical significance (p > 0.05).