Dose-Response and Dose-Toxicity Relationships for Glass 90Y Radioembolization in Patients with Liver Metastases from Colorectal Cancer

Abstract

Radioembolization based on personalized treatment planning requires established dose-response and dose-toxicity relationships. The aim of this study was to investigate dose-response and dose-toxicity relationships in patients with colorectal liver metastases (CRLMs) treated with glass ⁹⁰Y-microspheres. Methods: All CRLM patients treated with glass ⁹⁰Y-microspheres in our institution were retrospectively analyzed. The tumor-absorbed dose was calculated for each measurable metastasis (i.e.,¹⁸F-FDG-positive and more than a 5-cm³ tumor volume) on posttreatment ⁹⁰Y PET. Metabolic tumor response was determined on ¹⁸F-FDG PET/CT by measuring the total lesion glycolysis at baseline and at 3 mo after treatment. The relationship between tumor-absorbed dose and metabolic response was determined on a per-lesion and per-patient basis using a linear mixed-effects regression model. Clinical toxicity and laboratory toxicity were correlated with healthy liver-absorbed dose. Results: Thirty-one patients were included. The median tumor-absorbed dose of 85 measurable metastases was 133 Gy (range, 20-1001 Gy). Per response category, this was 196 Gy for complete response (CR), 177 Gy for partial response (PR), 72 Gy for stable disease, and 95 Gy for progressive disease (PD). A significant dose-response relationship was found on a tumor level, with a significantly higher tumor-absorbed dose in metastases with CR (+94%) and PR (+74%) than in metastases with PD (P < 0.001). A similar relationship was found on a patient level, with PR having a higher tumor-absorbed dose than did PD (+58%, P = 0.044). A tumor-absorbed dose of more than 139 Gy predicted a 3-mo metabolic response with the greatest accuracy (89% specificity and 77% sensitivity), whereas a tumor-absorbed dose of more than 189 Gy predicted response with 97% specificity and 45% sensitivity. The median healthy liver-absorbed dose was 63 Gy (range, 24-113 Gy). Toxicity was limited mostly to grades 1 and 2, with 1 case of radioembolization-induced liver disease in a patient who received the highest healthy liver-absorbed dose. A positive trend was seen for most laboratory parameters in our dose-toxicity analysis. Conclusion: A significant relationship was observed between dose and response in CRLM patients treated with glass ⁹⁰Y radioembolization.

Keywords: 90Y PET; colorectal liver metastases; dose–response relationship; radioembolization; total lesion glycolysis.

Graphical abstract

FIGURE 1.

Example of absorbed dose and total lesion glycolysis (TLG) calculation. (A) Threshold-based mask on baseline ¹⁸F-FDG PET to delineate 3 lesions and determine baseline TLG; lesion 3 had volume < 5 cm³ and was excluded. (B) VOIs registered to posttreatment ⁹⁰Y PET/CT to determine individual tumor-absorbed dose. Dose distribution was more heterogeneous in lesion 1. (C) TLG measurement on 3-mo follow-up ¹⁸F-FDG PET. Lesion 2 had decrease in metabolic activity of 96% (PR), whereas lesion 1 had only 53% decrease (PR). (D) Healthy liver–absorbed dose as measured on posttreatment ⁹⁰Y PET/CT. Liver contour was manually delineated; this VOI was subsequently expanded by 10 mm in all directions to include all hepatic activity. Healthy liver VOI was achieved by subtracting all lesion VOIs.

FIGURE 2.

Flowchart of patient inclusion and exclusion. FU = follow-up.

FIGURE 3.

Box plots demonstrating relationship between tumor-absorbed dose on tumor level and metabolic response at 3-mo follow-up. One outlier in complete CR category (1,001 Gy) is not depicted.

FIGURE 4.

Receiver-operating-characteristic curve demonstrating predictive value of tumor-absorbed dose for metabolic response (CR + PR), on tumor level. Area under curve (AUC) is based on analysis of clustered data, whereas receiver-operating-characteristic curve is not. Receiver-operating-characteristic curve is marked with corresponding tumor-absorbed dose in Gy.

FIGURE 5.

Relationship between tumor-absorbed dose on patient level and metabolic tumor response at 3-mo follow-up. White dots represent mean tumor-absorbed dose per response category, and 95% CIs are represented by black lines. Large bullets depict mean tumor-absorbed dose per patient. On patient level, only 1 patient had CR; thus, categories CR and PR were analyzed together. *Geometric mean of tumor-absorbed dose.

FIGURE 6.

Kaplan–Meier curve of overall survival in all patients (A), and curves for patients with and without metabolic tumor response at 3 mo (B).