Charlotte E.N.M. Rosenbaum

Insights into the Dose-Response Relationship of Radioembolization with Resin 90Y-Microspheres : A Prospective Cohort Study in Patients with Colorectal Cancer Liver Metastases

Randomized controlled trials are investigating the benefit of hepatic radioembolization added to systemic therapy in the first- and second-line treatment of patients with colorectal liver metastases (CRLM). Remarkably, administered activity may still be suboptimal, because a dose–response relationship has not been defined. The purpose of this study was to characterize the relationship between tumor-absorbed dose and response after 90Y radioembolization treatment for CRLM. Methods: Thirty patients with unresectable chemorefractory CRLM were treated with resin 90Y-microspheres in a prospective phase II clinical trial. Tumor-absorbed dose was quantified on 90Y PET. Metabolic tumor activity, defined as tumor lesion glycolysis (TLG*) on 18F-FDG PET, was measured at baseline and 1 mo after treatment. The relationship between tumor-absorbed dose and posttreatment metabolic activity was assessed per metastasis with a linear mixed-effects regression model. Results: Treated metastases (n = 133) were identified. The mean tumor-absorbed dose was 51 ± 28 Gy (range, 7–174 Gy). A 50% reduction in TLG* was achieved in 46% of metastases and in 11 of 30 (37%) patients for the sum of metastases. The latter was associated with a prolonged median overall survival (11.6 vs. 6.6 mo, P = 0.02). A strong and statistically significant dose–response relationship was found (P < 0.001). The dose effect depended on baseline TLG* (P < 0.01). The effective tumor-absorbed dose was conservatively estimated at a minimum of 40–60 Gy. Conclusion: A strong dose–response relationship exists for the treatment of CRLM with resin microsphere 90Y radioembolization. Treatment efficacy is, however, still limited, because the currently used pretreatment activity calculation methods curb potentially achievable tumor-absorbed dose values. A more personalized approach to radioembolization is required before concluding on its clinical potential.

Clinical and Laboratory Toxicity after Intra-Arterial Radioembolization with 90Y-Microspheres for Unresectable Liver Metastases

Objective To investigate clinical and laboratory toxicity in patients with unresectable liver metastases, treated with yttrium-90 radioembolization (90Y-RE). Methods Patients with liver metastases treated with 90Y-RE, between February 1st 2009 and March 31st 2012, were included in this study. Clinical toxicity assessment was based on the reporting in patient’s charts. Laboratory investigations at baseline and during a four-month follow-up were used to assess laboratory toxicity according to the Common Terminology Criteria for Adverse Events version 4.02. The occurrence of grade 3–4 laboratory toxicity was stratified according to treatment strategy (whole liver treatment in one session versus sequential sessions). Response assessment was performed at the level of target lesions, whole liver and overall response in accordance with RECIST 1.1 at 3- and 6 months post-treatment. Median time to progression (TTP) and overall survival were calculated by Kaplan-Meier analysis. Results A total of 59 patients, with liver metastases from colorectal cancer (n = 30), neuroendocrine tumors (NET) (n = 6) and other primary tumors (n = 23) were included. Clinical toxicity after 90Y-RE treatment was confined to grade 1–2 events, predominantly post-embolization symptoms. No grade 3–4 clinical toxicity was observed, whereas laboratory toxicity grade 3–4 was observed in 38% of patients. Whole liver treatment in one session was not associated with increased laboratory toxicity. Three-months disease control rates for target lesions, whole liver and overall response were 35%, 21% and 19% respectively. Median TTP was 6.2 months for target lesions, 3.3 months for the whole liver and 3.0 months for overall response. Median overall survival was 8.9 months. Conclusion The risk of severe complications or grade 3–4 clinical toxicity in patients with liver metastases of various primary tumors undergoing 90Y-RE is low. In contrast, laboratory toxicity grade 3–4 can be expected to occur in more than one-third of patients without any clinical signs of radiation induced liver disease.

The effect of intra-arterial angiotensin II on the hepatic tumor to non-tumor blood flow ratio for radioembolization: a systematic review.

Purpose Treatment efficacy of intra-arterial radioembolization for liver tumors depends on the selective targeting of tumorous tissue. Recent investigations have demonstrated that tumors may receive inadequate doses of radioactivity after radioembolization, due to unfavorable tumor to non-tumor (T/N) uptake ratios of radioactive microspheres. Hepatic arterial infusion of the vasoconstrictor angiotensin II (AT-II) is reported to increase the T/N blood flow ratio. The purpose of this systematic review was to provide a comprehensive overview of the effect of hepatic arterial AT-II on T/N blood flow ratio in patients with hepatic malignancies, and determine its clinical value for radioembolization. Methods This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A structured search was performed in the PubMed, EMBASE and Cochrane databases. Only studies that presented data on T/N ratios before and after infusion of AT-II into the hepatic artery, in human patients with hepatic malignancies, were selected. Median T/N ratios before, during and after AT-II infusion, and the median T/N ratio improvement factor were extracted from the selected articles. All data on systemic blood pressure measurements and clinical symptoms were also extracted. Results The search identified 524 titles of which 5 studies, including a total of 71 patients were considered relevant. Median T/N ratios before infusion of AT-II ranged from 0.4 to 3.4. All studies observed a substantial improvement of the T/N ratio after AT-II infusion, with median improvement factors ranging from 1.8 to 3.1. A transitory increase of systemic blood pressure was observed during AT-II infusion. Conclusions Infusion of AT-II into the hepatic artery leads to an increase of the tumor to non-tumor blood flow ratio, as measured by T/N uptake ratios. Clinical trials are warranted to assess safety aspects, optimal administration strategy and impact on treatment efficacy during radioembolization.