Long Term Results of a Phase I Dose-Escalation Trial and Subsequent Institutional Experience of Single-Fraction Stereotactic Radiation Therapy for Liver Metastases

Abstract

Stereotactic ablative radiotherapy (SabR) is an increasingly utilized treatment modality for liver metastases, but limited data are available on outcomes and toxicity from single fraction treatment. We report long term outcomes from a Phase I dose-escalation study to determine the maximum tolerated dose of single-fraction liver SabR pooled with our subsequent single institutional experience with patients treated post-protocol at the highest dose level (40 Gy) from the Phase I study. Patients with liver metastases from solid tumors located outside of the central liver zone, defined as a 2-cm expansion around the course of the portal vein to its bifurcation in the liver, were treated with single-fraction SabR on a Phase I dose escalation trial. At least 700 cc of normal liver had to receive <9.1 Gy. Seven patients were enrolled to the first dose level (prescription dose of 35 Gy). Dose was then escalated to 40 Gy in a single fraction, and seven more patients were treated. An additional 19 patients with liver metastases from solid tumors were subsequently treated to 40 Gy in a single fraction post-protocol. Treatment plan was defined by multidisciplinary team in all cases. Patients were followed for toxicity and underwent serial imaging to assess for local control. Median imaging follow up for the combined cohort (n = 33, 39 lesions) was 21.3 months; 38.9 months for protocol patients and 12.8 months for subsequent patients. Fourteen patients with 17 liver metastases were treated on protocol, and subsequently 19 additional patients with 22 liver metastases were treated to 40 Gy. All patients had confirmed metastatic disease, and 36.3% had other non-hepatic sites of metastatic disease at time of treatment. Median lesion size was 2.1 cm (range 0.5-5.0 cm). The majority of patients had colorectal (45.5%) or renal (21.1%) malignancies. As previously reported, there were no dose-limiting toxicities observed at either dose level for protocol patients, and only three Grade 2 toxicities (abdominal pain, nausea/vomiting, alkaline phosphatase elevation) were observed in the entire cohort, with no Grade ≥ 3 toxicities attributable to treatment. There were two local failures (5.1% crude rate of failure); one marginal failure in the protocol group in the 40 Gy cohort (73.5 months post-treatment), and one in-field failure in the subsequent group (14.5 months post-treatment); both patients’ lesions were colorectal histology. Four-year actuarial local control of irradiated lesions in the entire cohort was 96.2%; 100% in the protocol group and 91% in the subsequent patients, respectively. Two- and four-year overall survival for all treated patients was 80% and 45.7%, respectively. For selected patients with liver metastases, single-fraction SabR at doses of 35 and 40 Gy was safe and well-tolerated, and shows excellent local control with long term follow-up; results in subsequent patients treated with single-fraction SabR doses of 40 Gy confirm our earlier results.