Highly Conformal Partial Liver Irradiation for Chemorefractory Unresectable Colorectal Liver Metastases

Abstract

There is limited safety data regarding liver irradiation in patients that have been extensively pretreated for metastatic liver disease. The aim is to report toxicity and response data from a phase I study of partial liver irradiation using highly conformal radiotherapy (CRT) for unresectable colorectal liver metastases (CRLM) that have received all lines of therapy available. Eligible patients had unresectable or medically inoperable CRLM and received all standard therapies (chemotherapy, surgery, radiofrequency ablation), Childs score A and KPS > 60 and signed informed consent. CRT was delivered hypofractionated in 10 fractions over 2 weeks. Adaptive radiotherapy management was used with planning target volume being patient specific according to tumor motion characterized on 4DCT and cine MRI. Delivered dose was individualized according to volume of uninvolved liver irradiated to the prescribed dose in 3 dose bins: <30% = 40 Gy, 30-50% = 35 Gy, 50-70% = 30 Gy and to maintain the estimated risk of liver toxicity <5%. Six patients were entered in each dose bin. The primary endpoints were feasibility and toxicity, secondary local control, and survival. The toxicity was assessed using CTCAE v 3.0 scale: weekly during CRT, and at 1 month, then 3 monthly assessments also with imaging. Radiation induced liver disease (RILD) grade 4 within 12 weeks of radiation would have stopped recruitment. From Nov 2006 to March 2010, 18 patients were recruited and all completed CRT. Mean age 70 year (range, 44-85). Eight patients had metastatic disease at initial diagnosis. All patients had combination chemotherapy and or biological agents: median 2 lines (range, 1-4), 5 patients had hepatic resection and 7 also had radiofrequency ablation. The mean tumor volume was 85 cc (range, 3 cc to 395 cc). A total of 26 metastases were treated. The CRT tumor dose ranged from 30 Gy to 40 Gy (average 35 Gy. No grade 3/4/5 related acute toxicity was observed. No radiation-induced liver disease (RILD) was observed. Other toxicity within 3 months following CRT included grade 2: anemia (1), liver capsular pain (1), nausea (1) fatigue (2) and skin toxicity (1). Fifteen patients had at least 3 months of follow-up, in-field response assessed using CT at 3 months was: PR (6), MR/SD (5), PD (4). Median follow-up was 8.7 months (1.5 to 40 months). Median in field progression-free survival was 8.9 months. Median overall survival (OS) 17.7 months; 1 year OS 42% (95% CI 18-64%). On progression, 6 patients were re-challenged with chemotherapy. No late toxicities grades 3-5 were seen. In a heavily pretreated population with large liver burden disease this approach of individual dose CRT appears safe; with no additional toxicity observed in higher dose bin (40 Gy).