Phase 1 Trial of SPECT-Guided Liver-Directed Ablative Radiotherapy for Patients with Low Functional Liver Volume

Abstract

Traditional liver dose constraints specify that a critical volume of 700 cc of non-tumor liver should be spared from receiving a hepatotoxic dose. We evaluated the safety of liver-directed ablative radiotherapy for patients with hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), or liver metastases (LM) with Child-Pugh (CP) A5 liver function at baseline and with low functional liver volume as estimated by Tc-99m sulfur colloid single photon emission computed tomography (SPECT). We hypothesized that functional liver image guidance with SPECT would allow safe delivery of ablative radiotherapy in patients with limited liver volume. A phase 1 trial with a 3+3 design was conducted to evaluate the safety of comprehensive ablative radiotherapy to the liver disease using escalating functional non-target liver radiation dose constraints. Eligibility criteria included (1) a diagnosis of HCC, iCCA, or LM, (2) prior treatment with irinotecan or oxaliplatin chemotherapy or liver resection, and (3) a minimum functional liver volume of 400 cc as estimated by SPECT using a threshold of 40% maximum intensity. Patients with CP >A5 liver function, prior liver-directed radiotherapy, or prior Yttrium-90 therapy were excluded. The prescription dose was 67.5-75 Gy in 15 fractions or 75-100 Gy in 25 fractions. The volumetric dose constraint for functional non-target liver receiving <24 Gy for 15 fractions or <27 Gy for 25 fractions was determined by the dose level of trial enrollment: level 0 was ≥400 cc and level +1 was ≥300 cc. A level -1 was included if needed. We used standard 15 and 25 fraction dose constraints for other organs at risk. The following dose limiting toxicities (DLTs) were assessed within 6-8 weeks of completing radiotherapy: Grade 3 hypoalbuminemia, increase in INR, increase in bilirubin, or ascites, or Grade 4 hepatic failure or any radiation-related toxicity. Twelve patients enrolled between February 2016 and June 2022. The median (range) GTV was 36 (2-651) cc. The median CT anatomical non-tumor liver volume was 1584 (764-2699) cc, and the median SPECT functional liver volume was 1117 (570-1928) cc, with a Pearson correlation coefficient of 0.98 (p<0.001). The median non-target SPECT functional liver volume below the volumetric dose constraint was 684 (429-1244) cc. None of the 3 patients treated in dose level 0, and none of the 9 patients treated in dose level +1 experienced any DLTs. The 1-year in-treatment-field control rate was 55%, and 1-year overall survival was 71%. Ablative radiotherapy can be safely delivered using functional SPECT image guidance, which enables sparing lower volumes of functional liver than traditionally accepted in patients with CP A5 liver function. Further evaluation with a phase 2 study is warranted.