Outline Radiation Therapy for Liver Malignancies Albert J. Chang, M.D., Ph.D. Department of Radiation Oncology, UCSF March 23, 2014 Rationale for developing liver directed therapies Liver directed therapies Surgery Radiofrequency Ablation Stereotactic Ablative Radiotherapy Radiation Treatment for Hepatocellular Carcinoma Rationale for Liver-Directed Therapies in Metastatic Colorectal Cancer Survival after Resection of Liver Metastases ~150,000 cases of colorectal cancer per year in the United States ~70,000 cases with liver metastases Median survival of patients with metastastic colorectal cancer has improved from approx. ~12 months ~24 months Aggressive treatment may improved survival for patients with limited volume metastatic disease 1
Criteria for Patient Selection of Surgical Therapy Goal is to resect all metastases with negative (R0) histologic margins Two adjacent liver segments can be spared Adequate vascular inflow and outflow and biliary drainage can be preserved Volume of liver remaining after resection will be adequate (at least 20% of total estimated liver volume) Perioperative Mortality with Hepatic Resection Pawlik J et al. J Gastrointest Surg. 11: 1057-1077 (2007) Fong Y et al. Ann. Surg. 1999 Sept; 230(3): 309-318 Radiofrequency Ablation Local Control with RFA Van Dujinhoven FH et al. Ann Surg Oncol. 2006 May; 13(5): 651-8 2
LR with RFA according to size The Radiation Oncologist and Liver Tumors - SABR Tumors >6 cm not considered suitable for RFA Muller S et al. Ann Surg. 2005 Aug; 242(2): 158-71 Stereotactic Ablative Body Radiation (SABR) Highly conformal with steep dose distribution High dose per treatment Image guidance stereotactic Motion management Convenient - 5 treatments or less Biologic rationale Ablative technique Induce vascular damage Increase antigen release immune response, abscopal effect Overview of Liver SABR Outcomes Table 4 Results of SBRT for liver metastasis from selected studies Study Type n Number of lesions Dose Katz et al. (2007) 20 Retrospective 69 174 30 55 Gy in fractions of 2 6 Gy prescribed Van der Pool et al. (2010) 116 Retrospective (colorectal primary only) Ambrosino et al. (2009) 140 Prospective 27 1 3 lesions for each patient Herfarth et al. Prospective (2001) 21 (phase I II) Méndez-Romero et al. (2006) 117 Prospective (phase I II) Rusthoven et al. Prospective (2009) 15 (phase I II) Lee et al. Prospective (2009) 16 (phase I) Rule et al. Prospective (2011) 17 (phase I) to 80% 20 31 12.5 15 Gy 3 fractions prescribed to PTV 25 60 Gy in 3 fractions prescribed to 80% 33 56 14 26 Gy 1 fraction prescribed to 80% 14 34 12.5 Gy 3 fractions prescribed to 65% 47 63 12 20 Gy 3 fractions prescribed to isodose line covering PTV 70 143 27.7 60 Gy in 6 fractions prescribed to isodose line covering PTV (median: 41.4 Gy) 27 37 10 Gy 3 5 fractions to 12 Gy 5 fractions prescribed to 70 85% Median follow up (months) Outcomes 14.5 10-month and 20-month LC: 76% and 57%; 6-month and 12-month OS: 46% and 24% 26 2-year LC: 74%; 2-year OS: 83% Toxic effects Grade 3 or higher toxic effects: 0 Grade 3 or higher liver toxic effects: 2 patients 13 LC (crude): 74% Mild to moderate transient hepatic dysfunction: 9 patients; minor complications: 4 patients; progressive disease with liver failure: 2 patients 5.7 6-month, 12-month, and 18-month LC: 75%, 71% and 67%; 1-year OS: 72% (analysis including 4 patients with primary liver tumors) 12.9 1-year and 2-year LC: 100% and 86%; 1-year and 2-year OS: 85% and 62% 16 for assessable lesions 10.8 for 68 assessable patients 1-year and 2-year LC: 95% and 92%; 2-year OS: 30% 1-year LC: 71%; 18-month OS: 47%; median PFS: 3.7 months 20 24-month LC: (30 Gy) 56%; (50 Gy ) 89%; (60 Gy ) 100% Abbreviations: LC, local control; OS, overall survival; PFS, progression-free survival; PTV, planning treatment volume; RILD, radiation-induced liver disease. RILD: 0 Grade 3 toxic effects: acute (n = 3) and late (n = 1); grade 4 or higher toxic effects: 0 Grade 4 toxic effects: 0 Acute grade 3 toxicities: 10%; late grade 4 and 5 toxicities: 2.9% and 1.5% Maximum-tolerated dose not reached Lo SS et al. Nat. Rev. Clin Oncol. 8, 405-416 (2011) 3
Phase I Dose Escalation Study of Liver SABR 47 patients with 63 liver metastases 60 Gy in 3 fractions prescribed to 80-90% isodose line Major prognostic factor was tumor size 2 year LC 92% 28 Patients Dose Regimens 30 Gy in 3 fractions 50 Gy in 5 fractions 60 Gy in 5 fractions One grade 3 toxicity related to CBD obstruction from progression of disease No grade 4/5 toxicity Rule W et al. Ann Surg Oncol 18, 1081-1087 (2011) SABR vs. RFA for colorectal mets Hepatocellular Carcinoma (HCC) 30 pts with 35 CRC liver metastases Matched to pts treated with RFA by number and size of lesions 24-26 Gy in single fraction prescribed to 70% isodose line. BED low (~54-59 Gy) probability of local recurrence 1.0 0.8 0.6 0.4 0.2 number at risk RRS:35 RFA:35 12 22 11 median local DFS -- RRS: 34.4 months -- RFA: 6.0 months log-rank p<0.001 HR: 0.34 (0.18 0.64) 24 36 48 60 72 months since treatment 12 3 2 1 4 2 2 2 5 th leading cause of cancer worldwide (626,000 cases/yr) In US, ~20,000 cases/yr 5 year survival ~5% Leading cause of cancer-related death Figure 1. M edian local disease free survival (D FS) since treatment of liver metastases. Stintzing et al. Acta Oncologica 52, 971-977 (2013) 4
Indications for SABR in Hepatocellular Carcinoma Unsuitable for resection, transplant, or RFA Bridge to transplant Unsuitable or refractory to TACE Main Portal Vein Invasion Hepatocellular Carcinoma Challenging - Underlying liver disease i.e. cirrhosis Radiosensitive Med FU No. pts Dose/Fraction Tumor size Response Rate/ Survival (mo) Local control Blomgren, 98 9 5-15 Gy/1-3# NR NR 70% NR Choi, 06 20 50 Gy / 5-10# 3.8 cm 23 80% 1 yr: 70% (2-6.5cm) 2 yr: 43.1% 1 yr: 75% Mendez, 06 11 25 Gy / 5 # < 7 cm NR LC 1 yr: 82% CP A + B 30-37.5 Gy / 3# Tse, 08 31 36 Gy / 6 # 173 cc 18 LC 1 yr: 65% 1 yr: 48% (24-54 Gy) (3 1913 cc) 150 cc Louis, 10 25 45 Gy / 3# 13 86% 1 yr: 79% CP A + B 2 yr: 52% 3 yr: 59% Kwon, 10 42 30 39 Gy/ # 15.4 cc 29 86% CP A 90% (3-82 cc) LC 3 yr: 68% 37% Facciuto, 11 27 24-36/ 2-4# 2.0 cm +/- 0.8 22 2 yr: 82% cm 3 cm Andolino, 11 60 44 Gy /3# CP A 27 90% 2 yr: 67% CP A/B: 36/24 40 Gy /5# CP B Seo, 10 38 33-57Gy/ 3 <10cm 79% 68% Hepatocellular Carcinoma Underlying liver disease i.e. cirrhosis Radiosensitive Med FU No. pts Dose/Fraction Tumor size Response Rate/ Survival (mo) Local control Blomgren, 98 9 5-15 Gy/1-3# NR NR 70% NR Choi, 06 20 50 Gy / 5-10# 3.8 cm 23 80% 1 yr: 70% (2-6.5cm) 2 yr: 43.1% Mendez, 06 11 CP A + B 25 Gy / 5 # 30-37.5 Gy / 3# Tse, 08 31 36 Gy / 6 # (24-54 Gy) < 7 cm NR LC 1 yr: 82% 1 yr: 75% Serious toxicity (liver or GI bleed) in ~10-30% patients Increased risk in toxicity in Child Pugh B/C 173 cc (3 1913 cc) 18 LC 1 yr: 65% 1 yr: 48% Louis, 10 25 45 Gy / 3# 150 cc 13 86% 1 yr: 79% CP A + B 2 yr: 52% 3 yr: 59% Kwon, 10 42 30 39 Gy/ # 15.4 cc 29 86% CP A 90% (3-82 cc) LC 3 yr: 68% 37% Facciuto, 11 27 24-36/ 2-4# 2.0 cm +/- 0.8 22 2 yr: 82% cm 3 cm Andolino, 11 60 44 Gy /3# CP A 27 90% 2 yr: 67% CP A/B: 36/24 40 Gy /5# CP B Seo, 10 38 33-57Gy/ 3 <10cm 79% 68% SABR for HCC PMH experience Pooled analysis of 102 patietns treated with SBRT (55% tumor thrombus, 12% extrahepatic spread) CR in 11%, PR in 43% Local Control 87% Median OS 17 months 30% Gr 3 toxicity Alternative option to ablation/embolization strategies (NCCN guidelines, category 2B) Majority of data in Child Pugh A patients Bujold et al. J Clin Oncol 31: 1631-9 (2013) NCCN.org 5
RT and TACE Phase II: TACE +/- SABR Retrospective study 73 patients with incomplete response to TACE 35 TACE repeated 38 of the patients received radiotherapy Seong et al. Liver International 25: 119-1196 (2005) RTOG 1112 1⁰ objective: To determine if SABR OS added to sorafenib Eligibility: Child Pugh A, unresectable HCC, not eligible for transplant; extrahepatic metastases excluded SABR at UCSF 23 24 6
SABR at UCSF Cyberknife Treatment of Liver Lesion 25 26 Dose Guidelines Cyberknife Treatment of HCC SBRT 3-6 fractions 95% of PTV to receive prescription dose Mean normal liver dose (liver GTV) <13 Gy for HCC in 3 fractions <18 Gy for HCC in 6 fractions <15 Gy for liver mets in 3 fractions <20 Gy for liver mets in 6 fractions <6 Gy for HCC in Childs-Pugh B patients (4-6 Gy/fraction) Critical volume model At least 700 cc normal liver recieves 15 Gy in 3-5 fractions Prox Duodenum V33Gy <1cc V20Gy <3cc Pre-Treatment 3m Post-Treatment 28 7