Addictive Benefit of Transarterial Chemoembolization and Sorafenib in Treating Advanced Stage Hepatocelluar Carcinoma: Propensity Analysis Gwang Hyeon Choi, Ju Hyun Shim*, Min-Joo Kim, Min-Hee Ryu, Baek-Yeol Ryoo, Yoon- Koo Kang, Yong Moon Shin, Danbi Lee, Kang Mo Kim, Young-Suk Lim, Han Chu Lee, Young-Hwa Chung, Yung Sang Lee, and Dong Jin Suh Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine
Background Although sorafenib has become a standard of treatment for advanced-stage HCC, its benefit is limited. Llovet, NEJM 2008; Cheng, Lancet Oncol 2009 In the pre-sorafenib era, transarterial chemoembolization (TACE) could serve as an effective therapeutic options in such patients. Yoo, JGH 2011; Kim, JGH 2009; Georgiades, JVIR 2005; Lee, Cancer 1997; Luo, ASO 2011; Chung, Radiology 2011; Pinter, Radiology 2012 Recent phase II trials evaluating concurrent treatment with TACE and sorafenib have given encouraging results for unresectable HCC partly including advanced stage disease. Pawlik, JCO 2011; Park, JHEP 2012 There have been no comparative survival data between sorafenib plus TACE and sorafenib monotherapy in advancedstage HCC.
Study Objective and Design Objective To Investigate whether combining sorafenib with TACE provided additional clinical benefits in the current indication for sorafenib monotherpay Design Retrospective cohort study 512 consecutive patients with advanced-stage HCC who received sorafenib treatment 5 weeks at Asan Medical Center between 2007 and 2011 All patients classified as BCLC stage C: : Performance status 2 : Macroscopic vascular invasion or extrahepatic spread
Patients Selection Algorithm
Treatment Schedule Single group Standard protocol (usual policy) : Sorafenib 800 mg/day (400 mg bid) as a continuous dose Escalation protocol (hepatic impairment or severe cytopenia) : Sorafenib 400 mg/day (200 mg bid or 400 mg qd), and then ramped up to 800 mg/day depending on each patient s tolerance Combination group Conventional TACE on demand + Sorafenib 400~800 mg/day on an interrupted schedule (4~7 days pre- and post-tace) Chemolipiodolization only (n=37: PVTT, liver fx, tumor extent, etc.) Median session : 2 (range, 1-11)
Response Assessment and Statistical Analysis Tumor response Measured every 6~8 weeks by dynamic CT or MRI along with chest CT and/or bone scanning if applicable Based on the modified RECIST Effectiveness Endpoints Response rate, overall survival, time-to-progression Statistics To balance potential confounders Inverse probability of treatment weighting (IPTW) Propensity score (PS) matching
Baseline Characteristics Variables Combined group (n=164) Single group (n=191) P Male/female 139/25 166/25 0.56 Age, median (range) 52 (26-75) 54 (22-84) 60 years 37 (22.6%) 60 (31.4%) 0.06 <60 years 127 (77.4%) 131 (68.6%) Etiology of liver disease 0.48 HBV/HCV/Others 139/9/16 166/6/19 0.16 Liver cirrhosis 136 (82.9%) 147 (77.0%) 0.16 Child-Pugh score A/B 119/45 136/55 0.78 Type of tumor Nodular/Infiltrative 81/83 119/72 0.014 Bilobar involvement 87 (55.12%) 86 (45.0%) 0.13 Multiple tumors ( 2) 158 (96.3%) 182 (95.3%) 0.62
Baseline Characteristics (Cont d) Variables Combined group (n=164) Single group (n=191) Macrovascular invasion 106 (64.6%) 94 (49.2%) <0.01 Main portal vein/portal br. 26/75 34/47 Hepatic vein or IVC 5 (3.0%) 13 (6.8%) Distant organ metastasis 128 (78.1%) 155 (81.2%) 0.47 Lymph node metastasis 36 (22.0%) 54 (28.3%) 0.17 Serum AFP level ( 400 ng/ml) 83 (50.6%) 104 (54.5%) 0.47 Type of study therapy First-line/Rescue 23/141 44/147 0.03 Previous therapy Liver resection 22 (13.4%) 45 (23.6%) RFA or PEI 16 (9.7%) 28 (14.7%) TACE 140 (85.4%) 135 (70.7%) Cytotoxic chemotherapy 2 (1.2%) 17 (8.9%) Radiation therapy* 116 (70.7%) 77 (40.3%) Metastasectomy 0 4 (2.1%) *Intrahepatic lesions (8%); metastatic lesions (43%); PVTT (49%) P -
Treatment Duration and Dose Adjustment Treatment course Combined Single P Total treatment duration (weeks)* 15.4 (5.0-148.3) 12.6 (5.9-156.6) <0.01 Duration of sorafenib (weeks)* 13.1 (5.0-126.7) 11.0 (5.3-133.4) 0.05 Reduced starting dosage (400 mg) 57 (34.8%) 62 (22.5%) 0.56 Dose modification or interruption 80 (48.8%) 93 (48.7%) 0.99 Discontinuation due to A/E 49 (29.9%) 51 (26.7%) 0.51 70% of the standard daily dose 81 (49.4%) 113 (59.2%) 0.07 *median (range)
Balanced Characteristics after PS matching Variables Combined group (n=96) Single group (n=96) Gender (Male/female) 78/9 76/11 0.64 Age (<60 years/ 60 years) 68/19 68/19 0.99 Etiology (HBV/others) 77/10 78/9 0.81 Liver cirrhosis 71 (81.6%) 74 (85.1%) 0.53 Child score (A/B) 64/23 66/21 0.73 Tumor type (Nodular/infiltrative) 49/38 55/43 0.34 Bilobal involvement 39 (44.8) 37 (42.5) 0.77 Multiple tumors ( 2) 85 (97.7) 86 (98.9) 0.56 Macrovascular invasion 0.90 Main portal vein/portal vein br. 12/28 10/29 Hepatic vein or IVC 4 5 Distant organ metastasis 71 (81.6%) 77 (88.5%) 0.20 Lymph node metastasis 17 (19.5%) 13 (14.9%) 0.41 Serum AFP level ( 400 ng/ml) 44 (50.6%) 45 (51.7%) 0.88 First-line therapy 15 (17.2%) 10 (11.5%) 0.28 P
Treatment responses assessed by mrecist Best response Combined (n=164) Pooled cohort Single (n=191) P Combined (n=96) Matched cohort Single (n=96) P Response category <0.01 <0.01 CR 1.2% 0 1.0% 0 PR 10.4% 4.2% 12.1% 5.5% SD 57.9% 46.1% 67.0% 50.5% Response rate 11.6% 4.2% <0.01 13.2% 5.5% 0.06 Disease control rate 69.5% 50.3% <0.01 80.2% 56.0% <0.01
Time-to-Progression Analysis Pooled Cohort Matched Cohort P = 0.008 P = 0.011 During follow-up (median, 5.5 months), the combined group had longer median TTP (2.5 vs. 2.1 months; P = 0.008). In PS-matched cohort (96 pairs), median TTP was significantly longer in the combined group (2.7 vs. 2.1 months; P = 0.011).
Overall Survival Analysis Pooled Cohort Matched Cohort P = 0.009 P = 0.21 Median OS was significantly longer in the combined group than the single group (8.9 months vs. 5.9 months; P = 0.009). But in the propensity score-matched cohort, median OS did not differ by treatment group (9.1 vs. 6.7 months; P = 0.21)
Predictions of Time-Dependent Endpoints Combined Group vs. Single Group Analysis Hazard ratio 95% CI P Crude 0.75 0.61-0.93 <0.01 Time-toprogression Adjusted 0.74 0.60-0.92 <0.01 IPTW 0.73 0.56-0.94 0.01 Propensity matched 0.71 0.55-0.92 0.01 Crude 0.71 0.55-0.92 <0.01 Overall survival Adjusted 0.57 0.43-0.75 <0.01 IPTW 0.71 0.52-0.97 0.03 Propensity matched 0.80 0.57-1.13 0.21
Subgroup Analyses of Overall Survival
Summary The objective response rate and the disease control rate were significantly higher in the combined group (11.6% vs. 4.2% and 69.5% vs. 50.3%; P<0.01), and similar results were obtained after PSmatching (13.2% vs. 5.5%; P=0.06 and 80.2% vs. 56.0%; P<0.05). In multivariate analysis, additional TACE was an independent predictor of favorable TTP and OS (adjusted HRs, 0.74 and 0.57; P<0.05 for both), consistent with the outcomes of IPTW. In the PS-matched cohort, median TTP was significantly longer in the combined group (2.7 vs. 2.1 months; P=0.011), but median OS was not (9.1 vs. 6.7 months; P=0.21).
Conclusions The addition of TACE to established sorafenib has a demonstrable effect in delaying tumor progression in patients with advanced stage HCC. TACE plus sorafenib may offer survival advantage over sorafenib alone, especially against far-advanced HCC. These results invite further prospective, randomized trials that test the potential benefit of TACE in combination with sorafenib compared to monotherapy with sorafenib, the current standard of care in advanced stage HCC.