在使用Sorafenib治療肝細胞癌過程中患有 手足症候群的病人具有較好的存活時間 楊筱惠1 陳言丞1 李明哲1 楊穎勤1 花蓮慈濟醫院外科部1

Sorafenib in Advanced HCC SHARP study Asia-Pacific study GEDION study Prolonged nearly 3 months of median survival and time to radiologic progression than placebo 衛生福利部中央健康署 101/07/17

Adverse Events Lancet Oncol 2009; 10: 25–34 N Engl J Med 2008;359:378-90

Hand-foot Skin Reaction Lee, 2013: incidence of HFSR - Asia-Pacific study (45%) vs. SHARP study (21%) ethnic differences in single nucleotide polymorphisms (SNPs) Cancer 2013;119:136-42

skin compression/subclinical trauma Mechanism sorafenib eccrine sweat glands  toxic accumulation vascular remodeling Inflammation/ fibrosis skin compression/subclinical trauma resistant of blood flow Tissue hypoxia Release proangiogenetic factor TNF-α VEGF- VEGFR2 PDGF damaged vascular integrity c-kit/ Raf kinase keratinocyte injury JDDG;2010• 8:652–661 Cancer 2013;119:136-42

Purpose Treatment outcomes of Hualien Tzu-chi hospital Efficacy of sorafenib in patients with the most common adverse event- HFSR

於門診或住院期間開立sorafenib者 Our series: Retrospective chart review: Jan. 2011~May, 2016 一般外科診斷肝癌病人 於門診或住院期間開立sorafenib者 n= 51 No major vessel invasion or extra-hepatic disease n=2 Study group n= 49 Previous resection, n= 30

(n= 29) (n= 12) (n= 9) (n= 28)

Treatment Outcomes Median duration of administration: 90 days (range= 1-1269)

Median OS and PFS days Six-month survival rate= 47% (n=21/45) Median= 232 d (95% CI= 38-425) Median= 142 d (95% CI= 45-239) Six-month survival rate= 47% (n=21/45) One-year survival rate= 29% (n=13/45)

Adverse Events

Factors contributing to OS

Factors contributing to PFS

HFSR for OS & PFS HFSR(+) median= 440 d (95% CI= 223-656)

Severity of HFSR in OS and PFS Grade 1-2 Grade 3-4 P= .40 Grade 1-2 Grade 3-4 P= .80 Grade 1-2 median= 325 d (95% CI= 105-545) Grade 3-4 median= 806 d (95% CI= 1-1744) median= 159 d (95% CI= 15-303) median= 149 d (95% CI= 1-316)

Discussion Similar OS but better PFS than Asia-Pacific study and TVGH trial  poor response in Eastern country Our patients: older, more deteriorated liver function SHARP Asia-Pacific TVGH Tzu-chi Overall survival (m) 10.7 6.5 8.0 7.7 Progression-free (m) 5.5 2.8 2.5 4.7 Response rate 2% 3.3% 5.4% 0ne-year survival 44% 36% 29% Ref: N Engl J Med 2008;359:378-90 Lancet Oncol 2009; 10: 25–34 I-Cheng Lee, et al. Medicine. 2015:e688

HCC, BCLC C: n= 46 Iizuka, June 2009~ Dec. 2012 Progression-free survival Extrahepatic HCC and HFS are associated with prolonged TTP, also useful indicators of efficacy Ref: Yada M et al. Predicting sorafenib efficacy for HCC

Sorafenib in mRCC: 36 Japanese, May 2008~ Feb. 2012 Waterfall plot of tumor response Progression-free survival 74 % vs. 15% significantly better tumor response and PFS in HFSR (+) HFSR might be an independent predictive factor Ref: Kazuhiko, et al. Jpn J Clin Oncol 2013;43(10)1023–1029

In our series, 23 patients (47%) had hand-foot skin reaction. 17 patients (74%) had dose reduction, but the correlation was not available. - prolonged overall survival and progression-free survival despite dose reduction Duration Mean final dosage Full dose 800mg HFSR (+) 370 days 420mg 22% HFSR (-) 80 days 665mg 69%

Conclusion HFSR, diarrhea and peripheral pitting edema were most common adverse events, among them, patients with HFSR had significant longer OS and PFS HFSR predicts a good response to the anti-angiogenic activity of sorafenib in advanced HCC

References Josep M, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-90. Ann-Lii Cheng, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009; 10: 25–34. Masayoshi Yada, et al. Indicators of sorafenib efficacy in patients with advanced hepatocellular carcinoma. World J Gastroenterol 2014; 20(35): 12581-87 Sioulas, et al. Sorafenib-induced hand-foot syndrome. Clin Res Hepatol Gastro. (2015) Annette Degen, et al. The hand-foot-syndrome associated with medical tumor therapy – classification and management. JDDG;2010:652–661 Kazuhiko, et al. Hand–Foot Skin Reaction is Associated with the Clinical Outcome in Patients with Metastatic Renal Cell Carcinoma Treated with Sorafenib. Jpn J Clin Oncol 2013;43(10)1023–1029 Jordi Bruix, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: Subanalyses of a phase III trial. Journal of Hepatology 2012 vol. 57, 821–829 I-Cheng Lee, et al. Determinants of Survival After Sorafenib Failure in Patients With BCLC-C Hepatocellular Carcinoma in Real-World Practice. Medicine 94(14):e688) Marcia S. Brose, et al. Management of Sorafenib-Related Adverse Events: A Clinician’s Perspective. Semin Oncol 41:S1-S16

Hand-foot Skin Reaction Palmar-plantar erythrodysesthesia Sioulas, et al. Clin Res Hepatol Gastroenterol (2015)