1. 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

2. 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

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

4. 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

5. 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

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

7. 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

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

10. Treatment Outcomes
Median duration of administration: 90 days (range= )

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

13. Adverse Events

14. Factors contributing to OS

15. Factors contributing to PFS

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

17. 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= )
Grade 3-4 median= 806 d (95% CI= )
median= 159 d (95% CI= )
median= 149 d (95% CI= 1-316)

18. 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

19. 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

20. 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

21. 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%

22. 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

23. References
Josep M, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:
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):
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

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