Skip to main content

Advertisement

SpringerLink
Log in

Hand-foot-skin reaction of grade ≥ 2 within sixty days as the optimal clinical marker best help predict survival in sorafenib therapy for HCC

  • PRECLINICAL STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Background & Aims Sorafenib-related adverse events have been reported as clinical surrogates for treatment response in hepatocellular carcinoma (HCC); however, no consensus has been reached regarding the definition of responders. We evaluated the predictive abilities of different definitions for sorafenib response based on treatment-emergent adverse events, aiming to identify the most discriminatory one as a clinical marker. Methods From January 2010 to December 2014, 435 consecutive HCC patients treated with sorafenib were enrolled. Considering the type, severity and timing of adverse events, twelve different categories of sorafenib response were defined. By comparing their discriminatory abilities for survival, an indicative criterion was defined, the prognostic value of which was evaluated by time-dependent multivariate analysis, validated in various subsets and confirmed by landmark analysis. Results Using concordance (C)-index analysis and time-dependent receiver operating characteristic curves, the development of a hand-foot-skin reaction ≥ grade 2 within 60 days of sorafenib initiation (2HFSR60) showed the highest discriminating value. Based on this criterion, 161 (37.0%) sorafenib responders achieved decreased risk of death by 47% (adjusted HR 0.53, 95%CI 0.43–0.67, P < 0.001) and likelihood of progression by 26% (adjusted HR 0.74, 95%CI 0.58–0.96, P = 0.020) compared with non-responders. Notably, 2HFSR60 remained an effective discriminator among most subgroups and had superior predictive ability to previous definitions, even according to the landmark analysis. Conclusions Our study demonstrated that 2HFSR60, with the best discriminatory ability compared to currently available definitions of sorafenib-related adverse events, could be the optimal clinical marker to identify sorafenib responders with decreased risk of death by half.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

HCC:

Hepatocellular carcinoma

AASLD:

American Association for the Study of Liver Disease

EASL:

European Association for the Study of Liver disease

DAE:

Dermatologic adverse events

HR:

hazard ratio

TACE:

Transarterial chemoembolization

ECOG:

Eastern Cooperative Oncology Group

CT:

Computed tomography

MRI:

Magnetic resonance imaging

CTCAE:

Common Terminology Criteria for Adverse Events

OS:

Overall survival

TTP:

Time to progression

mRECIST:

Modified Response Evaluation Criteria in Solid Tumors

HFSR:

Hand-foot-skin reaction

DAE:

Dermatological adverse events (including rash or/and HFSR)

AE:

Any relevant adverse events (including HFSR, rash, diarrhea, alopecia and hypertension)

HFSR30:

Developing HFSR in 30 days after the initiation of sorafenib

2HFSR30:

Developing HFSR ≥ grade 2 in 30 days

DAE30:

developing DAE in 30 days

2DAE30:

Developing DAE ≥ grade 2 in 30 days

AE30:

Developing any AE in 30 days

2AE30:

Developing any relevant AE ≥ grade 2 in 30 days

HFSR60:

Developing HFSR in 60 days

2HFSR60:

Developing HFSR ≥ grade2 in 60 days

DAE60:

Developing DAE in 60 days

2DAE60:

Developing DAE ≥ grade2 in 60 days

AE60:

Developing any relevant AE in 60 days

2AE60:

Developing any relevant AE of ≥ grade 2 in 60 days

IQR:

Interquartile range

C-:

Concordance

ROC:

Receiver operating characteristic

PVTT:

Portal vein tumor thrombosis

EHS:

Extrahepatic spread

CI:

Confidence Interval

AUC:

Area under receiver operating characteristic curve

AFP:

α-fetoprotein

References

  1. Heimbach JK, Kulik LM, Finn RS, Sirlin CB, Abecassis MM, Roberts LR, Zhu AX, Murad MH, Marrero JA (2018) AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology 67(1):358–380. https://doi.org/10.1002/hep.29086

    Article  Google Scholar 

  2. Clinical Practice Guidelines EASL Management of hepatocellular carcinoma (2018). J Hepatol. https://doi.org/10.1016/j.jhep.2018.03.019

  3. Forner A, Reig M, Bruix J (2018) Hepatocellular carcinoma. Lancet. https://doi.org/10.1016/S0140-6736(18)30010-2

  4. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344(11):783–792. https://doi.org/10.1056/NEJM200103153441101

    Article  CAS  Google Scholar 

  5. Tsao MS, Sakurada A, Cutz JC, Zhu CQ, Kamel-Reid S, Squire J, Lorimer I, Zhang T, Liu N, Daneshmand M, Marrano P, da Cunha Santos G, Lagarde A, Richardson F, Seymour L, Whitehead M, Ding K, Pater J, Shepherd FA (2005) Erlotinib in lung cancer - molecular and clinical predictors of outcome. N Engl J Med 353(2):133–144. https://doi.org/10.1056/NEJMoa050736

    Article  CAS  PubMed  Google Scholar 

  6. Dalerba P, Sahoo D, Paik S, Guo X, Yothers G, Song N, Wilcox-Fogel N, Forgo E, Rajendran PS, Miranda SP, Hisamori S, Hutchison J, Kalisky T, Qian D, Wolmark N, Fisher GA, van de Rijn M, Clarke MF (2016) CDX2 as a prognostic biomarker in stage II and stage III Colon Cancer. N Engl J Med 374(3):211–222. https://doi.org/10.1056/NEJMoa1506597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Dhanasekaran R, Venkatesh SK, Torbenson MS, Roberts LR (2016) Clinical implications of basic research in hepatocellular carcinoma. J Hepatol 64(3):736–745. https://doi.org/10.1016/j.jhep.2015.09.008

    Article  PubMed  Google Scholar 

  8. Chaiteerakij R, Addissie BD, Roberts LR (2015) Update on biomarkers of hepatocellular carcinoma. Clin Gastroenterol Hepatol 13(2):237–245. https://doi.org/10.1016/j.cgh.2013.10.038

    Article  CAS  PubMed  Google Scholar 

  9. Cho JY, Paik YH, Lim HY, Kim YG, Lim HK, Min YW, Gwak GY, Choi MS, Lee JH, Koh KC, Paik SW, Yoo BC (2013) Clinical parameters predictive of outcomes in sorafenib-treated patients with advanced hepatocellular carcinoma. Liver Int 33(6):950–957. https://doi.org/10.1111/liv.12168

    Article  CAS  PubMed  Google Scholar 

  10. Bettinger D, Schultheiss M, Knuppel E, Thimme R, Blum HE, Spangenberg HC (2012) Diarrhea predicts a positive response to sorafenib in patients with advanced hepatocellular carcinoma. Hepatology 56(2):789–790. https://doi.org/10.1002/hep.25637

    Article  PubMed  Google Scholar 

  11. Koschny R, Gotthardt D, Koehler C, Jaeger D, Stremmel W, Ganten TM (2013) Diarrhea is a positive outcome predictor for sorafenib treatment of advanced hepatocellular carcinoma. Oncology 84(1):6–13. https://doi.org/10.1159/000342425

    Article  CAS  PubMed  Google Scholar 

  12. Estfan B, Byrne M, Kim R (2013) Sorafenib in advanced hepatocellular carcinoma: hypertension as a potential surrogate marker for efficacy. Am J Clin Oncol 36(4):319–324. https://doi.org/10.1097/COC.0b013e3182468039

    Article  CAS  PubMed  Google Scholar 

  13. Akutsu N, Sasaki S, Takagi H, Motoya M, Shitani M, Igarashi M, Hirayama D, Wakasugi H, Yamamoto H, Kaneto H, Yonezawa K, Yawata A, Adachi T, Hamamoto Y, Shinomura Y (2015) Development of hypertension within 2 weeks of initiation of sorafenib for advanced hepatocellular carcinoma is a predictor of efficacy. Int J Clin Oncol 20(1):105–110. https://doi.org/10.1007/s10147-014-0691-5

    Article  CAS  PubMed  Google Scholar 

  14. Vincenzi B, Santini D, Russo A, Addeo R, Giuliani F, Montella L, Rizzo S, Venditti O, Frezza AM, Caraglia M, Colucci G, Del Prete S, Tonini G (2010) Early skin toxicity as a predictive factor for tumor control in hepatocellular carcinoma patients treated with sorafenib. Oncologist 15(1):85–92. https://doi.org/10.1634/theoncologist.2009-0143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Otsuka T, Eguchi Y, Kawazoe S, Yanagita K, Ario K, Kitahara K, Kawasoe H, Kato H, Mizuta T, Saga Liver Cancer Study G (2012) Skin toxicities and survival in advanced hepatocellular carcinoma patients treated with sorafenib. Hepatol Res 42(9):879–886. https://doi.org/10.1111/j.1872-034X.2012.00991.x

    Article  CAS  Google Scholar 

  16. Shin SY, Lee YJ (2013) Correlation of skin toxicity and hypertension with clinical benefit in advanced hepatocellular carcinoma patients treated with sorafenib. Int J Clin Pharmacol Ther 51(11):837–846. https://doi.org/10.5414/CP201907

    Article  CAS  PubMed  Google Scholar 

  17. Reig M, Torres F, Rodriguez-Lope C, Forner A, LL N, Rimola J, Darnell A, Rios J, Ayuso C, Bruix J (2014) Early dermatologic adverse events predict better outcome in HCC patients treated with sorafenib. J Hepatol 61(2):318–324. https://doi.org/10.1016/j.jhep.2014.03.030

    Article  CAS  PubMed  Google Scholar 

  18. Zhao Y, Li H, Bai W, Liu J, Lv W, Sahu S, Guan S, Qin X, Wang W, Ren W, Mu W, Guo W, Gu S, Ma Y, Yin Z, Guo W, Wang W, Wang Y, Duran R, Fan D, Zhang Z, Han G (2016) Early sorafenib-related adverse events predict therapy response of TACE plus sorafenib: a multicenter clinical study of 606 HCC patients. Int J Cancer 139(4):928–937. https://doi.org/10.1002/ijc.30124

    Article  CAS  PubMed  Google Scholar 

  19. Zhong BY, Ni CF, Chen L, Zhu HD, Teng GJ (2017) Early Sorafenib-related biomarkers for combination treatment with Transarterial chemoembolization and Sorafenib in patients with hepatocellular carcinoma. Radiology 161975. https://doi.org/10.1148/radiol.2017161975

  20. Song T, Zhang W, Wu Q, Kong D, Ma W (2011) A single center experience of sorafenib in advanced hepatocellular carcinoma patients: evaluation of prognostic factors. Eur J Gastroenterol Hepatol 23(12):1233–1238. https://doi.org/10.1097/MEG.0b013e32834bd2d0

    Article  CAS  PubMed  Google Scholar 

  21. Di Costanzo GG, de Stefano G, Tortora R, Farella N, Addario L, Lampasi F, Lanza AG, Cordone G, Imparato M, Caporaso N (2015) Sorafenib off-target effects predict outcomes in patients treated for hepatocellular carcinoma. Future Oncol 11(6):943–951. https://doi.org/10.2217/fon.14.291

    Article  CAS  PubMed  Google Scholar 

  22. Ponziani FR, Bhoori S, Germini A, Bongini M, Flores M, Sposito C, Facciorusso A, Gasbarrini A, Mazzaferro V (2016) Inducing tolerability of adverse events increases sorafenib exposure and optimizes patient's outcome in advanced hepatocellular carcinoma. Liver Int 36(7):1033–1042. https://doi.org/10.1111/liv.13052

    Article  CAS  PubMed  Google Scholar 

  23. Howell J, Pinato DJ, Ramaswami R, Bettinger D, Arizumi T, Ferrari C, Yen C, Gibbin A, Burlone ME, Guaschino G, Sellers L, Black J, Pirisi M, Kudo M, Thimme R, Park JW, Sharma R (2017) On-target sorafenib toxicity predicts improved survival in hepatocellular carcinoma: a multi-Centre, prospective study. Aliment Pharmacol Ther 45(8):1146–1155. https://doi.org/10.1111/apt.13977

    Article  CAS  PubMed  Google Scholar 

  24. Ogawa C, Morita M, Omura A, Noda T, Kubo A, Matsunaka T, Tamaki H, Shibatoge M, Tsutsui A, Senoh T, Nagano T, Takaguchi K, Tani J, Morishita A, Yoneyama H, Masaki T, Moriya A, Ando M, Deguchi A, Kokudo Y, Minami Y, Ueshima K, Sakurai T, Nishida N, Kudo M (2017) Hand-foot syndrome and post-progression treatment are the good predictors of better survival in advanced hepatocellular carcinoma treated with Sorafenib: a multicenter study. Oncology 93(Suppl 1):113–119. https://doi.org/10.1159/000481241

    Article  PubMed  Google Scholar 

  25. Rimola J, Diaz-Gonzalez A, Darnell A, Varela M, Pons F, Hernandez-Guerra M, Delgado M, Castroagudin J, Matilla A, Sangro B, Rodriguez de Lope C, Sala M, Gonzalez C, Huertas C, Minguez B, Ayuso C, Bruix J, Reig M (2017) Complete response under sorafenib in patients with hepatocellular carcinoma: relationship with dermatologic adverse events. Hepatology. https://doi.org/10.1002/hep.29515

  26. Granito A, Marinelli S, Negrini G, Menetti S, Benevento F, Bolondi L (2016) Prognostic significance of adverse events in patients with hepatocellular carcinoma treated with sorafenib. Therap Adv Gastroenterol 9(2):240–249. https://doi.org/10.1177/1756283X15618129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wang W, Bai W, Wang E, Zhao Y, Liu L, Yang M, Cai H, Xia D, Zhang L, Niu J, Yin Z, Zhang Z, Fan D, Xia J, Han G (2017) mRECIST response combined with sorafenib-related adverse events is superior to either criterion alone in predicting survival in HCC patients treated with TACE plus sorafenib. Int J Cancer 140(2):390–399. https://doi.org/10.1002/ijc.30451

    Article  CAS  PubMed  Google Scholar 

  28. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Haussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J, Group SIS (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359(4):378–390. https://doi.org/10.1056/NEJMoa0708857

    Article  CAS  PubMed  Google Scholar 

  29. Roberts LR (2008) Sorafenib in liver cancer--just the beginning. N Engl J Med 359(4):420–422. https://doi.org/10.1056/NEJMe0802241

    Article  CAS  PubMed  Google Scholar 

  30. Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, Pracht M, Yokosuka O, Rosmorduc O, Breder V, Gerolami R, Masi G, Ross PJ, Song T, Bronowicki JP, Ollivier-Hourmand I, Kudo M, Cheng AL, Llovet JM, Finn RS, LeBerre MA, Baumhauer A, Meinhardt G, Han G, Investigators R (2017) Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 389(10064):56–66. https://doi.org/10.1016/S0140-6736(16)32453-9

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

National Natural Science Foundation of China (81172145 and 81420108020).

Author information

Author notes

  1. Enxin Wang, Dongdong Xia and Wei Bai contributed equally to this work.

Authors and Affiliations

  1. Department of Liver Disease and Digestive Interventional Radiology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 15 West Changle Road, Xi’an, 710032, China

    Enxin Wang, Dongdong Xia, Wei Bai, Zhexuan Wang, Qiuhe Wang, Lei Liu, Wenjun Wang, Jie Yuan, Xiaomei Li, Hui Chen, Yong Lv, Jing Niu, Chuangye He, Wengang Guo, Zhanxin Yin, Bohan Luo, Na Han, Zhengyu Wang, Tianlei Yu, Xulong Yuan, Kai Li, Jun Tie, Daiming Fan & Guohong Han

  2. Information Center, School of Stomatology, Fourth Military Medical University, Xi’an, China

    Hongwei Cai

  3. Department of Medical Statistics, Fourth Military Medical University, Xi’an, China

    Chanjuan Li & Jielai Xia

  4. Xijing Hospital of Digestive Diseases & State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi’an, China

    Daiming Fan

Authors
  1. Enxin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dongdong Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wei Bai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhexuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qiuhe Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lei Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wenjun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jie Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xiaomei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hui Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yong Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jing Niu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Chuangye He
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Wengang Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Zhanxin Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Bohan Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Na Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Zhengyu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Tianlei Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Xulong Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Kai Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Jun Tie
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Chanjuan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Hongwei Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Jielai Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Daiming Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Guohong Han
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Guohong Han.

Ethics declarations

Conflict of interest

None.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, E., Xia, D., Bai, W. et al. Hand-foot-skin reaction of grade ≥ 2 within sixty days as the optimal clinical marker best help predict survival in sorafenib therapy for HCC. Invest New Drugs 37, 401–414 (2019). https://doi.org/10.1007/s10637-018-0640-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-018-0640-7

Keywords

Search

Navigation