Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2009 Jan 21;2009(1):CD001199.
doi: 10.1002/14651858.CD001199.pub2.

Neoadjuvant and adjuvant therapy for surgical resection of hepatocellular carcinoma

Miny Samuel  1 , Pierce K-H Chow, Edwin Chan Shih-Yen, David Machin, Khee-Chee Soo
Affiliations
Meta-Analysis

Neoadjuvant and adjuvant therapy for surgical resection of hepatocellular carcinoma

Miny Samuel et al. Cochrane Database Syst Rev. .

Abstract

Background: Hepatocellular carcinoma is a disease of great concern. Surgery is the treatment of choice, but there is still a high recurrence rate after resection.

Objectives: To determine the benefits and harms of neoadjuvant and adjuvant therapies compared to surgery alone or surgery and placebo/supportive therapy after curative resection for operable hepatocellular carcinoma.

Search strategy: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, Chinese Biomedical Database, and US National Cancer Institute's Physician's Data Query Trials Database until 2005. References of the identified trials were also searched for identifying further trials.

Selection criteria: Randomised and quasi-randomised trials that compared hepatocellular carcinoma patients who were given and not given neoadjuvant/adjuvant therapy as a supplement to curative liver resection.

Data collection and analysis: Data were extracted independently by two authors and discrepancies resolved by consensus. The survival and disease-free survival curves were compared using their one, two, three, four, and five-year survival rates, median survival times, and the result of the significance tests (P-values).

Main results: A total of 12 randomised trials were identified, totaling 843 patients. The size of the randomised clinical trials ranged from 30 to 155 patients. Both preoperative (neoadjuvant) and postoperative (adjuvant), systemic and locoregional (+/- embolisation), chemo- and immunotherapy interventions were tested. Treatment regimens and patients selected were not comparable, so no pooling was done. Only one regimen using preoperative transcatheter arterial chemoembolisation with doxorubicin was similar in two trials. Four of the twelve trials reported survival benefit at five years when given adjuvant or neoadjuvant therapy. Disease-free survival was reported in nine trials, and the estimated hazard ratios show that disease-free survival was significant in two trials at five years. These two trials had not shown a survival advantage, but the recurrence was significantly lower in patients given adjuvant or neoadjuvant therapy. The highest toxicity rate was in a trial using oral 1-hexylcarbamoyl 5-fluorouracil which resulted in 12 out of 38 patients being withdrawn from the trial because of adverse events.

Authors' conclusions: There is no clear evidence for efficacy of any of the adjuvant and neo-adjuvant protocols reviewed, but there is some evidence to suggest that adjuvant therapy may be beneficial offering prolonged disease-free survival. In order to detect a realistic treatment advantage, larger trials with lower risk of systematic error will have to be conducted.

PubMed Disclaimer

Conflict of interest statement

We certify that we currently have no affiliations with or involvement in any organisation or entity with a direct financial interest in the subject matter of this review (e.g., employment, consultancy, stock ownership, honoraria, expert testimony).

Figures

1.3
1.3. Analysis
Comparison 1 Neoadjuvant and adjuvant therapy versus surgery for operable HCC, Outcome 3 Death (5 years).
1.4
1.4. Analysis
Comparison 1 Neoadjuvant and adjuvant therapy versus surgery for operable HCC, Outcome 4 Overall recurrence (5 years).
1.5
1.5. Analysis
Comparison 1 Neoadjuvant and adjuvant therapy versus surgery for operable HCC, Outcome 5 Death (4 years).
1.6
1.6. Analysis
Comparison 1 Neoadjuvant and adjuvant therapy versus surgery for operable HCC, Outcome 6 Overall recurrence (4 years).
See this image and copyright information in PMC

Update of

References

References to studies included in this review

Izumi 1994 {published data only}
    1. Izumi R, Shimizu S, Iyobe T, Ii T, Yagi M, Matsui O, et al. Postoperative adjuvant hepatic arterial infusion of lipiodol containing anticancer drugs in patients with hepatocellular carcinoma. Hepatology 1994;20:295‐301. [MEDLINE: ] - PubMed
Lai 1998 {published data only}
    1. Lai ECS, Lo CM, Fan ST, Liu CL, Wong J. Postoperative adjuvant chemotherapy after curative resection of hepatocellular carcinoma. Archives of Surgery 1998;133:183‐8. [MEDLINE: ] - PubMed
Lau 1999 {published data only}
    1. Lau WY, Leung TWT, Ho SKW, Chan M, Machin D, Lau J, et al. Adjuvant intra‐arterial lipidol‐iodine‐131 for resectable hepatocellular carcinoma: a prospective randomised trial. Lancet 1999;353:797‐801. - PubMed
Lygidakis 1995 {published data only}
    1. Lygidakis NJ, Pothoulakis J, Konstantinidou AE, Spanos H. Hepatocellular carcinoma: surgical resection versus surgical resection combined with pre‐ and post‐operative locoregional immunotherapy‐cemotherapy. A prospective randomised study. Anticancer Research 1995;15(2):543‐50. [MEDLINE: ] - PubMed
Lygidakis 1996 {published data only}
    1. Lygidakis NJ, Tsiliakos S. Multidisciplinary management of hepatocellular carcinoma. Hepato‐Gastroenterology 1996;43(12):1611‐9. [MEDLINE: ] - PubMed
Nishiguchi 2005 {published data only}
    1. Kubo S, Nishiguchi S, Hirohashi K, Tanaka H, Shuto T, Kinoshita H. Randomised clinical trial of long‐term outcome after resection of hepatitis C virus‐related hepatocellular carcinoma by postoperative interferon therapy. The British Journal of Surgery 2002;89:418‐22. - PubMed
    1. Kubo S, Nishiguchi S, Hirohashi K, Tanaka H, Shuto T, Yamazaki O, et al. Effects of long‐term postoperative interferon‐alpha therapy on intrahepatic recurrence after resection of hepatitis C virus‐related hepatocellular carcinoma. Annals of Internal Medicine 2001;134:963‐7. - PubMed
    1. Nishiguchi S, Tamori A, Kubo S. Effect of long‐term postoperative interferon therapy on intrahepatic recurrence and survival rate after resection of hepatitis C virus‐related hepatocellular carcinoma. Intervirology 2005;48:71‐5. - PubMed
Ono 1997 {published data only}
    1. Ono T, Nagasue N, Kohno H, Hayashi T, Uchida M, Yukaya H, et al. Adjuvant chemotherapy with epirubicin and carmofur after radical resection of hepatocellular carcinoma: a prospective randomized study. Seminars in Oncology 1997;24(2 Suppl 6):S6‐18‐S6‐25. [MEDLINE: ] - PubMed
Takayama 2000 {published data only}
    1. Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, Yamamoto J, et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet 2000;356:802‐7. - PubMed
Wu 1995 {published data only}
    1. Wu CC, Ho YZ, Lin Ho W, Wu TC, Liu TJ, P'eng FK. Preoperative transcatheter arterial chemoembolization for resectable large hepatocellular carcinoma: a reappraisal. The British Journal of Surgery 1995;82(1):122‐6. [MEDLINE: ] - PubMed
Yamamoto 1996 {published data only}
    1. Yamamoto M, Arii S, Sugahara K, Tobe T. Adjuvant oral chemotherapy to prevent recurrence after curative resection for hepatocellular carcinoma. The British Journal of Surgery 1996;83(3):336‐40. [MEDLINE: ] - PubMed
Yamasaki 1996 {published data only}
    1. Yamasaki S, Hasegawa H, Kinoshita H, Furukawa M, Imaoka S, Takahashi K, et al. A prospective randomized trial of the preventive effect of pre‐operative transcather arterial embolization against recurrence of hepatocellular carcinoma. Japanese Journal of Cancer Research 1996;87(2):206‐11. [MEDLINE: ] - PMC - PubMed
Yunxue 1999 {published data only}
    1. Yunxue H, Kangsun Z, Zaibo J. The significance of preoperative TACE in preventing postoperative recurrence of primary hepatic carcinoma. Journal of JiLin Medical College 1999;19(2):22‐3.

References to studies excluded from this review

Bao 2001 {published data only}
    1. Bao LQ, Peng YM, Yuan HY. Clinic study on the role of hydroxycamptothecin and mateling postoperative arterial infusion in the prevention of recurrence after curative resection for human hepatocellular carcinoma. Cancer Research on Prevention and Treatment 2001;28(4):303‐5.
Ikeda 2000 {published data only}
    1. Ikeda K, Arase Y, Saitoh S, Kobayashi M, Suzuki Y, Suzuki F, et al. Interferon beta prevents recurrence of hepatocellular carcinoma after complete resection or ablation of the primary tumor ‐ a prospective randomized study of hepatitis C virus‐related liver cancer. Hepatology 2000;32:282‐32. - PubMed
Li 2002 {published data only}
    1. Li Q, Hao X, Zhang Z, Song T, Hao J, Ma W, et al. Intraportal chemotherapy for hepatocellular carcinoma patients with tumor thrombosis of the portal vein. Chinese Journal of General Surgery 2002;17(4):209‐10.
Muto 1996 {published data only}
    1. Muto Y, Moriwaki H, Ninomiya M, Adachi S, Saito A, Takasaki K, et al. Prevention of second primary tumours by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. The New England Journal of Medicine 1996;334(24):1561‐7. [MEDLINE: ] - PubMed

Additional references

Child 1964
    1. Child CG III, Tourcotte JG. Surgery and portal hypertension. In: Child CG editor(s). The Liver and Portal Hypertension. 3rd Edition. Philadelphia, Pennsylvania: WB Saunders, 1964:1‐85.
El‐Serag 2004
    1. El‐Serag HB . Hepatocellular carcinoma: recent trends in the United States. . Gastroenterology 2004;127(5 Suppl 1):S27‐34. - PubMed
Finkelstein 2003
    1. Finkelstein SD, Marsh W, Demetris AJ, Swalsky PA, Sasatomi E, Bonham A, Subotin M, Dvorchik I. Microdissection‐based allelotyping discriminates de novo tumor from intrahepatic spread in hepatocellular carcinoma. Hepatology 2003;37(4):871‐9. - PubMed
Forner 2006
    1. Forner A, Hessheimer AJ, Isabel Real M, Bruix J. Treatment of hepatocellular carcinoma. Crit Rev Oncol Hematol 2006;60(2):89‐98. - PubMed
Gluud 2008
    1. Gluud C, Nikolova D, Klingenberg SL, Whitfield K, Alexakis N, Als‐Nielsen B, et al. Cochrane Hepato‐Biliary Group. About The Cochrane Collaboration (Cochrane Review Groups (CRGs)). 2008, Issue 3. Art. No.: LIVER.
Gomaa 2008
    1. Gomaa AI, Khan SA, Toledano MB, Waked I, Taylor‐Robinson SD. Hepatocellular carcinoma: epidemiology, risk factors and pathogenesis. World J Gastroenterol 2008;21(14 (27)):4300‐8. - PMC - PubMed
Higgins 2008
    1. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.0 [updated February 2008]. The Cochrane Colloboration, 2008. Available from www.cochrane‐handbook.org.
Huguet 1994
    1. Huguet C, Stipa F, Gavelli A. Primary hepatocellular cancer: Western experience. In: Blumgart L editor(s). Surgery of the Liver and Biliary Tract. London: Churchill Livingstone, 1994:1365‐9.
Kjaergard 2001
    1. Kjaergard LL, Villumsen J, Gluud C. Reported methodological quality and discrepancies between large and small randomized trials in meta‐analyses. Annals of Internal Medicine 2001;135(11):982‐9. - PubMed
Lai 1981
    1. Lai CL, Lam KC, Wong KP, Wu PC, Todd D. Clinical features of hepatocellular carcinoma: review of 211 patients in Hong Kong. Cancer 1981;47(11):2746‐55. [MEDLINE: ] - PubMed
Lai 1994
    1. Lai E, Wong J. Hepatocellular carcinoma: the Asian experience. In: Blumgart L editor(s). Surgery of the Liver and Biliary Tract. London: Churchill Livingstone, 1994:1349‐63.
LCSG Japan 1992
    1. Liver Cancer Study Group of Japan. The General Rules for the Clinical and Pathological Study of Primary Liver Cancer (In Japanese). 3rd edition. 3rd Edition. Tokyo: Kanehara, 1992:20‐6.
Lee 1982
    1. Lee NW, Wong J, Ong GB. The surgical management of primary carcinoma of the liver. World Journal of Surgery 1982;6(1):66‐75. [MEDLINE: ] - PubMed
Lovet 2008
    1. Llovet JM, Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu AX, Sherman M, Schwartz M, Lotze M, Talwalkar J, Gores GJ, Panel of Experts in HCC‐Design Clinical Trials. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 2008;100:698‐711. - PubMed
Moher 1998
    1. Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta‐analyses?. Lancet 1998;352:609‐13. - PubMed
Nagourney 1987
    1. Nagourney DM, Adson M. Major hepatic resections for hepatoma in the West. In: Wanebo HJ editor(s). Hepatic and Biliary Cancer. New York: Marcel Dekker, 1987:167‐85.
NCCN 2008
    1. National Comprehensive Cancer Network. Hepatobiliary Cancers. www.nccn.org 2008; Vol. V.2.
Okuda 1984
    1. Okuda K, Obata H, Nakajima Y, Ohtsuki T, Okazaki N, Ohnishi K. Prognosis of primary HCC. Hepatology 1984;4:3S‐6S. [MEDLINE: ] - PubMed
Okuda 1985
    1. Okuda K, Ohtsuki T, Obata H, Tomimatsu M, Okazaki N, Hasegawa H, et al. Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Study of 850 patients. Cancer 1985;56(4):918‐28. [MEDLINE: ] - PubMed
Okuda 1987
    1. Okuda K, Ryu M, Tobe T. Surgical management of hepatoma, the Japanese experience. In: Wanebo HJ editor(s). Hepatic and Biliary Cancer. New York: Marcel Dekker, 1987:219‐38.
Okuda 1997
    1. Okuda K. Epidemiology. In: Livaraghi Makuuchi M, Buscarini L editor(s). Diagnosis and Treatment of Hepatocellular Carcinoma. London: Greenwich Medical Media, 1997:3‐15.
Oon 1980
    1. Oon CJ, Okuda K, Pang R. Primary hepatocellular carcinoma in the Asian Pacific region. Annals of the Academy of Medicine, Singapore 1980;9(2):190‐2. [MEDLINE: ] - PubMed
Parmar 1998
    1. Parmar MKB, Torri V, Stewart L. Extracting summary statistics to perform meta‐analysis of the published literature for survival endpoints. Statistics in Medicine 1998;17(24):2815‐34. [MEDLINE: ] - PubMed
RevMan 2008 [Computer program]
    1. The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.0. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008.
Royle 2003
    1. Royle P, Milne R. Literature searching for randomized controlled trials used in Cochrane reviews: rapid versus exhaustive searches. International Journal of Technology Assessment in Health Care 2003;19(4):591‐603. - PubMed
Schulz 1995
    1. Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. Journal of the American Academy of Medicine 1995;273:408‐12. - PubMed
Schwartz 2002
    1. Schwartz JD, Schwartz M, Mandeli J, Sung M. Neoadjuvant and adjuvant therapy for resectable hepatocellular carcinoma: review of the randomised clinical trials. Lancet Oncol 2002;3(10):593‐603. - PubMed
Wang 1991
    1. Wang TL, Yap IL, Tan YO. Hepatocellular carcinoma‐a case series of 104 patients. Annals of the Academy of Medicine, Singapore 1991;20(2):215‐8. [MEDLINE: ] - PubMed
Wood 2008
    1. Wood L, Egger M, Gluud LL, Schulz KF, Jüni P, Altman GD, et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta‐epidemiological study. BMJ (Clinical Research Ed.) 2008;336:601‐5. - PMC - PubMed

References to other published versions of this review

Chan 1999
    1. Chan ES‐Y, Chow PK‐H, Tai B‐C, Machin D, Soo K‐C. Neoadjuvant and adjuvant therapy for operable hepatocellular carcinoma. Cochrane Database of Systematic Reviews 1999, Issue 3. [DOI: 10.1002/14651858.CD001199] - DOI - PubMed

MeSH terms

Substances