T Ishikawa, et al.
2012; 59(115-116): Ahead of print.
Combination PEG-IFN α-2b/Ribavirin Therapy Following
Treatment of Hepatitis C Virus-Associated Hepatocellular
Carcinoma is Capable of Improving Hepatic Functional Reserve
Toru Ishikawa, Kazuo Higuchi, Tomoyuki Kubota, Kei-ichi Seki, Terasu Honma,
Toshiaki Yoshida and Tomoteru Kamimura
Department of Gastroenterology and Hepatology, Saiseikai Niigata Second Hospital, Niigata, Japan
Corresponding author: Toru Ishikawa, M.D., Department of Gastroenterology and Hepatology, Saiseikai
Niigata Second Hospital, Teraji 280-7, Niigata 950-1104, Japan; Tel.: +81-25-233-6161, Fax: +81-25-233-
8880; E-mail: email@example.com
KEY WORDS: Secondary prevention; PEG-IFN a-2b/ribavirin therapy; Hepatic functional reserve; Hepatocellular
We investigated survival rate, metachronous recurrence and hepatic functional reserve in 54 patients with initial HCV-associated Stage I/II HCC; 29 patients were administered a preparation of PEG-IFN a-2b/RBV after HCC treatment(Secondary IFN group) and 25 were not (Non-secondary IFN group).
A significant difference was observed in cumulative survival rates among HCV-associated HCC patients with rates of 100% after 1year and 90.2% after 3 years in the secondary IFN group compared to 96.0% and 61.2%, respectively, in then on-secondary IFN group. Univariate analysis identified secondary IFN treatment, alanine amino transferase and albumin levels as factors contributing to survival. Serum albumin level decreased temporarily but subsequently increased and improved hepatic functional reserve was observed in PEG-IFN a-2b/RBV therapy.Conclusions: PEG-IFN a-2b/RBV therapy after HCC treatment can improve hepatic functional reserve and may therefore represent a therapeutic option in the event of recurrence. PEG-IFN a-2b/RBV therapy following HCC treatment shows promise for improving the prognosis of HCC.2
Even among patients with hepatitis C virus (HCV) associated hepatocellular carcinoma(HCC) who have received curative treatment via local therapies such as surgicalresection or percutaneous radiofrequency ablation (RFA) (1), metachronous recurrencemay sometimes occur (2,3). It is a serious problem keeping the outcomes ofhepatocellular carcinoma treatment from further improvement.
Chronic hepatitis C patients achieving eradication of the HCV virus through treatmentssuch as interferon (IFN) therapy can expect improvements in hepatic fibrosis and aslowing of cancer progression (4-6). IFN therapy after curative treatment forHCV-associated HCC has also been reported to inhibit the recurrence of liver cancerand improve prognosis (7-11).
However recurrence has been observed even in patients achieving sustained virological response (SVR: HCV-RNA negative at 24 weeks after end of treatment) after HCV-associated hepatocellular carcinoma treatment. The effects of antiviral therapy with IFN on hepatic functional reserve need to be examined in the future.Although eliminating the virus by providing IFN therapy after HCV-associated hepatocellular carcinoma treatment is considered important for improving hepatic function, preventing recurrence and extending survival, outcomes of treatment for hepatocellular carcinoma using PEG-IFN -2b/ribavirin (RBV) therapy have yet to be elucidated. We therefore investigated whether provision of PEG-IFN -2b/RBV therapy after treatment for hepatocellular carcinoma improves hepatic functional reserve.
Patients and methodsWe examined changes in cumulative survival rate, metachronous recurrence, virologicalresponse and hepatic functional reserve in 54 patients after curative treatment withinitial HCV-associated Stage I/II HCC. Patients were randomly allocated into 2 groups.
Of these, 29 were administered a preparation of PEG-IFN -2b (PegIntron, Schering Plough, Kenilworth, NJ, USA)/RBV (Rebetol, Schering Plough, Kenilworth, NJ, USA)after hepatocellular carcinoma treatment (Secondary IFN group) and 25 were not(Non-Secondary IFN group). PEG-IFN -2b was administered once a week and ribavirin was administered daily. The dose of PEG-IFN -2b was 1.5mg/kg body weight per week. The dose of ribavirin was 600mg/day for patients weighing <60kg,800mg/day for patients weighing 60-80kg, 1000mg/day for patients weighing >80kg,respectively. These groups were followed at intervals of 1 month for a median of 45.0months. The study was approved by the local ethics committee in accordance with the1975 Declaration of Helsinki and all patients provided written informed consent.
The chi-squared test and Fisher’s exact test were used to statistically analyze categorica ldata, the Mann-Whitney test was used to analyze ranked data and the Kaplan-Meiermethod was used with Wilcoxon rank sum test to analyze survival and recurrence.
Univariate and multivariate analysis with the Cox proportional hazards modeling wasused to investigate factors associated with survival and recurrence. Windows SA Sversion 9.2 software (SAS Institute, Cary, NC, USA) was used for all analyses.4RESULTSIn terms of baseline characteristics (Table 1) patients in the Secondary IFN group were slightly younger and tended to have higher platelet (PLT) counts than the non-secondary group.
A significant difference in cumulative survival rate was observed with rates of 100%after 1 year and 90.2% after 3 years in the secondary IFN group, compared to 96.0%after 1 year and 61.2% after 3 years in the non-secondary group (Figure 1). However no significant differences were observed in cumulative first recurrence rates (Figure 2).Univariate analysis identified secondary treatment, alanine aminotransferase (ALT)level and albumin (Alb) level as factors significantly contributing to survival (Table 2),while multivariate analysis identified secondary IFN treatment as a significant factor(Table 3).
Although a temporary decreasing trend in albumin levels was observed during IFNtherapy in the Secondary IFN group, a significant improvement was seen compared to the Non-Secondary IFN group after the conclusion of IFN therapy (Figure 3).In the Secondary IFN group, serum Alb levels temporarily decreased with PEG-IFN -2b/RBV therapy but subsequently increased and improved significantly in SVR patients (Figure 4). Even among non-SVR patients, Alb levels improved compared tobefore PEG-IFN -2b/RBV therapy (Figure 4), albeit slightly and improved hepaticfunctional reserve was observed.5
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide and occurs mainly from chronic hepatitis or hepatic cirrhosis attributable to persistent hepatitis B or HCV infection (12). Especially, hepatitis C virus (HCV) is an important cause of HCC in many areas of the world (13). Hepatocellular carcinoma can be broadly classified as occurring either through intra hepatic metastasis or multi-centric occurrence(14).
Multi-centric occurrence is further classified as either synchronous, with multiple tumors appearing simultaneously in different hepatic locations or metachronous, with new tumors forming a certain time after curative partial hepatic resection, percutaneous ethanol injection therapy (PEIT) (15), radio frequency ablation therapy (1) or other local therapy. In the context of metachronous multi-centric, IFN therapy is thought to be useful for preventing multi-centric occurrence and leading improved prognoses (16).
While the primary objective of IFN therapy for patients with HCV-related chronic liver disease is to eradicate persistent HCV infection and prevent progression of hepaticlesions (4-6), the effects of IFN therapy on hepatic functional reserve have not been sufficiently analyzed. Our previous investigation performed carcinogenic factors inpatients with HCV cirrhosis and advanced liver fibrosis for long-term follow-up examinations.
That study revealed high viral load, male gender and old age as significant carcinogenic factors (17). Hence, it is necessary to prevent hepatocellular carcinoma in patients with these risk factors.Recent intensive diagnostic imaging of hepatic cirrhosis patients and others at high risk of cancer has resulted in many cases of hepatocellular carcinoma being detected while still small ( 2cm diameter) (18,19).
Consequently, the proportion of patients expected to achieve adequately local disease control is increasing. Curative resection of such6patients can extend survival by only so much. Resection of hepatocellular carcinomahas become a safe operation with very low mortality as a result of advances in surgical techniques and preoperative management (20).
However, the long term prognosis remains unsatisfactory due to a high incidence of intra hepatic recurrence, ranging from50% to 60% (2,3).Furthermore, the problem of decompensation (i.e. death from hepatic failure) due to decreased hepatic functional reserve occurring with progression of chronic hepatic disease is more common. Improvement in hepatic functional reserve is thus considered important factor in improving the prognosis of HCV-related HCC.Some reports have examined the significance of interferon therapy as a secondary prevention to be administered after the treatment of hepatocellular carcinoma. Ikeda etal. confirmed an effect in preventing recurrence after administering IFN subsequent to resection or PEIT for HCV-positive hepatocellular carcinoma (7).Kubo et al. conducted a randomized controlled trial of postoperative IFN therapy inpatients with HCV-positive hepatocellular carcinoma observing a significant decrease in recurrence rates and an increase in survival rates in patients receiving IFN (8).
Theyalso reported that hepatocellular carcinoma patients receiving preoperative IFN therapy to control HCV showed a lower rate of postoperative recurrence. Shiratori et al.reported that IFN therapy did not suppress initial recurrence but contributed to suppression of second, third, and subsequent recurrences (9). Otherwise, Sakaguchi et al.reported that only 1 of 24 patients receiving low-dose IFN after RFA achieved SVR(10). While recurrence rates after 1 year did not differ significantly, low-dose IFN did contribute to suppressed recurrence rates after 2 and 3 years. Each of these investigations found that suppressing recurrence with IFN directly improved survival.7IFN has thus been recognized as an effective adjuvant therapy for suppressing recurrence after the treatment of HCV-positive hepatocellular carcinoma. IFN therapy delivers combined efficacy on two fronts, by suppressing multi-centric carcinogenesis through viral eradication and conferring anti tumor effects against occult hepatocellular carcinoma itself at an early stage.
The attachment of polyethylene glycol (PEG) to the IFN molecule is the most recent innovation in the treatment of HCV infection.Pegylation reduces the degradation and clearance prolonging the half-life of IFN,permitting less frequent, weekly, dosing while maintaining higher sustained IFN levels(21).As previous investigations did not use PEG preparations, simple comparison with thecurrent standard therapy such as PEG IFN/RBV therapy is impossible.
Although combination PEG-IFN -2b and RBV therapy has become the standard IFN therapy in recent years (22,23), the current literature does not mention post operative administration for hepatocellular carcinoma patients. The present investigation established that recurrence is better suppressed and hepatic functional reserve is improved in patients achieving SVR. As with PEG-IFN -2b therapy provided before the occurrence of hepatocellular carcinoma, striving for SVR is important, whenever possible, even after treatment for hepatocellular carcinoma. Although this does not mean all patients will achieve SVR, PEG-IFN -2b/RBV preparations did maintain hepatic functional reserve and contributed to survival in patients regardless ofvirological response.
This finding indicates that even after hepatocellular carcinoma treatment, attempted PEG-IFN -2b/RBV therapy itself represents the most significant factor contributing to the prognosis of HCV-associated hepatocellular carcinoma.
Obviously, maintaining compliance with treatment is important in postoperative8hepatocellular carcinoma patients ensuring to the fullest extent possible that cytopenia does not result in treatment dropout. Greater reductions in both neutrophil and platelet counts were significantly observed with PEG-IFN -2a compared to PEG-IFN -2b(24). This study selected PEG-IFN -2b/RBV therapy for administration after hepatocellular carcinoma treatment, and found favorable patient compliance.PEG-IFN -2b/RBV therapy administered after treatment of HCV-associated hepatocellular carcinoma not only serves an antiviral purpose but can also improve hepatic functional reserve and may therefore offer a viable therapeutic option in theevent of recurrence. The administration of PEG-IFN -2b/RBV following hepatocellular carcinoma treatment shows promise as a treatment strategy for improving the prognosis of hepatocellular carcinoma.
However, questions remaining to be addressed include 1) whether patients who have undergone hepatocellular carcinoma treatment and therefore have somewhat decreased general performance status are capable of adequately completing standard PEG-IFN -2b/RBV combination therapy, 2) at what postoperative period this therapy should be administered, and 3) how the dosage should be titrated.Administration of PEG-IFN -2b/RBV increased albumin levels and improved hepatic functional reserve through the antiviral effects. Given these benefits, this combination therapy may represent a viable option for treatment in the event of recurrence. Use of PEG-IFN -2b after treatment of hepatocellular carcinoma appears to contribute to improved prognosis in patients with hepatocellular carcinoma.Further studies with larger controlled groups and long-term follow up need to be performed to establish whether this therapy constitute optimal management of HCV infection after HCC treatment.
1. Rossi S, Garbagnati F, Lencioni R, et al.: Percutaneous radio-frequency thermal ablation of
non-resectable hepatocellular carcinoma after occlusion of tumor blood supply. Radiology 2000;
2. Nagasue N, Uchida M, Makino Y, et al.: Incidence and factors associated with intrahepatic
recurrence following resection of hepatocellular carcinoma. Gastroenterology 1993;
3. Yamamoto J, Kosuge T, Takayama T, et al.: Recurrence of hepatocellular carcinoma after
surgery Br J Surg 1996; 83:1219-1922.
4. Yoshida H, Shiratori Y, Moriyama M, et al.: Interferon therapy reduces the risk for
hepatocellular carcinoma: national surveillance program of cirrhotic and noncirrhotic patients
with chronic hepatitis C in Japan. Inhibition of Hepatocarcinogenesis by Interferon Therapy
Study Group. Ann Intern Med 1999; 131:174-181.
5. Shiratori Y, Imazeki F, Moriyama M, et al.: Histologic improvement of fibrosis in patients
with hepatitis C who have sustained response to interferon therapy. Ann Intern Med 2000;
6. Nishiguchi S, Sata M, Yamada G, Fujiyama S, Yoshida H, Omata M: Histologic
improvement of fibrosis in patients with hepatitis C who have sustained response to interferon
therapy. Ann Intern Med 2000; 132:517-524.
7. Ikeda K, Arase Y, Saitoh S, 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; 32:228-232.
8. Kubo S, Nishiguchi S, Hirohashi K, et al.: Effects of long-term postoperative
interferon-alpha therapy on intrahepatic recurrence after resection of hepatitis C virus-related
hepatocellular carcinoma. A randomized, controlled trial. Ann Intern Med 2001; 134:963-967.
9. Shiratori Y, Shiina S, Teratani T, et al.: Interferon therapy after tumor ablation improves
prognosis in patients with hepatocellular carcinoma associated with hepatitis C virus. Ann Intern
Med 2003; 138:299-306.
10. Sakaguchi Y, Kudo M, Fukunaga T, et al.: Low-dose, long-term, intermittent
interferon-alpha-2b therapy after radical treatment by radiofrequency ablation delays clinical
recurrence in patients with hepatitis C virus-related hepatocellular carcinoma. Intervirology
11. Ishikawa T: Secondary prevention of recurrence by interferon therapy after ablation therapy
for hepatocellular carcinoma in chronic hepatitis C patients. World J Gastroenterol 2008;
12. Llovet JM, Burroghs, Bruix J: Hepatocellular carcinoma. Lancet 2003; 362:1907-1917.
13. Sherlock S: Viruses and hepatocellular carcinoma. Gut 1994; 35:828-832.
14. Nakashima O, Kojiro M: Recurrence of hepatocellular carcinoma: multicentric occurrence
or intrahepatic metastasis? A viewpoint in terms of pathology. J Hepatobiliary Pancreat Surg
15. Notsumata K, Shimizu M, Unoura M, et al.: Study of percutaneous ethanol injection
therapy (PEIT) under ultrasonography in hepatocellular carcinoma. Nippon Shokakibyo Gakkai
Zasshi 1988; 85:2666-2672. (In Japanese with English abstract).
16. Suou T, Mitsuda A, Koda M, et al.: Interferon alpha inhibits intrahepatic recurrence in
hepatocellular carcinoma with chronic hepatitis C: a pilot study. Hepatol Res 2001; 20:301-311.
17. Ishikawa T, Ichida T, Yamagiwa S, et al.: High viral loads, serum alanine
aminotransferase and gender are predictive factors for the development of hepatocellular
carcinoma from viral compensated liver cirrhosis. J Gastroenterol Hepatol 2001; 16:1274-1281.
18. Bruix J, Sherman M: Practice Guidelines Committee, American Association for the Study
of Liver Diseases. Management of hepatocellular carcinoma. Hepatology 2005; 42:1208-1236.
19. Bruix J, Sherman M: Diagnosis of Small HCC. Gastroenterology 2005; 129:1364.
20. Fan ST, Lo CM, Liu CL, Lam CM, Yuen WK, Yeung C, Wong J: Hepatectomy for
hepatocellular carcinoma: toward zero hospital deaths. Ann Surg 1999; 229:322-330.
21. Dienstag JL, McHutchison JG: American Gastroenterological Association technical
review on the management of hepatitis C. Gastroenterology 2006; 130:231-264.
22. Strader DB, Wright T, Thomas DL, Seeff LB: American Association for the Study of
Liver Diseases. Diagnosis, management and treatment of hepatitis C. Hepatology 2004;
23. Fried MW, Shiffman ML, Reddy KR, et al.: Peginterferon alfa-2a plus ribavirin for
chronic hepatitis C virus infection. N Engl J Med 2002; 347:975-982.
24. Katano Y, Kumada T, Nakano I, et al.: Comparison of biochemical safety between
PEG-IFN -2a and PEG-IFN -2b. Hepato-gastroenterol 2009; 56:485-491.