OR WAIT null SECS
In North America, hepatocellular carcinoma (HCC) is one of only a few malignancies with an increasing incidence in recent years.
In North America, hepatocellular carcinoma (HCC) is one of only a few malignancies with an increasing incidence in recent years. Complicating matters further is the fact that the vast majority of our patients develop HCC in the setting of cirrhosis. Therefore, we must recognize the need to treat two diseases, each with a significant and often competing risk of mortality. The positive results of the SHARP and Asia-Pacific randomized clinical trials (RCTs) have now established sorafenib (Nexavar) as the standard of care for Barcelona Clinic Liver Cancer (BCLC) stage C patients with advanced HCC because of malignant portal vein invasion, lymph node involvement, or distant metastases.[2,3] Sorafenib also has a role in patients with intermediate BCLC stage B disease who have progressed following transarterial chemoembolization (TACE). Both the SHARP and Asia-Pacific studies demonstrated a remarkably similar mortality risk reduction with use of sorafenib, compared with placebo.[2,3] The lower median survival time of patients receiving sorafenib in the Asia-Pacific study, compared with patients in the SHARP study, is due to the inclusion of patients with more advanced HCC in the Asia-Pacific trial (95% vs 83% were BCLC stage C and 74% vs 46% were performance status ≥ 1).[2,3]
The positive results of the SHARP study have led to the investigation of sorafenib as adjuvant therapy in earlier-stage disease. Although potentially curative, both surgical resection and radiofrequency ablation (RFA) leave behind a cirrhotic liver and are associated with disease recurrence rates of approximately 70% after 5 years.[4,5] The STORM study has now completed enrollment, but it may be several years before we know if sorafenib is superior to placebo in preventing recurrence after curative-intent resection or RFA. Recurrence rates following transplantation are typically less than 15% if one respects the Milan criteria (single tumor < 5 cm or three tumors all < 3 cm). The article by Kim et al nicely summarizes the current experience using sorafenib after liver transplantation (LT) to treat recurrent disease.
One should recognize that in several of these LT series, patients also received m-TOR (mammalian target of rapamycin) inhibitors for immunosuppression. Sirolimus (rapamycin, Rapamune) and everolimus (Afinitor), which target the PI3K/Akt/m-TOR pathway, may have potential benefits in patients who receive LT for HCC. A recent retrospective analysis of the Scientific Registry of Transplant Recipients database has shown that patients with HCC, but not those transplanted for other reasons, have a survival benefit if they receive immunosuppression with sirolimus. There is limited experience with evaluating sorafenib as adjuvant therapy to prevent recurrence following LT; however, Saab et al recently reported a retrospective case-controlled study in which eight patients who received sorafenib after LT had lower recurrence rates (12.5% vs 50%) and improved 1-year survival (87.5% vs 62.5%) compared with eight matched controls. It does appear that dose reductions are necessary when using sorafenib after LT, which is not surprising given that sorafenib, as well as m-TOR and calcineurin inhibitor immunosuppressants, are all metabolized through CYP3A4.
A large RCT from Asia has failed to show superiority of sorafenib over placebo when given after TACE. The very high rate of hand-foot syndrome (HFS) in this study leads one to question if there may be increased toxicity when sorafenib is combined with traditional chemotherapy. However, in the phase II study of intravenous doxorubicin (Adriamycin) given with sorafenib or placebo, Abou-Alfa et al reported HFS in only 6.4% of patients receiving the combination of sorafenib and doxorubicin. The timing of sorafenib administration in relation to TACE is also a potentially important issue. Theoretically, if sorafenib is given prior to TACE it should block the upregulation of growth factors which are induced by the ischemia that follows chemoembolization. The SPACE study, which has now completed enrollment, randomized patients to sorafenib or placebo 1 week before their first TACE procedure. This RCT should better define the role for sorafenib in combination with TACE in patients with intermediate BCLC stage B HCC.
The biggest area of controversy relates to the role of sorafenib in advanced HCC patients who have Child-Pugh B (CPB) cirrhosis. Such patients were excluded from both the SHARP and Asia-Pacific trials, with < 5% being CPB at the time of randomization.[2,3] Therefore, there is no high-level evidence demonstrating a survival benefit of sorafenib in this patient population. Kim et al have summarized the limited published experience with use of sorafenib in CPB cirrhotics. The approximate 4-month median survival time (range, 2.0–7.0 months) and the acceptable “liver toxicity” is very difficult to interpret without the presence of an untreated control group in any of these studies. It is interesting that there appears to be less HFS in CPB patients, but this could be explained by the need for dose reductions in patients with more advanced liver failure.
When faced with a patient who has advanced CPB cirrhosis and HCC, many physicians opt for sorafenib because they want to offer something more than just best supportive care. However, I would caution oncologists to avoid this strategy until we have evidence from RCTs. Recently hepatologists learned this lesson “the hard way” in primary sclerosing cholangitis (PSC), a progressive liver condition with no effective medical therapy. An earlier RCT had found that ursodeoxycholic acid (UDCA), a well-tolerated naturally occurring bile acid, was ineffective at low doses, but a subsequent pilot study of higher doses showed promise and improved liver tests. Many clinicians, myself included, began to prescribe high-dose UDCA to our PSC patients while awaiting the results of a placebo-controlled RCT. Several years later, the results of this RCT confirmed that high-dose UDCA improved serum liver tests, but much to everyone’s surprise, high-dose UDCA also led to increased death and the need for LT, compared with patients who received placebo.
Sorafenib is very expensive and it has multiple side-effects that can impair quality of life. Remember that sorafenib failed to improve time to symptomatic progression in both the SHARP and Asia-Pacific studies.[2,3] Furthermore, although we can anticipate that the anti-tumor effect will be similar in CPB patients, we have no idea how anti-angiogenic drugs will affect the natural history of patients with significant portal hypertension. Unfortunately, the open-label experience in the GIDEON study of more than 3,000 patients, many of whom will have CPB cirrhosis, will provide very little useful information without a matched untreated control group. The efforts and resources being invested in the GIDEON study would be better spent in performing a well-designed placebo-controlled trial in CPB patients. To enhance recruitment, such a study could randomize patients 2:1 to sorafenib versus placebo, and to ensure equal distribution of patients with severe liver dysfunction, the trial should stratify randomization to 7 versus 8 or 9 Child-Pugh points. A trial roughly the same size as the Asia-Pacific study should have sufficient power to demonstrate the efficacy and safety of sorafenib in CPB patients.
Although regulatory bodies in the United States and Europe have provided sorafenib with an expanded label, reimbursement for the costs of sorafenib is more restrictive in the publicly funded health care system of Canada. The Alberta HCC Algorithm reflects our local practice, which restricts sorafenib to patients who would have been candidates for the SHARP study, namely BCLC stage C, with a performance status ≤ 2 and Child-Pugh class A cirrhosis. Although some will argue that these criteria are too restrictive, they are based on the strongest level of evidence, and until we have data from RCTs we cannot be certain that sorafenib is truly effective or safe in CPB patients. As physicians, we all want to help those unfortunate patients who present with both advanced HCC and advanced liver failure, but we must also remember our vow of primum non nocere...first, do no harm. It is my opinion that further RCTs are necessary before we can be certain that sorafenib therapy is truly helping rather than harming our CPB patients.
Financial Disclosure:Dr. Burak has participated in research funded by Bayer as a local principal investigator for the SHARP, STORM, and SPACE studies. No funding was received for the preparation of this commentary.
1. National Cancer Institute: Cancer Trends Progress Report-2009/2010 Update. Available at http://progressreport.cancer.gov. Accessed February 16, 2011.
2. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-90.
3. Cheng AL, Kang YK, Chen Z, 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.
4. Llovet JM, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology. 1999;30:1434-40.
5. Hasegawa K, Makuuchi M, Takayama T, et al. Surgical resection vs. percutaneous ablation for hepatocellular carcinoma: a preliminary report of the Japanese nationwide survey. J Hepatol. 2008;49:589-94.
6. Sorafenib as Adjuvant Treatment in the Prevention Of Recurrence of Hepatocellular Carcinoma (STORM). Available at http://www.clinicaltrials.gov/ct2/show/NCT00692770. Accessed February 16, 2011.
7. Mazzaferro V. Results of liver transplantation: with or without Milan criteria? Liver Transpl. 2007;13(Suppl 12):S44-7.
8. Kim R, Byrne M, Tan A, et al. What is the indication for sorafenib in hepatocellular carcinoma? A clinical challenge. Oncology (Williston Park). 2011;25:XX-XX.
9. Toso C, Merani S, Bigam DL, et al. Sirolimus-based immunosuppression is associated with increased survival after liver transplantation for hepatocellular carcinoma. Hepatology. 2010;51:1237-43.
10. Saab S, McTigue M, Finn RS, Busuttil RW. Sorafenib as adjuvant therapy for high-risk hepatocellular carcinoma in liver transplant recipients: feasibility and efficacy. Exp Clin Transplant. 2010;8:307-13.
11. Okita K, Imanaka N, Chida N, et al. Phase III study of sorafenib in patients in Japan and Korea with advanced hepatocellular carcinoma (HCC) treated after transarterial chemoembolization (TACE) (Abstract LBA 128). Presented at the 2010 American Society of Clinical Oncology Gastrointestinal Cancers Symposium, Orlando, FL, January 22-24, 2010.
12. Abou-Alfa GK, Johnson P, Knox JJ, et al. Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma. JAMA. 2010;304:2154-60.
13. A Phase II Randomized, Double-blind, Placebo-controlled Study of Sorafenib or Placebo in Combination With Transarterial Chemoembolization (TACE) Performed With DC Bead and Doxorubicin for Intermediate Stage Hepatocellular Carcinoma (HCC). Available at http://www.clinicaltrials.gov/ct2/show/NCT00855218. Accessed February 16, 2011.
14. Lindor KD. Ursodiol for primary sclerosing cholangitis. N Engl J Med. 1997;336:691-5.
15. Harnois DM, Angulo P, Jorgensen RA, et al. High-dose ursodeoxycholic acid as a therapy for patients with primary sclerosing cholangitis. Am J Gastroenterol. 2001;96:1558-62.
16. Lindor KD, Kowdley KV, Luketic VA, et al. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology. 2009;50:808-14.
17. Global Investigation of Therapeutic Decisions in Hepatocellular Carcinoma and of Its Treatment With Sorafenib (GIDEON). Available at http://www.clinicaltrials.gov/ct2/show/NCT00812175. Accessed February 16, 2011.
18. Burak KW, Kneteman NM. An evidence-based multidisciplinary approach to the management of hepatocellular carcinoma (HCC): the Alberta HCC Algorithm. Can J Gastroenterol. 2010;24:643-50.