See article in J. Gastroenterol. Hepatol. 2011; 26: 1612–1618.
Article first published online: 20 OCT 2011
© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd
Volume 26, Issue 11, pages 1585–1586, November 2011
Kim, D. Y. and Han, K.-H. (2011), Sorafenib, doesn't it have any competitor in advanced hepatocellular carcinoma?. Journal of Gastroenterology and Hepatology, 26: 1585–1586. doi: 10.1111/j.1440-1746.2011.06901.x
Based on the results from the Sorafenib Hepatocellular carcinoma Assessment Randomized Protocol (SHARP) trial and Asia-Pacific trial, sorafenib, an oral multikinase inhibitor, was globally approved for the treatment of unresectable, advanced hepatocellular carcinoma (HCC).1,2 In the design of both studies, inclusion criteria were advanced stage (vascular invasion or distant metastasis) of HCC and good hepatic reserve function (Child–Pugh A). That is, due to the peculiar characteristic of HCC that malignancy is mostly accompanied by the preneoplastic condition of cirrhosis, which itself affects overall survival, patients with Child–Pugh A were selected in those trials. Thus, the clinical utility of sorafenib in patients with Child–Pugh B or C remains unknown.
In addition, the positioning of sorafenib is still not concrete in nations where the cost of this drug is higher compared to other treatment modalities.3,4 For instance, in Korea, reimbursement from the national insurance system is largely restricted. Though the government commenced reimbursement of it from January 2011, the indications are just advanced HCC if patients were not eligible for or had disease progression after surgical or locoregional therapy (transarterial chemoembolization, ethanol injection, or radiofrequency ablation) with all of the following conditions; (i) Tumor Node Metastasis (TNM) stage III or IV, (ii) Child–Pugh class A, (iii) Eastern Cooperative Oncology Group (ECOG) performance status, 0–2. Rather similar restrictions apply to reimbursement for sorafenib in Australia. Even with this indication, reimbursement in Korea is only partial, with patient copayment being 50%, and the period of reimbursement is only one year.
In the USA, the Food and Drug Administration (FDA) authorized the use of sorafenib for patients with “unresectable HCC”, while in Europe, the indication is even extended as sorafenib is indicated for just “HCC”.5 Limited reimbursement policies and high cost of sorafenib in Asia-Pacific countries can lead to physicians treating patients with advanced HCC with other modalities, even though sorafenib is the only drug to show survival benefit in randomized, controlled trials. Under the aforementioned design of clinical trial and reimbursement environment, many physicians want to know the efficacy and safety of sorafenib in real clinical practice, especially in Barcelona Clinic Liver Cancer-C (BCLC-C) stage.
In this issue of the Journal, Kim et al. reported that sorafenib conferred better survival than other treatment modalities in patients with BCLC-C stage if they have extrahepatic spread or massive/infiltrative tumor characteristics.6 In their retrospective, single-institution study, the overall survival was compared between 123 patients treated with sorafenib over 6 weeks and 253 patients who were treated with other non-curative modalities, such as transarterial chemoembolization (TACE), radiation therapy, and cytotoxic chemotherapy. Considering that data on direct comparison between sorafenib and other treatments are rare, and that it is hard to conduct such trials in an optimal randomized fashion, we could get some information from retrospective study in spite of its intrinsic limitations and possible bias.
In their study, the independent prognostic factors affecting survival were what are usually found; high serum alpha fetoprotein (≥ 200 ng/mL), massive/infiltrative tumor, macrovascular invasion, extrahepatic metastasis, and TNM stage IV. The authors did a subgroup analysis and found that each favorable pre-treatment factor (AFP < 200 ng/mL, nodular HCC, no macrovascular invasion, TNM stage ≤ III) resulted in better survival with other treatments compared to sorafenib. Apart from the weaknesses of retrospective study and selection bias, the heterogeneity of other treatment modalities makes the interpretation of these results difficult. Moreover, it is unclear how many patients were treated with sorafenib for second line therapy. In real life clinical practice, we can see that baseline tumor characteristics significantly differ even in the same BCLC stage. Since advanced HCC is a difficult disease to cure, the current BCLC stage C needs to be more finely classified using other variables. The inclusion of just two factors, i.e. distant metastasis and portal vein invasion, in advanced stage might be too simple; the therapeutic outcome would not be the same between nodular HCC accompanied by portal vein branch invasion and diffuse HCC with main portal vein invasion.
Obviously, we don't yet know the best treatment modality in advanced HCC with different combinations of pre-treatment factors. A few promising results have been reported in studies adopting novel treatment options in advanced HCC. External radiotherapy combined with intra-hepatic arterial infusion chemotherapy showed a median survival of 13.1 months in a pilot study in which 40 HCC patients with portal vein invasion (either the main trunk or first branch) were enrolled.7
Recently, a European multicenter study reported the efficacy and safety of selective internal radiation therapy using Yttrium-90 in HCC.8 In 183 patients with BCLC-C, the median survival was 10.0 months. An investigator-initiated multi-center, randomized trial to compare sorafenib and Yttrium-90 radioembolization in HCC with advanced stage is about to start in Asia; it will address the issue of real clinical benefit of sorafenib in locally advanced HCC in comparison with other treatment. Hepatic arterial infusion chemotherapy (HAIC) is another therapeutic option in advanced HCC, in particular, disease in both lobes with portal vein tumor thrombus, for which there is currently no appropriate choice of treatment except sorafenib. Actually, there is no solid evidence that HAIC could significantly improve survival in patients with advanced HCC compared to supportive care or sorafenib. However, several series of studies in Japan and Korea demonstrated the efficacy and safety of HAIC using 5-fluorouracil (5-FU) and cisplatin.9,10 A randomized study to compare sorafenib and HAIC is now ongoing in Japan and will answer whether this kind of locoregional therapy would compete with sorafenib in advanced HCC.
To date, no beneficial effect has been observed with cytotoxic chemotherapy.11 However, recent data showing promising survival outcome with new combinations of anti-cancer agents suggest that systemic chemotherapy other than sorafenib may yet be another challenger to molecular target therapy in advanced HCC. In a phase III Asian trial of FOLFOX4 (5-FU/folinic acid plus oxaliplatin) compared with adriamycin, the time to progression (TTP) was 2.9 and 1.8 months respectively, with overall survival 6.4 and 4.9 months.12 This result is comparable to that of sorafenib Asian-Pacific trial in which the TTP and overall survival of sorafenib group was 2.8 and 6.5 months, respectively.2Table 1 summarizes the inclusion criteria and overall efficacy of sorafenib, external radiotherapy, Y-90 radioembolization, and cytotoxic chemotherapy in advanced HCC.
|Sorafenib SHARP trial1||External radiation7||Yttrium-90 radioembolization8||FOLFOX4 regimen12|
|Age||64 ± 11.2||50†||64.5 ± 10.8||49†|
|Sex (male) (%)||87||90||80.3||90|
|ECOG PS 0/1/2 (%)||54/38/8||NA||20.3/79.7‡||NA|
|Child–Pugh A/B (%)||95/5||72.5/27.5||74.9/25.1||89/11|
|Macrovascular invasion (%)||70||100||60.1||NA|
|Extrahepatic spread (%)||53||0||84.7||57|
|BCLC stage C (%)||82||100||100||79|
It is true that sorafenib has opened a window for hope to control this disease and to facilitate the development of other target agents. However, it is also true that physicians are not yet fully satisfied themselves with this drug in terms of its efficacy, adverse effect profile, and cost and availability. Importantly, to face the difficult and complex nature of HCC, we should be armed with all available modalities and should approach their use in a multidisciplinary manner.