Fig. 6.1
The Barcelona Clinic Liver Cancer (BCLC) staging system for Hepatocellular Carcinoma—revised 2011 [8]
The current recommendations based on the BCLC Staging System include:
1.
Patients who have a single lesion ≤ 5 cm, or 2–3 nodules ≤ 3 cm, can be offered surgical resection in the presence of cirrhosis with intact liver function, normal bilirubin, and hepatic vein pressure ≤ 10 mmHg.
2.
Liver transplantation is an effective option for patients with HCC who have a single lesion, with elevated bilirubin, and elevated hepatic vein pressure.
3.
For patients who are not candidates for liver transplantation due to co-morbid conditions and poor performance status, local ablation is a safe and effective therapy, which can also be used as a bridge to transplantation. In terms of ablation, alcohol injection and radiofrequency ablation (RFA) are equally effective for tumors less than 2 cm, but RFA has a more predictable necrotic effect.
4.
Transarterial chemoembolization (TACE) is recommended for patients who have multicentric disease without extrahepatic spread or vascular invasion, lesions > 3 cm, or patients who exhibit portal invasion without extra-hepatic spread/vascular invasion.
5.
Systemic chemotherapy has a limited role in HCC.
6.1.4 Targeted and Predictive Treatment in Hepatocellular Carcinoma
Systemic therapy with single-agent or combination chemotherapy has been studied extensively. However, cytotoxic chemotherapy traditionally has been associated with low response rates and questionable disease control.
6.1.4.1 Monotherapy: Doxorubicin
Single agent doxorubicin has been the most studied chemotherapy agent for advanced HCC. Although an early trial in 1975 reported dramatic clinical activity and a 79 % response rate [9], subsequent work suggests that the true objective response rate with doxorubicin monotherapy is 20 % or less with doses of 75 mg/m2 [10–15]. Lower doses ( ≤ 60 mg/m2 per cycle) are associated with even lower objective response rates [16,17]. Despite the modest objective response rate, one controlled trial involving 106 patients suggests that doxorubicin is associated with a small survival advantage compared to best supportive care alone (median survival 10.6 versus 7.5 weeks) [13]. The reason for the disparate survival outcomes in this trial is unclear, but patient selection may have played a role. 5-Fluorouracil (5-FU) has acceptably low toxicity and broad antitumor efficacy. Response rates with 5-FU monotherapy have been low. However, when given in combination with leucovorin, response rates as high as 28 % have been reported [18], although lower rates have been noted by others [19].
6.1.4.2 Molecular Targeted Therapy: Sorafenib
Sorafenib is a multi-targeted, orally active, small molecule tyrosine kinase inhibitor (TKI) that inhibits Raf kinase and the VEGFR intracellular kinase pathway [20].
The multi-center European Sorafenib HCC Assessment Randomized Protocol (SHARP) trial randomly assigned 602 patients with inoperable HCC and Child-Pugh A cirrhosis to sorafenib (400 mg twice daily) or placebo [21]. Overall survival, the primary endpoint, was significantly longer in the sorafenib-treated patients (10.7 versus 7.9 months), as was time to radiologic progression (5.5 versus 2.8 months). On the other hand, objective response rates were low (7 partial responses [2 %]). Treatment was well tolerated with manageable side effects. The only grade 3 or 4 adverse effects that occurred significantly more often in the treated group was diarrhea (8 versus 2 %) and hand-foot skin reaction (8 versus < 1 %). There were no differences in liver dysfunction or bleeding. The overall incidence of sorafenib-related side effects was low compared to that reported by others [22]. These results established sorafenib monotherapy as the new reference standard systemic treatment for advanced HCC and formed the basis for approval of sorafenib for unresectable HCC in the United States. The efficacy of sorafenib in Asian patients was the subject of a second placebo-controlled phase III trial, in which 226 patients with Child-Pugh A or B cirrhosis and no prior systemic therapy for HCC received sorafenib 400 mg twice daily or placebo [23]. Patients receiving sorafenib had significantly better median overall survival (6.5 versus 4.2 months) and time to progression (TTP) (2.8 versus 1.4 months). Grade 3 or 4 side effects included hand-foot skin reaction (11 %), diarrhea (6 %), and fatigue (3 %). The magnitude of benefit was markedly less in this trial than seen in the SHARP trial. In fact, the treated group in the Asian trial had shorter survival duration than the control group in the SHARP trial (6.5 versus 7.9 months), despite the fact that both trials used the same entry criteria. Nevertheless, patients accrued to the Asian study were more ill at the start of therapy than those in the SHARP trial, with a generally worse performance status and more advanced stage of disease [24].
6.1.5 Personalized Recommendations—Chemotherapy for Hepatocellular Carcinoma
HCC is an aggressive tumor that frequently occurs in the setting of chronic liver disease and cirrhosis. Hepatic reserve, as indicated by Child-Pugh class, often dictates the therapeutic options. Newer data on the efficacy of molecularly targeted agents have brought these agents, particularly sorafenib, to the forefront of therapy for advanced HCC.
Sorafenib offers the potential for prolonged survival, although objective tumor remissions are scarce. This molecular targeted therapy would be the first line treatment in patients with HCC who are not candidates to undergo liver transplant, surgical resection, TACE, or RFA. In terms of liver cirrhosis, the manufacturer recommends no dose adjustment for Child-Pugh class B impairment and makes no recommendation for Child-Pugh C cirrhosis. Nevertheless, the recommendation of an initial dose reduction to 200 mg twice daily in patients with a total bilirubin 1.5–3 times the upper limit of normal and that the drug not be administered to patients with more severe degrees of hyperbilirubinemia. For other patients with Child-Pugh B cirrhosis, standard dosing from the onset with dose modification as needed is appropriate. Given the poor prognosis of patients with HCC and Child-Pugh C cirrhosis, the associated significantly abnormal liver function and the high risk of treatment-related toxicity, most physicians would not prescribe sorafenib to these patients. The efficacy of cytotoxic chemotherapy is limited in patients with HCC. Even though few randomized trials have been conducted, no single regimen has emerged as superior to any other. Despite objective responses that are occasionally complete, median survival in all of these studies has been short (4.4–11.6 months).
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