The current treatment options for HCC are summarized in Table 22-6. At present, liver transplantation is considered the only potentially “curative” treatment. The current 1- and 5-year survival rates for patients with HCC undergoing orthotopic liver transplantation are 77.0% and 61.1%, respectively. The 5-year survival rate has steadily improved, from 25.3% in 1987 to 61.1% in the most recent period studied (1996-2001) (29). The authors attributed this improvement to the incorporation of the “Milan” criteria as guidelines for patient selection at most US liver transplantation centers. These criteria, as published by Mazzaferro et al, suggest that long-term survival after liver transplantation is highest in patients with HCC with either a single lesion 5 cm or smaller or three lesions 3 cm or smaller each and no evidence of gross vascular invasion (30). A large number of liver transplant candidates remain on the waiting list until they die of tumor progression or cirrhosis-related complications. Partial hepatectomy is the current standard treatment for localized T1 to T3, N0, M0 HCC. Resectability is determined by the extent of liver cirrhosis, the future liver remnant (FLR), and an adequate surgical margin. An FLR of 35% to 40% is considered the minimal cutoff for a safe liver remnant. Patients of Child-Pugh class B and C or with significant signs of portal hypertension are not surgical candidates.
Table 22-6Treatment Options for Management of Hepatocellular Carcinoma ||Download (.pdf) Table 22-6 Treatment Options for Management of Hepatocellular Carcinoma
|Treatment Option ||Comments |
|Liver transplantation ||Historically low survival rates (20%-36%). |
| ||Recent improvement (61.1%, 1996-2001), likely related to adoption of “Milan” criteria at US transplant centers. |
| ||Currently HCC represents 20% or more of liver transplants performed annually in the United States. |
|Surgical resection ||Historic 5-year survival rates 30%-40%. |
| ||Recent series indicated 5-year progression-free survival as high as 48%. A majority of patients develop recurrence or second primary tumors. |
| ||Resection in cirrhotic patients carries high morbidity and mortality. |
|Transarterial embolization/chemoembolization (TACE) ||Multiple trials showed objective tumor responses and “slowed” tumor progression but questionable survival benefit compared to supportive care. Greatest benefit seen in patients with preserved liver function, absence of vascular invasion, and smallest tumors. |
| ||Modest survival benefit demonstrated for repeated TACE (82% 1-year survival) versus supportive care (63%) in patients with preserved liver function, PS 0, small tumor burden. |
| ||Improvement in 1-year survival from 32% in control (supportive care) to 57% for TACE shown in randomized study of 279 primarily HBV+ patients with tumors <7 cm. |
|Percutaneous treatments (ethanol injection, thermal ablation, cryoablation, hypertonic saline injection) ||PEI well tolerated, high RR in small (<3 cm) solitary tumors. No randomized trial comparing resection to percutaneous treatments. Recurrence rates similar to postresection. |
|Hormonal therapy ||Antiestrogen therapy with tamoxifen studied in several trials; mixed results across studies, but generally considered ineffective. |
| ||Octreotide (somatostatin analogue) showed 13-month MS versus 4-month MS in untreated patients in a small randomized study. |
|Chemotherapy ||Adjuvant: No randomized trials showing benefit of neoadjuvant or adjuvant systemic therapy in HCC. Single trial showed decrease in new tumors in patients receiving oral synthetic retinoid for 12 months after resection/ablation. Results not reproduced. |
| ||Palliative: Regimens including as single agents or combinations of doxorubicin, cisplatin, 5-fluorouracil, interferon, epirubicin, and paclitaxel have not shown any survival benefit; RR ranged from 0%–25%. A few isolated major responses allowed patients to undergo partial hepatectomy. No published results from any randomized trial of systemic chemotherapy. |
Minor or major resection is based on the following criteria: (1) minor resection: Child A, normal LFTs (bilirubin ≤1.0 mg/dL), absence of ascites, and platelet count above 100,000/mm; and (2) major resection: minor criteria as in criterion 1, absence of portal hypertension, and portal vein embolization for a small future remnant (31). The perioperative mortality has decreased from 20% in the 1980s to less than 5% at present (31). The median disease-free survival after partial hepatectomy is about 2 years. Tumor size less than 5.0 cm (0.6 RR) was associated with improved survival, while the presence of vascular invasion, AFP greater than 2,000 mg/mL, and advanced Child-Pugh classification was associated with worse outcome. Patients with cirrhosis generally are not considered good candidates for surgical resection due to the high morbidity and mortality associated with cirrhosis and its complications. For those who do undergo resection, recurrence rates are among the highest of any solid tumor and approach 75% to 100% at 5 years. Estimated 5-year survival rates are in the range of 26% to 50%, and disease-free survival is 13% to 29% (32).
Locoregional Therapy for Hepatocellular Carcinoma
Hepatocellular carcinoma derives its blood supply almost exclusively from the hepatic artery. This important anatomic feature offers unique advantages for catheter-based therapies because arterial embolization interrupts blood flow to the tumor while preserving the portal vein and normal liver parenchyma. The combination of tissue ischemia with highly concentrated chemotherapy delivered into the hepatic artery enhances tumor necrosis. Transarterial chemoembolization (TACE) was first described by Yamada and incorporates these concepts (33). It has since become one of the most commonly utilized procedures in interventional radiology practice.
Landmark prospective randomized clinical trials published in 2002 validated the use of chemoembolization for unresectable advanced HCC. In the multicenter study by Llovet et al including 112 patients, when compared to bland embolization or best supportive therapy, patients who underwent TACE with a combination of doxorubicin and iodized oil followed by gelatin sponge demonstrated a clear survival advantage, leading to premature stoppage of the trial (34). Survival in the chemoembolization group at 1 and 2 years was 82% and 63%, respectively. Survival in the bland embolization group was 75% and 50%, respectively; in the best supportive care group, survival was 63% and 27%, respectively, and reached statistical significance.
Lo et al conducted a single-center study comparing 80 patients with unresectable HCC randomized to TACE with cisplatin and iodized oil followed by gelatin sponge or best supportive care (35). Survival in the chemoembolization group at 1 and 2 years was 57% and 31%, respectively. Survival for the patients randomized to the supportive care group was 32% and 11%, respectively, also reaching statistical significance. The difference in survival rates between the Llovet and Lo studies can be attributed to the inclusion of a larger proportion of patients with more advanced stages of underlying chronic liver disease in the latter study. Chemoembolization is contraindicated in patients with overt signs of portal hypertension and advanced underlying liver disease.
An important limitation of conventional chemoembolization using iodized oil lies in the uncontrolled washout of the cytotoxic drugs into the systemic circulation. Recently, a drug-eluting bead that allows controlled and sustained release of chemotherapeutic agents into the surrounding tumor was made available. This device enables delivery of a higher concentration of drugs with low systemic toxicity. Initial studies demonstrated that chemoembolization using drug-eluting beads is safe, with potentially increased effectiveness for patients with more advanced disease (36,37,38).
At MD Anderson, TACE is routinely utilized for patients with HCC with more than three lesions measuring up to 3 cm each or a single lesion greater than 5 cm. In patients with portal vein thrombosis, infiltrative disease, or more than four lesions, radio embolization with yttrium-90 microspheres is well tolerated and has been shown to improve outcomes. A recent study assessing the use of radio embolization in HCC showed response rates of 42% based on World Health Organization criteria (39).
Radiofrequency ablation causes tissue necrosis by controlled deposition of thermal energy. This technique is highly effective in the treatment of small and early HCC, with outcomes similar to surgical resection (40). Radiofrequency ablation is limited by lesion proximity to adjacent structures such as colon, gallbladder, and diaphragm. In addition, vascular structures adjacent to the target lesion steal heat from the area and decrease effectiveness of the ablation. The combination of chemoembolization followed by radiofrequency ablation may improve cell death because occlusion of blood flow leads to larger ablation zones (41,42).
Systemic Chemotherapy and Hormonal Therapy
A majority (>80%) of patients diagnosed with HCC have advanced disease at presentation and—based on the number, size, and location of lesions, as well as the severity of the underlying cirrhosis—are not candidates for transplantation, surgical resection, or liver-directed therapies. At present, systemic chemotherapy is ineffective in HCC, as evidenced by low response rates and no demonstrated survival benefit (see Table 22-6). HCCs are inherently chemotherapy resistant (43) and known to express the multidrug-resistance gene MDR-1 (44,45).
Few well-controlled, randomized chemotherapy trials have been published regarding HCC. That being said, we conducted a retrospective analysis of patients with unresectable HCC at MD Anderson who received either a conventional or a modified neoadjuvant PIAF chemotherapy regimen, consisting of cisplatin, interferon a-2b, doxorubicin, and 5-fluorouracil (5-FU). We found that select patients with HCC (patients who are noncirrhotic and without hepatitis B with good performance status [PS]) benefit from neoadjuvant-modified PIAF chemotherapy with improved response rates, resectability, and survival (46). Therefore, we consider this regimen in the neoadjuvant setting in select patients with unresectable tumors as bridge to surgery. Unfortunately, the ability to conduct controlled clinical trials of systemic regimens in patients with HCC has been hampered by many factors, including the multiple comorbidities of cirrhosis (Table 22-7), the advanced nature of HCC at presentation, rapid disease progression in many instances, and the distribution of patients primarily in developing nations, where multidisciplinary treatment of HCC may not be available.
Table 22-7Medical Comorbidities Complicating Hepatocellular Carcinoma ||Download (.pdf) Table 22-7 Medical Comorbidities Complicating Hepatocellular Carcinoma
|Problem ||Intervention |
|Esophageal, gastric varices ||Beta blockade for portal HTN for primary prophylaxis of GI bleeding |
| ||Endoscopic variceal banding for clinically significant GI bleeding |
|Thrombocytopenia ||Splenic artery embolization |
|Hypoalbuminemia ||Nutrition, caution with protein-bound medications |
|Ascites ||K+-sparing diuretics, fluid restriction |
|Chronic active hepatitis ||HCV: IFN/ribavirin have antiviral, antifibrotic effects. HBV: lamivudine, ±IFN |
|Coagulopathy ||PT most sensitive indicator of liver dysfunction |
Approximately 15% to 40% of HCCs are estrogen receptor positive. Hormonal therapy with tamoxifen or octreotide analogues has demonstrated some survival benefit (47); however, the results of other studies are conflicting.
Clinical Trials of Antiangiogenesis Agents
Several systemic targeted agents have recently been tested in clinical trials for patients with advanced HCC, including agents targeting the vascular endothelial growth factor (VEGF) pathway, either alone (48,49,50,51,52,53,54,55,56,57,58,59,60) or in combination with other systemic therapies (61,62,63,64,65,66,67,68). The cancer cell has been the only target of anticancer systemic therapy for more than 50 years. However, the cancer cell is genetically unstable, leading to accumulation of mutations. On the other hand, antiangiogenic therapy agents target endothelial cells that are genetically stable. Interestingly, the mechanism of action of thalidomide was thought to be partly based on its antiangiogenic effects. Nevertheless, several clinical trials of thalidomide showed rare responses, ranging from 0% to 6.3% (58,59).
Newer agents that target this antiangiogenic mechanism include sunitinib and sorafenib. Sunitinib is an oral multikinase inhibitor that exerts its antiangiogenic effects by targeting VEGF receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) tyrosine kinases. Sorafenib, another oral multikinase inhibitor, exerts its antitumor effect by targeting Raf/MEK/ERK signaling at the level of Raf kinase and possesses an antiangiogenic effect by targeting VEGFR-2/-3. Recently, two phase III trials of sorafenib have been reported (48,60). The pivotal randomized, placebo-controlled phase III trial of sorafenib in patients with advanced HCC (SHARP trial [Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol Study group trial]) reported modest activity with a 2.8-month improvement in median overall survival (OS) (P = .0006). In addition, it demonstrated an increased time to progression and disease control rate while showing a response rate of 2.3% as defined by RECIST criteria (48). This led to Food and Drug Administration (FDA) approval of sorafenib for advanced HCC in 2007, and it remains the only FDA-approved drug for this indication.
Other agents that target antiangiogenesis include bevacizumab and erlotinib. Bevacizumab is a recombinant, humanized monoclonal antibody that exerts its antitumor activity by targeting VEGF and may augment chemotherapy administration by making tumor vasculature less permeable, which decreases the elevated tumor interstitial pressure. Erlotinib is an oral tyrosine kinase inhibitor that blocks phosphorylation at the intracellular domain level of the EGFR. Most recently, we reported a phase II single-arm, open-label trial of bevacizumab and erlotinib that showed improved response rate, median OS, and progression-free survival (53).
Collectively, application of antiangiogenesis agents to patients with advanced HCC has eventually led to improved survival despite surprisingly low response rates. Notably, there is a poor correlation between survival benefit and conventional methods of response assessment, namely, RECIST. This poses questions regarding how best to evaluate response to antiangiogenic agents and quantify efficacy of antiangiogenic agents. Despite tumors increasing in size sometimes, the observation of tumor necrosis in many studies is intriguing. Therefore, in 2000, a panel of experts recommended that the response criteria be amended to take into account tumor necrosis induced by targeted agent therapy (69). Although its utility in assessing efficacy of anticancer agents in HCC needs to be established, tumor necrosis is a potentially significant clinical end point that warrants further investigation in future studies.
Targeted Therapies in Hepatocellular Carcinoma: Beyond Sorafenib
Given the paucity of available FDA-approved medications for advanced HCC, a number of other targeted agents have been tested in clinical trials in the adjuvant and advanced/metastatic setting. In the adjuvant setting, sorafenib did not show improved OS versus placebo in patients with previously resected or ablated HCC (70). Similar results were seen for orantinib, a multireceptor tyrosine kinase inhibitor of VEGFR2, PDGFR, and fibroblast growth factor receptor (FGFR), in patients who received previous transcatheter arterial embolization (71).
In the advanced, unresectable or metastatic setting, first-line therapy with linifanib (VEGFR and PDGFR tyrosine kinase inhibitor), sunitinib (VEGFR and PDGFR), and brivanib (VEGFR and FGFR) have all been tested in phase III trials against sorafenib with no improvement in OS (72,73,74). In the second-line setting, brivanib, everolimus (mTOR pathway inhibitor), and ramicirumab (fully human immunoglobulin G1 monoclonal antibody against VEGFR2) have all been tested versus placebo in patients who have either progressed on or were intolerant to sorafenib. None of these trials showed any significant improvement in OS (75,76,77). Two other agents, tivantinib (MET inhibitor) and cabozantinib (MET, RET, and VEGFR tyrosine kinase inhibitor) are currently being studied in clinical trials for patients in the second-line setting described. Enrollment in these trials is ongoing, and results are incomplete (78,79). At present, no therapy has better proven efficacy than sorafenib in the advanced, unresectable, or metastatic setting. Table 22-8 is a summary of targeted therapies in HCC.
Table 22-8Targeted Therapies in HCC ||Download (.pdf) Table 22-8 Targeted Therapies in HCC
|Trial ||Drug ||Primary End Point ||Median (Months) (Drug vs Placebo) ||Median (Months) (Drug vs Sorafenib) |
|Adjuvant trials |
| STORM ||NEXAVAR® (sorafenib) ||RFS ||33.4 vs 33.8 ||– |
| ORIENTAL ||TSU-68 (orantinib) ||OS ||Unknown, terminated ||– |
|First-line trials |
| NCT01009593 ||ABT-869 (linifanib) ||OS ||– ||9.1 vs 9.8 |
| NCT00699374 ||Sutent® (sunitinib) ||OS ||– ||7.9 vs 10.2 |
| BRISK-FL ||Brivanib ||OS ||– ||9.5 vs 9.9 |
|Second-line trials |
| BRISK-PS ||Brivanib ||OS ||9.4 vs 8.2 ||– |
| EVOLVE-1 ||Affinitor® (everolimus) ||OS ||7.6 vs 7.3 ||– |
| REACH ||Cyramza® (ramucirumab) ||OS ||9.2 vs 7.6 ||– |
| METIV-HCC ||Tivantinib ||OS ||Ongoing ||– |
| CELESTIAL ||XL184 (cabozantinib) ||OS ||Ongoing ||– |
Advances in our understanding of partial liver tolerance of RT, ability to visualize target tumors during respiration, and radiation planning and delivery techniques have permitted us to escalate the dose of radiation to focal HCCs without dose-limiting toxicity. This improved ability to deliver tumoricidal doses of RT safely has led to a resurgence of interest in treatment of HCC using RT. Promising clinical data from multiple studies suggested that HCCs are indeed radiosensitive. Sustained local control rates ranging from 71% to 100% have been reported following 30 to 90 Gy delivered over 1 to 8 weeks (80,81).
Investigators from Michigan have used conformal RT (1.5 Gy twice daily over 6-8 weeks) with concurrent hepatic arterial fluorodeoxyuridine to treat HCCs safely to doses as high as 90 Gy and achieved a median survival duration of 15.2 months (82). Analysis of these data suggested that doses greater than 75 Gy resulted in more durable in-field local control than lower doses.
A prospective French phase II trial administered 66 Gy in 33 fractions to HCCs ineligible for curative therapies and noted 92% tumor responses and 78% 1-year local control rates (83). Using higher doses and fewer fractions (hypofractionated RT), Canadian researchers have noted excellent local control rates ranging from 70% to 90% when the radiation beam can be directed from multiple planes (stereotactic RT) converging on the tumor; the majority of the liver can be spared from irradiation, and treatment is image guided (81,84,85).
In contrast to photon irradiation, for which the dose delivered to the tumor is limited by the entrance and exit doses that can potentially harm normal tissues, accelerated proton beams deposit a dose within the tumor without exiting through normal tissues beyond the tumor (86). Japanese investigators have reported mature results of the treatment of 162 patients with 192 unresectable HCCs with 72 Gy in 16 fractions of proton beam therapy (87). The 5-year local control rate of 87% and OS rate of 23.5% in the absence of significant toxicity are clinically noteworthy. Furthermore, an impressive 5-year survival rate of 53.5% was achieved in a subset of 50 patients with solitary tumors and Child-Pugh Class A cirrhosis.
Our own experience reflects these observations that higher doses are associated with better overall, in-field progression-free and biochemical progression-free survival (88). Across all partial liver radiation paradigms, the most common site of first recurrence is intrahepatic but outside the high-dose irradiated volume, and toxicities are more common in Child-Pugh class B patients.
Given the excellent local control rate as noted with RT alone, RT has been combined with TACE to overcome treatment resistance. Korean researchers initially noted more than 60% response rates and a significant drop in tumor marker levels using this combination treatment strategy (89,90). It was reported that TACE followed by RT improved OS over TACE alone in a retrospective analysis of this experience. Similar results have been reported by other groups as well (91,92,93).
For the treatment of unfavorable tumors, multiple groups have reported favorable outcomes in patients with portal venous tumor thrombus (PVTT) treated with RT (94,95,96,97,98,99,100,101,102,103). Response rates ranged from 37.5% to 100%, and median survival durations ranged from 3.8 to 10.7 months.
Taken together, these advances have permitted the escalation of radiation dose to unresectable HCCs without causing undue toxicity. Strategies that combine RT with other therapies merit continued evaluation to maximize the relative benefits of each approach.