Localized and systemic approaches to treating hepatocellular carcinoma.

VOLUME

33

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NUMBER

16

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JUNE

1

2015

JOURNAL OF CLINICAL ONCOLOGY

R E V I E W

A R T I C L E

Localized and Systemic Approaches to Treating Hepatocellular Carcinoma Jennifer J. Knox, Sean P. Cleary, and Laura A. Dawson All authors: University of Toronto, Princess Margaret Cancer Centre, Toronto, ON, Canada. Published online ahead of print at www.jco.org on April 27, 2015. Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article. Corresponding author: Jennifer J. Knox, MD, Princess Margaret Cancer Centre, University of Toronto, 610 University Ave, 5-210, Toronto, ON, Canada M5G 2M9; e-mail: [email protected]. © 2015 by American Society of Clinical Oncology 0732-183X/15/3316w-1835w/$20.00 DOI: 10.1200/JCO.2014.60.1153

INTRODUCTION

Although hepatocellular carcinoma (HCC) is the sixth most common cancer globally, the overall outcomes are poor with 5-year overall survival (OS) rates estimated at less than 12%.1 Relatively few patients are eligible for curative therapy because of the late appearance of symptoms despite the established efficacy of screening programs in at-risk individuals.2 Unlike other high-incidence malignancies, therapeutic decisions in HCC are hampered by the limits of high-quality evidence across all clinical scenarios. The selection of treatment modalities depends not only on the stage, the extent of tumor, and the patient’s performance status but also on the underlying liver function. The Barcelona Clinic Liver Cancer (BCLC) classification stratifies patients according to these factors and provides treatment recommendations3 (Fig 1), but it may oversimplify decision making that is best approached through multidisciplinary case discussions. Surgery or transplantation remain the mainstays of curative therapy for early disease. Ablative strategies can also cure small tumors. Transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and external beam radiation therapy (EBRT) can control locally advanced disease no longer amenable to cure. Systemic treatment for advanced HCC was not recognized as a standard until the approval of sorafenib for a modest improvement in median OS. This discovery resulted in a plethora of clinical trials aimed at advancing the field. Many targeted therapies are being explored as first- or second-line treatment options in advanced HCC, although results to date have been disappointing. Because more than 90% of cancers arise in patients with underlying cirrhosis, the treatment of HCC requires the management of both the concurrent malignancy and liver disease. Many patients presenting with HCC will require ongoing supportive care of their underlying liver disease such as hepatitis B virus (HBV) or hepatitis C virus (HCV) infections or nonalcoholic steatohepatitis. Because these conditions may also complicate cancer treatment strategies (eg, with a high risk for reactivation of HBV around most cancer treatments), antiviral

therapy for active infection should be considered a standard of care.4 Because HCV does not generally reactivate around cancer treatments, dedicated therapy is not necessary. However, the current advancements in new direct-acting antivirals such as sofosbuvir5 and others are so effective that shorter courses of therapy are associated with high sustained HCV response rates with relatively few toxicities. It is expected that patients with HCV will be treated early for viral clearance precirrhosis, even if they present later with HCC.

CURATIVE APPROACHES FOR HCC

Liver Transplantation Transplantation has the unique benefit of addressing both the cancer and tumorigenic cirrhotic liver. Initial experience with transplantation for HCC showed dismal results because of poor patient selection.6 The Milan Criteria (MC; solitary HCC ⱕ 5 cm or three or fewer multifocal tumors each ⱕ 3 cm)7 demonstrated actuarial 4-year disease-free survival and OS of 92% and 85%, respectively, from a small series of patients. This has been validated in numerous series and has thus become the standard eligibility criteria for orthotopic liver transplantation (OLT) in many countries. Some have criticized the MC for being too restrictive and have demonstrated acceptable outcomes with more liberal guidelines8 but with a stepwise decrease in OS as size and tumor number limits increase. The benefit of downstaging to within MC is uncertain; although response to therapy is encouraging, the initial pretreatment tumor characteristics seem to predict post-transplantation outcomes and lead some to suggest a period of observation before downstaged patients are listed for OLT.9 Similarly, treating patients with HCC while they are on the waiting list with bridging therapy to reduce the risk of dropping off the waiting list is not clearly defined. The expansion of criteria for OLT to higher-risk tumors, including those downstaged or outside MC, must be considered in the ethical context of limited cadaveric organ availability and the impact on noncancer patients on OLT waiting lists given the © 2015 by American Society of Clinical Oncology

Information downloaded from jco.ascopubs.org and provided by at NEW YORK UNIVERSITY MED CTR on June 3, 2015 Copyright © 2015 Americanfrom Society of Clinical Oncology. All rights reserved. 128.122.253.228

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Knox, Cleary, and Dawson

Fig 1. Barcelona Clinic Liver Cancer hepatocellular carcinoma staging. PS, performance status. Reprinted with permission.3

additional prioritization afforded to patients with cancer in many transplantation regions.10 Living donor liver transplantation (LDLT) is practiced in regions of the world where cadaveric organs are in short supply, especially Asia, as well as in selected high-volume centers in North America and Europe. Studies suggest that oncologic outcomes for OLT and LDLT are similar,11 but expediting LDLT for patients with advanced HCC may have a detrimental effect on outcomes by shortening the waiting time and limiting the ability to assess the biologic behavior of HCC.10 Patients with compromised liver function who are not candidates for curative intent resection or radiofrequency ablation (RFA) and whose tumors meet MC are best treated with OLT. Extrahepatic disease and macrovascular tumor thrombus are widely accepted contraindications for transplantation. Outcomes following transplantation are excellent with 1- and 5-year OS of more than 85% and 70%, respectively, in most centers. Limitations to OLT include the scarcity of cadaveric organs, constraints on patient eligibility, complications from life-long immunosuppression, and relatively poor outcomes in patients who develop recurrence. Surgical Resection Surgical resection of HCC can be considered in many cases through meticulous technique and surgical planning; patient selection and careful assessment of hepatic reserve are essential to achieve good outcomes. Traditionally, resection has been considered in patients with solitary or limited multifocal disease and well-preserved liver function with Child-Pugh class A (CP-A) or CP-B7 without severe portal hypertension (platelets ⬍ 100,000). However, variability in perioperative outcomes among CP-A patients requires more refined assessment of hepatic reserve and portal hypertension, including the model of end-stage liver disease score, indocyanine green retention, and a wedge hepatic venous pressure gradient (⬎ 10 mmHg) measurement to improve patient selection.10,11 An anticipated future remnant liver volume of more than 40% after resection has been 1836

© 2015 by American Society of Clinical Oncology

recommended as a cutoff in patients with cirrhosis to minimize postoperative liver dysfunction. In cases of inadequate residual volume, portal vein embolization can be used to increase the future remnant liver volume12 before surgery. Smaller lesions are generally treated by segmental resections, with lobar and extended hepatic resection reserved for large or multifocal tumors. Anatomic resection of HCC and the associated Couinaud hepatic segment12 as well as the anterior approach13 have been advocated in recent studies to improve surgical and oncologic outcomes.12,13 Laparoscopic resection of HCC is associated with decreased perioperative morbidity rates, especially in patients with cirrhosis, while offering similar oncologic outcomes and is emerging as the preferred surgical approach in appropriate patients and centers. Indications for resection are expanding modestly as improvements in patient selection, surgical technique, and postoperative care improve the safety of resection, with mortality rates less than 5%. Resection in patients with CP-B, portal vein thrombosis (PVT), and BCLC stage B remains controversial, with good outcomes reported in selected patients treated at high-volume surgical centers.14 Intrahepatic recurrence is a common complication after resection (approximately 60% at 5 years), with 5-year OS ranging from 60% to 73%.15 Tumor Ablation Ablation of small HCCs has become a highly effective treatment modality because of its high rates of local control and low morbidity. RFA is the most frequently used modality with emerging experience with microwave and high-intensity focused ultrasound technology; percutaneous ethanol injection and cryoablation are used less commonly because of more adverse effects and lower efficacy. In the majority of patients, RFA can be performed percutaneously by ultrasound or computed tomography guidance, whereas an open operative approach can be considered in patients on the basis of local expertise or lesions that are not accessible by using a percutaneous approach.16 JOURNAL OF CLINICAL ONCOLOGY


Treating Hepatocellular Carcinoma

HCC

Curative Approach Very Early Solitary < 2cm

Tumor stage Liver Function Management

Within Milan Critera

CP-A

CP-B

CP-C

RFA > Resection

RFA

Transplant

CP-A

Resection

RFA

Outside Milan Criteria

CP-B

CP-C

CP-A

CP-B/C

RFA or Transplant

Transplant

Resection (if possible)

Palliative Tx

Fig 2. Curative treatment algorithm. CP, Child-Pugh (classification system); HCC, hepatocellular carcinoma; RFA, radiofrequency ablation; Tx, therapy.

RFA is considered highly effective for small HCCs, which are more commonly well-differentiated lesions with lower rates of satellite lesions and microvascular invasion. Technical challenges that can limit the effectiveness of RFA include difficult access (eg, subdiaphragmatic locations), subcapsular lesions, and proximity to major biliary or vascular structures that would lead to risk of biliary injury and heat-sink effect, respectively. RFA is associated with low morbidity (⬍ 5%) and mortality (⬍ 1%) rates, which compare favorably to other treatments and can be used in CP-A and CP-B7 patients. Local progression rates vary widely between 5% and 15% in long-term retrospective studies, with tumor size, poorly differentiated histology, infiltrative tumor, high ␣-fetoprotein (AFP), and ablation margin associated with local recurrence. Five-year intrahepatic recurrence and OS rates range from 60% to 75% and 50% to 60%, respectively.17 Selection of Curative Therapy in HCC Despite a large number of comparative studies of curative treatment modalities in HCC, evidence-based decisions between management options remain difficult. Currently identified prognostic factors after transplantation, resection, and ablation are remarkably similar and include tumor number and size, differentiation, vascular invasion, and pretreatment hepatic function. Studies have attempted to compare hepatic resection and transplantation15 but are retrospective and are compromised by significant selection bias and study arms that are not comparable. In many studies, transplantation patients are younger and have lower volume of disease but have greater impairment in liver function compared with resection patients. Despite this, most studies indicate that compared with transplantation, hepatic resection is associated with higher intrahepatic recurrence rates but similar long-term OS. Several retrospective series, three randomized controlled trials (RCTs),18-20 and a systematic review21 have compared RFA and resection. Chen et al18 randomly assigned 180 patients with solitary HCC less than 5 cm to RFA or resection. Four-year OS and disease-free survival rates were similar, although 21 of 90 patients randomly assigned to RFA withdrew their consent and underwent resection. Feng et al20 randomly assigned 168 patients with up to two lesions of less than 4 cm and reported similar 3-year OS and relapse-free survival (RFS) between RFA and surgery with a trend (P ⫽ .122) toward improved OS after resection. Huang et al19 randomly assigned 230 patients within MC; the proportion of small (⬍ 3 cm) HCCs was higher in the RFA group despite random assignment. Three- and 5-year OS and RFS were significantly better after resection (P ⫽ .001 and P ⫽ .017, respectively), with this difference retaining statistical significance in all subgroups. www.jco.org

For early-stage HCC (1 to 6 cm), stereotactic body radiation therapy (SBRT; 30 to 40 Gy in three to five fractions)22,23,24 or proton therapy (33 to 88 GyE in 10 to 30 fractions)24a have been used with high rates of sustained HCC control (3- to 5-year local control, 87% to 93%; OS, 34% to 70%). SBRT should be considered in early-stage patients who are not eligible for resection or RFA and may also be used as bridge therapy for patients with HCC waiting for OLT. We propose an algorithm (Fig 2) based on a modification of the BCLC system for curative therapy. In general, early solitary HCC (⬍ 2.5 cm) may be treated with ablation or surgery, with strong consideration given to ablation, particularly in HCCs distant from major vascular and biliary structures and in CP-B patients. HCCs within MC may be treated with ablation, resection, or transplantation, depending on patient age, comorbidities, and hepatic function. Transplantation is generally preferred for patients with compromised liver function (CP-B and CP-C) and those not amenable to other curative modalities. HCCs outside MC should be treated with resection when possible or, alternatively, could be considered for downstaging treatment before transplantation or for noncurative therapies. Adjuvant Therapy After Curative-Intent Treatments No effective adjuvant treatment to prevent recurrence of HCC after curative treatment has been described. A meta-analysis of older adjuvant treatments conducted predominantly in Asian populations25 concluded that although there were data supporting adjuvant interferon that improved both RFS and OS, the benefits had to be weighed against its severe adverse effects. More recently, a global, randomized, placebo controlled trial (Sorafenib as Adjuvant Treatment in the Prevention Of Recurrence of Hepatocellular Carcinoma [STORM]) of daily sorafenib for up to 4 years offered in the adjuvant setting after potentially curative treatment (surgical resection or RFA) was completed.26 It did not reach its primary end point of improved RFS, and median RFS was 33 months in both arms. Median OS is still maturing, but there has been no sign of benefit from recent analyses. Currently, there is no adjuvant treatment with global acceptance in clinical practice, and observation remains the standard of care.

NONCURATIVE DISEASE (INTERMEDIATE STAGE, LOCALLY ADVANCED, METASTATIC, AND RECURRENT)

Liver-Dominant HCC The majority of patients with HCC present with locally advanced disease. Many patients treated with curative intent recur, and the © 2015 by American Society of Clinical Oncology


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Fig 3. Hepatocellular carcinoma (HCC) spread: recurrent and metastatic. IVC, inferior vena cava; LN, lymph node.

majority of recurrences are confined to the liver and hepatic vasculature.27 Compared with most other malignancies, there is less propensity for HCC to spread to regional nodes or distant organs, which provides good rationale for hepatic-directed therapies (Fig 3). Vascular invasion of the portal vein, hepatic vein, or inferior vena cava is common, is associated with an increased risk of diffuse microscopic HCC, and may precipitate liver failure, especially if tumor thrombi are occlusive. In addition to vascular invasion, overall tumor burden, high AFP level, and CP are prognostic factors. Because of the poor outcomes of patients with vascular invasion following systemic therapy, TACE, TARE, and EBRT have all been used in this setting, despite a lack of level 1 evidence. Similarly, there are reports of these treatments being used for patients with impaired liver function. The degree of liver failure is strongly linked with OS, and in patients with CP-B8 or worse liver function and/or decompensated cirrhosis, best supportive care is often the best treatment. Without doubt, there is a need for more successful trials of TACE, TARE, and EBRT for these high-risk patients with HCC. TACE In contrast to the hepatic parenchyma, HCC derives the majority (approximately 80%) of its blood supply from the hepatic artery, which provides a selective advantage for hepatic arterial– directed therapies such as TACE or TARE. TACE refers to the hepatic arterial delivery of embolic material with chemotherapy (usually doxorubicin alone or with cisplatin and/or mitomycin, mixed with radio-opaque lipiodol). Phase III studies and meta-analyses have shown that TACE is associated with a survival benefit compared with best supportive care, with a 2-year OS increase from 11% to 33% and from 27% to 63% in trials of patients with predominantly HBV and HCV, respectively.28,29 Patients with HCC with tumors less than 10 cm and multinodular CP-A without PVT are most likely to benefit from TACE. These patients are classified as BCLC stage B and are a heterogeneous group that may benefit from further subdivision around best therapies.30 Although best evidence does not support the use of TACE in the 1838


setting of PVT, TACE is sometimes used in patients with segmental PVT. The most common adverse effects after TACE are transient abdominal pain, nausea, fever, fatigue, increase of liver enzymes and, less commonly, worsening of liver function, bile duct injury, and abscess. TACE is planned to be repeated as long as there is disease control. However, deciding when to stop TACE and move on to other therapies can be a point of controversy. Ideally, the change to other therapies should be at a time when liver function is preserved and patients may be eligible for trials of novel therapies. Drug-eluting bead (DEB) TACE refers to the use of doxorubicinloaded bead-based TACE designed to deliver a high concentration of drug over a longer time with less systemic toxicity. A small randomized trial showed that tumor responses were similar with DEB TACE versus classic TACE, and pain, alopecia, and marrow suppression were reduced with DEB TACE. Patients with CP-B and bilobar HCC had higher response rates with DEB TACE (52% v 35% with classic TACE) but no survival benefit.31 Compared with classic TACE, DEB TACE has the downside of an increased risk of biliary damage.32 There is little consensus on the optimal TACE embolic materials and chemotherapy; however, DEB TACE tends to be offered to patients with more extensive HCC or higher risk of systemic toxicity. Transarterial embolization without chemotherapy is primarily used for the treatment of a ruptured HCC. Radioembolization TARE, referred to as selective internal radiation therapy, involves hepatic arterial delivery of radioactive particles (eg, iodine-131 [131I]lipiodol or yttrium-90 [90Y] microspheres delivered via glass [TheraSphere MDS Nordion, Ottawa] or resin microspheres [SIRSpheres SIRTeX Medical, Lake Forest, IL]) with minimal embolization. Studies of 131I have had mixed results in patients with HCC,33,34 and it is not routinely used to treat HCC. 90Y is increasingly being used for treatment of HCC.35-38 A prospective study of 90Y in 291 patients reported a time to progression (TTP) of 7.9 months and median OS of 17.2 months in CP-A patients and 7.7 months in CP-B patients.37 JOURNAL OF CLINICAL ONCOLOGY



Fig 4. Hepatocellular carcinoma with invasion to the right portal vein (yellow arrow) before and 4 months after stereotactic body radiation therapy (SBRT). External-beam radiation therapy for locally advanced hepatocellular carcinoma. AFP, ␣-fetoprotein.

Others have similar outcomes.35,38 90Y has been used for the treatment of HCC with PVT,35,39 with median OS ranging from 7.7 to 16.6 months and less toxicity compared with TACE. The best outcomes have been in patients with segmental (v main branch) PVT.39 Patients with noninfiltrative HCC (⬍ 70% of liver involved), without main branch PVT CP-A are the most likely to benefit from 90Y. Adverse effects include fatigue, transient abdominal pain, nausea and vomiting and, less commonly, worsening of liver function. EBRT In intermediate-stage HCC, fractionated conformal radiotherapy (RT), hypofractionated RT, and SBRT have been used instead of TACE, combined with TACE, or in recurrence after TACE. Nonrandomized comparative studies, mostly from Asia, have suggested improved local control and OS in patients with HCC treated with RT combined with TACE versus TACE alone, particularly for HCCs larger than 10 cm.22,23 Phase III studies in this setting are warranted. Conformal RT and SBRT have been used to treat HCC with PVT, with recanalization of the PVT seen in up to 75% of patients treated with SBRT (30 to 48 Gy in six fractions),24,40 with median OS ranging from 4 to 22 months (Fig 4).41 In a phase I/II study by Bujold et al,42 102 patients with locally advanced HCC (PVT in 55%; median size, 10 cm) were treated with six fractions of SBRT, with a 1-year local control rate of 87% and a median OS of 17 months. Adverse effects included fatigue, gastritis/duodenitis (if adjacent to stomach or duodenum), and worsening of liver function. SYSTEMIC THERAPY IN COMBINATION WITH LOCOREGIONAL THERAPY

TACE Plus Sorafenib Because sorafenib therapy became the standard of care in the advanced BCLC stage C setting, interest grew in the combination of this agent with TACE. There is a potential synergism because TACE www.jco.org

induces tumor necrosis and may create conditions that drive angiogenesis.43 Treatment with an antiangiogenic agent such as sorafenib may curtail the post-TACE increase in vascular endothelial growth factor (VEGF) –mediated signaling and prevent or delay tumor progression. Sorafenib peri-DEB TACE for BCLC stage B patients was investigated in the phase II randomized SPACE (Sorafenib or Placebo in Combination With Transarterial Chemoembolization [TACE] With Doxorubicin-Eluting Beads [DEBDOX]) trial.44 The primary end point was time to radiologic progression, and 307 patients were randomly assigned. Although the study met its primary end point of improving TTP with the addition of sorafenib to a regimen of DEB TACE, the difference was small and not clinically meaningful. The combination was well tolerated, although fewer than expected TACE procedures were delivered, possibly because of toxicity. A phase III study of sorafenib given 1 to 3 months after TACE in Japanese and Korean patients with unresectable HCC and CP-A cirrhosis who had tumor necrosis and/or shrinkage after TACE, concluded that sorafenib did not significantly prolong TTP in patients who responded to TACE.45 The current standard is to consider sorafenib only after TACE fails. We await results from ongoing phase III trials. RT Plus Systemic Therapy Despite the excellent local control of HCCs following RT or TARE, the majority of patients develop hepatic recurrences outside the treated tumor field, which provides a rationale for combining RT with systemic therapies. Hepatic arterial fluorodeoxyuridine46 or fluorouracil47 have safely been combined with fractionated conformal RT, with a median survival of 15.2 and 13.1 months, respectively. Capecitabine has also been combined with conformal RT with high response rates and low rates of toxicity.48 There is a rationale for combining anti-VEGF therapies and RT,49 and better than expected clinical outcomes have been seen following conformal RT combined with sorafenib or sunitinib.19,46,47,50 One phase II study demonstrated a median OS of 14 months in patients treated with 40 to 60 Gy RT in 2 to 2.5 Gy fractions with concomitant © 2015 by American Society of Clinical Oncology


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SYSTEMIC THERAPIES

Historically, chemotherapy was offered to patients with advanced HCC largely on the basis of single-arm studies. Doxorubicin alone has been used as well as in combinations with no clear evidence of OS benefit. When the promising cisplatin, interferon, doxorubicin and fluorouracil regimen was studied in a phase III trial versus single-agent doxorubicin, there was no significant difference in OS (median OS, 8.7 v 6.8 months, respectively; hazard ratio [HR], 0.97; P ⫽ .83), and there was concerning treatment-related toxicity.53 Thus, chemotherapy is not generally recommended. The promise for advancement in systemic treatments is believed to lie with newer targeted strategies currently under development. The key signaling pathways that have been implicated in the pathogenesis of HCC include those mediated by epidermal growth factor, VEGF, platelet-derived growth factor, Ras/Raf/MAP kinase, Wnt/␤-catenin, PI3K, Akt/mammalian target of rapamycin (mTOR), insulin growth factor (IGF)54 and the mesenchymal-epithelial transition (MET) factor receptor for the hepatocyte growth factor.55 There does not appear to be a true dominant pathway at play. However, many of these pathways have targets for putative drugs and are under review in HCC and other cancers. Some targeted agents simultaneously hit more than one target, and this multiple targeting could enhance the therapeutic efficacy of these agents. First-Line Systemic Therapy Sorafenib is the first targeted therapy proven to provide OS benefit in patients who have progressed past the benefit of surgery or locoregional therapies (Fig 5). Sorafenib is an oral multikinase inhibitor with antiangiogenic and antiproliferative actions. Two phase III trials, the SHARP (Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol) trial56 and the Asia-Pacific trial (Efficacy and Safety of Sorafenib in Patients in the Asia-Pacific Region With Advanced Hepatocellular Carcinoma),57 have demonstrated a survival advantage over placebo in patients with preserved liver function (defined as CP-A), with a similar magnitude (HR, 0.69; Table 1). Subgroup analyses showed that sorafenib consistently improved OS and control rates compared with placebo, irrespective of disease etiology, performance status, HCC burden, stage, and prior therapy.56 The observation of greater improvement in survival in the HCV 1840


1.0

Probability of Survival

sorafenib.50 However, there is an increased risk of GI toxicity, highest in patients with larger volumes irradiated and with SBRT versus conventional fractionation, which suggests using caution when combining sorafenib and RT outside clinical trials.46,47,50,51 A randomized trial comparing SBRT followed by sorafenib versus sorafenib alone is ongoing (Radiation Therapy Oncology Group 1112 [RTOG 1112]; NCT01730937; Sorafenib Tosylate With or Without Stereotactic Body Radiation Therapy in Treating Patients With Liver Cancer). Sequential TARE with 90Y and sorafenib has been used with no reported increased toxicity,52 and randomized trials of TARE versus sorafenib are also ongoing (NCT01482442, Sorafenib Versus Radioembolization in Advanced Hepatocellular Carcinoma; NCT01887717, Efficacy Evaluation of TheraSphere to Treat Inoperable Liver Cancer With Blockage of the Portal Vein; and NCT01135056, Study to Compare Selective Internal Radiation Therapy [SIRT] Versus Sorafenib in Locally Advanced Hepatocellular Carcinoma [HCC]).

0.8

0.6

0.4 Sorafenib Placebo

0.2

P < .001

0 No. at risk Sorafenib Placebo

1

2

3

4

5

6

7

8

9 10 11 12 13 14 15 16 17

Time From Random Assignment (months) 299 290 270 249 234 213 200 172 140 111 89 68 303 295 272 243 217 189 174 143 108 83 69 47

48 37 34 31 23 14

7 6

1 3

0 0

Fig 5. Sorafenib prolongs overall survival in Barcelona Clinic Liver Cancer stage C Child-Pugh class A patients with hepatocellular carcinoma. Reprinted with permission.56

group is intriguing (14 v 8.7 months) but may be explained by imbalance of important factors between the etiologic subsets, warrants further study,65 and argues for stratification of viral etiology. Common adverse effects of sorafenib are diarrhea, weight loss, and hand-foot skin reaction. Unfortunately, neither study demonstrated symptomatic improvement or improved quality of life. Patients with more advanced liver failure were excluded from these studies (CP-B or CP-C), because deaths related to advanced liver disease might have masked any significant effect of sorafenib. Existing data do not support of the use of sorafenib in patients with CP-B or CP-C liver function. These two trials do provide definitive evidence of an OS benefit in patients with CP-A liver status and good performance status; thus, they have become the standard of care and a new benchmark to surpass in this first-line systemic agent setting. Clinical variables such as PVT, Eastern Cooperative Oncology Group performance status, and baseline AFP and alkaline phosphatase concentrations predict for survival in advanced HCC. In a subsequent article, the authors of the SHARP study presented data on a panel of 10 potential plasma biomarkers across 491 patients from the randomized trial. Although baseline angiopoietin-2 and VEGF levels were prognostic for survival, no predictor of response was seen.66 Any specific tumor biomarker could not be evaluated because tumor sample was not a requirement for most patients on the study. Thus, the trials to date have not provided any biomarkers to predict benefit for sorafenib. Many studies that have been completed or are underway aimed at improving on the results seen with sorafenib therapy (agents and presumed targets in listed in Table 1). In the first-line setting, sorafenib has served as the control arm in three RCTs evaluating other oral tyrosine kinase inhibitors with noninferiority designs. Sunitinib,60 linafenib,61 and brivanib62 all failed to demonstrate noninferiority to sorafenib. In fact, the sunitinib trial was stopped early because of a trend toward harm. The HCV subgroup again appeared to survive longer with sorafenib—17.6 versus 9.2 months with sunitinib—arguing that sorafenib has unique activity outside the VEGF receptor (VEGFR) inhibition the two agents share, which is hypothesized to be related to RAF inhibition. Demonstrated across these three large, JOURNAL OF CLINICAL ONCOLOGY


www.jco.org


Global Study Looking at the Combination of RAD001 Plus Best Supportive Care (BSC) and Placebo Plus BSC to Treat Patients With Advanced Hepatocellular Carcinoma Comparison of Brivanib and Best Supportive Care to Placebo for Treatment of Liver Cancer for Those Subjects Who Have Failed Sorafenib Treatment Study of Ramucirumab (IMC-1121B) and Best Support Care (BSC) vs Placebo and BSC As Second-Line Treatment in Participants With Hepatocellular Carcinoma After First-Line Therapy With Sorafenib Study of Tivantinib in Subjects With Inoperable Hepatocellular Carcinoma Who Have Been Treated With One Prior Therapy Study of Cabozantinib (XL184) vs Placebo in Subjects With Hepatocellular Carcinoma Who Have Received Prior Sorafenib Study of Regorafenib After Sorafenib in Patients With Hepatocellular Carcinoma Ph 3 ADI-PEG 20 Versus Placebo in Subjects With Advanced Hepatocellular Carcinoma Who Have Failed Prior Systemic Therapy

Sorafenib Tosylate With or Without Doxorubicin Hydrochloride in Treating Patients With Locally Advanced or Metastatic Liver Cancer

Nexavar-Tarceva Combination Therapy for First Line Treatment of Patients Diagnosed With Hepatocellular Carcinoma

Phase III Trial of Linifanib vs Sorafenib in Patients With Advanced Hepatocellular Carcinoma Brivanib vs Sorafenib As First-Line Therapy in Patients With Unresectable, Advanced Hepatocellular Carcinoma A Multicenter, Open-Label, Phase 3 Trial to Compare the Efficacy and Safety of Lenvatinib (E7080) Versus Sorafenib in First-Line Treatment of Subjects With Unresectable Hepatocellular Carcinoma

Sunitinib vs Sorafenib in Advanced Hepatocellular Cancer

Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol Efficacy and Safety of Sorafenib in Patients in the Asia-Pacific Region With Advanced Hepatocellular Carcinoma

Study Title

Pegylated arginine deaminase v placebo

VEGFR1, 2, 3, PDGFR, FGFR, c-KIT, RET, B-RAF Arginine-dependent tumor cells

c-MET, VEGFR2 inhibitor

VEGFR2

Cabozantinib v placebo Regorafenib v placebo

Ramucirumab v placebo

Zhu et al59

VEGF, FGF

c-MET inhibitor

Brivanib v placebo

Llovet et al58

mTOR inhibitor

VEGFR2, PDGFR, FLT3, RET, c-KIT, RAF plus EGFR inhibitor VEGFR2, PDGFR, FLT3, RET, c-KIT, RAF plus cytotoxic agent

VEGFR1-3, FGFR1-4, RET, KIT, PDGF␤

VEGF, FGF

VEGFR, PDGFR

VEGFR, PDGF

VEGFR2, PDGFR, FLT3, RET, c-KIT, RAF VEGFR2, PDGFR, FLT3, RET, c-KIT, RAF

Molecular Targets

Tivantinib v placebo

Everolimus v placebo

Sorafenib plus erlotinib v sorafenib plus placebo Sorafenib plus doxorubicin v sorafenib

Lenvatinib v sorafenib

Brivanib v sorafenib

Zhu et al64

Zhu et al63

Johnson et al62

Linifanib v sorafenib

Sunitinib v sorafenib

Cheng et al60 Cainap et al

Sorafenib v placebo

Cheng et al57

61

Sorafenib v placebo

Strategy

Llovet et al56

Reference

9.2 v 7.6

8.2 v 9.4

7.6 v 7.3

9.5 v 8.5

9.5 v 9.9

9.1 v 9.8

7.9 v 10.2

6.5 v 4.2

10.7 v 7.9

OS (months)

1.3

0.68

0.69

HR

⬍ .001

.014

⬍ .001

P

3.5 v 2.6

4.1 v 2.7 (PFS)

3.0 v 2.6

3.2 v 4.0

4.2 v 4.1

4.1 v 4.0

2.8 v 1.4

5.5 v 2.8

TTP (months)

Ongoing

Ongoing

High c-MET selected population; ongoing Ongoing

Negative study; subgroup: high AFP suggests OS benefit

Negative study

Negative study

Negative study; increased toxicity with combination Ongoing

Positive study; new standard of care Positive study; confirms benefit in different population Negative study; sunitinib inferior Negative study (noninferiority) Negative study (noninferiority) Ongoing

Comment

Abbreviations: c-MET, c-mesenchymal-epithelial transition factor; EGFR, epidermal growth factor receptor; FGF, fibroblast growth factor; FGFR, FGF receptor; FLT3, Fms-like tyrosine kinase 3; HCC, hepatocellular carcinoma; mTOR, mammalian target of rapamycin; PDGF, platelet-derived growth factor; PDGFR, PDGF receptor; RET, rearranged during transfection; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.

Metiv-HCC (NCT01755767) CELESTIAL (NCT01908426) RESORCE (NCT01774344) Polaris ADI-PEG-20 (NCT01287585)

REACH

BRISK-PS

Second-line treatment in advanced disease EVOLVE-1

CALGB 80802 (NCT01015833)

First-line combinations in advanced disease SEARCH (NCT00901901)

(NCT01761266)

BRISK-FL

Asian-Pacific

First-line single agent in advanced disease SHARP

Study Acronym (NCT No.)

Table 1. Recent/Ongoing Phase III Trials of Systemic Therapy in Advanced HCC



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newer trials with diverse geographic and etiologic populations, the median survival for all patients treated with sorafenib was consistently close to 10 months, as was seen in the original SHARP trial; sorafenib was numerically superior to the other agents. Recognizing that HCCs have tremendous molecular heterogeneity, it is suggested that therapeutic advancements may require simultaneous targeting of more than one molecular pathway. Combining targeted agents in patients has been challenging because of the increase and overlap of toxicities.67,68 Despite many phase I/II trials, few combinations have distinguished themselves with efficacy signals that would justify advancing to phase III. One phase III trial combining erlotinib and sorafenib versus sorafenib alone has reported no advantage.63 On the basis of promising phase II signals, we await phase III data of sorafenib plus doxorubicin versus sorafenib alone (Cancer and Leukemia Group B [CALGB] 80802; NCT01015833; Sorafenib Tosylate With or Without Doxorubicin Hydrochloride in Treating Patients With Locally Advanced or Metastatic Liver Cancer), the combination of bevacizumab plus erlotinib,69 and other drugs and drug combinations in large RCTs. Second-Line Systemic Therapy Equally disappointing to date are the results of trials evaluating new therapies after sorafenib failure (Table 1). Several unique agents with suggested activity in phase II trials have been studied in this second-line setting compared with best supportive care alone, given a lack of established effective treatments. The oral mTOR inhibitor everolimus demonstrated no significant difference in median OS (7.6 v 7.3 months) compared with placebo.64 Similar negative results were obtained with the novel agent brivanib in the phase III BRISK-PS (Comparison of Brivanib and Best Supportive Care to Placebo for Treatment of Liver Cancer for Those Subjects Who Have Failed Sorafenib Treatment) trial.58 Survival of more than 7 months in the placebo arm was longer than anticipated and suggests that patients with better biology were accrued to these studies. Other agents evaluated against placebo in the second-line setting include cabozantinib (NCT01908426; Study of Cabozantinib [XL184] vs Placebo in Subjects With Hepatocellular Carcinoma Who Have Received Prior Sorafenib), and also regorafenib (NCT01774344; Study of Regorafenib After Sorafenib in Patients With Hepatocellular Carcinoma), and we await the findings of these studies. The REACH (A Study of Ramucirumab [IMC-1121B] and Best Supportive Care [BSC] Versus Placebo and BSC as 2nd-Line Treatment in Patients With Hepatocellular Carcinoma After 1st-Line Therapy With Sorafenib) trial evaluating ramucirumab, a monoclonal antibody targeting VEGFR, also failed to meet its primary end point.59 There was a numerical improvement favoring the ramucirumab arm (9.2 v 7.6 months), which was more pronounced in the preplanned subgroup of patients with baseline AFP more than 400. This potential benefit in a selected subgroup warrants further study. Tivantinib is an oral selective c-MET inhibitor. A randomized controlled phase II trial of tivantinib versus placebo in the second-line setting reported that tivantinib improved TTP most significantly in patients with high MET expression, a factor found to be associated with poor prognosis.70 In addition, this subgroup with high MET demonstrated a 3.4-month improvement in OS with tivantinib compared with placebo (7.2 v 3.8 months; HR, 0.38; P ⫽ .01). No improvements in TTP or OS were observed with tivantinib in patients with low MET expression tumors. A phase III randomized, double-blind study 1842


of tivantinib in preselected patients with high c-MET HCC by immunohistochemistry in the second-line setting is currently accruing patients (NCT01755767; Study of Tivantinib in Subjects With Inoperable Hepatocellular Carcinoma Who Have Been Treated With One Prior Therapy). We look forward to the results of this progressive biomarker-driven trial. Novel Strategies Thinking outside the VEGF-driven pathways may be required to advance the field, and several strategies are in dedicated early HCC trials. Developing a dose and schedule specific for patients with HCC and exploring biomarkers early on is a big step forward. We will follow with interest immunotherapeutic strategies such as nivolumab, an anti-programmed death-1 (anti-PD-1) antibody (PD-1 inhibitor; NCT01658878; Study to Evaluate the Effectiveness, Safety and Tolerability of Nivolumab in Subjects With Advanced Liver Cancer Anti-PD-1 HCC [Anti-Programmed-Death-1 Hepatocellular Carcinoma]). JX-594 (Pexa-Vec) is an oncolytic and immunotherapeutic vaccinia virus that is infused into HCC tumors and has shown early activity.71 ADI-PEG-20 is a pegylated arginine deaminase that potentially targets the HCC tumor cell dependence on external arginine and is currently in a phase III study (Table 1; NCT01287585; Ph 3 ADIPEG 20 Versus Placebo in Subjects With Advanced Hepatocellular Carcinoma Who Have Failed Prior Systemic Therapy). GC33 (Chugai, Tokyo, Japan) is a novel recombinant humanized monoclonal antibody that binds to human glypican 3 (GPC3) expressed on HCC cells, but a strategy for a phase III trial has not yet been optimized.72 By using a new RNA interference therapeutic strategy, TKM PLK1 (Tekmira Pharmaceuticals, Vancouver, British Columbia, Canada) targets polo-like kinase 1, a protein involved in tumor cell proliferation, and it has moved into a phase I/II HCC trial (NCT02191878; Safety, Pharmacokinetics and Preliminary Anti-Tumor Activity of Intravenous TKM-080301 in Subjects With Advanced Hepatocellular Carcinoma). Other compounds that target pathways in hepatocarcinogenesis, such as IGF and its receptor (cixutumumab; NCT00639509, IMC-A12 in Treating Patients With Advanced Liver Cancer), as well as the Wnt/␤-catenin or PI3K/Akt/mTOR pathways are under early-stage evaluation in HCC. SUMMARY AND FUTURE DIRECTIONS

HCC is a common cancer with high mortality, and therapeutic progress has been slow. Treatment strategies are complex and are best determined by a multidisciplinary team with access to appropriate surgical, hepatology, pathology, interventional radiology, medical, and radiation oncologists plus supportive and palliative care teams. This likely requires an experienced cancer center with a dedicated HCC program, and there is still much room for optimization of evidence-based strategies discussed in this review. Improving standards of care is the first priority for patients with HCC. The development of effective adjuvant therapies after curative intent treatments is another priority, but future adjuvant trials will need to await further breakthroughs in systemic treatment beyond sorafenib. Meanwhile, the importance of driving global education around prevention cannot be overemphasized. We are now in an era in which HBV prevention, HCV treatments, and appropriate surveillance of other patients at risk is a goal within reach for many. JOURNAL OF CLINICAL ONCOLOGY



Given that the majority of patients still present with locally advanced, incurable HCC, improving locoregional control must be given high priority, and several good trials with combined modalities are underway (eg, RTOG 1112). Similarly, more effective systemic agents are the other high priority for research studies. It is becoming abundantly clear that demonstrating superiority over sorafenib is challenging, despite its modest impact and, in addition, no novel agent has shown clear benefit after failure of sorafenib therapy. The use of standard radiologic response or progression-free survival criteria for phase II efficacy have not predicted for success in the phase III setting, but unfortunately, to date, new agents have been tested in largely unselected groups. There may well be subgroups that benefit that were missed with these agents and there may be targets worth revisiting. Dynamic imaging protocols may prove more predictive if they are validated in prospective studies. How convincing a phase II signal is and assumptions around clinical benchmarks must be carefully reconsidered, including even the best definitions of liver function, when designing new trials. Biomarker discovery must be considered as the highest goal in this arena, considering the benefits of identification of predictive biomarkers for new agents in therapeutic efficacy, as well as limiting exposure to toxicity in those unlikely to respond. Given the heterogeneity of the patient population and of HCC itself, this is absolutely necessary to advance the field. Therefore, translational studies need to be a standard component of earlier-stage discovery REFERENCES 1. El-Serag HB: Hepatocellular carcinoma. N Engl J Med 365:1118-1127, 2011 2. Sarasin FP, Giostra E, Hadengue A: Costeffectiveness of screening for detection of small hepatocellular carcinoma in western patients with Child-Pugh class A cirrhosis. Am J Med 101:422434, 1996 3. Forner A, Llovet JM, Bruix J: Hepatocellular carcinoma. Lancet 379:1245-1255, 2012 4. Lim SM, Jang JW, Kim BW, et al: [Hepatitis B virus reactivation during chlorambucil and prednisolone treatment in an HBsAg-negative and antiHBs-positive patient with B-cell chronic lymphocytic leukemia] [in Korean]. Korean J Hepatol 14:213-218, 2008 5. Lawitz E, Mangia A, Wyles D, et al: Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 368:1878-1887, 2013 6. Penn I: Hepatic transplantation for primary and metastatic cancers of the liver. Surgery 110: 726-734, 1991 7. Mazzaferro V, Regalia E, Doci R, et al: Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 334:693-699, 1996 8. Yao FY, Ferrell L, Bass NM, et al: Liver transplantation for hepatocellular carcinoma: Expansion of the tumor size limits does not adversely impact survival. Hepatology 33:1394-1403, 2001 9. Toso C, Mentha G, Kneteman NM, et al: The place of downstaging for hepatocellular carcinoma. J Hepatol 52:930-936, 2010 10. Clavien PA, Lesurtel M, Bossuyt PM, et al: Recommendations for liver transplantation for hepatocellular carcinoma: An international consensus conference report. Lancet Oncol 13:e11-e22, 2012 11. Lo CM, Fan ST, Liu CL, et al: Living donor versus deceased donor liver transplantation for early www.jco.org

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AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Disclosures provided by the authors are available with this article at www.jco.org.

AUTHOR CONTRIBUTIONS Conception and design: Jennifer J. Knox Financial support: Jennifer J. Knox Administrative support: Jennifer J. Knox Collection and assembly of data: All authors Data analysis and interpretation: All authors Manuscript writing: All authors Final approval of manuscript: All authors

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AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Localized and Systemic Approaches to Treating Hepatocellular Carcinoma The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc. Jennifer J. Knox Research Funding: Pfizer, AstraZeneca Sean P. Cleary Honoraria: Olympus Canada

www.jco.org

Laura A. Dawson Research Funding: Bayer HealthCare Pharmaceuticals (Inst) Patents, Royalties, Other Intellectual Property: Raysearch image registration software license



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