NCCN Guidelines Insights: Hepatobiliary Cancers, Version 1.2017

The NCCN Guidelines for Hepatobiliary Cancers provide treatment recommendations for cancers of the liver, gallbladder, and bile ducts. The NCCN Hepatobiliary Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding locoregional therapy for treatment of patients with hepatocellular carcinoma.

Abstract

The NCCN Guidelines for Hepatobiliary Cancers provide treatment recommendations for cancers of the liver, gallbladder, and bile ducts. The NCCN Hepatobiliary Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding locoregional therapy for treatment of patients with hepatocellular carcinoma.

NCCN: Continuing Education

Target Audience: This activity is designed to meet the educational needs of physicians, nurses, and pharmacists involved in the management of patients with cancer.

Accreditation Statement

Physicians: National Comprehensive Cancer Network is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

NCCN designates this journal-based CE activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nurses: National Comprehensive Cancer Network is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center‘s Commission on Accreditation.

NCCN designates this educational activity for a maximum of 1.0 contact hour.

Pharmacists: National Comprehensive Cancer Network is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: 0836-0000-17-005-H01-P

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the educational content; 2) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/80708; and 3) view/print certificate.

Release date: May 10, 2017; Expiration date: May 10, 2018

Learning Objectives:

Upon completion of this activity, participants will be able to:

  • Integrate updates to the NCCN Guidelines for Hepatobiliary Cancers into the management of patients with hepatocellular carcinoma, with a focus on locoregional therapy

  • Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Hepatobiliary Cancers, with a focus on locoregional therapy for hepatocellular carcinoma

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NCCN Guidelines Insights: Hepatobiliary Cancers, Version 1.2017

Version 1.2017 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 5; 10.6004/jnccn.2017.0059

NCCN Categories of Evidence and Consensus

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

Overview

Incidence and mortality rates for cancer overall are declining, but rates for hepatocellular carcinoma (HCC) are increasing.1 Risk factors for the development of HCC include viral infections such as those caused by hepatitis B virus and/or hepatitis C virus, and cirrhosis from any cause (eg, alcohol cirrhosis).2 Some nonviral causes include inherited errors of metabolism (relatively rare), such as hereditary hemochromatosis, porphyria cutanea tarda, and alpha-1 antitrypsin deficiency; Wilson disease; and stage IV primary biliary cirrhosis.3 There is growing evidence for an association between the sequelae of nonalcoholic fatty liver disease, such as nonalcoholic steatohepatitis (a spectrum of conditions characterized by histologic findings of hepatic steatosis with inflammation in individuals who consume little or no alcohol) in the setting of metabolic syndrome or diabetes mellitus and the development of HCC.4,5

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NCCN Guidelines Insights: Hepatobiliary Cancers, Version 1.2017

Version 1.2017 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 5; 10.6004/jnccn.2017.0059

HCC Treatment

The management of patients with HCC is complicated by the presence of underlying liver disease. Furthermore, it is possible that the different etiologies of HCC and their effects on the host liver may impact treatment response and outcome. The treatment of patients with HCC often necessitates multidisciplinary care with the involvement of hepatologists, diagnostic and interventional radiologists, transplant surgeons, pathologists, and medical and surgical oncologists, thereby requiring careful coordination of care.6

The NCCN panel considers locoregional therapy to be the preferred approach for treating patients with unresectable disease confined to the liver (category 2A; see HCC-5; page 565). Locoregional therapies are directed toward inducing selective tumor necrosis and are broadly classified into ablation and arterially directed therapies (both category 2A options). External-beam radiation therapy (EBRT) is recommended as a category 2B option. A number of factors are involved in measuring the effectiveness of locoregional therapies, and the criteria for evaluating tumor response are evolving.711 Patients with extensive intrahepatic disease burden and/or significant vascular involvement (eg, extensive main portal vein involvement) may not be appropriate for locoregional therapies and should be evaluated for systemic therapy.

Ablation

Radiofrequency ablation (RFA) and percutaneous alcohol injection (PEI) are 2 commonly used ablation therapies for HCC. The safety and efficacy of RFA and PEI in the treatment of Child-Pugh class A patients with early-stage HCC tumors (either a single tumor ≤5 cm or multiple tumors [up to 3 tumors] each ≤3 cm) has been compared in a number of randomized controlled trials (RCTs).1219 Independent meta-analyses of randomized trials that have compared RFA and PEI have concluded that RFA is superior to PEI with respect to overall survival (OS) and tumor response in patients with early-stage HCC, particularly for tumors >2 cm.2022 Results of some long-term studies show survival rates of >50% at 5 years for patients with early-stage HCC treated with RFA.2326 However, the reported OS and recurrence rates vary widely across studies for patients treated with RFA, which is most likely due to differences in the size and number of tumors and, perhaps more importantly, tumor biology and the extent of underlying liver function. In multivariate analysis, Child-Pugh class, tumor size, and tumor number were independent predictors of survival.2426

Some investigators consider RFA as the first-line treatment in highly selected patients with HCC tumors ≤2 cm in diameter, in an accessible location, and away from major biliary structures.27,28 In one study, RFA as the initial treatment in 218 patients with a single HCC lesion ≤2 cm induced complete necrosis in 98% of patients.27 After a median follow-up of 31 months, the sustained complete response (CR) rate was 97%. More recently, in a retrospective comparative study, Peng et al28 reported that percutaneous RFA was better than resection in terms of OS and recurrence-free survival (RFS), especially for patients with central HCC tumors <2 cm. The 5-year OS rates in patients with central HCC tumors were 80% for RFA compared with 62% for resection (P=.02); corresponding RFS rates were 67% and 40%, respectively (P=.033). Cryoablation may be safe and effective for small lesions, but studies are inconsistent regarding how outcomes compare with those for RFA.29

Microwave ablation (MWA) is emerging as an alternative to RFA for the treatment of patients with small or unresectable HCC.3034 So far, only 2 randomized trials have compared MWA with resection and RFA.30,34 In the RCT that compared RFA with percutaneous microwave coagulation, no significant differences were observed between these 2 procedures in terms of therapeutic effects, complication rates, and rates of residual foci of untreated disease.30 In a recent randomized study that evaluated the efficacy of MWA and resection in the treatment of HCC conforming to Milan criteria, MWA was associated with lower disease-free survival (DFS) rates than resection with no differences in OS rates.34

Panel consensus is that evidence (although inconclusive) suggests that the choice of ablative therapy for patients with early-stage HCC should be based on tumor size and location, as well as underlying liver function, and overall management should be considered in the context of a multidisciplinary review and institutional expertise.35,36 Ablative therapies are most effective for tumors <3 cm (preferably <2 cm) that are in an appropriate location away from other organs and major vessels/bile ducts. All tumors should be amenable to ablation such that the tumor and, in the case of thermal ablation, a margin of normal tissue is treated. Tumors should be in a location accessible for laparoscopic, percutaneous, or open approaches. Lesions in certain portions of the liver may not be accessible for ablation. Similarly, ablative treatment of tumors located on the liver capsule may cause tumor rupture with track seeding. Tumor seeding along the needle track has been reported in <1% of patients with HCC treated with RFA.3739 Lesions with subcapsular location and poor differentiation seem to be at higher risk for this complication.37 During an ablation procedure, major vessels in proximity to the tumor can absorb large amounts of heat (ie, the “heat sink effect”), which can decrease the effectiveness and significantly increase local recurrence rates.40,41 The panel emphasizes that caution should be exercised when ablating lesions near major bile ducts and other intra-abdominal organs, such as the colon, stomach, diaphragm, heart, and gallbladder, to decrease complications.

Arterially Directed Therapies

Arterially directed therapy involves the selective catheter-based infusion of particles targeted to the arterial branch of the hepatic artery feeding the portion of the liver in which the tumor is located.42 Arterially directed therapy is made possible by the dual blood supply to the liver. Furthermore, HCC tumors are hypervascular resulting from increased blood flow to tumor relative to normal liver tissue. Arterially directed therapies currently in use include transarterial bland embolization (TAE), transarterial chemoembolization (TACE), TACE with drug-eluting beads (DEB-TACE), and transarterial radioembolization (TARE) with yttrium-90 microspheres.

The principle of TAE is to reduce or eliminate blood flow to the tumor, resulting in tumor ischemia followed by tumor necrosis. TAE has been shown to be an effective treatment option for patients with unresectable HCC.4346 TACE is distinguished from TAE in that the goal of TACE is to deliver a highly concentrated dose of chemotherapy to tumor cells, prolong the contact time between the chemotherapeutic agents and the cancer cells, and minimize systemic toxicity of chemotherapy.47 Results of 2 randomized clinical trials have shown a survival benefit for TACE compared with supportive care in patients with unresectable HCC.48,49 Many of the clinical studies evaluating the effectiveness of TAE and/or TACE in the treatment of patients with HCC are confounded by the use of a wide range of treatment strategies, including types of embolic particles, chemotherapy, and emulsifying agents (for studies involving TACE), and number of treatment sessions. The relative effectiveness of TACE over TAE has not been established in randomized trials.

TACE causes increased hypoxia leading to an upregulation of vascular endothelial growth factor receptor (VEGFR) and insulin-like growth factor receptor 2 (IGFR-2).50 Increased plasma levels of VEGFR and IGFR-2 have been associated with the development of metastasis after TACE.51,52 These findings have led to the evaluation of TACE in combination with sorafenib in patients with residual or recurrent tumor not amenable to additional locoregional therapies.5360 Results from nonrandomized phase II studies and a retrospective analysis suggest that concurrent administration of sorafenib with TACE or DEB-TACE may be a treatment option for patients with unresectable HCC.5461 However, in a phase III randomized trial, when given after treatment with TACE, sorafenib did not significantly prolong time to progression or OS in patients with unresectable HCC that responded to TACE.60

DEB-TACE has also been evaluated in patients with unresectable HCC.6269 In a randomized study (PRECISION V) of 212 patients with localized unresectable HCC with Child-Pugh class A or B cirrhosis and without nodal involvement, TACE with doxorubicin-eluting embolic beads induced statistically nonsignificant higher rates of CR, objective response, and disease control compared with conventional TACE with doxorubicin (27% vs 22%; 52% vs 44%; and 63% vs 52%, respectively).64 Overall, DEB-TACE was not superior to conventional TACE with doxorubicin in this study. However, DEB-TACE was associated with a significant increase in objective response (P=.038) compared with conventional TACE in patients with Child-Pugh class B, ECOG performance status (PS) 1, bilobar disease, and recurrent disease. DEB-TACE was also associated with improved tolerability with a significant reduction in serious liver toxicity and a significantly lower rate of doxorubicin-related side effects compared with conventional TACE.64 A recent randomized study compared DEB-TACE versus conventional TACE in 177 patients with intermediate-stage unresectable, persistent, or recurrent HCC. The study revealed no significant efficacy or safety differences between the approaches; however, DEB-TACE was associated with less postprocedural abdominal pain.69 Conversely, Dhanasekaran et al66 reported a survival advantage for DEB-TACE over conventional TACE in a prospective randomized study of 71 patients with unresectable HCC. However, these results are from underpowered studies and need to be confirmed in large prospective studies. A recent randomized trial comparing the effectiveness of TAE with that of doxorubicin-based TACE in 101 patients with HCC70 found no statistically significant differences in response, progression-free survival (PFS), and OS between the groups.

TARE is a method that involves internal delivery of high-dose beta radiation to the tumor-associated capillary bed, thereby sparing the normal liver tissue.42,71 TARE is accomplished through the catheter-based administration of microspheres (glass or resin microspheres) embedded with yttrium-90, an emitter of beta radiation. A growing body of literature suggests that radioembolization might be an effective treatment option for patients with liver-limited, unresectable disease,7277 but additional randomized clinical trials are needed to determine the harms and benefits of TARE with yttrium-90 microspheres in patients with unresectable HCC.78 Although radioembolization with yttrium-90 microspheres, such as TAE and TACE, involves some level of particle-induced vascular occlusion, it has been proposed that such occlusion is more likely to be microvascular than macrovascular, and that the resulting tumor necrosis is more likely to be induced by radiation rather than ischemia.72 Reported complications of TARE include cholecystitis/bilirubin toxicity, gastrointestinal ulceration, and abscess formation.72,74,79 TARE with yttrium-90 microspheres has an increased risk of radiation-induced liver disease in patients with bilirubin >2 mg/dL.74

All HCC tumors, irrespective of location in the liver, may be amenable to arterially directed therapies, provided that the arterial blood supply to the tumor can be isolated.45,49,72,80 Complications common to TAE and TACE include nontarget embolization (including cholecystitis); complications after TACE include acute portal vein thrombosis (PVT), bone marrow suppression, and pancreatitis (very rare), although the reported frequencies of serious adverse events vary across studies.81,82 A postembolization syndrome involving fever, abdominal pain, and intestinal ileus is relatively common in patients undergoing these procedures.81,82 TAE or TACE can increase the risk of liver failure, hepatic necrosis, and liver abscess formation in patients with biliary obstruction; therefore, the panel recommends that a total bilirubin level >3 mg/mL be considered a relative contraindication for TACE and TAE unless segmental injections can be performed. Minimal extrahepatic disease is considered a “relative” contra-indication for arterially directed therapies. Arterially directed therapies are relatively contraindicated in patients with main PVT and are contraindicated in patients with Child-Pugh class C cirrhosis.83

Tumors between 3 and 5 cm may be treated with a combination of ablation and arterially directed therapies to prolong survival, as long as the tumor location is favorable to ablation.8486 The panel recommends that patients with unresectable or inoperable lesions >5 cm be considered for treatment using arterially directed therapies or systemic therapy. An evaluation of the arterial anatomy of the liver, patient PS, and liver function is necessary before the arterially directed therapy. In addition, more individualized patient selection that is specific to the particular arterially directed therapy being considered is necessary to avoid significant treatment-related toxicity.

Locoregional therapy may be used as part of downstaging therapy, which is used to reduce the tumor burden in selected patients with more advanced HCC (without distant metastasis) who are beyond the accepted liver transplant criteria.87,88 Prospective studies have demonstrated that downstaging (before transplant) with PEI,89 RFA,89,90 TACE,8992 TARE with yttrium-90 microspheres,92 and transarterial chemoinfusion93 improves DFS after transplant. However, such studies have used different selection criteria for the downstaging therapy and different transplant criteria after successful downstaging. Further validation is needed to define the end points for successful downstaging before transplant.

External-Beam Radiation Therapy

EBRT allows focal administration of high-dose radiation to liver tumors while sparing surrounding liver tissue, thereby limiting the risk of radiation-induced liver damage in patients with unresectable or inoperable HCC.94,95 Advances in EBRT, such as intensity-modulated radiation therapy (IMRT), have allowed for enhanced delivery of higher radiation doses to the tumor while sparing surrounding critical tissue. Stereotactic body radiation therapy (SBRT) is an advanced technique of EBRT that delivers large ablative doses of radiation. There is growing evidence (primarily from non-RCTs) supporting the usefulness of SBRT for patients with unresectable, locally advanced, or recurrent HCC.96100

In a phase II trial of 50 patients with inoperable HCC treated with SBRT after incomplete TACE, SBRT induced CRs and partial responses in 38.3% of patients within 6 months of completing SBRT.99 The 2-year local control rate, OS, and PFS rates were 94.6%, 68.7%, and 33.8%, respectively. In another study that evaluated the long-term efficacy of SBRT for patients with primarily small HCC ineligible for local therapy or surgery (42 patients), SBRT induced an overall CR rate of 33%, with 1- and 3-year OS rates of 92.9% and 58.6%, respectively.96 In patients with recurrent HCC treated with SBRT, tumor size, recurrent stage, and Child-Pugh classification were identified as independent prognostic factors for OS in multivariate analysis.98 A retrospective analysis comparing RFA and SBRT in 224 patients with inoperable, nonmetastatic HCC showed that SBRT may be a preferred option for tumors ≥2 cm.101 SBRT has also been shown to be an effective bridging therapy for patients with HCC and cirrhosis awaiting liver transplant.102104

Most safety and efficacy data on the use of SBRT are available for patients with HCC and Child-Pugh class A liver function; limited safety data are available for the use of SBRT in patients with Child-Pugh class B or poorer liver function.97,100,105107 Those with Child-Pugh class B cirrhosis can safely be treated but may require dose modifications and strict dose constraint adherence. The safety of SBRT for patients with Child-Pugh class C cirrhosis has not been established, because clinical trials are not likely to be available for this group of patients with a very poor prognosis.

In 2014, American Society for Radiation Oncology (ASTRO) released a model policy supporting the use of proton beam therapy (PBT) in some oncology populations.108 In a recent phase II study, 94.8% of patients with unresectable HCC who received high-dose hypofractionated PBT demonstrated >80% local control after 2 years, as defined by RECIST criteria.109 In a recent meta-analysis including 70 studies, charged particle therapy (mostly including PBT) was compared with SBRT and conventional radiotherapy.110 OS (relative risk [RR], 25.9; 95% CI, 1.64–408.5; P=.02), PFS (RR, 1.86; 95% CI, 1.08–3.22; P=.013), and locoregional control (RR, 4.30; 95% CI, 2.09–8.84; P<.001) through 5 years were greater for charged particle therapy than for conventional radiotherapy. No significant differences in these outcomes were seen between charged particle therapy and SBRT. Analyses from a prospective RCT including 69 patients with HCC showed that PBT tended to be associated with improved 2-year local control (P=.06), better PFS (P=.06), and fewer hospitalization days after treatment (P<.001) compared with TACE.111 The panel advises that PBT may be considered and appropriate in select settings for treating HCC. During the 2017 panel meeting, the panel discussed the role of PBT in HCC treatment and decided to add a statement in the “Principles of Locoregional Therapy” emphasizing the importance of centers with experience (see HCC-E 2 of 3; page 566). Several ongoing studies are continuing to investigate the impact of hypofractionated PBT on HCC outcomes (eg, ClinicalTrials.gov identifiers: NCT02395523 and NCT02632864), including randomized trials comparing PBT versus RFA (NCT02640924) and PBT versus TACE (NCT00857805).

All tumors, irrespective of their location, may be amenable to SBRT, IMRT, or 3-dimensional conformal RT. The panel recommends EBRT as a category 2B recommendation for patients with unresectable disease or those who are medically inoperable due to comorbidity. The panel recommends that SBRT can be considered as an alternative to ablation and/or embolization techniques or when these therapies have failed or are contraindicated (in patients with unresectable disease characterized as extensive or otherwise not suitable for liver transplantation, and those with local disease but who are not considered candidates for surgery due to PS or comorbidity). SBRT (1–5 fractions) is often used for patients with 1 to 3 tumors with minimal or no extrahepatic disease. There is no strict size limit, so SBRT may be used for larger lesions if there is sufficient uninvolved liver and liver radiation dose constraints can be respected. The panel encourages prospective clinical trials evaluating the role of SBRT in patients with unresectable, locally advanced, or recurrent HCC. Palliative EBRT is appropriate for symptom control and/or prevention of complications from metastatic HCC lesions in bone or brain.112

Summary

For patients not amenable to surgery or liver transplantation, locoregional therapy (eg, ablation, arterially directed therapies, and EBRT) is the preferred treatment approach. Ablation alone may be curative in select patients with small tumors, whereas embolization is generally not considered curative. Tumors between 3 and 5 cm may be treated with a combination of ablation and arterially directed therapies to prolong survival, as long as the tumor location is favorable to ablation, and patients with unresectable or inoperable lesions >5 cm should be considered for treatment using arterially directed therapies or systemic therapy. Advances in EBRT, such as IMRT, have allowed for enhanced delivery of higher radiation doses to the tumor while reducing damage to surrounding critical tissue. Evidence supports the usefulness of SBRT and PBT for treatment of patients with unresectable HCC.

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