JSH Consensus-Based Clinical Practice Guidelines for the Management of Hepatocellular Carcinoma: 2014 Update by the Liver Cancer Study Group of Japan

Abstract

The Clinical Practice Guidelines for the Management of Hepatocellular Carcinoma proposed by the Japan Society of Hepatology was updated in June 2014 at a consensus meeting of the Liver Cancer Study Group of Japan. Three important items have been updated: the surveillance and diagnostic algorithm, the treatment algorithm, and the definition of transarterial chemoembolization (TACE) failure/refractoriness. The most important update to the diagnostic algorithm is the inclusion of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging as a first line surveillance/diagnostic tool. Another significant update concerns removal of the term “lipiodol” from the definition of TACE failure/refractoriness.

Introduction

Four years have passed since the 2010 version of the Consensus-Based Clinical Practice Guidelines proposed by the Japan Society of Hepatology (JSH) [1] was adopted, and recent efforts have been made to produce a revised, updated version. Most members of JSH who specialize in liver cancer also belong to the Liver Cancer Study Group of Japan (LCSGJ); consequently, a consensus meeting was held at the 50th Annual Meeting of the Liver Cancer Study Group of Japan (June 5-6, 2014, Kyoto) (Congress President: Prof. Masatoshi Kudo) to update these clinical practice guidelines as proposed by JSH. At the consensus meeting, members discussed revision of (1) the surveillance and diagnostic algorithm, (2) the treatment algorithm, and (3) the definition of transarterial chemoembolization (TACE) failure. Approximately 350 experts in the diagnosis and treatment of liver cancer participated in this consensus development session. Items that were approved by at least 67% of experts through a voting system were included in the final version of the consensus-based guidelines. The Surveillance and Diagnostic Algorithm, Treatment Algorithm, and Definition of TACE Failure sections of the consensus-based guidelines were subsequently presented at The 4th International Kyoto Liver Cancer Symposium (4th IKLS; June 7-8, 2014, Kyoto) (Congress President: Prof. Masatoshi Kudo), and more than two-thirds of participants at this international symposium agreed the 2014 update of the Clinical Practice Guidelines proposed by the JSH-LCSGJ. Thus, the new versions of the surveillance and diagnostic algorithm, the treatment algorithm, and the definition of TACE failure are also recognized internationally.

Surveillance and Diagnostic Algorithm

Major changes were made to this section of the guidelines compared to the 2010 version. Revisions were based on the surveillance and diagnostic algorithm created primarily by Prof. Osamu Matsui as part of a research project supported by the Japanese Ministry of Health, Labour and Welfare (Primary Investigator: Prof. Shigeki Arii) [2]. Various studies have verified the usefulness of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (Gd-EOB-DTPA-MRI) in the diagnosis of hepatocellular carcinoma (HCC) [2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89], although this method is not yet included in the guidelines of the American Association for the Study of Liver Diseases [90], the European Association for the Study of the Liver [91], or the Asian Pacific Association for the Study of the Liver [92] guidelines [93, 94]. Only the updated JSH-LCSGJ diagnostic algorithm includes Gd-EOB-DTPA-MRI as a first-line surveillance and diagnostic tool for HCC. While surveillance of patients at super-high risk for HCC (i.e., those with hepatitis B or C cirrhosis) and patients at high risk for HCC (i.e., those with chronic hepatitis B/C or cirrhosis of another etiology) is essentially performed using ultrasonography (US) or tumor markers according to the JSH guideline [1,95], it is recommended that super-high risk patients also undergo dynamic multidetector computed tomography (MDCT) or MRI every 6-12 months to pick up small HCC even when US shows no evidence of such a tumor [1,95]. At institutions specializing in liver cancer in Japan, it is recommended that Gd-EOB-DTPA-MRI be used instead of dynamic MDCT even when no tumor is detected on US. If Gd-EOB-DTPA-MRI shows a hypervascular mass with venous washout, a definitive diagnosis of HCC can be made. If Gd-EOB-DTPA-MRI shows a hypervascular mass without venous washout, a diagnosis of HCC can be made if the mass shows hypointensity in the hepatobiliary phase of Gd-EOB-DTPA-MRI. Also, in this case, high-flow type hemangioma should be ruled out by using another modality because it can exhibit similar characteristics. If the mass is isointense or hyperintense in the hepatobiliary phase of Gd-EOB-DTPA-MRI, biopsy is necessary to confirm the diagnosis. Hypovascular masses on Gd-EOB-DTPA-MRI that are isointense or hyperintense in the hepatobiliary phase can enter the routine surveillance protocol. However, hypointense masses in the hepatobiliary phase have a high potential for malignant transformation [9, 11, 18, 22, 23, 37, 40, 41, 54, 55, 59, 86, 96, 97, 98, 99, 100, 101, 102], and therefore contrast-enhanced ultrasonography (CEUS) using Sonazoid (Sonazoid CEUS) is strongly recommended. HCC can be correctly diagnosed by Sonazoid CEUS if hypervascularity and/or a defect in the Kupffer phase [103] is observed. Even when a mass is hypovascular on CEUS and there is no defect in the Kupffer phase, hypointensity in the hepatobiliary phase of Gd-EOB-DTPA-MRI is highly suggestive of malignancy [7]. Accordingly, biopsy is recommended for small nodules of 1-1.5 cm or larger for differential diagnosis between early HCC [103] and a dysplastic nodule (DN). If a mass is diagnosed as a DN or a borderline lesion, intensive follow-up every 3 to 6 months with GD-EOB-DTPA-MRI (or dynamic MDCT) is recommended. The intensive follow-up is also recommended for small nodules of less than 1-1.5 cm (fig. 1).

Fig. 1.

Surveillance and Diagnostic Algorithm of HCC (Proposed by the Liver Cancer Study Group of Japan 2014). SPIO=superparamagnetic iron oxide; CTAP=computed tomographic arterial portography; CTHA=computed tomographic hepatic arteriography. ^aCavernous hemangioma may show hypointensity on equilibrium (transitional) phase of dynamic Gd-EOB-DTPA MRI (pseudo-washout). It should be excluded by other sequences of MRI and/or other imaging modalities. ^bCavernous hemangioma usually shows hypointensity on hepatobiliary phase of Gd-EOB-DTPA MRI. It should be excluded by other sequences of MRI and/or other imaging modalities. ^cBiopsy may be considered for confirmation.

Of course, institutions that cannot perform GD-EOB-DTPA-MRI every 6-12 months as the first-line modality may use dynamic MDCT as the first step of screening when no nodule is evident on US, but it is absolutely essential to perform GD-EOB-DTPA-MRI or Sonazoid CEUS when dynamic MDCT does not show hallmark of HCC (i.e., arterial enhancement with venous washout) in the mass detected by MDCT. This algorithm was approved by more than 90% of participants and is, therefore, now the new surveillance and diagnostic algorithm recommended by the JSH and LCSGJ (fig. 1).

Treatment Algorithm

No new treatments or molecular targeted agents have been developed for HCC since the 2010 JSH consensus-based treatment algorithm [1,104] was adopted, so few changes were made to this section.

Decreased uptake in the Kupffer phase on CEUS was added to the third item of the annotations as an indicative finding in the diagnosis of early HCC [103]. In addition, although sorafenib is recommended for patients with minor portal vein invasion or portal invasion at the first portal branch (Vp1-3), the new algorithm reflects the consensus that it is not recommended for patients with portal invasion at the main portal branch (Vp4) due to the risk of hepatic failure. However, hepatic arterial infusion chemotherapy (HAIC) is still strongly recommended for patients with Vp4, and therefore recommendations regarding HAIC were left unchanged [105]. Moreover, because locoregional therapy for Child-Pugh C patients is now widely used and many studies have reported its survival benefits, it is now described as a “well accepted treatment” rather than an “experimental treatment” in the revised algorithm (fig. 2) [106, 107, 108, 109, 110].

Fig. 2.

JSH-LCSGJ Consensus-based Treatment Algorithm for Hepatocellular Carcinoma revised in 2014. ^aTreatment should be performed as if extrahepatic spread is negative when extrahepatic spread is not regarded as a prognostic factor. ^bSorafenib is the first choice of treatment in this setting as a standard of care. ^cIntensive follow-up observation is recommended for hypovascular nodules by the Japanese Evidence-Based Clinical Practice Guidelines. However, local ablation therapy is frequently performed in the following cases: 1) when the nodule is diagnosed pathologically as early HCC, 2) when the nodules show decreased uptake on hepatobiliary phase Gd-EOB-DTPA-MRI, 3) when the nodules show decreased portal flow by CTAP or 4) decreased uptake is shown on Kupffer phase of Sonazoid enhanced US, since these nodules are known to frequently progress to the typical hypervascular HCC. ^dEven for HCC nodules exceeding 3 cm in diameter, combination therapy of TACE and ablation is frequently performed when resection is not indicated. ^eTranscatheter arterial chemoembolization (TACE) is the first choice of treatment in this setting. Hepatic arterial infusion chemotherapy (HAIC) using reservoir system is also recommended for TACE refractory patients. The regimen for this treatment is usually low-dose FP (5FU+CDDP) or 5FU infusion combined with systemic interferon therapy. Sorafenib is also a treatment of choice for TACE refractory patients with Child Pugh A liver function. ^fResection is sometimes performed even when the number of nodules is greater than 4. Furthermore, ablation is sometimes performed in combination with TACE. ^gMilan criteria: Tumor size ≤ 3 cm and tumor number ≤ 3; or solitary tumor ≤ 5cm. Even when liver function is good (Child-Pugh A/B), transplantation is sometimes considered for frequently recurring HCC patients. ^hSorafenib and HAIC are recommended for HCC patients with Vp1,2 (minor portal vein invasion) or Vp3 (portal invasion at the 1st portal branch). Sorafenib is not recommended for HCC patients with Vp4 (portal invasion at the main portal branch), whereas HAIC is recommended for such patients with tumor thrombus in the main portal branch. ⁱResection and TACE is frequently performed when portal invasion is minor such as Vp1 (portal invasion at the 3rd or more peripheral portal branch) or Vp2 (portal invasion at the 2nd portal branch). ^jEven in Child-Pugh A/B patients, transplantation is sometimes performed for relatively younger patients with frequently or early recurring HCC after curative treatments. ^kLocal ablation therapy or subsegmental TACE is performed even for Child-Pugh C patients (CP score 10 and 11) within Milan criteria when transplantation is not indicated. In the case, patients with no hepatic encephalopathy, no uncontrollable ascites, and a low bilirubin level (< 3.0mg/dl) are selected for treatment. Although these are well-accepted treatments in the routine clinical setting, there is no high-level evidence of its survival benefit in Child-Pugh C patients. A prospective study is necessary to clarify this issue.

Definition of TACE Failure/Refractoriness

In the 2010 version of the JSH consensus-based treatment algorithm [1], TACE failure/refractoriness was defined assuming the use of superselective lipiodol TACE—which has been widely used worldwide and particularly in Japan—and areas with lipiodol deposition were considered to be necrotic. However, this concept is not well accepted internationally [111]. Furthermore, following the approval in Japan in February 2014 of emolic drug-eluting beads, an embolic material that does not use lipiodol, the phrase needed to be changed from “lipiodol deposition” to “necrotic lesion or viable lesion.” Accordingly, the section was revised to define TACE failure as an ineffective response after two or more consecutive TACE procedures that is evident on response evaluation CT or MRI after 1-3 months, even after chemotherapeutic agents are changed and/or the feeding artery is reanalyzed. In addition, the appearance of more lesions in the liver than the number of lesions recorded at the previous TACE procedure (other than the nodule being treated) was added definition of TACE failure/refractoriness. Following discussion of the other issues concerning continuous elevation of tumor markers, vascular invasion, and extrahepatic spread, descriptions similar to those in the previous version were approved (table 1). The revision of these TACE failure definitions were approved by more than 85% of HCC experts.

Table 1.

Definition of TACE Failure/Refractoriness (LCSGJ)

(1) Intrahepatic lesion
i. Two or more consecutive ineffective responses seen within the treated tumors (viable lesion >50%), even after changing the chemotherapeutic agents and/or reanalysis of feeding artery, on response evaluation CT/MRI after 1-3 months following adequately performed selective TACE
ii. Two or more consecutive progressions in the liver (including an increase in the number of tumors compared to that before the previous TACE procedure), even after changing the chemotherapeutic agents and/or reanalysis of feeding artery, on response evaluation CT/MRI after 1-3 months following adequately performed selective TACE
(2) Tumor marker
Continuous elevation of tumor markers right after TACE even though transient minor reduction is observed.
(3) Appearance of vascular invasion
(4) Appearance of extrahepatic spread

Conclusion

We report here the 2014 updated versions of the Surveillance and Diagnostic Algorithm, Treatment Algorithm, and Definition of TACE Failure/Refractoriness sections of the 2010 Consensus-Based Clinical Practice Guidelines proposed by JSH that were discussed and approved at the consensus meeting held at the 50th Annual Meeting of the Liver Cancer Study Group of Japan (June 5-6, 2014, Kyoto).