Research ArticleClinical Studies

Conversion Hepatectomy for Huge Hepatocellular Carcinoma With Arterioportal Shunt After Chemoembolization and Lenvatinib Therapy

NOBUTAKA SATO, TORU BEPPU, KOICHI KINOSHITA, HIDEAKI YUKI, KOICHI SUYAMA, SUGURU CHIYONAGA, TOSHIHIKO MOTOHARA, YOSHIHIKO KOMOHARA, AKIO HARA and SHINICHI AKAHOSHI
Anticancer Research October 2019, 39 (10) 5695-5701; DOI: https://doi.org/10.21873/anticanres.13768

Abstract

Large tumor size and arterioportal shunt are poor prognostic factors for hepatocellular carcinoma. Lenvatinib is a novel and potent multi-tyrosine kinase inhibitor developed in Japan. A 66-year-old woman with hepatocellular carcinoma and untreated hepatitis C was referred to our hospital. She was judged as unresectable and was treated with four sessions of transarterial chemoembolization; however, the therapeutic effect was unsatisfactory because of major arterioportal shunt. Lenvatinib was sequentially administered for 4 months. Thereafter, we observed tumor shrinkage, complete disappearance of arterioportal shunt, and obvious improvement in liver function. A curative conversion hepatectomy was successfully accomplished. The extremely high levels of tumor markers almost normalized; the pretreatment levels were 1,008,021 ng/ml for alpha-fetoprotein. At 1 year after the primary treatment, the patient has not experienced recurrence. To our knowledge, this is the first case of a patient with initially unresectable hepatocellular carcinoma with arterioportal shunt who underwent conversion hepatectomy after multidisciplinary treatment, including lenvatinib.

Hepatocellular carcinoma (HCC) is a type of solid cancer for which multidisciplinary treatment is common and effective (1, 2). Large tumor size contributes to poor prognosis in both resectable and unresectable HCC (3, 4). A patient with a huge HCC (defined as ≥10 cm), even resectable HCC, has a worse prognosis than a patient with a non-huge HCC (3).

Arterioportal shunt (AP shunt) is associated with poor prognosis and is one of the reasons for a worse indocyanine green (ICG) value. For the treatment of an AP shunt, transarterial chemoembolization (TACE) with various embolic materials has been used (5-8). Gelatin sponge alone or embolic coil has a limited effect. Ethanol-soaked gelatin sponge is reported to be effective (7); however, intravascular use of ethanol is not officially permitted in Japan.

The ICG retention rate at 15 min (ICGR15) and the remnant liver volume are the gold standard index for estimating the resectability (9, 10). For right-side huge HCC, an extended hemi-hepatectomy is usually required. Even after portal embolization, such hepatectomy can be used in patients with an ICGR15 value <20% (11).

Lenvatinib is a newly developed multi-tyrosine kinase inhibitor that exerts a stronger effect on tumor vasculature and larger tumor regression effect compared to sorafenib (12-16). From March 2018, lenvatinib became available for use in daily medical practice in Japan and spread all over the world.

We managed a patient with a huge HCC, an excessive AP shunt, and impaired liver function. After multiple TACE and lenvatinib administration, obvious tumor shrinkage was recognized, and the AP shunt disappeared. Liver function almost normalized; therefore, extended liver resection was successfully achieved. To our knowledge, there have been no reports of conversion case after lenvatinib treatment. The present report provides important details of this rare conversion case of HCC.

Case presentation

A 66-year-old woman with a history of essential tremor and hypertension visited a primary doctor. She complained of fatigue, pain in the entire abdomen, and postprandial diarrhea. She had been diagnosed with hepatitis C 12 years previously; however, she did not receive any therapy for hepatitis C and had not undergone any medical check-up during the previous 5 years. A computed tomography (CT) scan showed a huge tumor in the right liver, and she was referred to our hospital. A mass, approximately 10 cm in size, was palpable at the right hypocostal area. Laboratory examination showed poor liver function; the serum albumin level was 2.8 g/dl (normal range=4.1-5.1), total bilirubin was 2.6 mg/dl (normal range=0.4-1.5), aspartate transaminase was 101 IU/l (normal range=13-30), alanine transaminase was 31 IU/l (normal range=7-23), alkaline phosphatase was 835 (normal range=106-132) IU/l, prothrombin activity was 80.7% (normal range=70%-140%), and ICG R15 was 24.0% (normal range ≤10%). The etiology included hepatitis B surface antigen (−), anti-hepatitis C (HCV) antibody (+), HCV ribonucleic acid 2.8 log IU/ml, and genotype 2. The levels of tumor markers before the initial treatment were extremely high; alpha-fetoprotein (AFP) level was 1,008,021 (normal range ≤10) ng/ml and protein induced by the absence of vitamin K or antagonist-II (PIVKA-II) was 133, 298 (≤40) mAU/ml. In contrast, the ALP-L3 value was normal at 6% (≤10%). Enhanced CT showed two typical HCCs that occupied almost the entire right liver (Figure 1A-C). The inferior vena cava was tremendously stretched by the tumor.

The tumor was judged to be unresectable because an extended right hepatectomy was required; nevertheless, she had insufficient liver function, as indicated by Child-Pugh stage B (8 points) and poor ICG R15 level. Molecular targeted therapy was ruled out because of the high Child-Pugh score. She was initially treated with transarterial chemoembolization (TACE) with cisplatin suspended in lipiodol and gelatin sponge containing epirubicin (17). At the time of the 1st TACE, enormous AP shunt was existed, so sufficient TACE was impossible (Figure 2A). We attempted to diminish the AP shunt with gelatin sponge and metallic coil); however, the AP shunt reduced but existed. Four sessions of TACE were performed using a total dose of cisplatin (285 mg) suspended in lipiodol (20.5 ml) and gelatin sponge containing epirubicin (88 mg). One week after the third TACE, molecular target therapy with lenvatinib was started. Lenvatinib was orally administered at 8 mg/day to patients weighing <60 kg in the outpatient clinic by a medical oncologist. Hypertension (Grade 3), abdominal pain (Grade 2), and hypothyroidism (Grade 2) were observed. The patient sometimes skipped medication because of some adverse events without dose reduction. About 4 months after the initiation of lenvatinib therapy, she was admitted due to hematemesis from ruptured esophageal varices. An endoscopic physician performed endoscopic variceal ligation; thereafter, complete hemostasis was obtained. Subsequently, lenvatinib therapy was interrupted. After 3 weeks, 4th TACE was performed and the disappearance of the AP shunt was confirmed (Figure 2B). One month thereafter, liver function improved substantially. The ICGR15 value normalized to 8.8%. The laboratory parameters improved considerable; serum albumin was 3.52 g/dl, total bilirubin was 0.4 mg/dl, and prothrombin activity was 111.4%. The Child-Pugh stage was A (6 points) and the levels of tumor makers decreased, however, remained very high; AFE was 177,655 ng/ml, PIVKA-II was 13,280 mAU/ml, and ALP-L3 was 11.2%. Patient status was so-called triple positive status with highly malignancy (18). According to the response evaluation criteria in solid tumors (RECIST) and the modified RECIST (mRECIST) criteria, she exhibited partial response (19). The volumetric liver resection rate was estimated at 21.4%. When compared to pre-TACE and pre-hepatectomy, the estimated remnant left liver volume increased from 781 mm3 to 1,001 mm3.

Conversion hepatectomy was conducted. The maximal tumor size was markedly decreased (Figure 1C and D); the preoperative stage was T4N0M0, Stage IVA as per the classification of the Liver Cancer Study Group of Japan (20). An extended right hepatectomy with partial diaphragmatic resection was performed 2 months after the 4th TACE. The cessation time of lenvatinib was about 3 months. The operative time was 487 minutes, and the bleeding amount was 1400 g. Four units of red blood cells and 6 units of fresh frozen plasma were administered intraoperatively.

The pathological diagnosis was moderately >poorly differentiated and compact type >trabecular type HCC. Finally, the patient was determined to have pathological Stage IV disease (microscopic portal invasion positive), and curative resection was achieved. Background liver was diagnosed as liver cirrhosis with moderate activity. The cut surface of the resected specimen and the pathological findings are shown in Figure 3. Multinodular well-circumscribed masses with a gray-white and green-yellow color were separated by fibrous septa. Non-cancerous liver tissue showed a micronodular pattern, indicating liver cirrhosis. Hematoxylin and eosin staining showed three regions with distinct morphological features; 75% of the tumor area had coagulation necrosis because of TACE treatment. Lipiodol deposition was common in the arteries. Viable hepatocellular carcinoma was visible in 16% of the tumor area, and clusters of cancer cells with striking anaplasia were focally observed. Many foamy macrophages were accumulated in 9% of the tumor area, indicating tissue reaction to lenvatinib.

There were no serious postoperative complications expect minor wound dehiscence. She was discharged on postoperative day 15. All tumor markers almost normalized. Changes in the levels of tumor markers and treatments are summarized in Figure 4. At 3 months after hepatectomy and 1 year after diagnosis, her condition is stable with no tumor recurrence.

Figure 1.
Figure 1.

Contrast-enhanced computed tomography findings. Axial images of the portal phase before treatment (A, B). Coronal images of the portal phase before treatment (C) and before surgery (D). Main (arrow) and satellite HCC (arrow head) was found in the right liver and in segment 5, respectively. The maximal tumor size decreased from 24 to 15 cm (37.5% reduction).

Discussion

In this patient, tumor shrinkage and marked improvement in liver function was observed following TACE and lenvatinib therapy. Liver function improvement could be caused by the disappearance of the AP shunt and good regeneration of the future remnant liver. In fact, the ICG R15 value normalized (24-8.8%) and the Child-Pugh score improved from 8 to 5 points. AP shunt occlusion caused recanalization of the left portal flow, accelerating the regeneration of the left liver. Good portal flow is essential for excellent liver regeneration (21). To our knowledge, this case represents the first established conversion hepatectomy for initially unresectable HCC treated with multidisciplinary treatment including lenvatinib.

AP shunt is frequently caused by direct invasion of HCC into the portal system (5). AP shunt is a factor contributing to poor prognosis in patients treated with TACE because it often makes the delivery of anticancer agents and embolic materials into the tumor vessels difficult (6). TACE with ethanol-soaked gelatin sponge has been shown to accomplish quite high compete occlusion rate of AP shunt (89%); however, with unsatisfactory median survival time (382 days) (7). Using this method, the feeding arteries must be injured as well as tumor vessels, so repeated TACE will be difficult. Changes in liver function after disappearance of the AP-shunt were unclear. In contrast, our patient could undergo four sessions of TACE because of the use of gelatin sponge without ethanol.

Molecular targeted therapy is recommended for HCC patients in Barcelona Clinic Liver Cancer (BCLC)-C with Child-Pugh classification A (2). When our patient was identified as TACE refractory after 3 TACE sessions, targeted therapy was started nevertheless the Child-Pugh stage was B (7 points). Lenvatinib was preferred over sorafenib because of its higher tumor regression and tumor necrosis effect not only on the main tumor, but also portal vein invasion (13, 14). The Child-Pugh score is unlikely to deteriorate after lenvatinib therapy, even with an initial Child-Pugh score of 7 (15). In our patient, lenvatinib was orally administered at 8 mg/day for 4 months without any serious adverse event. After endoscopic ligation of the ruptured esophageal varices and 4th TACE, the disappearance of AP shunt was confirmed.

Figure 2.
Figure 2.

Angiography with iodine contrast agent. (A) Before treatment. (B) Before surgery. AP shunt (arrow) disappeared after TACE and lenvatinib administration.

Figure 3.
Figure 3.

Pathological image of liver tumor. A: Gross appearance of liver tumor with formaldehyde fixation is presented. B: Hematoxylin and eosin section picture figures of viable cancer cells, foamy macrophages, and coagulation necrosis are presented.

Figure 4.
Figure 4.

Changes in the levels of tumor markers and treatments. AFP, Alpha-fetoprotein; PIVKA-II, protein induced by the absence of vitamin K or antagonist-II; EVL, endoscopic variceal ligation. White arrows show 1st to 4th transarterial chemoembolization.

Lenvatinib is a strong inhibitor of vascular endothelial growth factor receptor, fibroblast growth factor receptor, and platelet-derived growth factor receptor alpha (12); therefore it can reduce AP shunt and/or portal vein tumor invasion. Existence of major portal vein invasion was not a prognostic factor for patients treated with lenvatinib in a Japanese multi-center study (16). As per a recent report, a HCC patient with macroscopic portal vein tumor thrombosis survived more than 4 years after near-complete response to lenvatinib (22). However, the hypervascular tumor became hypovascular after lenvatinib therapy but became hypervascular again during the drug cessation period. This patient is in a well-controlled general condition; however, she needs to continue lenvatinib therapy for more than 4 years. The effect of lenvatinib should be assessed based on both tumor regression and tumor necrosis effect. The latter is well investigated using the mRECIST and Choi criteria (23). Further, decrease in arterial tumor perfusion is a useful biomarker of the early response of lenvatinib therapy (24). Based on the RECIST and mRECIST criteria, our patient was judged to exhibit PR.

Our patient showed a considerably high level of tumor markers before treatment; in particular, the AFP level was >1×106 ng/ml. Thus, we believe this case was that of a rare HCC. In fact, the newest 19th follow-up survey of 20,850 primary liver cancers has shown that an AFP value of 100,000 ng/ml is only observed in 2.2% of all HCC patients (25). Pathological examination of the resected specimen demonstrated viable cancer cells instead of an obvious decrease in the levels of tumor markers. With respect to this point, conversion hepatectomy is strongly recommended. We have already demonstrated the utility of conversion surgery after induction of sorafenib for unresectable HCC (26). We had managed 4 actual 5-year survivors, including 2 patients who were undergoing hepatectomy, 2 who were undergoing radiofrequency ablation, and 1 with lung resection. The adequate interval of lenvatinib cessation until surgical intervention remains unknown. The half-life of the plasma concentrations of lenvatinib and sorafenib is relatively short at approximately 28-35 h and 25-48 h, respectively (27-30). The Cancer Chemotherapy Manual recommends that it may be appropriate to discontinue therapy for 10 days before hepatectomy after sorafenib (31); therefore, about 10 days is believed to be sufficient as a cessation time for lenvatinib.

In conclusion, multidisciplinary treatments, comprising conversion hepatectomy, TACE, and lenvatinib therapy can be a potent treatment option for advanced HCC with AP shunt. Careful clinical examination is crucial to detect any improvement in liver function.

Footnotes

  • Authors' Contributions

    NS and TB identified the concept and wrote the draft of the paper; KK, HY, KS, SC, TM, AH, and SA actually performed surgical and non-surgical treatments and provided critical revisions; YK examined pathological findings.

  • Conflicts of Interest

    The Authors have no conflict of interest.

  • Received August 9, 2019.
  • Revision received August 22, 2019.
  • Accepted August 28, 2019.

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Conversion Hepatectomy for Huge Hepatocellular Carcinoma With Arterioportal Shunt After Chemoembolization and Lenvatinib Therapy
NOBUTAKA SATO, TORU BEPPU, KOICHI KINOSHITA, HIDEAKI YUKI, KOICHI SUYAMA, SUGURU CHIYONAGA, TOSHIHIKO MOTOHARA, YOSHIHIKO KOMOHARA, AKIO HARA, SHINICHI AKAHOSHI
Anticancer Research Oct 2019, 39 (10) 5695-5701; DOI: 10.21873/anticanres.13768
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