Combination therapy strategy based on selective internal radiation therapy as conversion therapy for inoperable giant hepatocellular carcinoma: A case report

Abstract

BACKGROUND

Hepatocellular carcinoma (HCC) has become a growing health concern globally. Microvascular invasion and high tumor burden are key factors limiting the curative effect of selective internal radiation therapy (SIRT).

CASE SUMMARY

This case study reports a 49-year-old woman who was diagnosed with China Liver Cancer Staging (CNLC) IIIa HCC and > 15 cm tumor diameter. Initially, due to insufficient future liver remnant and vascular invasion, the tumor was unresectable; however, radical hepatectomy was performed after successful conversion therapy with SIRT using yttrium-90 (⁹⁰Y) resin microspheres followed by hepatic arterial infusion chemotherapy (HAIC) with tyrosine kinase inhibitor (TKI) and anti-programmed death-1 (PD-1) antibody. SIRT using ⁹⁰Y resin microspheres was given by the right hepatic artery and chemoembolization was simultaneously performed in the tumor’s feeding vessels from the right diaphragmatic artery. HAIC was followed every three weeks with lenvatinib and tislelizumab. At 4 months post-SIRT, the tumor was downstaged to CNLC Ib and the patient successfully underwent hepatectomy. The histopathological examination of the resected specimen showed extensive necrosis.

CONCLUSION

This case study provides evidence for an integrated treatment strategy combining SIRT and HAIC with TKI and anti-PD-1 antibodies for patients with large HCC and microvascular invasion. Further confirmatory trials are required in the future.

Key Words: Selective internal radiation therapy; Hepatic arterial infusion chemotherapy; Yttrium-90 resin microspheres; Hepatocellular carcinoma; Conversion therapy; Case report

Core Tip: Although selective internal radiation therapy (SIRT) has been used to treat unresectable hepatic cancers for more than 20 years, it is mainly employed to treat patients with ≤ 8 cm tumor size. This research reports a hepatocellular carcinoma patient with > 15 cm hepatic mass, microvascular invasion, and China Liver Cancer Staging (CNLC) IIIa who received radical hepatectomy after successful conversion therapy with SIRT using yttrium-90 resin microspheres followed by hepatic arterial infusion chemotherapy using anti-programmed death-1 antibody and tyrosine kinase inhibitor. After 4 months of SIRT, the tumor was downstaged to CNLC Ib and the future liver remnant increased from 434 mL to 802 mL.

INTRODUCTION

Hepatocellular carcinoma (HCC) is a growing global health concern and > 80% of the patients are inoperable[1]. Insufficient future liver remnant (FLR) and microvascular invasion are the key limiting factors for surgical intervention[2,3]. Using yttrium-90 (⁹⁰Y) resin microspheres in selective internal radiation therapy (SIRT) can induce contralateral liver lobe enlargement and shrink the affected liver lobe, thereby effectively increasing FLR while controlling the tumor[4]. A comprehensive German study reviewed 11014 liver cancer cases treated with ⁹⁰Y-SIRT between 2012 and 2019. Of 11014 patients, 39.7% had primary liver cancer with a maximum tumor diameter of ≤ 8.0 cm[5]. However, HCC in China typically presents with a higher tumor burden. Global epidemiological surveys have indicated that the largest median longitudinal diameter of HCC is in Chinese patients[1].

Conversion therapy might provide greater opportunities for patients with inoperable HCC to undergoing a surgical resection. The currently available conversion therapy methods include systemic (drug) therapy and locoregional therapies such as transarterial chemoembolization (TACE), SIRT, radiotherapy, and hepatic arterial infusion chemotherapy (HAIC)[3]. Recent research has shown that the use of TACE plus immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) markedly enhance objective response rate (ORR) in cases of inoperable advanced HCC[6,7]. However, TACE or HAIC often proves to be insufficient for promoting residual liver volume proliferation while controlling tumor burden in large HCC, warranting the exploration of novel combination approaches capable of effectively reducing the tumor size while also promoting liver regeneration simultaneously.

This research reports an HCC patient with a giant tumor (15 cm), which was initially unresectable; however, after SIRT followed by HAIC with anti- programmed death-1 (PD-1) antibody and TKI treatment, the patient underwent successful tumor resection.

CASE PRESENTATION

Chief complaints

Due to recurrent discomfort in area of liver for 1 month.

History of present illness

A 49-year-old woman was admitted on 24 October 2023.

History of past illness

She had a history of chronic hepatitis B for > 40 years.

Personal and family history

No history of drinking alcohol.

Physical examination upon admission

She had mild tenderness in the upper right abdomen.

Laboratory examinations

Serum alpha-fetoprotein (AFP) and antagonist-II (PIVKA-II) were 46699 ng/mL and 38949 mAU/mL, respectively. In addition, with a height of 168 cm and weight of 65 kg, the FLR of this case was 434 mL.

Imaging examinations

Her magnetic resonance imaging results showed a giant mass (15.8 cm × 11.4 cm × 14.8 cm) in the right hepatic lobe. The tumor indicated arterial hyperenhancement, was washed out in the portal vein, and was in delayed phases. Furthermore, the tumor was accompanied by invasion of the right portal vein as well as right and middle hepatic veins (Figure 1A and B).

Figure 1 Imaging examinations. A and B: Enhanced magnetic resonance imaging on 24 October 2023, showed the giant tumor in size of 15.8 cm × 11.4 cm × 14.8 cm, accompanied by the invasion of the right portal vein as well as right and middle hepatic veins; C and D: Enhanced magnetic resonance imaging on 28 February 2024, showed a tumor size of 11.6 cm × 7.7 cm × 10.1 cm, indicating a complete response according to mRECIST; E and F: The hepatic tissue size was 17 cm × 14 cm × 10 cm. Upon incision, a grayish yellow and grayish white mass with a size of 13.5 cm × 12 cm × 9.5 cm was observed as a nodular gray-white and grayish red mass with extensive necrosis.

MULTIDISCIPLINARY EXPERT CONSULTATION

After the multidisciplinary liver tumor board consenses, SIRT was recommended to the patient for conversion therapy. Because of the reduced efficacy of SIRT alone in the transformation therapy of giant HCC, HAIC with TKI and anti-PD-1 antibody were recommended as subsequent combination therapy methods.

FINAL DIAGNOSIS

China Liver Cancer Staging (CNLC) IIIa stage HCC.

TREATMENT

On 31 October 2023, before SIRT, a mapping procedure was carried out (Figure 2A and B). The angiography showed that an aberrant blood vessel originates from the right diaphragmatic artery and is involved in blood supply of some tumors. And 5 mL temperature-sensitive liquid embolic agent loaded with 30 mg Epirubicin and 1 g polyvinyl alcohol embolic microspheres (500-700 µm) was embolized by selectively inserting into this artery. After embolization, the tumor vessel’s blood flow was obstructed and the peripheral tumor staining disappeared. The main artery supplying blood to the tumor came from the right hepatic artery. The prescription dose was 110 Gy, calculated through a partition model. SIRT was carried out on 7 November. After a 2.6 Fr microcatheter was superselectively inserted into the right hepatic artery, and ⁹⁰Y resin microspheres (3.8 GBq; SIR-Spheres^®, Sirtex Medical) were given under fluoroscopic guidance. The dose delivery was verified through liver SPET/CT scanning after 1 hour of injection (Figure 2C and D).

Figure 2 Treatment. A: The angiography revealed that the right diaphragmatic artery emitted an aberrant vessel, which was involved in some tumor blood supply; B: The angiography revealed that the main blood supply artery of the tumor came from the right hepatic artery; C: The lung shunting fraction was 12.68%, with a T/N of 4.28. The partition model revealed that the prescription activity was 3.8 GBq at a tumoral dose of 110 Gy; D: Single-photon emission computed tomography/computed tomography at 1 hour after selective internal radiation therapy showed that the right lobe of liver mass was covered with yttrium-90 resin microspheres. There is no significant shunt in the extrahepatic tissues within the field of vision. Multiple enlarged lymph nodes in the hepatic hilum and retroperitoneum. Right oblique fissure pleural calcification, slight chronic inflammation in both lungs, and slight pleural effusion in the right chest.

On the second day post-SIRT, the patient was treated with lenvatinib (8 mg/day; Levima^®, Eisai, Tokyo, Japan) and 200 mg of tislelizumab (every 3 weeks). On the third day post-SIRT, the patient was discharged.

HAIC was scheduled to be administered every 3 weeks for 4 cycles, with the first session occurring on day 21 after SIRT. The HAIC procedure was conducted under local anesthesia. Briefly, the right femoral artery was punctured, a catheter sheath was inserted, and a 4F rehabilitation catheter was placed for the celiac artery’s selective angiography. Then, a microcatheter was inserted and securely fixed in the proper hepatic artery. The patient was then transferred back to the ward for chemotherapy drugs infusion. The chemotherapy regimen consisted of lobaplatin 30 mg administered for 2 hours and raltitrexed 4 mg for 2 hours on day 1. The interventional procedures were carried out by physicians with over 15 years of surgical and clinical experience.

OUTCOME AND FOLLOW-UP

After SIRT, mild anorexia was observed on the first day, which disappeared on the second day. No other adverse events were observed. After HAIC, no adverse events was observed. Laboratory tests of liver and renal function showed no significant abnormalities on the third and tenth day respectively.

After 2 months of SIRT, the tumor decreased to 13.2 cm and then further reduced to 11.6 cm, there was no vascular invasion, indicating a complete response according to mRECIST. On 1 March 2024, it was observed that the tumor was downstaged to CNLC Ib, serum AFP was reduced to 14 ng/mL, and PIVKA-II levels decreased to 55 mAU/mL, and FLR increased to 802 mL (Figure 1C and D). Right hepatectomy and caudate lobectomy were performed 4 months after SIRT. The histopathological analysis after the surgery revealed a tumor bed measuring 13.5 cm × 12 cm × 9.5 cm with extensive necrosis (≥ 85%) (Figure 1E and F). One month after the hepatectomy, serum AFP and PIVKA-II reduced to 5 ng/mL and 16 mAU/mL, respectively (Figure 3). Currently, the patient is under standardized follow-up.

Figure 3 Serum alpha-fetoprotein and antagonist-II dropped to normal levels 4 months after selective internal radiation therapy. AFP: Alpha-fetoprotein; PIVKA: Antagonist-II.

DISCUSSION

For more than 20 years, SIRT (using ⁹⁰Y resin microspheres) has been used to treat unresectable hepatic cancers with tumors ≤ 8 cm in size[5]. Much literature supports the application of SIRT for HCC conversion therapy. The rates of successful downstaging to curative therapy range from 32% to 78%[8-10]. Furthermore, when the tumor burden is high (median size = 8.75 cm) or the tumor is complicated by portal vein tumor thrombus, the surgical conversion rate is only 22%[11].

The principal surgical conversion therapies for patients with insufficient FLR volume include associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) and portal vein embolization (PVE). However, PVE is primarily limited by the risk of tumor progression during the contralateral liver lobe enlargement[12,13]. Furthermore, although ALPPS is effective in rapidly increasing liver volume, it is constrained by the high incidence of serious complications and mortality risks during the perioperative period[14]. Conversely, SIRT stimulates liver regeneration by constantly enhancing pro-regeneration molecules (fibroblast growth factor 19 and hepatocyte growth factor) and pro-inflammatory cytokines [interleukin (IL)-6 and IL-8], thereby playing a crucial role in FLR hypertrophy[15]. Moreover, SIRT has the dual benefit of controlling tumor growth while increasing FLR, presenting a significant advantage in managing cases with high tumor burden.

A multicenter retrospective research indicated that for unresectable HCC patients with high tumor burden and portal vein tumor thrombus, HAIC combined with lenvatinib and tislelizumab resulted in a high ORR[16]. In 2001, the results of a phase III randomized controlled study that enrolled 74 patients with colorectal cancer with liver metastases (CRLM) showed that patients who received a single dose of ⁹⁰Y resin microspheres in combination with once-monthly fluorouridine HAIC had a significantly increased tumor ORR (50% vs 24%, P = 0.03) and a significant improvement in the median time to disease progression (12 months vs 7.6 months, P = 0.04) compared with those who received fluorouridine-only hepatic artery perfusion[17]. This successful study of SIRT combined with HAIC in the treatment of CRLM promotes our exploration of SIRT combined with HAIC plus systemic therapy for unresectable giant HCC.

HAIC can promote or regulate the release of tumor antigens and enhance the response of immunotherapy. The combination of HAIC and systematic therapy is expected to improve the outcome of inoperable HCC[18]. A recent multicenter retrospective study has shown that addition of ICI has better efficacy for inoperable HCC receiving HAIC and lenvatinib[19].

In this case, due to tumor downsizing and liver hypertrophy, FLR increased from 434 mL in baseline to 802 mL post-SIRT, making the patient eligible for resection. Futhermore, the complexity of the surgery did not increase after SIRT, as confirmed in our case.

The giant tumor with invasion of large blood vessels was downstaged from CNLC IIIa at diagnosis to CNLC Ib after SIRT followed by HAIC with TKIs and anti-PD-1 antibody. The initially inoperable patient was converted to a candidate for surgical resection, and underwent a radical right hepatectomy and caudate lobectomy successfully. Thus, an combination therapy strategy based on SIRT has the potential to improve the resection rate.

There are several limitations in this report: (1) The study is based on a single case, which limits the generalizability of the findings; (2) Long-term follow-up data are needed to assess the overall survival benefits; and (3) In the future, further research will be conducted to explore the timing and optimal application population of SIRT combined with HAIC, and to explore mechanisms underlying the therapy, such as the regulatory effects of SIRT combined with HAIC on the tumor microenvironment and immune response. Therefore, in the future, it is necessary to conduct larger, prospective clinical trials to validate the efficacy and safety of this combination therapy in a broader patient population and investigate the molecular mechanisms underlying the synergistic effects of SIRT, HAIC, TKIs, and anti-PD-1 antibodies to optimize the treatment regimen further.

CONCLUSION

In summary, this case study provided evidence for the surgical resection of large HCC with microvascular invasion via an integrated treatment strategy combining SIRT and HAIC with TKI and anti-PD-1 antibody. Further clinical trials are required to validate these results for future application.