Lung metastasis following temporary discontinuation of lenvatinib and tislelizumab in hepatocellular carcinoma: A case report

Abstract

BACKGROUND

Hepatocellular carcinoma (HCC) is a prevalent malignancy in China, primarily diagnosed at advanced stages, which limits treatment options and increases mortality rates. Conversion therapy, which includes systemic and locoregional treatments, aims to render unresectable tumors resectable. Nonetheless, research is scant on the risks of disease progression during the temporary cessation of targeted drugs and immune checkpoint inhibitors before surgery.

CASE SUMMARY

This report describes a 58-year-old male with HCC who developed lung metastases following the discontinuation of lenvatinib and tislelizumab, revealing the necessity for further investigation into the management of HCC patients during the perioperative period, particularly concerning the timing and duration of targeted therapy and immunotherapy.

CONCLUSION

Our study highlights the complex challenges in managing advanced HCC and emphasizes the critical need for ongoing research to refine treatment strategies and improve patient outcomes.

Key Words: Hepatocellular carcinoma; Hepatic arterial infusion chemotherapy; Lenvatinib; Tislelizumab; Conversion therapy; Case report

Core Tip: In recent years, targeted therapies, immunotherapies with immune checkpoint inhibitors, and localized interventions have effectively managed advanced or non-resectable hepatocellular carcinoma (HCC). Despite these advances, few studies have addressed the crucial need for management strategies during the perioperative period for patients with HCC. To our knowledge, this is the first report to illuminate the potential risk of disease progression and lung metastasis after the temporary cessation of targeted therapy with lenvatinib and immunotherapy with tislelizumab. This finding reveals the importance of refining treatment protocols to reduce the risks of recurrence and metastasis.

INTRODUCTION

Liver cancer is the fourth most common malignant tumor in China[1], with hepatocellular carcinoma (HCC) constituting over 80% of primary liver cancer cases[2]. A comprehensive review of the treatment landscape for HCC in China indicates that a majority of patients are diagnosed at intermediate to advanced stages [China Liver Cancer stage IIb, IIIa, and IIIb, encompassing a proportion of patients with Barcelona Clinic Liver Cancer (BCLC) stage B and all patients with BCLC stage C][3]. This late-stage diagnosis typically precludes surgical options, contributing significantly to the high mortality rates associated with HCC.

In this context, the advent of conversion therapy has transformed the treatment paradigm for patients with intermediate or advanced HCC. Conversion therapy aims to render unresectable HCC resectable, thereby facilitating surgical resection[4]. This approach includes a combination of systemic and locoregional treatments, such as transcatheter arterial chemoembolization (TACE), hepatic arterial infusion chemotherapy (HAIC), and radiotherapy. Systemic therapies, particularly those combining anti-angiogenic drugs with immunotherapy, have demonstrated an objective response rate of approximately 30%[5], with associated promising median survival times extending up to 20 months[6-8]. Locoregional treatments, such as TACE and HAIC, have also proven effective in conversion therapy for unresectable HCC, with HAIC showing greater efficacy than TACE[9].

Despite these advancements, a critical gap persists in our understanding of the risks associated with discontinuing targeted drugs and immune checkpoint inhibitors (ICIs) during the pre-surgical waiting period. We present the first case of lung metastasis occurring during a cessation period of lenvatinib, which was planned prior to surgical resection. This case reveals the urgent need for further research into optimal management strategies during this critical phase of treatment, aiming to minimize the risks of disease progression and metastasis while patients await surgery.

CASE PRESENTATION

Chief complaints

A 58-year-old man was referred to our hospital due to being diagnosed with chronic hepatitis type B and HCC in October 2023.

History of present illness

The patient was incidentally diagnosed with chronic hepatitis B virus infection during a routine examination. Subsequent ultrasonography at a local hospital revealed a large tumor at the transition zone between the left and right lobes of the liver.

History of past illness

The patient had no significant medical history prior to this diagnosis.

Personal and family history

The patient denied any familial history of HCC.

Physical examination

Physical examination revealed no symptoms of jaundice, vascular spiders, palmar erythema, or other abnormal signs.

Laboratory examinations

Initial laboratory tests showed the following results: Alanine aminotransferase 28 U/L, aspartate aminotransferase 78 U/L, total bilirubin albumin 16.0 μmol/L, and prothrombin time 12.6 s. Tumor biomarkers were notably elevated with alpha-fetoprotein (AFP) at 60500 ng/mL and Prothrombin Induced by Vitamin K Absence or Antagonism Type II (PIVKA-II) at 23099.79 mAu/mL. Quantitative HBV-DNA testing indicated a viral load of 1.11 × 10² IU/mL.

Imaging examinations

During the first admission, magnetic resonance imaging showed a large mass located at the transition zone between the left and right lobes of the liver, measuring approximately 14 cm (Figure 1).

Figure 1 Imaging of liver and lung during different periods. A: Radiologic assessments showed a partial response based on the modified Response Evaluation Criteria in Solid Tumors criteria; B: Computed tomography imaging examination indicated multiple metastatic sites in the lung on February 23, 2024. mRECIST: Modified Response Evaluation Criteria in Solid Tumors; PR: Partial response; SD: Stable disease.

FINAL DIAGNOSIS

The conclusive diagnosis for the case was HCC with no pulmonary metastasis (Figure 2).

Figure 2 Liver Biopsy. The outcome confirmed the diagnosis of hepatocellular carcinoma (poor differentiation) on December 06, 2023. A and B: The microscopic view of the liver biopsy.

TREATMENT

Considering the extensive tumor burden, surgical resection was deemed potentially unsuitable for the patient. Consequently, a multimodal therapeutic approach was employed. The patient received HAIC followed by treatment with tyrosine kinase inhibitors (TKIs) and ICIs. The HAIC regimen included oxaliplatin at a dose of 85 mg/m², leucovorin at 400 mg/m², and intra-arterial 5-fluorouracil at 400 mg/m² on day 1.

This was followed by a repeated infusion of 5-fluorouracil at a dose of 2400 mg/m² on days 2–3, with a three-week interval between each treatment cycle. The treatment strategy involved evaluating the patient after every two cycles of HAIC. Initially, on October 30, 2023, the FOLFOX regimen was first administered to the patient. Following nearly three days of infusion chemotherapy, the patient was proposed to commence daily lenvatinib (8 mg) and intravenous tislelizumab 200 mg, an anti-PD-1 monoclonal antibody, every three weeks (Figure 3). Additionally, considering the HBV burden, the patient was prescribed daily antiviral therapy with tenofovir amibufenamide (25 mg). The primary adverse reactions during HAIC treatment included abdominal pain and nausea.

Figure 3 Timeline of treatment. After four courses of the hepatic arterial infusion chemotherapy regimen, lenvatinib and tislelizumab were canceled, preparing for surgery. Multiple metastatic sites were found in the lung on February 27, 2024. HAIC: Hepatic arterial infusion chemotherapy; TACE: Transcatheter arterial chemoembolization.

Since February 4, 2024, after four cycles of the planned HAIC, TKIs, and ICIs, TACE was integrated into the adjuvant therapy regimen instead of HAIC to further enhance treatment efficacy. Concurrently, lenvatinib and tislelizumab were temporarily halted in preparation for the upcoming surgical intervention.

OUTCOME AND FOLLOW-UP

After four cycles of therapy, a response evaluation was conducted. Notably, there was a decrease in PIVKA-II levels to 65.58 mAu/mL and AFP levels to 288.70 ng/mL (refer to Figure 4). Radiologic imaging showed partial response (PR) in the lesions (Figure 2A). Based on these improvements in tumor biomarkers and the modified Response Evaluation Criteria in Solid Tumors criteria, the patient was considered potentially eligible for surgical resection due to well-restricted tumor activity. Since February 04, 2024, TACE replaced HAIC in the adjuvant therapy regimen to further enhance treatment effectiveness. Concurrently, lenvatinib and tislelizumab were temporarily suspended in preparation for surgery.

Figure 4 Trends of tumor markers during the treatment. A: Alpha-fetoprotein levels of different periods, drastic decrease could be observed during the combined therapy, while a decrease was observed after supplementary transcatheter arterial chemoembolization on February 4, 2024, replacing hepatic arterial infusion chemotherapy with lenvatinib and tislelizumab; B: Prothrombin Induced by Vitamin K Absence or Antagonism Type II levels of different periods, continuous decline was observed. HAIC: Hepatic arterial infusion chemotherapy; TACE: Transcatheter arterial chemoembolization; AFP: Alpha-fetoprotein; PIVKA-II: Prothrombin Induced by Vitamin K Absence or Antagonism Type II.

On February 21, 2024, the patient returned to Tongji Hospital for surgical resection. Upon arrival, a comprehensive preoperative assessment was initiated to evaluate his suitability for surgery. Unfortunately, computed tomography imaging revealed multiple metastatic sites in the lungs (Figure 1B), necessitating the cancellation of the planned operation.

DISCUSSION

As previously noted, most HCC patients are diagnosed at intermediate or advanced stages[3], where direct surgical intervention may offer better outcomes than non-surgical approaches in a small, carefully selected subset of patients[10]. However, the high recurrence rate post-surgery indicates that surgery often fails to provide a curative outcome for late-stage patients[11]. Meanwhile, advancements in systemic and locoregional therapies have improved response rates among those with unresectable or advanced HCC[5]. These therapies have enabled tumor downstaging to the point where surgical resection becomes feasible, a strategy known as conversion therapy.

Recent systemic therapies combining TKIs and ICIs have shown favorable effects. Zhu et al[12] reported that among 63 patients initially diagnosed with unresectable liver cancer, 15.9% achieved conversion to resection through combined PD-1 inhibitors and TKI therapy. Disappointing results from monotherapy have steered the trend towards integrating local and systemic therapies in managing advanced HCC. In a randomized controlled trial comparing the efficacy of HAIC and sorafenib vs sorafenib alone in patients with HCC and portal vein invasion, 12.8% of patients in the combination therapy group experienced downstaging post-treatment and underwent radical surgical resection[13]. This reveals the potential of combining HAIC (FOLFOX) with TKIs and PD-1 inhibitors to achieve superior tumor shrinkage and extend survival, making this combination a promising approach for improving outcomes in HCC management.

In this case study, we report on a patient where conversion therapy nearly succeeded using a combined treatment regimen of HAIC with FOLFOX, lenvatinib, and tislelizumab. While this approach effectively restricted tumor growth, lung metastasis unexpectedly developed after the cessation of lenvatinib and tislelizumab in preparation for radical surgery. Recent findings suggest a strong correlation between the duration of targeted therapy in melanoma and reduced risk of disease progression following drug discontinuation[14]. However, the relationship between cessation of targeted therapies and the development of new metastatic sites in HCC remains unclear. Lung metastasis might be part of the natural progression of HCC. This case highlights the urgent need for a revised management strategy that considers the timing of drug discontinuation and addresses the risk of recurrence or disease progression. Currently, there is no consensus on the optimal timing for surgical intervention in patients with advanced HCC that would prevent metastasis and manage primary tumor progression effectively.

CONCLUSION

In conclusion, our case report of a 58-year-old male with HCC who developed lung metastases after the temporary discontinuation of lenvatinib and tislelizumab underscores the complexities in managing advanced HCC. It highlights the challenges in managing advanced HCC and emphasizes the need for ongoing research to optimize treatment strategies and improve patient outcomes.

ACKNOWLEDGEMENTS

The authors would like to thank our patient for allowing his case to be presented.