Preliminary Evaluation of Local Treatment Combined with Systemic Therapy for Tumor Recurrence after Surgery for Dual-Phenotype Hepatocellular Carcinoma

doi:10.21203/rs.3.rs-4625989/v1

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Preliminary Evaluation of Local Treatment Combined with Systemic Therapy for Tumor Recurrence after Surgery for Dual-Phenotype Hepatocellular Carcinoma

https://doi.org/10.21203/rs.3.rs-4625989/v1

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Objective: To explore the clinical efficacy of interventional treatment combined with targeted therapy and immune checkpoint inhibitors（ICIs） in patients with postoperative recurrence of dual-phenotype hepatocellular carcinoma(DPHCC).

Methods: A retrospective study was conducted on the clinical data of 8 patients with postoperative recurrence of dual-phenotype hepatocellular carcinoma treated at Xiamen Traditional Chinese Medicine Hospital from January 2019 to March 2023. The clinical outcomes such as progression-free survival and overall survival after comprehensive treatment were analyzed and evaluated.

Results: All 8 patients received transcatheter arterial chemoembolization(TACE) or hepatic Artery InfusionChemotherapy(HAIC) combined with immune checkpoint inhibitors(ICIs) and anti-angiogenic drugs, with a median survival time of 4.9 months (range 1-57.2 months) and a median progression-free survival of 1.5 months (range 0-21 months). Except for patients 2 and 4, tumors continued to progress in all cases, resulting in a disease control rate of only 25%. Conclusion: The efficacy of TACE/HAIC combined with ICIs and targeted drugs for treating dual-phenotype hepatocellular carcinoma may be limited.

Health sciences/Diseases/Cancer

Health sciences/Gastroenterology/Hepatology/Liver

Health sciences/Gastroenterology/Hepatology/Liver diseases

dual-phenotype hepatocellular carcinoma

liver cancer

Local Treatment

systematic treatment

Dual-phenotype hepatocellular carcinoma (DPHCC) is a new subtype of hepatocellular carcinoma proposed in 2011, accounts for about 10% of all hepatocellular carcinoma patients. It can express protein markers of both hepatocellular carcinoma and cholangiocarcinoma simultaneously. Compared with ordinary hepatocellular carcinoma, DPHCC has a higher degree of biological malignancy, making it more prone to metastasis and recurrence¹. The diagnosis of DPHCC relies on immunohistochemical detection, and it can only be diagnosed when tumor tissue with a single hepatocellular carcinoma component strongly expresses any hepatocellular carcinoma (such as Heppar-1, CK18, CEA, etc.) and cholangiocarcinoma (such as CK7, CK19, MUC-1, etc.) protein markers with cancer cells exceeding 15%². This means that biopsy results obtained through puncture have a high probability of misdiagnosis. Currently, there is no difference in treatment between DPHCC and ordinary hepatocellular carcinoma, and there is a lack of clinical studies designed for patients with DPHCC. The effectiveness of various methods including interventional treatment, targeted therapy, and ICIs on DPHCC remains unknown. This study retrospectively analyzed the clinical data of 8 patients with postoperative recurrence of DPHCC treated with TACE/HAIC combined with targeted therapy and ICIs at Xiamen Traditional Chinese Medicine Hospital from January 2019 to March 2023, and preliminarily evaluated the effectiveness of the treatment.

General Information

In this study, all 8 patients were diagnosed with DPHCC based on postoperative pathology and experienced recurrence shortly after surgery. Six of them were male, with a median age of 44 years (Table 1). The general condition before surgery was good, with an ECOG-PS score of 2 for all. All patients were discharged smoothly within 2 weeks after surgery without any severe complications. The median time to recurrence after surgery was 3.9 months (range 1-15.6 months), with a median survival time after recurrence of 4.9 months (range 1-57.2 months) and a median progression-free survival of 1.5 months (range 0–21 months). Five patients have died (Table 2). All 8 patients received TACE/HAIC combined with ICIs and targeted drugs after recurrence.

Table 1

Baseline characteristics in 8 patients
Patient Number	Sex	old	BCLC	modus operandi	Postoperative pathology	Child-pugh	Recurrent condition
1	famale	32	A	Local resection of the right liver	Medium-low differentiation	A	Multiple lesions in the liver
2	male	49	0	Local resection of the right liver	moderately differentiated	A	Single lesions in the liver
3	male	38	B	right hemi-hepatectomy	moderately differentiated	A	Multiple lesions in the liver
4	male	62	0	Left outer lobe resection	poorly differentiated	A	Single lesions in the liver
5	male	37	A	Local resection of the right liver	moderately differentiated	A	Multiple lesions in the liver
6	male	39	C	Left hemi-hepatectomy	moderately differentiated	A	Multiple lesions in the liver
7	male	71	A	Laparoscopic partial liver resection	moderately differentiated	A	lung metastases、Multiple lesions in the liver
8	famale	64	B	Laparoscopic partial liver resection	moderately differentiated	A	Single lesions in the liver

Table 2

Treatment regimens and outcomes for 8 patients
Patient number	Local treatment	targeted therapy	ICIs	PFS(months)	OS(months)	outcome
1	TACE	lenvatinib, regorafenib	Tislelizumab	4	5.8	die
2	TACE	regorofenib, apatinib, and lenvatinib	Camrelizumab、Tislelizumab	6.5	46.5	survival
3	TACE	regorafenib	Camrelizumab	0	2	die
4	TACE	lenvatinib	Sintilimab	21	57.2	survival
5	HAIC	lenvatinib	Camrelizumab	0	2.7	die
6	TACE	lenvatinib, regorafenib	Camrelizumab	2	8	survival
7	TACE	lenvatinib,Bevacizumab	Tislelizumab	1	4	die
8	TACE	lenvatinib	Tislelizumab	0	1	die

For single and localized small lesions (<3cm) in the liver after surgery, TACE treatment was used. For multiple lesions in the liver or distant metastases, a treatment regimen combining TACE/HAIC with ICIs and targeted drugs was adopted. When the tumor continues to progress, we switch to alternative targeted drugs or perform interventional treatments to control the lesion.Targeted drugs included lenvatinib, regorafenib, and bevacizumab; ICIs included tislelizumab and carrelizumab. All drugs were administered based on body weight and used periodically (Fig. 1).

Observation Indicators

The main research indicators included the overall efficacy rate, progression-free survival, and overall survival after starting comprehensive treatment. The overall efficacy rate was assessed using mRECIST v1.1, and subjects were divided into: (1) complete response: all arterial enhancement in target lesions disappeared; (2) partial response: the sum of the long diameters of active lesions (arterial phase enhancement) decreased by at least 30%; (3) stable disease: any case that did not meet the criteria for partial response or progressive disease; (4) progressive disease: the sum of the long diameters of surviving (enhanced) target lesions increased by at least 20%.

Overall survival was defined as the time from the start of comprehensive treatment to death or the last follow-up. Progression-free survival was defined as the time from the start of comprehensive treatment to disease progression or the last follow-up.

Follow-up

The 8 patients included in the study had different follow-up times due to individual differences and other objective factors, but they were generally reviewed every 3–6 weeks. Review items included: upper abdominal enhanced MRI/CT, alpha-fetoprotein, CA199, CEA, and a full set of biochemical tests.

Statement of ethics

This study was approved by the Institutional Ethics Committee of Xiamen Traditional Chinese Medicine Hospital and written informed consent was obtained from all study participants. All procedures were performed in accordance with the World Medical Association Declaration of Helsinki in 1964 and its later amendments or comparable ethical standards.

As of now (December 30, 2023), patients 2, 4, and 6 are still alive, while the rest have died. According to the mRECIST v1.1 standard, patients 2 and 4 achieved longer progression-free survival during treatment, with 6.5 months and 21 months, respectively, and overall survival of 46.5 months and 57.2 months. Patients 1, 3, 5, 7, and 8 experienced rapid disease progression after tumor recurrence until death, with progression-free survival of 4 months, 0 months, 0 months, 1 month, and 0 months, respectively, and overall survival of 5.8 months, 2 months, 2.7 months, 4 months, and 1 month. Patient 6's tumor lesions are currently progressing.

DPHCC can express protein markers of both hepatocellular carcinoma and cholangiocarcinoma simultaneously. Compared with ordinary hepatocellular carcinoma, DPHCC has a higher degree of biological malignancy, making it more prone to metastasis and recurrence. In recent years, including interventional treatment, targeted therapy, and immune checkpoint inhibitors have shown good efficacy in hepatocellular carcinoma recipients, but their role in DPHCC recipients remains unknown. The main reason is that the diagnosis of DPHCC mainly relies on postoperative pathology, but most patients do not have the opportunity to undergo surgery, making it impossible to obtain an accurate pathological diagnosis before treatment, which prevents us from making the best treatment decisions before and during surgery. Therefore, the effectiveness of interventional treatment combined with targeted therapy and immune checkpoint inhibitors for DPHCC recipients needs further exploration and research to determine the best treatment strategy for DPHCC recipients.

In this study, all 8 recipients were patients with postoperative recurrence of DPHCC who received TACE or HAIC combined with targeted and immune checkpoint inhibitor drugs after recurrence. Patients 2 and 4 had the best prognosis, which may be related to their early preoperative staging and the recurrence of only a single lesion in the liver after surgery. The median survival time after recurrence for the 8 patients was 4.9 months (range 1-57.2 months), with a median progression-free survival of 1.5 months (range 0–21 months) and a disease control rate of only 25%, far lower than the response to traditional antitumor treatment observed in patients with ordinary hepatocellular carcinoma.

In our study, the prognosis of patients with postoperative recurrence of DPHCC was poor, which may be related to the high degree of biological malignancy of DPHCC. Cong³ observed 1530 surgically resected HCC samples and found that DPHCC had a lower degree of differentiation compared to ordinary HCC, with higher rates of capsule invasion (61.3% vs. 34.0%), satellite lesions (65.2% vs 29.9%), and tumor thrombus (54.2% vs 30.2%). The overall survival of DPHCC patients was (30.4 ± 3.7) months, and the disease-free survival was (13.2 ± 2.0) months, both significantly lower than the (43.6 ± 3.9) months and (23.4 ± 2.5) months of ordinary hepatocellular carcinoma patients. Therefore, during surgery, we may need to perform an expanded liver segment and hepatic lobe resection to achieve radical purposes, and adjuvant therapy should be administered as soon as possible after surgery to improve patient survival and reduce recurrence rates.

We also found that DPHCC was insensitive to TACE or HAIC treatment, which may be related to its high expression of CK7 and CK19. Jing⁴ revealed through a prognostic nomogram that CK7 and CK19 double positivity is an independent predictor affecting the overall survival of hepatocellular carcinoma recipients receiving adjuvant TACE. Wang⁵ studied the serum CK19 fragment CYFRA21-1 in hepatocellular carcinoma patients before and after TACE surgery and found that postoperative positivity suggests that such patients are insensitive to therapeutic TACE, with poor long-term efficacy. Even after receiving TACE or HAIC treatment, it is difficult to completely control the progression of lesions in the patients in this study, and the mechanism still needs further research and discussion.

The patients in this study received anti-angiogenic targeted drugs and ICIs, but the efficacy was not optimistic, indicating that DPHCC patients may also be insensitive to such drugs. Zhuo⁶ found in a study of subsequent treatment of liver cancer patients with post-transplant recurrence that sorafenib, apatinib, and 5-fluorouracil could not promote cell growth inhibition and apoptosis, and only observed that regorafenib had an effect on CK19 + hepatocellular carcinoma. Therefore, for DPHCC patients, regorafenib may be a potentially effective antitumor drug.

As observed in this study, we tried various drugs and interventional treatments, but none could effectively control the progression of tumors in DPHCC patients. DPHCC is likely naturally insensitive to TACE/HAIC, anti-angiogenic, and immune checkpoint inhibitor drugs. In the future, we still need to further study the origin and characteristics of DPHCC to provide differentiated treatment strategies for this group of patients.

CONFLICT OF INTEREST STATEMENT

The authors have no conflict of interest to disclose.

FUNDING INFORMATION

Sources of support: Fujian Provincial Natural Science Foundation Project (2023D001), Xiamen Health Guidance Project (3502Z20244D1191)

Author Contribution

Study concept and design: Heping Zhu，Zhenyu YinDrafting of the manuscript: Heping Zhu Critical revision of the manuscript for important intellectual content:Heping Zhu，Ruichao Shen，Peipei Li，Fuqiang Wang，Zhenyu YinAll authors approved the final draft submitted.

Data Availability

Te datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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No competing interests reported.

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You are reading this latest preprint version

Preliminary Evaluation of Local Treatment Combined with Systemic Therapy for Tumor Recurrence after Surgery for Dual-Phenotype Hepatocellular Carcinoma

Status:

Version 1

Abstract

Figures

INTRODUCTION

General Information

Treatment Methods

Observation Indicators

Follow-up

Statement of ethics

Results

Discussion

Declarations

CONFLICT OF INTEREST STATEMENT

FUNDING INFORMATION

Author Contribution

Data Availability

References

Additional Declarations

Status:

Version 1