Resection Combined with Hyperthermic Intra-peritoneal Chemotherapy Prevents Peritoneal Implantation Metastasis of Hepatocellular Carcinoma with Spontaneous Rupture

doi:10.21203/rs.3.rs-3963514/v1

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Research Article

Resection Combined with Hyperthermic Intra-peritoneal Chemotherapy Prevents Peritoneal Implantation Metastasis of Hepatocellular Carcinoma with Spontaneous Rupture

https://doi.org/10.21203/rs.3.rs-3963514/v1

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Background

Hepatocellular carcinoma with spontaneous rupture (rHCC) is managed through conservative treatment, emergency resection, and trans-arterial embolisation. However, peritoneal implantation metastasis (PIM) remains highly likely owing to intraperitoneal free cancer cell dispersion within the abdominal cavity before achieving haemostasis. Although resection combined with hyperthermic intra-peritoneal chemotherapy (R-HIPEC) is used in cancer treatment, its effectiveness in preventing PIM of rHCC remains uncertain. This study aimed to evaluate the effectiveness of R-HIPEC in reducing peritoneal implantation metastasis of rHCC.

Methods

Data from 83 rHCC patients treated at Zhujiang Hospital of Southern Medical University between February 2013 and July 2023 were retrospectively analysed. Patients were categorised into interventional, resection, and R-HIPEC groups. PIM rates, time to recurrence-free survival (RFS), survival time, and other risk factors were analysed using the logistic or Cox regression model. Variables with P < 0.1 in the univariate analysis were included in the multivariate analysis.

Results

The resection and intervention groups showed no significant differences in PIM (64.5% vs 61.9%, P = 0.848), RFS (3.7 vs 4.3 months, P = 0.852), and overall survival (OS) (20.5 vs 6.9 months, P= 0.054). The R-HIPEC group exhibited lower PIM rates (23.1% vs 63.5%, P= 0.009) and longer OS (P = 0.045) than the non-HIPEC group, and the median OS was not reached in the R-HIPEC group. The R-HIPEC group had superior RFS (5.8 vs 3.6 months, P = 0.084) than the non-HIPEC group; however, the difference was not statistically significant. Multivariate analysis revealed that R-HIPEC was associated with lower PIM (odds ratio: 0.235, 95% confidence interval 0.056–0.981, P = 0.047).

Conclusions

R-HIPEC significantly reduced the occurrence of PIM, extended the RFS and OS in rHCC patients, and enhanced the overall prognosis.

Spontaneous rupture of hepatocellular carcinoma

Hyperthermic intraperitoneal chemotherapy

Peritoneal implantation metastasis

Survival time

Primary liver cancer poses a global challenge, with its incidence and mortality rates increasing annually. According to 2020 data from the World Health Organization’s International Agency for Research on Cancer, liver cancer has the fourth-highest cancer mortality rate and the sixth-highest incidence rate in the world.[1, 2] Hepatocellular carcinoma (HCC) is the main type of liver cancer and accounts for 90% of all cases.[3] Typically, the incidence of extrahepatic metastases resulting from HCC ranges from 13–42%. Lung metastases, the most common site for extrahepatic metastases, account for approximately 55%, and peritoneal implantation metastases, the least common site, account for approximately 11%.[4] Spontaneous rupture and haemorrhage are serious complications of HCC, with a rapid onset, often accompanied by acute haemorrhagic shock, and a mortality rate as high as 25–75% in the acute phase.[5] Distant complications cause intra-abdominal organ metastasis, peritoneal metastasis, etc., representing a worse prognosis.[6] Currently, for HCC with spontaneous rupture (rHCC), conservative treatment, emergency surgical resection, or trans-arterial embolization (TAE) can be chosen based on various factors, such as haemodynamic status, underlying liver function, tumour characteristics, and staging.[7–9] However, even with surgical or interventional treatment, the incidence of intra-abdominal metastasis is high because intraperitoneal free cancer cells (IFCCs) have a great capacity to diffuse into the abdominal cavity before haemostasis. The recurrence rate is as high as 67–100%, and no guidelines suggest that these treatment modalities reduce the rate of abdominal implant metastases in patients.[10, 11]

To reduce the rate of peritoneal implantation metastasis, resection combined with hyperthermic intra-peritoneal chemotherapy (R-HIPEC) has been continuously studied, combining the three aspects—intra-peritoneal lavage, chemotherapy, and hyperthermia—to produce a sensitising effect. Previously, it was mostly applied to ovarian, gastric, and colorectal cancers.[12–15] Recently, it has been gradually applied to hepato-biliary diseases; however, this practice remains relatively rare and controversial. For HCC without spontaneous rupture, Mehta et al.[16] conducted a retrospective analysis of 21 patients with peritoneal metastasis of HCC and found that R-HIPEC chemotherapy drug dosage was associated with recurrence-free survival (RFS) improvement. Paeissa et al.[17] found that R-HIPEC prolonged overall survival (OS) by analysing 7 patients with peritoneal metastases of HCC who underwent R-HIPEC compared with 14 patients who did not undergo HIPEC. These studies suggest that R-HIPEC improves RFS and OS in patients with peritoneal metastases of HCC. However, these studies did not address bleeding from rHCC. In contrast with rHCC, Ruan et al.[18] showed that the differences in RFS and OS between R-HIPEC treatment and surgery in patients were not statistically significant. However, none of these studies conducted a primary analysis of the peritoneal implantation metastasis rates for rHCC.

Therefore, for the first time, this study aimed to analyse the value of R-HIPEC in reducing peritoneal implantation metastasis of rHCC by comparing treatment outcomes from interventional therapy, surgical resection therapy, and R-HIPEC in patients with rHCC. The objective was to explore their therapeutic effects and provide a reliable basis for guiding clinical treatment.

Patients

The clinical data of patients with rHCC admitted to Zhujiang Hospital of Southern Medical University from February 2013 to July 2023 were selected for retrospective analysis.

The inclusion criteria were as follows: (1) pre-operative diagnosis of rHCC by clinical manifestations, tests, and imaging; (2) post-operative diagnosis of HCC, Barcelona Clinic Liver Cancer staging classification (BCLC) stage A; (3) patients aged 18–80 years; (4) no surgical or systemic treatments for the tumour before the initial surgery (including molecular and targeted drug treatments, except for interventional haemostasis within 2 weeks); (5) patients who signed and completed the informed consent form for the surgery; (6) Child–Pugh class A or class B who can reach the A stage after liver protection and albumin correction, without absolute contraindications to surgery; and (7) no post-operative hepatic failure, post-operative haemorrhage, septic infection, multi-organ failure, and other major complications, as well as a smooth discharge from the hospital.

The exclusion criteria were as follows: (1) pre-operative computed tomography (CT)/magnetic resonance imaging (MRI) suggesting that peritoneal implantation metastasis had occurred and (2) concurrent suffering from other active malignant tumours.

Treatment procedures

All patients were treated to ensure that there were no absolute contraindications before the intervention. They were administered anti-shock agents, oxygen, corrective measures for acid–base and water–electrolyte imbalances, and maintenance of vital signs.

Intervention procedure

The right femoral artery was punctured and intubated using the Seldinger technique. A 5F vascular sheath was inserted with an exchange guide wire. The abdominal artery and superior mesenteric artery were intubated for imaging, and the tube was then inserted in the target vessel after locating the liver rupture and the artery supplying blood to the tumour based on the imaging results. Iodine oil (10 mL) was injected, and gelatin sponge particles were used for embolisation to block the bleeding foci. Post-operative imaging confirmed the absence of bleeding, following which the puncture site was compressed and bandaged to stop bleeding. Symptomatic treatments, such as anti-infection, rehydration, and blood transfusion, were administered, and changes in vital signs were closely monitored.

Surgical procedure

An anterior approach laparoscopy or caesarean section was performed under general endo-tracheal anaesthesia. According to the location of the tumour, the volume of the remaining liver, and the situation during the operation, appropriate surgical resection methods, such as local resection of the HCC, left hepatic lobectomy, left hemi-hepatectomy, and right hemi-hepatectomy, were selected. Tumour margins were required to be greater than 1 cm. The patient’s blood pressure and central venous pressure were closely monitored; if necessary, the patient’s blood pressure was elevated and the central venous pressure was lowered to reduce blood seepage from the incision for the benefit of the operation. Delicate handling of the liver tissue was employed to avoid damage to the organ tissue and blood vessels. The hepatic portal blocking technique was reasonably applied, and the blocking time was no more than 15 min per time. Following the surgery, the abdominal cavity was rinsed with 3 L of sterile warm saline. Patients in the surgery group were fitted with 1–2 peritoneal drainage tubes in the hepatic section, whereas those in the R-HIPEC group had four abdominal heat perfusion tubes placed at the hepatic apex, splenic fossa, and left and right pelvic cavities.

R-HIPEC procedure

After the operation, when the patient's vital signs were stable, HIPEC was carried out 1–3 times, depending on the patient's condition. The machine used in this procedure was BR-TRG-II (Guangzhou Poly Medical Technology Co., Ltd.). The type of drug used was platinum drugs, dissolved in 3 L of sterile physiological saline, with the temperature of the circulating perfusion liquid maintained at 43°C. The circulating pump flow rate was set at 400 mL/min, and the circulation perfusion time was 60 min.

Follow-up

Post-operative discharge follow-up was conducted via out-patient clinic visits and telephone calls. Follow-up began at the time of review in the first post-operative month, after which patients were followed up every 1–3 months in the first year and then every 3–6 months from the second year onwards. The follow-up was concluded upon the patient’s death, or on 15 December 2023. During each review, patients were examined for serum alpha-fetoprotein levels, abdominal ultrasonography, and enhanced CT or MRI of the chest and abdomen. Recurrence and metastasis were determined based on the identification of de novo nodules or inhomogeneous enhancement foci in CT or MRI findings. The primary endpoint of this study was the rate of peritoneal implantation metastasis, and the secondary endpoints were RFS and OS.

Statistical analysis

The data were processed using SPSS software (version 25.0). The measurements conforming to a normal distribution are presented as mean ± standard deviation (\(\stackrel{-}{X}\pm S\)). Skewness was described as median as well as inter-quartile spacing. Comparisons between groups were made using the independent samples t-test or the two independent samples rank sum test. Count data are presented as frequencies (n) or proportions (%), and comparisons between groups were made using the χ² test or Fisher's exact probability method. RFS and OS cumulative curves were plotted using the Kaplan–Meier method, and comparisons between groups were made using the log-rank test. Independent risk factors for relapse were analysed using the logistic or Cox regression model. Variables with P < 0.1 in the results of the univariate analysis of the logistic regression model for the peritoneal implantation metastasis rate were substituted into the logistic regression model for multivariate analysis. Similarly, RFS and OS were substituted into the Cox regression model for multivariate analysis of risk ratios and 95% confidence intervals (CIs), respectively. In this study, statistical significance was set at P < 0.05.

Flowchart of baseline patient characteristics and analysis

A total of 83 patients with rHCC were enrolled, and 16 were excluded from further analysis because of loss to follow-up and lack of treatment (shown in Fig. 1). The clinical characteristics of the study population are presented in Table 1. Overall, 62 patients were classified as Child–Pugh A and 3 as Child–Pugh B. By 15 December 2023, 55 patients had intrahepatic recurrence or progression, 36 had peritoneal implantation metastases, and 25 had lung metastases.

Table 1

Patient clinical characteristics
Characteristics	All patients (N = 65), N (%)
Gender (male)	53 (81.5)
Age (years, ≥ 60)	23 (35.4)
Hepatitis (positive)	57 (87.7)
Platelet (10⁹/L, ≥ 100)	57 (87.7)
Hb (g/L, ≥ 115)	22 (33.8)
Serum ALT (U/L, <40)	39 (60.0)
Bilirubin (mmol/L, >21)	16 (24.6)
Albumin (g/L, ≥ 35)	32 (49.2)
Cirrhosis (yes)	23 (35.4)
Prothrombin time (sec, ≥ 14.6)	11 (16.9)
AFP (µg/L, ≥ 400)^§	27 (42.2)
Tumour size (cm, ≥ 10 cm)	16 (24.6)
Child–Pugh stage
A	62 (95.4)
B	3 (4.6)
Recurrence
Intrahepatic	55 (84.6)
Peritoneal metastasis	36 (55.4)
Lung	25 (38.5)

§, two patients' data are deleted; Hb, haemoglobin; AFP, alpha-fetoprotein; PVTT, portal vein tumour thrombus; BCLC, Barcelona clinic liver cancer staging classification; ALT, alanine aminotransferase

Baseline characteristics and long-term prognosis

Comparison between the intervention group and the resection group

Comparison between the intervention group and the resection group was conducted with balanced baselines to ensure more reliable outcomes (Additional Table S1). All patients, 21 in the intervention group and 31 in the resection group, were followed up. For BCLC stage A, 13 of 21 patients in the interventional group (61.9%) and 20 of 31 patients in the resection group (64.5%) had peritoneal implantation metastases; however, the difference in peritoneal implantation metastasis rates between the two groups was not statistically significant (P = 0.85, shown in Fig. 2). In addition, 48 of the 52 patients experienced disease recurrence or progression, including intrahepatic or extrahepatic recurrence (92.3%), and 36 patients died due to tumour-related causes (69.2%). The median RFS in the resection group was slightly poorer than that in the intervention group; however, the difference was not statistically significant (3.7 vs 4.3 months, P = 0.852, shown in Additional Fig. S1A). Although the median OS of the resection group was superior to that of the intervention group, the difference was not statistically significant (20.5 vs 6.9 months, P = 0.054, shown in Additional Fig. S1B).

Comparison between the non-HIPEC group and the R-HIPEC group

Because there was no statistically significant difference in the rate of peritoneal implantation metastases between the intervention and resection groups, the two groups were combined into a non-HIPEC group for the next step of the analysis, with the two groups balanced at baseline (Table 2). Of the 65 patients, 52 were treated with non-HIPEC and 13 with R-HIPEC. There was no statistically significant difference in the baseline data between the groups.

Table 2

Baseline clinical characteristics of patients with rHCC undergoing non-HIPEC or R-HIPEC
Characteristics	Non-HIPEC (n = 52), N (%)	R-HIPEC (n = 13), N (%)	P-value
Gender (male)	44 (84.6)	9 (69.2)	0.38
Age (years, ≥ 60)	20 (38.5)	3 (23.1)	0.48
Hepatitis (positive)	45 (86.5)	12 (92.3)	0.64
Platelet (10 ⁹/L, ≥ 100)	45 (86.5)	12 (92.3)	0.93
Hb (g/L, ≥ 115)	20 (38.5)	2 (15.4)	0.21
Serum ALT (U/L, <40)	32 (61.5)	7 (53.8)	0.61
Bilirubin (mmol/L, >21)	15 (28.8)	1 (7.7)	0.22
Albumin (g/L, ≥ 35)	26 (50.0)	6 (46.2)	0.80
Cirrhosis (yes)	20 (38.5)	3 (23.1)	0.48
Prothrombin time (sec, ≥ 14.6)	11 (21.2)	0	0.16
AFP (µg/L, ≥ 400)	23 (45.1) ^¶	4 (30.8)	0.35
Tumour size (cm, ≥ 10 cm)	12 (23.1)	4 (30.8)	0.83
Child–Pugh stage			0.38
A	49 (94.2)	13 (100)
B	3 (5.8)	0

§, two patients with HCV (positive); ¶, two patients' data are deleted; non-HIPEC, without HIPEC (contains TAE and resection); R-HIPEC, resection combined with HIPEC; rHCC, rupture of HCC; HIPEC, hyperthermic intraperitoneal chemotherapy; Hb, haemoglobin; ALT, alanine aminotransferase; AFP, alpha-fetoprotein; BCLC, Barcelona clinic liver cancer staging classification; HCV, hepatitis C virus.

All patients were followed up. Peritoneal implant metastasis occurred in 33 patients in the non-HIPEC group (33/52 cases, 63.5%) and in 3 in the R-HIPEC group (3/13 cases, 23.1%). The rate of peritoneal implant metastasis was significantly lower in the R-HIPEC group than in the non-HIPEC group (P = 0.009, Fig. 3A).

At a median follow-up of 31.8 months, 57 of the 65 patients experienced disease recurrence, including intrahepatic or extra-hepatic recurrence (87.7%), and 39 patients died of tumour-related causes (60.0%). The 3-month, 6-month, and 1-year RFS rates were 57.7, 28.3, and 15.4% in the non-HIPEC group and 69.2, 46.2, and 30.8% in the R-HIPEC group, respectively. The median RFS in the R-HIPEC group (5.8 months, 95% CI: 0–17.2 months) was superior to that in the non-HIPEC group (3.6 months, 95% CI: 2.4–4.9 months); however, there was no statistically significant difference (P = 0.084, Fig. 3B). The 6-month, 1-year, and 2-year OS rates were 72.9, 44.1, and 34.0% in the non-HIPEC group and 100, 90.9, and 63.6% in the R-HIPEC group, respectively. The median OS in the R-HIPEC group was not reached, and it was significantly better than that of the non-HIPEC group (9.8 months, 95% CI: 7.0–12.6), with a statistically significant difference (P = 0.007, shown in Fig. 3C).

Risk factor analysis

All patients were included, and variables with P < 0.1 in the univariate analysis were included in the multivariate analysis. In the multivariate logistic model, we used the peritoneal implant metastasis rate as the primary indicator and found that R-HIPEC was associated with a lower peritoneal implant metastasis rate (odds ratio: 0.235, 95% CI 0.056–0.981, P = 0.047, Table 3). Next, to represent the degree of impact and nature of differentiation, forest plots were used to represent the results of the multivariate Cox proportional risk model analyses (Additional Fig. S2A-B). The results showed that in the multivariate analysis, alpha-fetoprotein level (≥ 400 µg/L) was associated with RFS and OS.

Table 3

Univariate and multivariate logistic regression model for peritoneal implant metastasis
Variable	Univariate		Multivariate
Variable	OR (95% CI)	P-value	OR (95% CI)	P-value
R-HIPEC (Y vs N)	0.173 (0.042–0.706)	0.015	0.235 (0.056–0.981)	0.047
Gender (M vs F)	1.304 (0.372–4.576)	0.678
Age(years, ≥ 60 vs < 60)	1.414 (0.503–3.975)	0.511	-	-
Hepatitis (Y vs N)	1.148 (0.319–4.139)	0.833	-	-
Hb (g/L, ≥ 115 vs < 115)	0.796 (0.281–2.252)	0.667
Platelet (10⁹ /L, < 100 vs ≥ 100)	2.700 (0.502–14.525)	0.247	-	-
AFP (µg/L, ≥ 400 vs < 400)	2.111 (0.756–5.899)	0.154
Serum ALT (U/L, ≥ 40 vs < 40)	1.988 (0.715–5.532)	0.188	-	-
Albumin (g/L, ≥ 35 vs < 35)	0.933 (0.351–2.483)	0.890
Prothrombin time (sec, ≥ 14.6 vs < 14.6)	10.769 (1.288–90.062)	0.028	7.826 (0.915–66.929)	0.060
Cirrhosis (Y vs N)	1.875 (0.656–5.357)	0.241
Tumour size, cm (≥ 10 cm vs < 10 cm)	0.750 (0.242–2.325)	0.618

Variables in all patients are selected for multivariable analysis based on the results of the univariate analysis with a threshold of P < 0.1. Y, yes; N, no; F, female; M, male; AFP, alpha-fetoprotein; Hb, haemoglobin; R-HIPEC, resection combined with HIPEC; HIPEC, hyperthermic intraperitoneal chemotherapy; ALT, alanine aminotransferase

The rHCC is one of the serious complications of liver cancer, and the incidence of rupture is about 10% among patients with HCC. Spontaneous rupture starts rapidly, usually accompanied by acute haemorrhagic shock. The mortality rate in its acute stage can be as high as 25–75%.[5, 19] Because IFCCs spread throughout the abdominal cavity after rupture, they cause peritoneal metastasis and the planting of metastasis in intra-abdominal organs in the distant stage, significantly threatening the lives of patients.[6, 20] When no rupture occurs, the rate of peritoneal metastasis in HCC is approximately 11%, making it the least common site of metastasis.[4] However, when rupture occurs, the risk of abdominal metastasis increases, and the recurrence rate is as high as 67–100%, with a median survival of only 8.9 weeks.[11, 21] Recent studies have demonstrated higher recurrence rates and lower survival rates after rupture.[6, 18] In our study, the peritoneal implant metastasis rate was 53% in patients with rHCC. However, in the absence of HIPEC, the rate of abdominal implant metastasis was even higher (63.5%), which is consistent with previous findings that rHCC often leads to a worse prognosis.

Although medical technologies are constantly developing, treating rHCC remains an insurmountable challenge. Conservative treatment, TAE, or surgical resection can be used to treat rHCC. TAE only achieves haemostasis but does not cure the tumour or remove the IFCCs remaining in the abdominal cavity, which infiltrate the peritoneum, organ mesentery, and greater omentum, increasing the incidence of tumour implantation and metastasis.[20, 22] With the popularity of laparoscopic hepatectomy and precision hepatectomy and the rise of machine-assisted arm technology, previous studies[7, 23] have concluded that patients with resectable HCC and well-preserved hepatic function should be operated as early as possible, suggesting that the primary tumour can be resected to reduce the recurrence rate. Clinically, 2 L of distilled water is routinely used to irrigate the abdominal cavity after hepatic cancer resection and has been proven to prevent peritoneal metastasis and improve RFS.[24] However, this measure has several limitations due to the difficulty of removing free tumour cells attached to the deeper parts of the abdominal cavity and organs after the rupture and bleeding of HCC. In our study, by comparing the prognostic indicators between the intervention and resection groups, there was no significant difference in the rate of peritoneal implantation metastasis in BCLC stage A. In the early BCLC stage, no significant difference was observed in the RFS or OS between the two groups. For OS in the early stage, it is possible that the difference between the two groups was not statistically significant due to the short follow-up period, indicating that surgical resection at the early stage of rHCC may offer better outcomes than interventional treatments. Second, this study further confirms that simple surgical resection and postoperative abdominal flushing cannot reduce the peritoneal implantation metastasis rate because abdominal flushing alone cannot completely flush and kill IFCCs in the abdominal cavity. There is an urgent need for a means of killing free cells in the abdominal cavity, which could further reduce the rate of peritoneal implantation metastasis.

R-HIPEC is designed to kill residual microscopic lesions and further reduce the incidence of peritoneal implantation metastases through pharmacokinetic effects, sustained mechanical washout, thermal effects, and the synergistic effects of thermal impacts and chemotherapeutic agents.[25–28] R-HIPEC can adequately eliminate IFCCs and tiny cancer tissues that are not visible to the naked eye and those that are visible to the naked eye in the peritoneal cavity after surgery. Since 1980, when Spratt et al.[29] first used cytoreduction combined with HIPEC to treat a patient with appendiceal pseudo-mucinous neoplasm, R-HIPEC has been applied to ovarian, gastric, colorectal, and pancreatic cancers, as well as peritoneal metastasis of HCC, all of which have exhibited good efficacy.[12–15, 30] With the deepened understanding of the mechanism of R-HIPEC and the study of ruptured bleeding and peritoneal implantation metastasis of HCC over the past decade, many researchers have confirmed that R-HIPEC has unique therapeutic efficacy for peritoneal metastasis of advanced HCC, which prolongs RFS and OS. Multiple studies have shown that R-HIPEC improves the RFS and OS rates in patients with peritoneal metastases of HCC.[16, 17, 31] Thus, first, considering the characteristics of peritoneal metastasis in HCC, R-HIPEC can be employed to improve the prognosis. Second, based on the characteristics of peritoneal implantation metastasis, which tends to occur after the spontaneous rupture of HCC, the study of Ruan et al.[18] showed that the differences in RFS and OS between R-HIPEC treatment and surgery in patients with rHCC were not statistically significant. This may be due to the small number of cases and the fact that they were all in the early stages of HCC, which makes them less representative of the population as a whole. However, none of these studies conducted a primary analysis of the rate of peritoneal implantation metastasis, which, according to the definition of RFS, includes not only recurrence in the peritoneal cavity but also recurrence or metastasis in other sites, such as the intrahepatic region or lungs, and therefore cannot fully represent the effect on peritoneal implantation metastasis alone. Thus, in our study, we first analysed the rate of peritoneal implantation metastasis as the primary index. The rate of peritoneal implantation metastasis was lower in the R-HIPEC group than in the non-HIPEC group, and the OS and RFS in the R-HIPEC group were superior to those in the non-HIPEC group. Combined with the above analysis, interventional therapy and surgery alone could not reduce the peritoneal implantation metastasis rate in the patients, and only R-HIPEC could reduce the peritoneal implantation metastasis rate, improve the OS, and improve the RFS in the patients to a certain extent. However, in the future, other improved methods are needed to reduce the intrahepatic recurrence rate.

In the multivariate logistic model, R-HIPEC was associated with a lower peritoneal implant metastasis rate and offered a good survival prognosis for patients, probably because it could reduce the rate of peritoneal implantation metastasis, thus improving the RFS in the patients to a certain extent; however, further studies are still needed to confirm this observation.

This study had some limitations. First, this was a single-centre, retrospective cohort study; therefore, we applied stratified analyses to reduce selection bias caused by confounding factors and ensure balanced comparability of baseline data between the two groups. Prospective multicentre randomised controlled clinical trials are needed to confirm these findings and make them more credible. Our centre is currently registering a multicentre, randomised clinical trial to evaluate the efficacy and safety of surgical resection combined with hyperthermic intra-peritoneal chemotherapy in patients with rHCC. Second, the sample size of this study was relatively small; thus, a further increase in the number of cases is needed.

This study presents novel findings indicating that surgical resection alone does not yield superior results in reducing the incidence of peritoneal implantation metastasis compared with interventional haemostasis. Conversely, R-HIPEC significantly reduced the occurrence of peritoneal implantation metastasis, extended the OS in patients with rHCC, and enhanced the overall clinical prognosis in these individuals.

hepatocellular carcinoma (HCC), HCC with spontaneous rupture (rHCC), trans-arterial embolization (TAE), intraperitoneal free cancer cells (IFCCs), resection combined with hyperthermic intra-peritoneal chemotherapy (R-HIPEC), recurrence-free survival (RFS), overall survival (OS), Barcelona Clinic Liver Cancer (BCLC), computed tomography (CT), magnetic resonance imaging (MRI), confidence interval (CI)

Ethics approval and consent to participate

This retrospective study adhered to the ethical guidelines of the Declaration of Helsinki and was approved by the Ethics Committee of our centre (2023-KY-078-02,NCT06247293). The analysis used anonymous clinical data obtained after each patient agreed to treatment by written consent, and the patients agreed to either surgery or HIPEC.

Consent for publication

Not applicable.

Availability of data and materials

All data results generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author.

Competing interests

All authors declare no conflicts of interest related to this article.

Funding

This study was supported by the Guangdong Basic and Applied Basic Research Foundation of China (2021B1515230011) and Science and Technology Projects in Guangzhou of China (2023B03J1247).

Author contributions

Feng ZB, Xu YY, Zhang C, Wen YH, and Pei JY were involved in study design, collected and analysed data, and drafted the paper; Feng JN, Tan HK, Wang CM, Liu WX, Cai L, and He GL collected and checked data; Fu SJ and Pan MX designed and supervised the study; and all authors wrote the paper.

Corresponding author

Correspondence to Pan Mingxin and Fu Shunjun.

Acknowledgements

We would like to thank Editage (www.editage.cn) for English language editing. We are also grateful to all our colleagues for their assistance in this study.

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No competing interests reported.

Additionalfiles.docx
Additional files Additional Figure S1 A, Kaplan–Meier analysis of RFS between the TAE group and resection group. B, Kaplan–Meier analysis of OS between the TAE group and resection group. All P-values are calculated using the log-rank test for each comparison without adjustments. TAE, trans-arterial embolisation; RFS, recurrence-free survival; OS, overall survival Additonal Figure S2 A, Multivariate Cox regression model for RFS in all patients; B, Multivariate Cox regression model for OS in all patients. 95%CI, 95% confidence intervals; HR, hazard ratio; R-HIPEC, resection combined with hyperthermic intraperitoneal chemotherapy; AFP, alpha-fetoprotein; Hb, haemoglobin; RFS, recurrence-free survival; OS, overall survival. Additonal Table S1 Baseline clinical characteristics of patients with TAE or resection

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Resection Combined with Hyperthermic Intra-peritoneal Chemotherapy Prevents Peritoneal Implantation Metastasis of Hepatocellular Carcinoma with Spontaneous Rupture

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Abstract

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Background

Methods

Patients

Treatment procedures

Follow-up

Statistical analysis

Results

Flowchart of baseline patient characteristics and analysis

Baseline characteristics and long-term prognosis

Comparison between the intervention group and the resection group

Comparison between the non-HIPEC group and the R-HIPEC group

Risk factor analysis

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

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