The combination of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), interventional hepatoma therapy, targeted therapy, and immunotherapy: a case series of a novel AITI conversion therapy model

Introduction

Background

Approximately 10–37% of patients worldwide diagnosed with hepatocellular carcinoma (HCC) can undergo radical resection initially (1). Hepatic resection represents a relatively safe, effective, and potentially curative treatment for patients diagnosed with HCC (2). However, many patients miss the opportunity for surgical treatment upon initial presentation. The focus of conversion therapy lies in turning unresectable tumors into resectable ones. Targeted and immunotherapy have also emerged as focal points in conversion therapy in recent years, but overall, the outcomes have been unsatisfactory (3).

Rationale and knowledge gap

The absence of an adequate future liver remnant (FLR) following extensive hepatectomy is a significant barrier preventing direct surgical intervention for some patients with HCC (2). The associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure has been demonstrated to rapidly induce liver hypertrophy, thereby increasing FLR and enabling resection of more than 70% of the liver volume (4). However, it has been reported that the residual liver may not proliferate sufficiently within the short interval between the two stages, leading to failure to proceed with the second-stage surgery. Additionally, tumor progression during the interval between stages may also impact the success rate of ALPPS (5).

The efficacy of combined targeted therapy and immunotherapy has been demonstrated in several large-scale clinical trials (6-8). The combination of targeted therapy, immunotherapy, and interventional hepatoma therapy has been confirmed to reduce tumor activity and size, indicating an anti-tumor effect in advanced HCC (9,10). Although it has been shown to significantly contribute to patient survival, the method of combining targeted therapy, immunotherapy, and interventional hepatoma therapy as a conversion therapy has not been well-documented and has yielded unsatisfactory conversion outcomes.

Objective

Considering the unclear effectiveness of traditional conversion therapy, we integrated the ALPPS, interventional hepatoma therapy, targeted therapy, immunotherapy and proposed a novel conversion therapy named AITI. This innovative method aims to broaden surgical indications for HCC patients, potentially enabling more individuals to undergo radical resection and ultimately improving survival outcomes. We present this article in accordance with the PROCESS reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-204/rc) (11).

Case presentation

A total of 323 patients were diagnosed with HCC and 5 patients received the AITI conversion therapy between September 2021 to April 2024 at The First Affiliated Hospital of Chongqing Medical University (the demographic data of them were detailed in Table 1 and the liver volume data before the two stage surgeries were described in Table 2). Recurrence and metastasis in all patients were evaluated through imaging examinations, including ultrasound and computed tomography (CT). All procedures performed in this study were in accordance with the ethical standards of the Ethics Committee of The First Affiliated Hospital of Chongqing Medical University (No. 2024.7.29/2024-082-01) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patients for the publication of this case series and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Traditional ALPPS

The technical aspects of the surgical approach—including patient positioning, trocar placement, and hepatic hilum occlusion technique—were detailed in our prior publications (12,13). During the first stage of ALPPS, the first hepatic hilum was dissected using dissecting forceps. Following identification, the right portal vein was selectively occluded with a nonabsorbable Hem-O-lock ligating clip (JNJ, Inc., New Jersey, USA). Hepatic parenchymal transection proceeded along the demarcated ischemic boundary and the middle hepatic vein, utilizing a Harmonic scalpel (JNJ, Inc.). Vascular and biliary structures encountered during transection were secured with Hem-O-lock clips. In the second-stage procedure, definitive division involved occlusion and transection of the right portal vein, right hepatic artery, and right hepatic duct, each managed with Hem-O-lock ligating clips. Completion of the hepatectomy was achieved by dissecting the perihepatic ligaments and abdominal adhesions (12,14).

Interventional hepatoma therapy

Interventional hepatoma therapy is employed for advanced HCC and typically includes procedures such as transcatheter arterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC). Patients undergo either TACE or HAIC based on their medical condition and personal preference. The procedure begins with superselective catheterization of the right femoral artery. During TACE, chemotherapeutic agents such as oxaliplatin, fluorouracil, pirarubicin, among others, along with embolization agents like Ethiodized Poppyseed Oil (Hengrui Medical, Jiangsu, China), are slowly injected into the hepatic artery targeting the tumor-bearing area. The HAIC procedure typically utilizes the FOLFOX (fluorouracil, leucovorin and oxaliplatin) chemotherapeutic regimen.

Targeted therapy and immunotherapy

After excluding contraindications, targeted therapy and immunotherapy were administered. The primary targeted therapy was Lenvatinib (Eisai, Tokyo, Japan), dosed at 12 mg for patients weighing more than 60 kg or 8 mg for those weighing 60 kg or less. Additionally, some patients received bevacizumab (Genentech, San Francisco, USA) at a dosage of 15 mg/kg. Immunotherapy consisted of camrelizumab (Hengrui Pharma, Lianyungang, China), tislelizumab (BeiGene, Shanghai, China), or sintilimab (Innovent Biologics, Suzhou, China), administered at a dose of 200 mg. Throughout treatment, medication dosages and timing were adjusted based on individual patient’s adverse reactions.

Case 1

A 33-year-old male patient presented with right upper abdominal pain persisting for 15 days. His alpha fetoprotein (AFP) level was 5,909 ng/mL and platelet were 68×10⁹/L. Enhanced CT revealed a large mass measuring approximately 12 cm × 9 cm × 10 cm in the right lobe of the liver (Figure 1A-1C). The indocyanine green 15-minute retention rate (ICG-R15) was 10.5%. The right hemi-hepatic volume was 820 mL, comprising 68% of the total liver volume of 1,201 mL. Due to the cirrhosis observed on CT, high ICG-R15 and low FLR, undergoing a right hemi-hepatectomy posed a high risk of postoperative liver failure, the patient finally underwent AITI conversion therapy.

Figure 1 The clinical data of case 1. (A-C) The initial CT and MRI images upon the patient’s first visit. (D,E) Intraoperative images during the first-stage ALPPS procedure. (F) Image during the TACE procedure. (G,H) Preoperative CT images for second-stage ALPPS. (I,J) Intraoperative images during second-stage ALPPS. (K) Trend in AFP level. (L) Treatment timeline of the patient. (G, circle labeled) Emerging tumor in the left lobe. AFP, alpha fetoprotein; ALPPS, associating liver partition and portal vein ligation for staged hepatectomy; CT, computed tomography; IVC, inferior vena cava; MHV, middle hepatic vein; MRI, magnetic resonance imaging; RHV, right hepatic vein; RPV, right portal vein; TACE, transcatheter arterial chemoembolization.

The patient received first-stage laparoscopic ALPPS procedure and the surgery lasted 160 minutes with a blood loss of 200 mL (Figure 1D,1E). Postoperatively, the patient received daily lenvatinib 8 mg and was administered camrelizumab 200 mg intravenously a week after the first-stage ALPPS surgery. Three weeks postoperatively, TACE was subsequently undertaken, utilizing oxaliplatin 150 mg, fluorouracil 750 mg, pirarubicin 30 mg, and 20 mg of Ethiodized Poppyseed Oil (Figure 1F). Repeat TACE was conducted after 7 weeks.

After treatment, the AFP level decreased to 139 ng/mL. However, an enhanced CT before second surgery, indicated a 11.5 cm × 9.0 cm mass and emerging tumors in the S3 and S4 liver segments, suggesting intrahepatic metastasis (Figure 1G,1H). The left hemi-hepatic volume was 460 mL, comprising 38.3% of total liver volume. A laparoscopic second-stage ALPPS procedure was undertaken 11 weeks after the first surgery. Intraoperative ultrasound identified tumors in segments 3 and 4, with one located at the liver’s edge treated with resection and another deep-seated tumor treated with radiofrequency ablation (Figure 1I,1J). The operation lasted 255 minutes with a blood loss of 500 mL. No recurrence or metastasis has been detected for 2 years (Figure 1K,1L).

Case 2

A 48-year-old male patient was admitted to the hospital with a complaint of epigastric distension persisting for 1 month. Upper abdominal enhanced CT revealed a right liver mass measuring approximately 7.6 cm × 7 cm, accompanied by tumor thrombus in the right branch of the portal vein (Figure 2A-2C). Given the presence of portal vein tumor thrombus, the patient was scheduled for right hemi-hepatectomy. ICG-R15 was 5.2%. The FLR volume was calculated at 398 mL, representing 31.9% of the total liver volume of 1267 mL. Considering the clinical condition and liver cirrhosis, AITI conversion therapy was chosen as the treatment approach.

Figure 2 The clinical data of case 2. (A-C) CT and MRI images taken before the patient’s treatment. (D,E) Intraoperative images during first-stage ALPPS. (F) Image during the TACE procedure. (G,H) Preoperative CT images for second-stage ALPPS. (I,J) Intraoperative images during second-stage ALPPS. (K) Trend in AFP level. (L) Treatment timeline of the patient. (G, circle labeled) Reduced portal vein tumor thrombus. AFP, alpha fetoprotein; ALPPS, associating liver partition and portal vein ligation for staged hepatectomy; CT, computed tomography; IVC, inferior vena cava; MHV, middle hepatic vein; MRI, magnetic resonance imaging; RHV, right hepatic vein; RPV, right portal vein; TACE, transcatheter arterial chemoembolization.

The patient underwent laparoscopic first-stage ALPPS (Figure 2D,2E). The procedure lasted 170 minutes with a blood loss of 100 mL. Subsequently, oral Lenvatinib at a dose of 12 mg once daily was initiated. TACE was undertaken after 3 weeks (Figure 2F), involving the slow injection of 30 mg of pirarubicin and embolization using 7 mL of Ethiodized Poppyseed Oil.

Follow-up CT indicated a residual mass in the right liver measuring approximately 5.8 cm × 5.5 cm, along with a smaller right portal vein tumor thrombus compared to previous imaging (Figure 2G,2H). The FLR volume had increased to 458 mL, accounting for 37.3% of the total liver volume of 1,227 mL. Subsequently, patient received laparoscopic second-stage ALPPS after 11 weeks (Figure 2I,2J). The procedure lasted 260 minutes with a blood loss of 400 mL. The patient has been regularly followed up at our center post-surgery, and no recurrence or metastasis has been detected for 2 years (Figure 2K,2L).

Case 3

A 40-year-old male patient was admitted to the hospital with an enhanced CT of the upper abdomen revealing a large tumor in the right lobe of the liver, with less than 30% of left residual liver volume. Tumor markers were within normal limits. Due to the high surgical risk, the patient underwent AITI conversion therapy.

Initially, the patient received seven cycles of TACE combined with 200 mg of sintilimab and daily oral lenvatinib at 8 mg. TACE involved the use of the same dose of chemotherapy drugs and embolization with Ethiodized Poppyseed Oil. Post-treatment CT scans showed significant reduction in tumor size (Figure 3A,3B). Liver volumes were reassessed and revealed a total liver volume of 3,547 mL, tumor volume of 2,109 mL, right hemi-hepatic volume of 2,694 mL, and residual liver volume of 24%.

Figure 3 The clinical data of case 3. (A,B) Preoperative images for first-stage ALPPS. (C,D) Preoperative images for second-stage ALPPS. (E) Treatment timeline of the patient. (A and C, circle and arrow labeled) Tumor bearing area. ALPPS, associating liver partition and portal vein ligation for staged hepatectomy; TACE, transcatheter arterial chemoembolization.

The first-stage open ALPPS was undertaken, lasting 200 minutes with a blood loss of 250 mL. Postoperatively, the patient continued regular lenvatinib. Liver volumes were reevaluated after a month, showing a total liver volume of 3,749 mL, tumor volume of 1,799 mL, right hemi-hepatic volume of 2,638 mL, and residual liver volume of 30% (Figure 3C,3D). After a month, patient received second-stage open ALPPS, lasting 240 minutes with a blood loss of 300 mL. No recurrence or metastasis has been detected for a year (Figure 3E).

Case 4

A 58-year-old male with a 30-year history of hepatitis B infection presented with an AFP level of 783 ng/mL. Enhanced CT of the upper abdomen revealed multiple liver masses in the right lobe with tumor thrombus in the right branch of the portal vein (Figure 4A-4C). ICG-R15 was 3.1%. The total liver volume was 1,461 mL, with a left liver volume of 426 mL, resulting in a residual liver volume of 29%. Given the presence of portal vein tumor thrombus, limited left liver volume and the liver cirrhosis, the patient underwent AITI conversion therapy.

Figure 4 The clinical data of case 4. (A-C) CT and MRI images taken before the patient’s treatment. (D,E) Intraoperative images during first-stage ALPPS. (F) Image during the TACE procedure. (G,H) Preoperative CT images for second-stage ALPPS. (I) Trend in AFP level. (J) Trend in PIVKA-II. (K) Treatment timeline of the patient. AFP, alpha fetoprotein; ALPPS, associating liver partition and portal vein ligation for staged hepatectomy; CT, computed tomography; MHV, middle hepatic vein; MRI, magnetic resonance imaging; PIVKA-II, protein concentration induced by vitamin K absence or antagonist-II; RPV, right portal vein; TACE, transcatheter arterial chemoembolization.

Patient received laparoscopic first-stage ALPPS, lasting 160 minutes with 100 mL of blood loss (Figure 4D,4E). A week postoperatively, the patient received TACE combined with chemotherapy drugs and Ethiodized Poppyseed Oil embolization, along with tislelizumab 200 mg (Figure 4F). Postoperative AFP level decreased to 46.4 ng/mL. Subsequent evaluation showed a total liver volume of 1,506 mL, with a left liver volume of 555 mL, representing 36% of total liver volume (Figure 4G,4H). After evaluation, the patient underwent laparoscopic second-stage ALPPS after a month, which lasted 210 minutes with 400 mL of blood loss (Figure 4I-4K).

Case 5

The patient presented with abdominal pain and an enhanced CT of the upper abdomen revealed a large mass in the right liver measuring approximately 11 cm × 10 cm × 9 cm, along with a portal vein tumor thrombus in the right branch of the main trunk (Figure 5A,5B). Initial AFP level was 304 ng/mL and the protein concentration induced by vitamin K absence or antagonist-II (PIVKA-II) level was 8,360 mAU/mL. ICG-R15 was 9.2%. Liver volumetrics showed a total liver volume of 2439 mL, left liver volume of 819 mL, tumor volume of 629 mL, and a residual liver volume of 33.5%. Given these findings, the patient received AITI conversion therapy.

Figure 5 The clinical data of case 5. (A,B) CT and MRI images from the patient’s initial visit. (C) Intraoperative image during the first HAIC procedure. (D) Image during the last HAIC procedure. (E,F) Images before first-stage ALPPS. (G) Image during TACE between the two stages of surgery. (H,I) Preoperative images for second-stage ALPPS. (J) Trend in AFP level. (K) Trend in PIVKA-II. (L) Treatment timeline of the patient. AFP, alpha fetoprotein; ALPPS, associating liver partition and portal vein ligation for staged hepatectomy; CT, computed tomography; FOLFOX, fluorouracil, leucovorin and oxaliplatin; HAIC, hepatic arterial infusion chemotherapy; MRI, magnetic resonance imaging; PIVKA-II, protein concentration induced by vitamin K absence or antagonist-II; TACE, transcatheter arterial chemoembolization.

Initially, treatment consisted of HAIC combined with targeted therapy and immunotherapy. HAIC was undertaken using FOLFOX chemotherapy in combination with gamrelizumab 200 mg and lenvatinib 12 mg daily (Figure 5C). Due to inadequate tumor shrinkage and tumor progression, treatment was modified to HAIC combined with sintilimab 200 mg and bevacizumab 15 mg/kg (Figure 5D). Follow-up CT scans indicated a reduction in liver mass size to 9.8 cm × 7.5 cm × 8.3 cm with emerging segment 8 tumor (Figure 5E,5F). Updated liver volumetrics showed a total liver volume of 2,055 mL, left liver volume of 842 mL, tumor volume of 528 mL, and a residual liver volume of 40.9%. Post-treatment AFP level decreased to 124 ng/mL and PIVKA-II level to 432 mAU/mL.

With significant tumor marker reduction and size decrease, the patient underwent first-stage laparoscopic ALPPS after four cycles of treatment, lasting 185 minutes with 400 mL of blood loss. A week postoperatively, TACE was undertaken (Figure 5G). AFP level was 147 ng/mL and PIVKA-II level was 350 mAU/mL before second surgery. Subsequent liver volume showed a total liver volume of 1,904 mL, left liver volume of 913 mL, and a residual liver volume of 48% (Figure 5H,5I). Patient received second-stage open ALPPS a month after first surgery, with a surgical duration of 205 minutes and 400 mL of bleeding (Figure 5J-5L).

Discussion

Key findings

We propose a novel AITI conversion therapy model which combines ALPPS with interventional therapy, targeted therapy, and immunotherapy to improve the conversion rate for patients with advanced HCC. Our cases suggest that AITI conversion therapy model is feasible and represents a novel approach to conversion therapy.

Strengths and limitations

We intervened either preoperatively or between stages of surgery with the aim of reducing surgical complications and improving the conversion rate. Following treatment, all patients underwent tumor resection successfully. In cases 1, 2, 4, and 5, there was a decrease in tumor markers, reduced tumor activity, and a reduction in tumor size. Additionally, cases 2, 4, and 5 showed significant reduction in tumor thrombus size. Cases 3 and 5, who received preoperative therapy, demonstrated tumor response and subsequently became eligible for resection. These findings collectively underscore the efficacy of the anti-tumor treatments. All five patients included in our study were infected with hepatitis B virus. Among them, cases 1, 2, 4 and 5 had underlying liver cirrhosis. All patients had Child-Pugh class A liver function. These findings suggest that our conversion strategy may also be effective in patients with underlying cirrhosis. Consequently, a combination of interventional therapy, targeted therapy, and immunotherapy was administered initially, followed by successful tumor resection at a later stage, with no complications such as bile leakage, liver failure, or wound infection. The strategy aims to expand surgical opportunities for more patients with HCC.

However, the extended interval between the two stages may result in increased intra-abdominal adhesions. In our cases, compared to the first stage, the duration of surgery and volume of bleeding during the second-stage of ALPPS were notably higher. Furthermore, a study has indicated that the perioperative risks associated with surgical resection after conversion therapy are higher than those of direct resection, affecting both surgical complexity and postoperative outcomes (15). This suggests that second-stage surgery is more complex and poses greater risks compared to conventional and first-stage surgery. Therefore, it is imperative that the procedure be undertaken by a highly experienced surgeon.

Comparison with similar research

A previous study involving 320 patients undergoing ALPPS indicated that approximately 86% recovered sufficiently after first-stage surgery to proceed to second-stage ALPPS, while about 14% required a longer recovery period or even missed the opportunity for subsequent surgery (16). ALPPS presents a higher complication and mortality rate compared to standard hepatectomy, and encounters similar challenges regarding postoperative recurrence (17). Previously reported elevated Ki-67 level of tumor between two stages of ALPPS, suggested relatively high tumor activity (18). The precursor to ALPPS, portal vein embolization (PVE), has also been shown to potentially stimulate tumor growth and could be linked to increased disease recurrence (19). This observation suggests that during the interval between the two stages of ALPPS, certain tumor cells exhibit heightened activity, potentially leading to the development of new lesions and negatively affecting long-term prognosis. Considering this, we pose the question of whether incorporating additional treatments between the two stages of ALPPS could mitigate tumor activity, reduce tumor size, and halt tumor progression, thereby enhancing the conversion rate.

Explanations of findings

HCC receives dual blood supply from both the portal vein and the hepatic artery, with the majority supplied by the hepatic artery. After the first-stage ALPPS, portal vein flow on the affected side is obstructed, while the hepatic artery continues to supply blood to the tumor, resulting in ongoing activity and proliferation of tumor cells in the patient. During TACE, chemotherapeutic agents are infused to reduce tumor activity and diminish the likelihood of tumor proliferation, while high-dose embolic agents deprive tumor cells of their blood supply from the hepatic artery. As a result, several patients exhibit significant necrosis and reduced tumor activity following this combined approach. Furthermore, some patients are scheduled for right hemi-hepatic resection due to cancerous thrombus in the right branch of the portal vein. HCC with portal vein thrombosis is generally aggressive and represents a high-risk factor for complications such as liver failure and portal hypertension, underscoring the necessity for more aggressive treatment measures (20).

Embolization and chemotherapy administered to patients after first-stage ALPPS is not thought to affect liver hypertrophy and regenerative capacity (21). A case of ALPPS has been reported that due to the insufficient FLR after first-stage ALPPS, second-stage ALPPS was completed after using HAIC and achieved good results (22). Therefore, this treatment allows for a sufficient interval between first-stage and second-stage of ALPPS, enabling adequate time for hypertrophy of the residual liver. By the time liver hypertrophy is largely completed, the patient’s physical condition has typically returned to normal. This may help reduce surgical complications and potentially lower the long-term incidence of postoperative liver failure.

Implications and actions needed

This novel conversion therapy aims to provide more initially unresectable HCC patients with the opportunity for curative resection. However, further studies are needed to validate its safety, efficacy, and feasibility.

Conclusions

In conclusion, we propose a novel AITI conversion therapy. This treatment approach, holds potential to increase the likelihood of radical resection in previously unresectable patients. The combined therapies may yield improved conversion outcomes, enhance anti-tumor effects, and potentially reduce perioperative complications.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PROCESS reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-204/rc

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-204/prf

Funding: This study was supported by the General Project of Natural Science Foundation of Chongqing (No. cstc2021jcyj-msxmX0604) and Chongqing Doctoral “Through Train” Research Program (No. CSTB2022BSXM-JCX0045).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-204/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the Ethics Committee of The First Affiliated Hospital of Chongqing Medical University (No. 2024.7.29/2024-082-01) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patients for the publication of this case series and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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