Reassessment of palliative surgery in conversion therapy of previously unresectable hepatocellular carcinoma: Two case reports and review of literature

Abstract

BACKGROUND

Most patients with hepatocellular carcinoma (HCC) have lost the opportunity for direct surgery at the time of diagnosis. Transarterial chemoembolization (TACE) combined with immune checkpoint inhibitors or tyrosine kinase inhibitors (TKI) can partially transform some unresectable HCC and improve the prognosis effectively. However, based on the promising prospects of combined targeted and immunotherapy for the effective treatment of HCC, the positive role of palliative surgery in the conversion treatment of advanced HCC urgently needs further intensive re-assessment.

CASE SUMMARY

In this study, we describe two successful cases of "conversion therapy for unresectable HCC" achieved mainly by palliative surgery combined with TACE plus immunotherapy and TKIs. A 48-year-old patient with newly diagnosed HCC, presenting with a 6-cm mass in the segment VII/VIII of the right liver with multiple intrahepatic metastases, could not undergo one-stage radical surgical resection. He underwent palliative surgery with radiofrequency of metastatic lesions and the palliative resection of the primary mass, and received subsequent TACE treatments twice in the early postoperative period (2 weeks and 6 weeks), in addition to targeted and immune combination therapy with sintilimab injection and oral lenvatinib. No evidence of recurrence was observed during the 11-month follow-up period after surgery. The other patient was a 47-year-old patient with massive HCC (18 cm × 15 cm × 4.5 cm) in the left liver with severe cirrhosis. The left portal branch was occluded and a tumor thrombus formed, and the tumor partly involved the middle hepatic vein. The patient underwent palliative surgery of left hemihepatectomy (including resection of the middle hepatic vein) for HCC, followed by three TACE procedures and oral TKIs 2 weeks after surgery. Six months later, the re-examination via computed tomography revealed no tumour activity in the remaining right liver, while magnetic resonance imaging revealed slight local tumor enhancement in the caudate lobe of the liver considered, TACE was performed once again, and during the next follow-up of 10 months did not reveal new intrahepatic lesions or distant metastases.

CONCLUSION

These cases demonstrate that the addition of palliative surgery to conversion therapy in a selected population with a high tumor burden could benefit patients with initially unresectable HCC.

Key Words: Hepatocellular carcinoma; Transarterial chemoembolization; Immunotherapy; Conversion Therapy; Tyrosine kinase inhibitors; Case report

Core Tip: We herein present two successful cases of "conversion Therapy for unresectable hepatocellular carcinoma (HCC)" achieved mainly by palliative surgery combined with transarterial chemoembolization (TACE) plus immunotherapy and tyrosine kinase inhibitors. For some selected advanced HCC with a high risk of tumor overload and metastasis, if liver function permits, early palliative surgery combined with local subsequent TACE, along with targeted and immunotherapy, may be a tolerable and effective strategy, which may provide the opportunity for the ultimate cure for the initially unresectable HCC and effectively improve the long-term survival based on the promising prospects of combined targeted and immunotherapy.

INTRODUCTION

Hepatocellular carcinoma (HCC) is currently the sixth most common malignancy and the third leading cause of patient mortality worldwide[1]. Hepatectomy and liver transplantation are the most effective radical treatments for HCC. However, approximately 70% of HCC patients cannot undergo direct surgery due to the advanced stage at the time of initial diagnosis[2]. For unresectable patients, simple epidermal growth factor receptor-tyrosine kinase inhibitor (TKI) targeted therapy and/or immunotherapy can also control tumor progression to a certain extent, prolong the survival time, and significantly improve the current status and prognosis of HCC treatment[3-5]. Furthermore, the emerging "conversion therapy" has achieved a better prognosis for patients with HCC, that is, achieving tumor regression in unresectable HCC by other means, such as the combination of targeted and immunotherapy, and then regaining the access to operation to cure the tumor radically[6,7].

At present, the current conversion therapy is a comprehensive program that mainly relies on transarterial chemoembolization (TACE), mostly combined with targeted and/or immunotherapy[8,9]. However, the cure rate of HCC still remains low even some studies have confirmed that complete tumor necrosis can be achieved in some patients[10,11]. Moreover, new therapeutic drugs such as immune checkpoint inhibitors (ICIs) and TKIs are emerging and indications are expanding continuously[11-13]. The clinical trials of conversion therapy have not been completed currently which lacks effective studies on large sample, and have not established international expert consensus standards. Yet it's worth noting that the positive role of palliative surgery in conversion therapy has always been overlooked and more in-depth researches are urgently needed for reassessment simultaneously in this new era.

In this study, two patients with advanced HCC achieving conversion therapy with firstly palliative surgical resection and radiofrequency ablation (+/-) were reported. Considering its excessive tumor burden and limited location in the liver with a high risk of metastasis, a palliative surgical resection plan was firstly adopted. Early postoperative combined TACE with targeted and/or immunotherapy were followed effectively to achieve successful imaging complete remission (CR) and improve the prognosis of HCC.

CASE PRESENTATION

Chief complaints

Case 1: On February 10, 2021, a 48-year-old male patient was admitted to the hospital due to computed tomography (CT) scan showed a mass in the right lobe of the liver, and he has a history of hepatitis B virus infection for more than 30 years without liver cirrhosis.

Case 2: On December 10, 2021, a 47-year-old male patient was admitted to the hospital because his routine examination showed a huge mass in the left liver who had a history of hepatitis B virus infection for more than 20 years and accompanied with liver cirrhosis.

History of present illness

Review of systems was negative.

History of past illness

Case 1: The patient has a history of hepatitis B virus infection for more than 30 years without liver cirrhosis.

Case 2: The patient had a history of hepatitis B virus infection for more than 20 years and accompanied with liver cirrhosis.

Personal and family history

All other personal and family medical history was noncontributory.

Physical examination

Case 1: Physical examination revealed a large palpable mass in the right upper quadrant, with no other obvious concerning findings. Abdomen was soft, non-tender, non-distended, and without other palpable masses; bowel sounds were present.

Case 2: Physical examination revealed a large mass in the left upper quadrant, with no other obvious concerning findings. Abdomen was soft, non-tender, non-distended, and without other palpable masses; bowel sounds were present.

Laboratory examinations

Case 1: The hepatobiliary enzymes were normal with a Child-Pugh score of A, and tumor markers were elevated with his serum alpha-fetoprotein (AFP) 2.2 ng/mL, des-γ-carboxyprothrombin (DCP) 811 mAU/mL, and albumin 4.4 g/L.

Case 2: The hepatobiliary enzymes were normal with a Child-Pugh score of A, and tumor markers were elevated with his serum AFP > 80000.0 ng/mL, DCP 24132 mAU/mL, and albumin 4.8 g/L on admission.

Imaging examinations

Case 1: Dynamic contrast-enhanced CT scan and magnetic resonance imaging (MRI) of the liver revealed a right hepatic mass in segments VII/VIII (S7/8, 6.5 cm × 5.5 cm × 6.2 cm) with multiple intrahepatic metastasis, without large vessel invasion or extrahepatic metastasis (Figure 1A-D).

Figure 1 Preoperative computed tomography and magnetic resonance imaging of case 1. A-D: Contrast-enhanced computed tomography and magnetic resonance imaging of the liver revealed a 65 mm × 55 mm lesion in the S7/8 lobe with multiple intrahepatic metastases in the arterial phase; E: Macroscopic findings of the tumor revealed the major lesion with satellite micronodules (with a diameter of 0.3-1 cm); F: Microscopic diagnosis revealed moderately differentiated hepatocellular carcinoma with negative surgical margins (magnification, 40 ×).

Case 2: Dynamic contrast-enhanced CT and MRI scans of the liver revealed massive HCC (18 cm × 15 cm × 4.5 cm) in the left liver with multiple intrahepatic foci, tumor thrombus formation in the left branch of the portal vein, involvement of the left hepatic vein, liver cirrhosis, splenomegaly, and no extrahepatic metastasis (Figure 2A-D).

Figure 2 Preoperative computed tomography and magnetic resonance imaging of case 2. A and B: Contrast-enhanced computed tomography showed an 18 cm × 15 cm massive lesion in the left liver, with multiple intrahepatic foci, contrast enhancement in the arterial phase and relatively low density in the delayed phase, tumor thrombus formation in the left branch of the portal vein (arrow); C and D: T1-weighted enhanced magnetic resonance imaging confirmed two of the multiple intrahepatic foci, contrast enhancement in the arterial phase (arrow), and relatively low signal in the portal phase (arrow); E: Macroscopic findings of the tumor showed the major lesion accompanied by multiple subfoci; F: Microscopic diagnosis showed moderately differentiated hepatocellular carcinoma with microvascular tumor thrombus and negative surgical margins (magnification, 40 ×).

FINAL DIAGNOSIS

Case 1

HCC with multiple intrahepatic metastasis, hepatitis B virus infection.

Case 2

HCC with multiple intrahepatic foci, tumor thrombus formation in the left branch of the portal vein, liver cirrhosis, splenomegaly.

TREATMENT

Case 1

After excluding contraindications, radiofrequency ablation of intrahepatic lesions was performed on February 18, 2021. A Cool-Tip needle was punctured into 4 nodules in the liver (two in liver S4, one S4/8, and one S6) and continuous ablated for 7 minutes (power 150 W), stopped radiofrequency ablation, and ablated the needle tract when met hyperechoic covering mass. On February 25, 2021, resection of the main lesion of HCC was performed under general anesthesia. The pathological dissection showed that the major lesion was single with a size of 5.5 cm × 4.5 cm × 6 cm, surrounded by 5 satellite lesions (with a diameter of 0.3 cm-1 cm). Postoperative pathological diagnosis is moderately differentiated HCC with negative surgical margins (Figure 1E and F).

The patient's liver function recovered after postoperative reexamination and preventive TACE treatment was subsequently performed twice on March 8, 2021 and April 13, 2021, respectively. After angiography, microcatheter superselection was used to perform TACE on the tumor supplying artery and its branches, and chemotherapy (150 mg oxaliplatin, 4 mg raltitrexed, 30 mg epirubicin), 5 mL iodized oil suspoemulsion, and appropriate amount of polyvinyl alcohol particles (diameter 100-300 um) for embolization were injected through the catheter until the tumor staining disappeared after re-contrasted imaging. During the treatment, the patient had no obvious adverse reactions except for mild fever. Two weeks after surgery (March 8, 2021), the patient received PD-1 immunization (sintilimab injection) every 3 weeks, combined with TKIs via oral lenvatinib.

Case 2

Left hepatectomy palliative surgery for liver cancer including resection of the middle hepatic vein was performed on December 13, 2021 after excluding contraindications. Pathological dissection showed that the main lesion was solitary, with a size of 20 cm × 15 cm × 3.5 cm, accompanied by multiple subfocal lesions with microvascular tumor thrombus more than 5 foci. The postoperative pathological diagnosis was moderately differentiated HCC, with negative surgical margins (Figure 2E and F).

The patient recovered and began to take a long-term oral lenvatinib therapy 2 weeks later after the operation. After a month, the patient changed to regorafenib due to skin rash and new focal HCC recurrence mainly in caudate lobe and multiple intrahepatic foci in right liver (Figure 3). On January 24, March 10, May 20 in 2022, TACE was performed respectively with 150 mg oxaliplatin chemotherapy perfusion through microcatheter, followed by chemoembolization with 10 mg of idarubicin, 3 mL of liquefied lipiodol suspension emulsion, and an appropriate amount of 300-500 μm micron Meriton blank microspheres and gelatin sponge for embolism until the tumor staining disappeared in the postoperative angiography. During treatment period, the patient had no obvious adverse reactions except for mild fever. 6 months later after surgery, the liver enhancement CT scan revealed normal changes after resection of left hemi-hepatectomy, lipiodol deposition in the liver lesions, and no indication of tumor activity in the right liver. While the MRI imaging showed local slight tumor enhancement in the caudate lobe of the liver suspected, which might be concerned with tumor activity. Subsequently, an additional TACE was performed on July 21, 2022 despite that the patient's tumor biomarker of serum AFP and DCP levels had returned to the baseline.

Figure 3 Post-operative magnetic resonance imaging of case 2 (1-month). A-C: T1-weighted enhanced magnetic resonance imaging (MRI) indicated new focal hepatocellular carcinoma recurrence in the caudate lobe, which revealed a high signal in diffusion-weighted imaging, contrast enhancement in the arterial phase and relatively lower signal in the portal phase; D-F: T1-weighted enhanced MRI revealed multiple intrahepatic foci in the remaining right liver, with a high signal in diffusion-weighted imaging, contrast enhancement in the arterial phase and relatively lower signal in the hepatobiliary phase.

OUTCOME AND FOLLOW-UP

Case 1

The patient was re-examined with serial AFP and DCP every month and Liver contrast-enhanced CT scan or MRI every 3 months after surgery. The contrast-enhanced MRI of the liver did not indicate tumor recurrence until 11 months since the hepatectomy surgery. Liver contrast-enhanced MRI was performed when blood sampling showed an increase in DCP to 300 mAU/mL after 12 months of the operation (March 20, 2022) and discovered a new intrahepatic focus in S2 Lobe (0.9 cm × 0.8 cm), suggesting HCC recurrence. On March 25, 2022, radiofrequency ablation of the S2 focus of the liver was performed. During follow-up until December 25, 2022, no tumor recurrence was indicated based on serum AFP and DCP levels combined with enhanced MRI of the liver.

Case 2

After the operation, serum AFP and DCP were rechecked monthly and Liver contrast-enhanced CT scan or MRI performed every 3 months. According to the results of AFP, DCP and MRI manifestations, since the 6^th month after surgery, the activity of the patient's intrahepatic lesions had been basically controlled (Figure 4). Date to the follow-up ended on May 26, 2023, no new intrahepatic lesions or distant metastasis was detected again, and the caudate lobe lesions shrunk completely to CR according to enhanced MRI of the liver, accompanied by the continuous control of the serum AFP and DCP levels at the baseline.

Figure 4 Post-operative magnetic resonance imaging of case 2 (6 months). A: Diffusion-weighted phase revealed no obvious tumor activity in the residual liver; B and C: T1-weighted enhanced magnetic resonance imaging showed extensive tumor necrosis in the caudate lobe, and local slight enhancement around the tumor showing high signal in arterial phase and venous phase; D: Coronal delayed phase confirmed extensive tumor necrosis in the caudate lobe with marginal local slight enhancement (arrow) and no tumor activity in the remaining right liver.

DISCUSSION

Based on the current consensus guidelines[14-17] for the diagnosis and treatment of liver cancer, the first-line treatment for unresectable HCC is usually TACE, radiofrequency and targeted- or immune therapy, such as sorafenib, lenvatinib, atezolizumab -bevacizumab or durvalumab-tremelimumab, etc., while the second-line drugs, including regorafenib, cabozantinib, and tislelizumab injection are used if the tumor progresses during first line treatment. At present, the commonly used TKIs or ICIs themselves are only about 20% effective, and the combination of ICIs and targeted drugs can partially improve the treatment efficiency of HCC[13,17,18]. In previous studies, direct surgery is usually not particularly recommended or controversial for HCC with more than 4 intrahepatic lesions[19,20], and TACE combined with other comprehensive treatments is usually first-line recommended[8,21]. However, based on the advantages of combined targeted and immunotherapy in the new era, we chose these 2 patients with excessive tumor burden and high risk of metastasis, performed palliative resection of the main HCC lesion plus TACE, radiofrequency ablation combined with targeted and immunotherapy, thus successfully achieved the goal of eradicating HCC in imaging. Through reasonable case screening, for those patients with excessive tumor burden and high risk of metastasis, this treatment strategy, which mainly relies on palliative surgical resection and supplemented by other comprehensive treatments, may provide a new option for some selected patients with unresectable HCC.

As the first-line treatment of the advanced HCC currently, TACE could significantly prolong the patients’ overall survival time with its advantage in controlling tumor progression and preventing tumor recurrence[7,19]. Pembrolizumab, which is the first PD-1 inhibitor included in the HCC treatment guidelines, had a significant therapeutic effect on some HCC but at a high cost[22]. In recent years, a variety of low-cost PD-1 inhibitor have been developed in China with similar efficacy[23-25]. Two patients in this study selected the relatively cheaper PD-1 inhibitor sintilimab injection combined with lenvatinib for targeted therapy. Relevant studies have confirmed that combined TACE with immunotherapy drugs play a synergistic anti-tumor effect compared with TACE alone. In the procedure of Conversion Therapy for unresectable HCC, TACE could cause tumor ischemia and necrosis by embolizing tumor blood vessels, and utilize the toxicity of chemotherapy drugs to kill tumor cells, while Sintilimab injection induced tumor cell apoptosis by sensitizing endogenous anti-tumor T cell responses[19,23,26]. In this study, these two patients underwent early preventive TACE assistance after palliative surgery of HCC in a month, combined with targeted and immune therapy, and both patients achieved successful tumor CR in the subsequent follow-up imaging features.

Nowadays, there is still no clear standard for how to best evaluate the efficacy of conversion therapy, and imaging response evaluation criteria in solid tumors (RECIST) and modified RECIST (mRECIST) criteria are commonly used for evaluation[27,28]. Compared with the RECIST, mRECIST criteria focuses more on the blood supply of tumors, which is beneficial for displaying tumor active ingredients and more accurate in reflecting the therapeutic effect[29]. Therefore, in this study, following with TACE and the other comprehensive therapies on postoperative patients for HCC, we selected the mRECIST criteria to evaluate the therapeutic efficacy. During the follow-up process until tumor recurrence, both patients were observed that the serum AFP and DCP decreased to baseline levels, and finally achieved imaging CR for HCC for 11 and 10 months separately. This study proved that mRECIST criteria could be effective in assessing the effect of Conversion Therapy for HCC, however, if combined with tumor biomarkers and pathological biopsy results, the accuracy of evaluation on therapeutic effect could be further improved, which needs to be confirmed by further large-scale research.

Concerning the palliative surgery for HCC, based on the multiple intrahepatic lesions and high risk of tumor dissemination during the removal of the main liver cancer lesion, open surgery may be relatively safer[30]. Although some studies have shown that laparoscopic hepatectomy for HCC is superior to open hepatectomy in terms of surgical effect and hospital stay, which also reduces the difficulty for reoperation and the incidence of reoperation complications after tumor recurrence, and does not affect the long-term survival of patients[30-33]. However, these findings are more suitable for simple or selected patients with cirrhosis undergoing major hepatectomy in laparoscopic surgery, rather than the complicated surgical resection of those huge liver cancers with strict requirements for incisal margins[30].

In this study, considering the difficulty in surgical negative incisal margins for the palliative surgery of HCC, one case with a tumor size greater than 18 cm, and the other with multiple sub-foci around the main lesion, making it difficult to ensure the resection margins negative, thus forcible laparoscopy surgery may increase the risk of metastasis and the incidence of surgical complications. Therefore, on the basis of the patient's surgical safety, we ultimately chose open hepatectomy surgery. However, it is not inaccessible or impossible to perform palliative surgery with laparoscopy if reasonable patient screening, sufficient surgical experience, skilled surgical techniques and precise tumor localization are available. We performed left hemi-hepatectomy for the second patient which did not involve the resection of the caudate lobe in order to preserve the remnant liver volume as much as possible. However, we suffered with early tumor recurrence that mainly located in the caudate lobe, which could not rule out the possibility of tumor cell dissemination in the portal vein tumor thrombus during the surgery. Subsequently, after multiple times of TACE, the tumor was basically controlled, which indicated that for patients with HCC invading the left branch of the portal vein, left hemi-hepatectomy combined with resection of the caudate lobe could effectively improve the prognosis and reduce the risk of recurrence if the residual liver volume and function permitted.

Nevertheless, liver transplantation is currently the treatment of choice for unresectable HCC which confined to the liver without distant metastasis or extrahepatic vascular invasion[34,35]. The prognosis of liver transplantation is better than resection because it could cure patients along with liver cirrhosis completely. However, considering the high risk of late recurrence and shortage of donor livers, if we could identified those unresectable HCC patients sensitive to conversion therapy and achieve effective decline in liver cancer during the waiting period of the donor liver by receiving a reasonable comprehensive treatment strategy[36], it could be expected to improve the prognosis of liver transplantation effectively, thus achieving the longer tumor-free survival. These two patients were mainly treated with palliative surgery, supplemented by a comprehensive strategy of TACE and radiofrequency (+/-) combined with targeted and immunotherapy, which effectively obtained the imaging CR that conformed to the mRECIST criteria, and both the serum AFP and DCP decreased to the baseline during the follow-up. This study provides a new selective treatment strategy for patients with HCC waiting for liver transplantation. We demonstrated that for some HCC patients with high risk of tumor overload and metastasis, the combination of palliative surgery and conversion therapy could benefit those initially unresectable HCC patients from the palliative resection, which prolonged the waiting time for transplantation and was expected to improve the prognosis of HCC significantly. However, this new treatment strategy requires appropriate patient screening criteria effectively, and the positive role of palliative surgery in the treatment of advanced HCC still needs to be confirmed through further large sample studies.

CONCLUSION

These two cases indicate that for some selected advanced HCC with a high risk of tumor overload and metastasis, if the liver function permits, early palliative surgery combined with local subsequent TACE, along with targeted and immunotherapy, may be a tolerable and effective strategy, which can provide the opportunity for ultimate cure for the initially unresectable HCC and effectively improve the long-term survival. However, the screening criteria for selected patients and the positive role of palliative surgery in the conversion therapy of unresectable HCC still need to be further confirmed by subsequent large sample studies.