**Title: Analysis of the Clinical Effects and Toxic Side Effects of Gamma Knife (γ-knife) and Transcatheter Arterial Chemoembolization (TACE) Treatment Sequence in Patients with Primary Liver Cancer Accompanied by Portal Vein Tumor Thrombosis**
**Authors:** Kang Jingbo, Nie Qing, Zhang Liping, Chi Jun, Li Chengming
**Department of Radiation Oncology, Navy General Hospital, Capital City, 100037**
**Abstract:**
Objective: To analyze the clinical effects and toxic side effects of different treatment sequences of γ-knife and transcatheter arterial chemoembolization (TACE) in patients with primary liver cancer accompanied by portal vein tumor thrombosis (PVTT).
Methods: From February 2004 to March 2008, 101 patients with primary liver cancer accompanied by PVTT were treated. Among them, 34 cases received γ-knife treatment first, followed by TACE; 37 cases received TACE first, followed by γ-knife; and 30 cases received only γ-knife treatment.
Results: Three months after treatment, the overall effective rate was 87.1% (88/101). For the group receiving only γ-knife treatment, the 1-year and 2-year local control rates were 43.3% (12/30) and 20.0% (6/30), respectively, with a median survival of 12 months. The 1-year and 2-year survival rates were 50.0% and 23.3%, respectively. For the group receiving γ-knife followed by TACE, the 1-year and 2-year local control rates were 55.9% (19/34) and 29.4% (10/34), respectively, with a median survival of 17 months. The 1-year and 2-year survival rates were 58.8% and 29.4%, respectively. For the group receiving TACE followed by γ-knife, the 1-year and 2-year local control rates were 51.4% (19/37) and 24.3% (9/37), respectively, with a median survival of 15 months. The 1-year and 2-year survival rates were 54.1% and 27.0%, respectively. One to three months after treatment, ultrasound examination showed that the effective rate of portal vein tumor thrombosis was 66.7% (20/30) for the γ-knife-only group, 73.5% (25/34) for the γ-knife followed by TACE group, and 70.3% (26/37) for the TACE followed by γ-knife group. Regarding changes in liver function grading one to three months after treatment, the deterioration rates were 30.0% (9/30) for the γ-knife-only group, 32.4% (12/34) for the γ-knife followed by TACE group, and 40.5% (15/37) for the TACE followed by γ-knife group. There was no significant difference in liver function deterioration between the γ-knife-only group and the γ-knife followed by TACE group, but there was a significant difference compared to the TACE followed by γ-knife group. No severe radiation complications were observed during follow-up.
Conclusion: Combining γ-knife with TACE is an effective local treatment method for primary liver cancer accompanied by PVTT. Performing TACE before γ-knife may have some impact on liver function.
**Keywords:** Primary liver cancer, Portal vein tumor thrombosis (PVTT), Gamma knife, Transcatheter arterial chemoembolization (TACE)
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**Main Text:**
Primary liver cancer accompanied by portal vein tumor thrombosis (PVTT) has an incidence rate of approximately 30-40%. It can lead to portal hypertension, intrahepatic dissemination, and pulmonary metastasis, resulting in poor prognosis. Few patients diagnosed with this condition have the opportunity for surgical resection. To explore treatment options for liver cancer with PVTT, from February 2004 to March 2008, our department treated some cases of PVTT-associated primary liver cancer patients with γ-knife treatment first, followed by TACE, while others received TACE first, followed by γ-knife treatment. Here, we analyze their treatment outcomes and toxic side effects.
### **1. Materials and Methods**
#### **1.1 Case Data**
From February 2004 to March 2008, 101 patients with PVTT-associated primary liver cancer were treated. Among them, there were 69 female and 32 male patients, aged between 19 and 79 years, with a median age of 53 years. Pathological diagnosis was confirmed in 76 cases, and 25 cases were diagnosed using PET-CT imaging and alpha-fetoprotein (AFP) tests. Among these, 34 cases received γ-knife treatment first, followed by TACE 2-3 weeks later; 37 cases received TACE first, followed by γ-knife treatment 2-3 weeks later; and 30 cases received only γ-knife treatment.
#### **1.2 Gamma Knife Treatment Method**
The equipment used was the OUR-QGD type stereotactic body γ-ray radiotherapy system. Patients were positioned either prone or supine on a 3D stereotactic frame, with vacuum compression bags placed inside the frame to immobilize the body. CT scans of the lesion were performed with a slice thickness of 3-5 mm. N-type scale values, repeat positioning scale values, and X, Y, Z coordinate parameters on the patient's surface landmarks were recorded and carefully verified. The obtained image data and related parameters were input into the treatment planning system for 3D reconstruction, delineation of the tumor target area, and planning of the treatment area. A dose of 50%-70% of the isodose curve surrounded the planned target area, with a dose of 2.8 Gy to 4.5 Gy per session. Treatment sessions ranged from 10 to 13, with a total radiation dose of 30.8 Gy to 49.5 Gy. Treatment was administered daily or every other day. All 101 patients received γ-knife treatment.
#### **1.3 Hepatic Arterial Chemoembolization Treatment Method**
Using the Seldinger technique, catheters were inserted via the femoral artery into the proper hepatic artery. After angiography, the catheter was super-selected into the tumor-feeding artery as close to the tumor as possible, and chemotherapy drugs and embolic agents were injected. Chemotherapy drugs included fluorouracil (600 mg to 1000 mg) and cisplatin (30 mg to 50 mg). Hydroxycamptothecin (20 mg) or epirubicin (40 mg to 60 mg) was mixed with 40% lipiodol (20 ml) to form an emulsion and injected into the hepatic artery for embolization. In the γ-knife followed by TACE group, 34 cases underwent biochemical blood tests and routine blood tests two weeks after γ-knife treatment. If the results were normal, TACE treatment was performed, with 25 cases undergoing a second TACE four weeks later. In the TACE followed by γ-knife group, 37 cases underwent 1-2 sessions of hepatic arterial chemoembolization, with 23 cases undergoing one session and 14 cases undergoing two sessions, spaced four weeks apart. Two to three weeks after the completion of TACE treatment, routine blood tests, liver function tests, and renal function tests were conducted. If the results were normal, γ-knife treatment was initiated. Sixteen cases underwent another session of hepatic arterial chemoembolization one month after γ-knife treatment.
#### **1.4 Observation Indicators**
Efficacy was evaluated every three months after radiotherapy. The evaluation criteria were as follows:
- Complete Response (CR): Total disappearance of the tumor for at least four weeks without new lesions.
- Partial Response (PR): Reduction in tumor size ≥50%, lasting at least four weeks without new lesions.
- No Change (NC): Tumor reduction <50% or increase ≤50%.
### **2. Results**
#### **2.1 AFP Improvement Rate**
Among the 37 cases in the TACE followed by γ-knife group, AFP improvement was observed in 26 cases, with an improvement rate of 70.2% (26/37).
#### **2.2 Local Control Rates and Survival Rates**
For the γ-knife-only group, the 1-year and 2-year local control rates were 43.3% (12/30) and 20.0% (6/30), respectively, with a median survival of 12 months. The 1-year and 2-year survival rates were 50.0% and 23.3%, respectively. For the γ-knife followed by TACE group, the 1-year and 2-year local control rates were 55.9% (19/34) and 32.4% (11/34), respectively, with a median survival of 17 months. The 1-year and 2-year survival rates were 58.8% and 29.4%, respectively. For the TACE followed by γ-knife group, the 1-year and 2-year local control rates were 48.6% (18/37) and 24.3% (9/37), respectively, with a median survival of 15 months. The 1-year and 2-year survival rates were 54.1% and 27.0%, respectively.
#### **2.3 Adverse Reactions**
During treatment, patients experienced varying degrees of fatigue, loss of appetite, nausea, etc. Fever occurred in 22 cases (temperature around 38°C), including 11 cases in the γ-knife-only group, 13 cases in the γ-knife followed by TACE group, and 15 cases in the TACE followed by γ-knife group. The incidence of Grade I + II chronic bone marrow suppression was 29.6% (9/30) in the γ-knife-only group, 41.2% (14/35) in the γ-knife followed by TACE group, and 45.9% (17/37) in the TACE followed by γ-knife group. Symptoms improved after symptomatic treatment. One to three months after treatment, changes in liver function grading were as follows: In the γ-knife-only group, 7 cases progressed from grade A to B, and 2 cases progressed from grade B to C, with a deterioration rate of 30.0% (9/30). In the γ-knife followed by TACE group, 8 cases progressed from grade A to B, 1 case progressed from grade A to C, and 2 cases progressed from grade B to C, with a deterioration rate of 32.4% (11/34). In the TACE followed by γ-knife group, 10 cases progressed from grade A to B, 3 cases progressed from grade A to C, and 2 cases progressed from grade B to C, with a deterioration rate of 40.5% (15/37). There was no significant difference in liver function changes between the γ-knife-only group and the γ-knife followed by TACE group, but a significant difference was observed when comparing the γ-knife-only group with the TACE followed by γ-knife group. No other serious complications were observed during follow-up.
### **3. Discussion**
Hepatic arterial chemoembolization (TACE) has become one of the main treatments for intermediate-stage liver cancer that cannot be surgically resected. However, for liver cancer accompanied by PVTT, portal vein obstruction or partial blockage may occur. If the hepatic artery is also embolized, the liver may become ischemic, leading to liver tissue necrosis or liver failure [1]. Therefore, there is some controversy regarding the use of TACE in patients with PVTT. Some scholars believe that TACE should not be used in such patients, while others [2] argue that it is safe if performed appropriately. In recent years, TACE treatment for PVTT-associated liver cancer has gradually developed. Izaki et al. [3] reported that among 10 patients with PVTT-associated liver cancer treated solely with TACE, the median survival time was 9.7 months, with cumulative 1-year, 2-year, and 3-year survival rates of 26.7%, 13.3%, and 13.3%, respectively, proving that TACE is effective and safe. The effectiveness of TACE is due to the fact that PVTT not only receives blood supply from the portal vein but also from the hepatic veins. Some studies [4] have shown that pathological examinations confirm that TACE treatment not only induces necrosis in liver cancer but also in PVTT. However, the short-term efficacy of TACE alone is still not ideal.
Conformal radiotherapy has shown certain effects in treating PVTT-associated liver cancer [5,6]. Wu Yanhua et al. [7] treated 94 patients with unresectable primary liver cancer (including 2 cases with portal vein tumor thrombosis) using a combination of TACE followed by 3D conformal radiotherapy (3DCRT), achieving satisfactory results. They suggested that comprehensive treatment shows better therapeutic effects in patients with portal vein tumor thrombosis and recommended active and comprehensive treatment strategies for such patients. Mianbiao et al. [8] reported that body stereotactic radiotherapy for PVTT-associated liver cancer resulted in a tumor thrombus regression rate of 62.8%.
To explore treatment options for PVTT-associated liver cancer, we treated some cases with γ-knife first, followed by TACE, while others received TACE first, followed by γ-knife. The results showed higher effectiveness, control rates, and survival rates compared to the γ-SBRT-only group, but the TACE followed by γ-knife group showed less benefit in terms of liver function compared to the SBRT-only group, indicating that TACE may have some impact on liver function in PVTT patients. Administering γ-knife treatment first to reduce PVTT and improve portal vein blood supply, followed by TACE, may both enhance efficacy and reduce complications.
The rationale for performing TACE first, followed by γ-knife, is based on the following [10]: Normal liver tissue receives 25%-30% of its blood supply from the hepatic artery. For patients with partial portal vein blockage, drugs administered during TACE can circulate back to the tumor thrombus, controlling and shrinking the tumor. Subsequent γ-knife treatment helps expand the target area, increase radiation dosage, enhance the therapeutic effect on the tumor, and reduce damage to surrounding normal liver tissue, further eliminating or suppressing residual cancer cells after TACE. Our results showed that liver function damage in the TACE followed by γ-knife group was significantly greater than in the γ-knife-only group, indicating that TACE has some impact on liver function.
Gamma knife is a special form of radiation therapy. Combining this method sequentially with TACE can produce synergistic effects, compensating for each other's shortcomings and achieving better results. The regression of PVTT in all three groups was similar, suggesting that the regression may primarily be due to the effects of the gamma knife.
In summary, the adverse reactions in the γ-knife-only group and the γ-knife combined with TACE group were relatively mild, with no significant differences in bone marrow suppression. Symptomatic treatment allowed all patients to complete the treatment process. The impact of TACE followed by γ-knife on liver function was more pronounced and requires close monitoring of relevant indicators and timely intervention.
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