Liver cancer is the second leading cause of cancer death in men, with about half of liver cancers occurring in China.
Hepatocellular carcinoma (HCC) is the most common type of liver cancer, and HCC prefers to invade the portal vein system and form a portal vein carcinoma suppository (PVTT). According to statistics, about 10%-40% of HCC patients have already developed PVTT at the time of diagnosis, which means that their prognosis is very poor.
PVTT can not only accelerate the occurrence of intrahepatic and extrahepatic metastasis of tumors, but also lead to portal hypertension, and even cause serious adverse events such as rupture of variceal veins in the esophagus and gastric floor. Treatment at this stage is very difficult, and if treatment is abandoned, the patient's life enters the countdown, leaving only 2.7 to 4.0 months of survival [1].
Oral sorafenib is one of the first-line treatments for HCC patients with PVTT, but its therapeutic effect is also greatly reduced in patients with severe PVTT [2-3]. According to Japanese and Chinese guidelines, hepatic artery perfusion chemotherapy (HAIC) is recommended for HCC patients with PVTT, particularly those with severe PVTT [4-5]. So, will the addition of HAIC to sorafenib therapy further improve the prognosis of HCC patients with PVTT?
Recently, a randomized controlled trial led by Professor Wang Xiaodong of Peking University Cancer Hospital published in the prestigious journal Radiology revealed the answer to this question.
Their findings show that a two-pronged approach to sorafenib and HAIC can extend the overall survival of patients by nearly 10 months, reducing the risk of disease progression by 74% and the risk of death by 72%. Treatment of patients with liver cancer with PVTT may be at dawn [9].
Screenshot of the first page of the paper
The trial was an open-label, phase II, single-center trial that included 64 patients aged 18 to 75 with advanced HCC. None of these patients had a surgical opportunity and had severe PVTT, including portal vein trunk (Vp4) and first branch (Vp3) carcinoma thrombosis.
In addition, they had not previously received intraarterial therapy, systemic chemotherapy, or other systemic therapy, had liver function grades of Child-Pugh A, a physical status score of 0-2, and a life expectancy of 2 months or more, and assessed organ function adequacy based on blood routine and biochemical indicators.
The researchers stratified all patients according to the level of portal vein invasion and randomly divided them into the sorafenib group and the sorafenib + HAIC group, with baseline feature balance in both groups. It should be noted that in order to prevent repeated catheterization from affecting patient compliance with HAIC, the sorafenib +HAIC group used a standardized percutaneous catheter system.
Research flowcharts
Every 4 weeks is a treatment cycle, and both groups of patients take oral sorafenib (400 mg twice/day). On the basis of oral sorafenib + HAIC, the HAIC regimen was added: on the first to third day of each cycle, oxaliplatin (35 mg/㎡) was infused at 0-2 hours, 5-FU (600 mg/㎡) was infused at 2-24 hours, starting from 5-FU infusion, and daily intravenous infusion of calcium folinate (200 mg/㎡) was given for two hours. One HAIC treatment lasts for 3 days and ISIC treatment is given every 4 weeks. These patients receive up to 6 times of HAIC treatment, followed by treatment with sorafenib. Within 3 days of carrying out HAIC treatment, the dose of sorafenib is reduced to 200 mg BID.
The researchers gave all patients abdominal CT or MRI enhancement scans every 2 months, as well as chest X-rays, until the disease progressed. Liver and kidney function and blood routine tests are performed on days 7 and 27 of each cycle. Alpha-fetoprotein levels are measured every 4 weeks during treatment and every 8 weeks after discontinuation or after treatment. Patients are followed up every 3 months after the study is terminated or the study is completed. The primary endpoints of the study were overall survival (OS), with secondary endpoints including objective response rate (ORR), progression-free survival (PFS), and safety.
The test results showed that the median OS of the Sorafenib +HAIC group and the sorafenib group alone was 16.3 months and 6.5 months (HR=0.28, P<0.001), and the median PFS was 9.0 months and 2.5 months (HR=0.26, P<0.001), respectively. That is, patients treated with sorafenib + HAIC had a 72 percent lower risk of death and a 74 percent lower risk of disease progression.
In addition, the ORR in the sorafenib + HAIC group was nearly 12 times that of the sorafenib group alone (41% vs 3%, P<0.001), and 5 patients in the sorafenib combined HAIC group achieved complete remission.
Overall survival (OS) of patients with invasion of the first portal vein branch (B) or portal vein trunk (C) in the intended treatment population (A)
After stratification by portal vein infiltration level, the researchers found that both patients with a classification of Vp3 or Vp4 achieved a longer median OS (Vp3: 16.3 month vs 5.5 months, HR= 0.35; Vp4: 13.6 months vs 6.5 months, HR = 0.27) and PFS (Vp3: 9.September vs 2.5 months, HR = 0.34; Vp4: 6.August vs 2.5 months, HR = HR= 0.34) compared with the sorafenib group 0.26）。
It can be seen that the combination of the two methods can significantly prolong the survival time of patients, better control disease progression, and patients have more opportunities to obtain objective remission of the disease. The grading of PVTT does not affect the effectiveness of combination therapy.
Progression-free survival (PFS) in patients with portal vein first invasion (B) or portal trunk invasion (C) in population intended for treatment (A)
So, will the results change depending on the patient's condition? In other words, was the positive result robust in different subgroups?
The researchers then conducted a subgroup analysis of the patients' OS-related factors, and the results showed that sorafenibal HAIC was almost always more beneficial than sorafenib alone. However, in patients with extrahepatic dissemination, the USE of sorafenib alone is longer (HR = 1.4).
In terms of safety, the overall incidence of adverse events in the Sorafenib +HAIC group and the Sorafenib group was similar (91% vs 88%), but grade 3 or 4 adverse events were more common in the Sorafenib + HAIC group (59% vs 25%), with no treatment-related deaths occurring.
The forest plot shows OS-related factors in patients receiving sorafenib alone or in combination with SORAFENIB in combination with HAIC
Overall, this study shows that in patients with HCC with PVTT (Vp3 or Vp4), the combination of sorafenib and HAIC can achieve better treatment results than sorafenib alone. Not only did the patient's overall survival and progression-free survival increase, but the objective response rate was also significantly improved. The safety of both is comparable, and the adverse events are controllable.
Based on two major trials, SHARP and Asia-Pacific trials, sorafenib became the standard treatment regimen for advanced HCC. However, in the SHARP study, the median OS of HCC patients with PVTT was only 8.1 months. In addition, updated data from the IMbrave150 study showed that the median OS for the treatment of such patients by the targeted immunity combination regimen of bevacizumab and altelizumab was only 7.6 months.
To date, only three randomized controlled trials have compared the survival benefits of SORAFENICA HAIC with sorafenib alone, with two positive and one negative results, respectively [6-8]. The study also further demonstrates the efficacy and safety of sorafenib in combination with HAIC in patients with BCLC-C HCC combined with PVTT, but more randomized controlled trials are needed to validate the findings.
As for why the trial achieved good results for OS up to 16.3 months, the researchers believe that there is a potential synergy between HAIC and sorafenib.
It is well known that RAF1 is one of the therapeutic targets of sorafenib, and the inhibition of RAF1 by sorafenib can induce apoptosis of cancer cells, thereby improving patient resistance to oxaliplatin and 5-FU. At the same time, HAIC treatment can shrink the tumor in time, increasing the patient's tolerance to sorafenib. The two treatments complement each other, prolonging the treatment time and the natural results are better. Finally, good treatment results also give more patients the opportunity to receive follow-up treatment. Because of this, the combination of sorafenib and HAIC can achieve a therapeutic effect of one plus one greater than two [9].
bibliography
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