Management of hepatocellular carcinoma with portal vein tumor thrombus: new evidence and perspectives
Hepatocellular carcinoma ( HCC ) is responsible for over 600,000 deaths annually. In addition, hepatocellular carcinoma is characterized by its propensity to invade the liver vasculature.
Macrovascular invasion (MVI) is one of the two types of invasion of the hepatic vasculature. MVI is gross invasion into the main portal veins or their branches, hepatic veins or their branches, or the inferior vena cava in the liver. Of these, portal vein tumor thrombosis ( PVTT ) is the most common form of MVI of hepatocellular carcinoma.
It is reported that approximately 10% to 60% patients with hepatocellular carcinoma have PVTT at the time of diagnosis.
Patients with hepatocellular carcinoma in the presence of PVTT have much poorer prognoses than those without PVTT. The reported overall survival rates have ranged from only 2 to 4 months after supportive care.
Clinically, hepatocellular carcinoma with PVTT is associated with large tumor size, greater tumor number, poorer tumor grade, worse liver function and higher serum alpha-fetoprotein.
Combined effects by many factors will lead to poor prognosis of HCC patients with PVTT, such as impaired liver function, intrinsic aggressiveness of hepatocellular carcinoma, reduced intolerance to anti-neoplastic treatment and a high rate of developing complications related to portal hypertension.
In regards to initial treatment, some official guidelines consider the presence of PVTT as a contraindication of hepatic resection or transarterial chemoembolization ( TACE ).
These guidelines recommend Sorafenib ( Nexavar ) for patients with PVTT.
However, other official guidelines consider hepatic resection or TACE as a choice of treatment for HCC patients with PVTT.
In recent decades, some new concepts in the management of hepatocellular carcinoma with PVTT have emerged.
Monotherapy modality and prognosis
A) TACE or transarterial chemotherapy ( TAC ) - TACE is a standard treatment for patients with unresectable hepatocellular carcinoma. However, TACE has been contraindicated for the treatment of patients with hepatocellular carcinoma and PVTT involving the main trunk or a first-order left or right branch of the portal vein because of the potential risk of hepatic insufficiency resulting from ischemia after TACE. In 1997, Lee and coworkers reported that TACE could be safely performed in hepatocellular carcinoma with main trunk PVTT.
However, no statistical survival benefit of TACE was detected. Since then, more and more studies have explored the role of TACE/TAC for hepatocellular carcinoma with PVTT.
The majority of studies have used TACE, rather than TAC. In addition, most studies have not reported complications and mortality. The median survival time reported is 9 ( 4 to 16 ) months, and the median 1-, 2- and 3-year overall survival rates are 48%, 32% and 18%, respectively.
Some studies have compared the efficacy of hepatic resection to TACE/TAC.
The study by Liu and coworkers included 247 HCC patients with PVTT who underwent hepatic resection and 181 who underwent TACE. The estimated 1-, 3- and 5-year overall survival rates were 85%, 68% and 61% and 60%, 42% and 33%, respectively ( p less than 0.001 ). In the propensity model, the overall survival benefit of hepatic resection remained significant. In addition, patients receiving TACE had a 2.044-fold increased risk of mortality compared with patients receiving hepatic resection.
In another study by Peng and coworkers, the 1-, 3- and 5-year overall survival rates of the hepatic resection and TACE groups were 42.0%, 14.1% and 11.1% and 37.8%, 7.3% and 0.5%, respectively ( p less than 0.001 ). On subgroup analyses, the overall survival rates of the hepatic resection group were better than those of the TACE group for type I PVTT and type II PVTT ( all p less than 0.05 ), but not for type III PVTT or type IV PVTT ( all P less than 0.05 ).
The third study also found TACE was associated with worse overall survival than hepatic resection for hepatocellular carcinoma with PVTT.
In general, TACE is an option for patients with hepatocellular carcinoma and PVTT, and especially for those with a type III PVTT or a type IV PVTT. However, compared with TACE, hepatic resection provides survival benefits for selected patients with resectable hepatocellular carcinoma with PVTT and preserved liver function.
B) Radiotherapy - Some decades ago, conventional radiotherapy was not recommended for patients with hepatocellular carcinoma with or without PVTT because the lack of precise localized radiotherapy may have led to liver damage or even liver failure.
The preliminary study in which radiotherapy was used to treat hepatocellular carcinoma with PVTT was reported by Chen and coworkers in 1994. In that study, radiotherapy was demonstrated as safe, but lacked significant efficacy.
Many other studies appeared after 2000.
With the development of radiotherapy technology, three-dimensional conformal radiotherapy ( 3D-CRT ) gradually became a clinical frequently-used radiotherapy strategy with low radiotoxicity.
Other radiotherapy methods currently in use include proton beam therapy, intensity-modulated radiotherapy and stereotactic radiotherapy.
Bae and coworkers reported the results of their study of 47 patients with hepatocellular carcinoma and PVTT following 3D-CRT. The median survival time was 8 months, with a 1-year survival rate of 15% and a response rate of 40%.
Rim and coworkers reported that 3D-CRT was associated with 6.7% complete remission rate, 55.6% partial response rate, 31% stable disease rate and 6.7% progressive disease rate.
Other similar studies have also suggested that radiotherapy could improve overall survival in HCC patients with PVTT and proposed it as feasible and safe for these patients.
Though these small studies have suggested that such patients can benefit from liver-directed radiotherapy, strong evidence of efficacy is still lacking.
Im et al. published a large multicenter study investigating the outcomes of radiotherapy in 985 patients with hepatocellular carcinoma and PVTT in the main trunk and/or first branch. The response rate of PVTT was 51.8%, and the median overall survival time was 10.2 months.
Therefore, modern radiotherapy should be an option for patients with unresectable hepatocellular carcinoma and PVTT.
C) Radioembolization with Yttrium-90 - Radioembolization is a transarterial form of brachytherapy in which intra-arterially injected Yttrium-90-loaded microspheres serve as a source for internal radiation purposes.
Transarterial radioembolization with Yttrium-90 is a novel therapy for hepatocellular carcinoma with PVTT.
In 2015 and 2016, six comparative or cohort studies investigating the role of radioembolization with Yttrium-90 for hepatocellular carcinoma with PVTT were reported.
The median reported survival time was 8 ( 3 to 18 ) months. The median reported 1-, 2- and 3-year overall survival rates were 38%, 26% and 14%, respectively.
A systematic review was published that included fourteen clinical studies and three abstracts, involving 722 patients with hepatocellular carcinoma and PVTT. The median time to progression was 5.6 months, and median disease control rate was 74.3%. The median reported value of patients with complete response, partial response and stable disease were 3.2%, 16.5% and 31.3%, respectively. The median survival time was 9.7 months. The common toxicities were fatigue, nausea / vomiting and abdominal pain; most of these, however, did not require medical intervention.
Therefore, radioembolization with Yttrium-90 may be a safe and effective treatment for hepatocellular carcinoma with PVTT.
It is important to note, however, that the current data are all based on retrospective studies or non-controlled prospective studies, and evidence from randomized controlled trials with large sample size is still needed.
D) Sorafenib - After publication of the two alleged positive trials of Sorafenib in patients with advanced hepatocellular carcinoma, the safety and efficacy profiles of Sorafenib were explored for patients with hepatocellular carcinoma and PVTT.
In the study by Jeong and coworkers, the median overall survival of the 30 patients with hepatocellular carcinoma and PVTT ( Vp3 or Vp4 ) after Sorafenib monotherapy was only 3.1 months.
Giorgio and coworkers performed a randomized controlled trial in 99 cirrhotic patients with hepatocellular carcinoma and PVTT treated with Sorafenib plus radiofrequency ablation or Sorafenib alone. The 1-, 2- and 3-year overall survival rates were 60%, 35% and 26% and 37%, 0% and 0%, respectively.
In the study by Nakazawa and coworkers, patients with hepatocellular carcinoma and PVTT in the main trunk or the first branch had similar median survival time after Sorafenib ( 4.3 months ) or radiotherapy ( 5.9 months; p = 0.115 ).
However, better median survival time was noted in the radiotherapy group than in the Sorafenib group after propensity score matching ( 10.9 vs. 4.8 months; p = 0.025 ).
The study by Song and coworkers compared the efficacy of TAC to Sorafenib in HCC patients with PVTT. The disease control rate in the TAC group was significantly higher than that in the Sorafenib group ( p less than 0.001 ). The median overall survival was also significantly longer in the TAC group than in the Sorafenib group ( 7.1 vs. 5.5 months; p = 0.011 ).
The fifth study compared the efficacy of Sorafenib plus TACE to Sorafenib alone for hepatocellular carcinoma with main PVTT. The disease control rate was similar between the two groups, and the median overall survival was 7.0 and 6.0 months for the Sorafenib-TACE group and the Sorafenib group, respectively ( p = 0.544 ).
In general, the efficacy of Sorafenib monotherapy is inferior to other monotherapy or combined treatments. These results lead us to question the wisdom of palliative Sorafenib therapy for patients with hepatocellular carcinoma and PVTT.
The greatest survival benefit of such therapy appears to be less than 3 months. This slim benefit seems negligible in comparison to the prohibitive cost of Sorafenib and risk of adverse effects.
E) Hepatic resection - Three decades ago, only studies from Eastern countries reported the role of hepatic resection for hepatocellular carcinoma with PVTT.
In the 1980s, hepatic resection was an option only for patients with a tumor thrombus in a first-order branch of the portal vein, particularly not involving the confluence of the left and right portal veins.
Some years later, however, the role of hepatic resection for tumor thrombus extending to the main portal trunk was reported.
Since then, hepatic resection with or without thrombectomy for hepatocellular carcinoma with PVTT has gradually been refined and standardized to become a commonly used procedure currently, especially in Asian liver centers.
Though the role of hepatic resection for hepatocellular carcinoma with PVTT is still controversial and not recommended by Western official guidelines, more and more comparative or cohort studies, mostly from Asian countries, have demonstrated hepatic resection to be safe and effective for selected patients with hepatocellular carcinoma and PVTT. Most patients in those studies have been Asian.
The median reported postoperative complication and mortality rates are 26% ( range, 3–42% ) and 4.1% ( range, 0–23.7% ), respectively.
The median reported survival time is 25.4 ( 8 to 64 ) months, and the median 1-, 2- and 3-year overall survival rates are 62%, 52% and 41%, respectively.
From the 18th follow-up survey of primary liver cancer in Japan, which encompassed 1021 patients who underwent Vp3 or Vp4 hepatic resection, the Liver Cancer Study Group of Japan reported a survival rate of 18.3% at 5 years.
Systematic review of 24 studies involving 4389 patients with hepatocellular carcinoma with MVI showed that hepatic resection was associated with median mortality of 2.7% ( range, 0–24% ) and median overall survival ranging from 18% at 5 years to 50% at 1 year.
A new large retrospective study from Japan compared overall survival of 2093 HCC patients with PVTT who underwent hepatic resection and 4381 patients who received other treatments. The median overall survival lengths of the two groups were 2.87 and 1.10 years ( p less 0.001 ), respectively. However, hepatic resection showed no overall survival benefit among patients in whom PVTT affected the main trunk or contralateral branch ( Vp3 or Vp4 ).
These results argue for expanding treatment strategy in official guidelines to recognize hepatic resection as a first-line therapeutic option for selected patients with hepatocellular carcinoma and PVTT and preserved liver function, especially for those with type I or II ( or Vp0-Vp3 ) PVTT.
Surgeons should consider hepatic resection when it is feasible, although they should be prepared for the fact that the procedure is technically demanding.
Multimodality treatment and prognosis
a) Surgical multimodality treatment - Hepatocellular carcinoma is a complex disease. Though hepatic resection appears to provide better outcomes than TACE/TAC, radiotherapy, radioembolization with Yttrium-90, Sorafenib or nonsurgical multimodality treatment for selected patients with hepatocellular carcinoma and PVTT, the long-term overall survival after hepatic resection is still unsatisfactory because of the high rate of tumor recurrence or low rate of disease-free survival.
Surgical multimodality treatment is now being recommended by more and more liver centers in Eastern and Western countries.
On one hand, hepatic resection will eliminate the original tumor nodule and PVTT; on the other hand, eliminating the PVTT will improve liver function, consequently making a foundation for further treatment.
Li and coworkers compared outcomes of 45 patients with hepatocellular carcinoma and main PVTT who underwent neoadjuvant 3D-CRT plus hepatic resection and 50 patients who received hepatic resection alone. They found that neoadjuvant 3D-CRT plus resection significantly decreased the rates of HCC recurrence and HCC-related death, with hazard ratios of 0.36 and 0.32, respectively.
In addition, adjuvant TACE or TAC may also a choice of treatment. Collectively, the available evidence indicates that surgery-based interdisciplinary therapy is effective and should be explored in future studies.
b) Nonsurgical multimodality treatment - Though nonsurgical multimodality treatments are palliative, they have the characteristics of less trauma, low risk of mortality and rapid recovery.
Nonsurgical multimodality treatments are clearly essential for the management of hepatocellular carcinoma and are of particularly high value in cases of hepatocellular carcinoma with PVTT.
Many nonsurgical multimodality treatment types have been reported, such as Sorafenib combined radiofrequency ablation, Sorafenib combined TACE/TAC, radiotherapy combined with TACE or TACE combined with radiotherapy, TACE plus microwave or ethanol ablation, etc.
Among these, TACE combined with radiotherapy is the most used treatment.
Because of the heterogeneity of the included patients, however, it is hard to compare the efficacy of different nonsurgical multimodality treatment type.
Hepatic resection to treat hepatocellular carcinoma is associated with the best outcomes when the patient has early or intermediate stage disease and preserved liver function.
For most HCC patients with Vp1-3 PVTT and preserved liver function, hepatic resection may also be the first-line therapy.
However, no curative treatment is currently available for hepatocellular carcinoma with Vp4 PVTT.
Currently, findings from various and worldwide studies suggest that hepatectomy-based multiple interdisciplinary treatments are effective options for many patients with hepatocellular carcinoma and PVTT, as long as preserved liver function is adequate.
The optimal timing and details of neoadjuvant or adjuvant treatments combined with hepatectomy in patients with hepatocellular carcinoma and PVTT remains an interesting topic for future research.
In the research field, there remains a need for better focusing on selection criteria to further enhance the prognostic benefits of resection.
Nonetheless, for patients with unresectable hepatocellular carcinoma and PVTT, TACE/TAC, radiotherapy or radioembolization with Yttrium-90 should be considered. ( Xagena )
Jun Yin et al, J Clin Transl Hepatol 2017; 5: 169–176
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