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Corresponding author. Address: AP-HP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, service d’hépato-gastroentérologie, unité de soins intensifs d’hépatologie, Paris, France & Brain Liver Pitié-Salpêtrière (BLIPS) Study Group, INSERM UMR_S 938, Centre de recherche Saint-Antoine, Maladies métaboliques, biliaires et fibro-inflammatoire du foie, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France; Tel.:+33(0)1 42 17 57 55, fax: +33(0)1 42 16 11 06.
Sorbonne Université, AP-HP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Service d’hépato-gastroentérologie, Unité de Soins Intensifs d’hépatologie, Paris, FranceBrain Liver Pitié-Salpêtrière (BLIPS) Study Group, INSERM UMR_S 938, Centre de Recherche Saint-Antoine, Maladies Métaboliques, Biliaires et Fibro-inflammatoire du Foie, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
Portal hypertension (PHT) and hepatocellular carcinoma (HCC) often coexist, and their association impairs the prognosis of patients with cirrhosis. The interplay between these two conditions is of major therapeutic significance, both from the perspective of offering adequate treatment for HCC and for preventing or managing the complications of PHT. Recommendations on the management of PHT were heavily revised at the last Baveno VII conference, redefining screening and extending the indications for prophylaxis. PHT can preclude locoregional therapies, and TIPS placement can be discussed in patients with HCC. New systemic therapies for HCC can influence the level of PHT and favour bleeding. Complications of PHT should be prevented and treated adequately in all patients, especially those presenting with advanced HCC. Specific aspects of the management of both conditions will be discussed in the present expert opinion, which considers very recent data in the HCC field.
Portal hypertension (PHT) and hepatocellular carcinoma (HCC) are major complications of cirrhosis. The management of patients with PHT has dramatically improved, leading to better control of PHT and a significant increase in survival. This increase in survival has paralleled (and maybe partly explains) an increasing incidence of HCC in patients with PHT. Hence, PHT and HCC often coexist and must be managed together. During the last Baveno VII conference,
recommendations on the diagnosis and management of PHT were revised, extending indications for non-invasive screening of PHT, and for medical therapy. Meanwhile, new systemic treatments for HCC, which can influence PHT, are emerging rapidly. Hence, in this review, we will focus on the clinical management of PHT in patients with cirrhosis and HCC, in the era of Baveno VII and in the context of new systemic therapies for HCC.
Clinically significant portal hypertension (CSPH, defined as a hepatic venous pressure gradient [HVPG] >10 mmHg) is predictive of HCC occurrence independently of the severity of underlying cirrhosis.
The prevalence of PHT in patients with HCC depends on the severity of cirrhosis, and probably the stage of HCC. In patients with early-HCC, PHT ranged from 35% to 52%. In patients with advanced HCC, the presence of PHT is almost never stated in clinical trials.
However, its prevalence is probably higher than in resectable HCC, because of more severe liver disease and potential portal invasion. Of concern, the presence of HCC is independently associated with mortality in case of PHT-related bleeding.
A higher level of PHT could be the culprit here: indeed, HCC increases HVPG via arteriovenous shunting and modifications to liver architecture; moreover, HCC can be associated with vascular invasion of the portal vein and/or its branches and contributes to increased PHT. Hence, the evaluation of PHT in patients with HCC is mandatory to ensure that adequate prophylaxis for acute variceal bleeding (AVB) is provided.
Fig. 1Indications for screening and treatment of PHT in patients with cirrhosis with or without HCC in the era of Baveno VII.
(A) In patients with HCC: screening endoscopy is indicated in patients with LSM <25 kPa. Beta-blockers are to be prescribed to patients with LSM >25 kPa, in the absence of contra-indication/intolerance, without endoscopy. Endoscopy is indicated in patients with contra-indication/intolerance to beta-blockers and LSM >25 kPa. (B) In patients without HCC: CSPH can be ruled out in patients with LSM <15 kPa associated with platelet count >150,000/μl (“Favourable Baveno VII criteria”). Patients with favourable Baveno VI/VII criteria should be monitored by regular LSM and platelet assessment. Patients with LSM >25 kPa are at high probability of having CSPH (patients with alcohol-, metabolic- [except obese], or viral hepatitis-related cirrhosis): they should be treated with beta-blockers (carvedilol preferably), EV banding indications now being restricted to patients with intolerance/contra-indications to beta-blockers. Screening endoscopy is indicated in patients within the grey zone of LSM between 20-25 kPa, and below 20 kPa if platelet count is below 150,000/μl. CSPH, clinically significant portal hypertension; EV, oesophageal varice; HCC, hepatocellular carcinoma; LSM, liver stiffness measurement; PHT, portal hypertension.
Screening, surveillance and prophylaxis of PHT in the era of Baveno VII in patients with HCC (Fig. 1)
Until recently, screening of PHT in patients with cirrhosis (without HCC) paralleled the screening of high-risk varices, i.e. medium/large oesophageal varices (EVs).
Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
Upper endoscopy was indicated at the diagnosis of cirrhosis in all patients except those with favourable Baveno VI criteria (platelet count >150,000/μl and liver stiffness measurement [LSM] <20 kPa). A recent landmark trial showed that treating CSPH with beta-blockers significantly decreased the occurrence of decompensation (mainly ascites).
β blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial.
Thus, the Baveno VII consensus introduced the idea of targeting CSPH instead of varices, consequently dramatically decreasing the indications for upper endoscopy, and then starting primary prophylaxis with beta-blockers regardless of EV status. As HVPG is not performed in routine practice, LSM measurement (combined with platelet count) is now the tool of choice to rule in or rule out CSPH. Screening algorithms for CSPH and indications for endoscopy in patients without HCC are depicted in Fig. 1B. Regarding secondary prophylaxis after AVB, transjugular intrahepatic portosystemic shunt (TIPS) placement, in its preemptive indication, should be considered as soon as possible after AVB (within 72 h, but ideally within 24 h), in selected high-risk patients.
In this regard, the risk of false negatives when using Baveno VII criteria for the detection of high-risk EVs is very low. However, platelet levels may also be impacted (with an increase in their absolute number) by HCC,
leading to decreased sensitivity for the detection of high-risk EVs. Consequently, waiting for clinical studies, we do not think that Baveno VI and VII criteria are accurate to rule out high-risk EVs; hence, we think that screening endoscopy is indicated in patients with HCC, platelets >150,000/μl and LSM <15/20 kPa.
Question 2: Can we avoid upper endoscopy in patients with LSM >25 kPa?
The first consideration here is that HVPG is probably not a perfect estimate of the degree of PHT in patients with HCC, because vascular invasion also increases PHT.
β blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial.
Consequently, the risk/benefit of treating patients with beta-blockers is clearly in favour of treatment.
Banding has never shown its superiority to beta-blockers in primary prophylaxis, and may be risky in patients with HCC, because of their increased risk of bleeding,
especially in patients receiving bevacizumab. For these reasons, we favour beta-blockers vs. banding for primary prophylaxis in patients with HCC.
Hence, as we await further clinical studies, we think that upper endoscopy can be avoided in patients with HCC and LSM >25 kPa, and that those patients should be treated with beta-blockers, regardless of their EV status.
Question 3: How should PHT be monitored in patients with HCC?
Except for patients with LSM >25 kPa under beta-blockers, regular endoscopies every 2/3 years
Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
are advised. Moreover, PHT can progress faster, because of the occurrence of vascular invasion, or worsening of liver disease due to HCC and its therapies.
Thus, in our expert opinion, monitoring of PHT should include regular endoscopies in all patients, apart from those with LSM >25 kPa who are receiving beta-blockers as primary prevention, with a smaller interval between endoscopies in patients with HCC (1 year seems reasonable).
Question 4: How should primary prophylaxis of PHT-related decompensation be conducted in patients with HCC?
Which beta-blocker should be used remains an open question. Many studies were performed with propranolol. However, carvedilol has been shown to have a significantly greater effect on PHT decrease, and is now recommended as first choice, except in patients with decompensated cirrhosis.
As we await further clinical studies, we think that carvedilol should be the treatment of choice for the primary prevention of PHT-related decompensation in patients with HCC.
Question 5: How should secondary prophylaxis after AVB be conducted in patients with HCC? Is TIPS contraindicated?
Secondary prophylaxis includes a combination of beta-blockers and banding.
Hence, despite fears of post-banding bleeding, combination therapy remains the rule in patients with HCC requiring secondary prophylaxis.
The prognosis of AVB in patients with cirrhosis has improved significantly in the past 10 years, especially because of the widespread use of TIPS. The presence of HCC may preclude TIPS placement because of concerns relating to liver failure and HCC spread.
We recently described our experience of TIPS placement in patients with HCC and AVB: TIPS placement always was feasible, avoiding HCC route. We never observed any HCC spread, nor liver failure.
As we await more clinical data, we think that TIPS can be discussed in patients with HCC, and that HCC is not a contraindication to TIPS per se, if feasible technically.
TIPS in patients with HCC requiring locoregional therapies
CSPH impacts the choice of HCC treatment. CSPH is a well identified predictive factor for liver decompensation and death after liver resection. Currently, optimal surgical candidacy for resection is based on a multiparametric evaluation, including compensated Child-Pugh class A liver function with model for end-stage liver disease score <10, alongside grade of PHT, acceptable remaining parenchyma and the possibility of a laparoscopic/minimally invasive approach. CSPH is also associated with decreased overall survival after ablation and transarterial chemoembolization (TACE). Moreover, most locoregional treatments for HCC are contraindicated in case of refractory ascites or decompensated cirrhosis, owing to the risk of liver failure. In that case, liver transplantation (LT) remains the only treatment for well-selected patients (within Milan criteria worldwide or AFP score <3 in France).
TIPS could enable patients to access HCC treatments that would otherwise be contraindicated because of PHT levels/ascites: pre-operative TIPS before liver resection, and before ablation in small HCC, especially when a laparoscopic approach is discussed, is an attractive option. TIPS could be indicated before external radiation therapy, selective internal radiation therapy, or TACE, mainly in the context of downstaging before LT. Here, the consequences of TIPS may be different depending on the type of locoregional therapy. There is concern regarding the potentially increased risk of liver failure after TACE, and a decrease in the efficacy of HCC treatments.
Efficacy of TACE in TIPS patients: comparison of treatment response to chemoembolization for hepatocellular carcinoma in patients with and without a transjugular intrahepatic portosystemic shunt.
Safety and efficacy of segmental yttrium-90 radioembolization for hepatocellular carcinoma after transjugular intrahepatic portosystemic shunt creation.
suggesting that tolerance may be better in those patients, and that radioembolization should be preferred to TACE, when possible. In our recent study, TIPS enabled all patients to access potentially curative treatment, and was not associated with worsening of liver function or tumour spreading.
All patients were eventually transplanted for their HCC and are still alive. Hence, we now consider TIPS in selected patients with CSPH, in order to allow for minimally invasive treatments for HCC, such as ablation or radiotherapy, either in order to bridge patients to LT, or to allow for alternative curative treatments.
Management of PHT in patients with advanced HCC, particular in the context of TKI and atezolizumab-bevacizumab treatment
Question 1: How should PHT be screened before systemic therapy in patients with advanced HCC? How should PHT be monitored?
During the last decades, tyrosine kinase inhibitors (TKIs) were the standard of care for advanced HCC. Sorafenib and lenvatinib were used as first-line treatment while regorafenib, ramucirumab and cabozantinib were used in the second line.
All of these TKIs target VEGFR (vascular endothelial growth factor receptor) and may impact PHT. However, whereas a higher rate of treatment-emergent ascites was observed with TKIs, no effect on bleeding was noted.
The effect of the new combination of atezolizumab plus bevacizumab on PHT remains to be studied. Bevacizumab is an antibody directed against vascular endothelial growth factor. Atezolizumab is an immune checkpoint inhibitor (ICI) that aims to restore antitumour immunity. In the IMbrave 150 study, bleeding events were more frequently observed with the combination bevacizumab/atezolizumab than with sorafenib (25.2% vs. 17.3%), including gastrointestinal bleeding in 7% vs. 4.5%, respectively, and PHT-related AVB in 2.4% vs. 0.6%
; notably, this was in well-selected patients (patients benefitted from optimal PHT prophylaxis and were excluded in case of PHT-related bleeding <6 months before therapy). The increased bleeding risk under bevacizumab ranged from 9%
in the two previous phase II studies, depending on PHT prophylaxis. In our recent study in a selected population of patients under atezolizumab/bevacizumab, history of AVB was significantly associated with a higher risk of bleeding
Larrey E, Campion B, Evain M, Sultanik P, Blaise L, Giudicelli H, et al. A history of variceal bleeding is associated with further bleeding under Atezolizumab-Bevacizumab in patients with HCC. Liver Int 2022.Dec;42(12):2843-2854.
Preliminary evidence of safety and tolerability of atezolizumab plus bevacizumab in patients with hepatocellular carcinoma and Child-Pugh A and B cirrhosis: a real-world study.
regimens either. These data suggest that ICI monotherapy or ICI combination immunotherapy does not increase bleeding risk; bleeding risk is especially increased with combination immunotherapy regimens containing bevacizumab, suggesting that the inhibition of the wound healing effect and increased PHT induced by bevacizumab lead to AVB.
Portal vein invasion is another issue which could precipitate PHT-related events. Sub-analysis of the IMbrave 150 study showed that AVB events were more frequent in patients with HCC and portal vein invasion (14%) than in those without invasion (1%), suggesting that complete obstruction of the main portal vein increases pressure in varices. As this event occurs often, frequent PHT monitoring is warranted.
Altogether, we think that a strict work-up of PHT before starting treatment with atezolizumab-bevacizumab in all patients who are not already under primary prophylaxis is mandatory, and beta-blockers should be started when needed. Surveillance should be performed regularly, probably at a periodicity higher than that recommended in patients who are not receiving systemic therapy (endoscopies at 6-monthly intervals could be suggested). Whether these recommendations will be necessary with new ICI regimens that do not include bevacizumab remains to be determined. In our opinion, in patients with a history of AVB, these new regimes may be favoured.
Question 2: How to handle banding in patients under systemic therapies?
Banding is indicated in primary prophylaxis in case of contraindication/intolerance to beta-blockers, and in secondary prophylaxis. There is no fear of a higher bleeding rate under TKIs or ICI therapy without bevacizumab. The question is that of banding in patients under bevacizumab, which could delay post-banding ulcer healing as well as bleeding control. Because of this, a 4-week interval is usually recommended after surgery before starting bevacizumab, which can be reduced to 7 to 14 days for less invasive procedures. Banding sessions are generally performed at 2-week intervals, and usually 3 to 4 sessions are necessary to eradicate varices.
We do not recommend delaying the delivery of systemic therapy for too long after banding, because of the fear of HCC progression, and consider that a delay of 2 weeks after first banding is reasonable prior to starting therapy.
In case of bleeding under atezolizumab/bevacizumab, we advise stopping bevacizumab and maintaining atezolizumab as monotherapy. However, this assertion should be tempered by 2 points: (1) there might be an indication for TIPS instead of combination therapy in those patients, even outside the criteria for preemptive TIPS; (2) the forthcoming availability of other regimens without bevacizumab will certainly help in this instance.
Question 3: In case of cruoric portal thrombosis, should anticoagulation be stopped before bevacizumab?
Curative anticoagulation is often prescribed because of cruoric portal thrombosis, to limit its extension. Portal thrombosis increases portal hypertension, and itself favours AVB.
For some physicians, curative anticoagulants could be a potential contraindication for atezolizumab/bevacizumab, because patients receiving curative anticoagulation were excluded from the IMBRAVE 150 trial.
However, we believe that stopping anticoagulation in these patients would probably increase portal pressure. Indeed, except for patients under bevacizumab, there is no evidence that anticoagulation increases bleeding, which is related to PHT and portal thrombosis, and not mucosal injury. In addition, for the particular subgroup of patients receiving bevacizumab, and in patients with other tumours, anticoagulant therapy, including new oral direct-oral anticoagulants, are not contraindicated. Hence, we recommend pursuing any kind of anticoagulant. In patients who have undergone banding, we would favour low-molecular-weight heparin, to facilitate management of bleeding if necessary.
Conclusion
In conclusion, the combination of PHT and HCC is associated with poorer prognosis in patients with cirrhosis. Screening and treatment of PHT is of major importance to prevent complications in patients with HCC. Upper endoscopy should be performed in patients with cirrhosis and HCC, except in those with CSPH who are being treated with beta-blockers. TIPS represents an appealing option in patients with HCC and should always be discussed when needed. In advanced HCC, regular screening before first-line treatment with atezolizumab plus bevacizumab is mandatory, and primary prophylaxis (ideally with beta-blockers) should be started before systemic therapy. The risk of bleeding is not increased in patients receiving ICIs alone, and banding must be performed cautiously in these patients.
Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
β blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial.
Efficacy of TACE in TIPS patients: comparison of treatment response to chemoembolization for hepatocellular carcinoma in patients with and without a transjugular intrahepatic portosystemic shunt.
Safety and efficacy of segmental yttrium-90 radioembolization for hepatocellular carcinoma after transjugular intrahepatic portosystemic shunt creation.
Larrey E, Campion B, Evain M, Sultanik P, Blaise L, Giudicelli H, et al. A history of variceal bleeding is associated with further bleeding under Atezolizumab-Bevacizumab in patients with HCC. Liver Int 2022.Dec;42(12):2843-2854.
Preliminary evidence of safety and tolerability of atezolizumab plus bevacizumab in patients with hepatocellular carcinoma and Child-Pugh A and B cirrhosis: a real-world study.
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