The importance of the hepatic venous pressure gradient (HVPG) in selecting patients with
hepatocellular carcinoma (HCC) for liver resection (LR) has been somewhat controversial. Recently,
Boleslawski et al. prospectively evaluated a cohort of 40 patients undergoing LR for HCC; the
authors aimed to identify the impact of HVPG values and clinical signs of portal hypertension
(esophageal varices or splenomegaly with a platelet count <100,000/mm3) on
postoperative outcomes (11. Boleslawski E, Petrovai G, Truant S, Dharancy S, Duhamel A, Salleron J, et al.
Hepatic venous pressure gradient in the assessment of portal hypertension before liver resection in
patients with cirrhosis. Br J Surg 2012;99(6):855-63,
http://dx.doi.org/10.1002/bjs.8753.
http://dx.doi.org/10.1002/bjs.8753...
). The study showed that liver
dysfunction and 90-day postoperative mortality rates were associated with high HVPG values
(p = 0.017 and 0.026, respectively). In contrast, the presence of clinical features
of portal hypertension was not associated with either liver dysfunction or short-term mortality. The
authors concluded that the HVPG should be measured routinely in HCC patients prior to LR. Clinical
practice guidelines from the European Association for the Study of the Liver (EASL) and the American
Association for the Study of Liver Diseases (AASLD) suggest that clinical parameters can be used as
an alternative to HPVG in determining the presence of clinically relevant portal hypertension (22. European Association For The Study Of The Liver; European Organisation For
Research And Treatment Of Cancer. EASL-EORTC Clinical Practice Guidelines: Management of
hepatocellular carcinoma. J Hepatol. 2012;56(4):908-43.,33. Simpson KJ, Finlayson ND. Clinical evaluation of liver disease. Baillieres Clin
Gastroenterol 1995;9(4):639-59, http://dx.doi.org/10.1016/0950-3528(95)90054-3.
http://dx.doi.org/10.1016/0950-3528(95)9...
). Consequently, HVPG
assessment may not be necessary in all LR candidates (44. Bruix J, Castells A, Bosch J, Feu F, Garcia-Pagan JC, Visa J, et al. Surgical
resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal
pressure. Gastroentrology. 1996; 111(4):1018-22,
http://dx.doi.org/10.1016/S0016-5085(96)70070-7.
http://dx.doi.org/10.1016/S0016-5085(96)...
).
Although the Boleslawski et al. study examined an important aspect of LR for HCC patients, some
concerns should be addressed.
There is no clear maximum tumor size that contraindicates LR in HCC patients with a single nodule
(22. European Association For The Study Of The Liver; European Organisation For
Research And Treatment Of Cancer. EASL-EORTC Clinical Practice Guidelines: Management of
hepatocellular carcinoma. J Hepatol. 2012;56(4):908-43.,33. Simpson KJ, Finlayson ND. Clinical evaluation of liver disease. Baillieres Clin
Gastroenterol 1995;9(4):639-59, http://dx.doi.org/10.1016/0950-3528(95)90054-3.
http://dx.doi.org/10.1016/0950-3528(95)9...
). Nevertheless,
in a patient with well-preserved liver function and a single tumor up to 5 cm, the presence of
portal hypertension is accepted as an adverse prognostic factor that is associated with reduced and
long-term patient survival (55. Llovet JM, Fuster J, Bruix J. Intention-to-Treat analysis of surgical treatment
for early hepatocellular carcinoma: resection versus transplantation. Hepatology.
1999;30(6):1434-40, http://dx.doi.org/10.1002/hep.510300629.
http://dx.doi.org/10.1002/hep.510300629...
,66. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update.
Hepatology. 2011;53(3):1020-2, http://dx.doi.org/10.1002/hep.24199.
http://dx.doi.org/10.1002/hep.24199...
). In 1996, Bruix et al. first reported the negative impact of significant portal
hypertension on liver resection outcomes (55. Llovet JM, Fuster J, Bruix J. Intention-to-Treat analysis of surgical treatment
for early hepatocellular carcinoma: resection versus transplantation. Hepatology.
1999;30(6):1434-40, http://dx.doi.org/10.1002/hep.510300629.
http://dx.doi.org/10.1002/hep.510300629...
). Twenty-nine
cirrhotic Child-Turcotte-Pugh (CPT) class A patients who underwent LR were evaluated to determine
the role of increased portal pressure in developing postoperative hepatic decompensation. Eleven of
the 29 patients developed persistent liver decompensation within the first three months after
surgery, and HVPG was the only independent factor that predicted hepatic decompensation in a
multivariate analysis (p<0.001). Subsequently, the same researchers updated
their results, suggesting that either HVPG or clinical signs of portal hypertension could be used to
select HCC patients for resection or liver transplantation (66. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update.
Hepatology. 2011;53(3):1020-2, http://dx.doi.org/10.1002/hep.24199.
http://dx.doi.org/10.1002/hep.24199...
). Note that patients with a single tumor >5 cm do not fulfill the Milan criteria, and
liver transplantation is not usually considered a treatment alternative (22. European Association For The Study Of The Liver; European Organisation For
Research And Treatment Of Cancer. EASL-EORTC Clinical Practice Guidelines: Management of
hepatocellular carcinoma. J Hepatol. 2012;56(4):908-43.,33. Simpson KJ, Finlayson ND. Clinical evaluation of liver disease. Baillieres Clin
Gastroenterol 1995;9(4):639-59, http://dx.doi.org/10.1016/0950-3528(95)90054-3.
http://dx.doi.org/10.1016/0950-3528(95)9...
,77. Llovet JM, Di Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu AX, et al. Design
and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst.
2008;100(10):698-711.). Therefore, the presence of portal hypertension as an absolute criterion for selecting
patients for liver transplantation, rather than resection, is of most relevance to the subgroup of
patients who could undergo either resection or transplantation. Given the limited efficacy of other
treatment options for this patient subset, such as transarterial chemoembolization, patients with a
single tumor >5 cm may still be best served by liver resection, even in the presence of portal
hypertension. The study by Boleslawski et al. did not mention tumor number or size in the 40
enrolled patients, and this information may aid in interpreting their data and conclusions. Note
that in their series, not all of the patients performed poorly (despite liver resection in the
presence of a HVPG >10 mmHg), and portal hypertension clinically-based (PH-CB) was not predictive of
patient outcomes.
In light of the uncertainties surrounding the role of portal hypertension in selecting HCC
patients for liver resection, we recently undertook a multicenter (in Australia, Spain, and Brazil),
exploratory analysis of 105 CPT A HCC patients (with a single nodule ≤5 cm on imaging) who were
treated with primary liver resection (unpublished data). After a median follow up of 51 months
(range, 1-159 months), the 1-, 3-, and 5-year survival rates were 97%, 83%, and 66%, respectively.
As in other studies, significant portal hypertension was defined as having an HVPG ≥10 mmHg or the
presence of gastro-esophageal varices, splenomegaly (spleen length ≥12 cm) with a platelet count
<100,000/mm3, or the need for diuretics to control ascites. PH-CB was defined with the
same criteria but without the HVPG variable. No pre-operative characteristic predicted the
likelihood of survival after assessing all of the variables recommended by the Panel of Experts in
HCC-Design Clinical Trials (77. Llovet JM, Di Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu AX, et al. Design
and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst.
2008;100(10):698-711.). In other words, our results
suggest that liver resection for CPT A HCC patients with a single tumor ≤5 cm offers survival rates
similar to liver transplantation, independent of any pre-operative characteristics (88. Germani G, Gurusamy K, Garcovich M, Toso C, Fede G, Hemming A, et al. Which
matters most: Number of tumors, size of the largest tumor, or total tumor volume? Liver Transpl.
2011;17(suppl 2);S58-S66, http://dx.doi.org/10.1002/lt.22336.
http://dx.doi.org/10.1002/lt.22336...
).
We have summarized the published studies evaluating liver resection for patients with cirrhosis
and HCC (Table 1). It is clear that the data regarding
the prognostic factors for HCC patients undergoing liver resection are scarce. Current
recommendations for patient selection for liver resection versus liver
transplantation for tumors ≤5 cm are still based on the original Barcelona group publication, which
was based on a retrospective analysis of a case series from the 1990s (55. Llovet JM, Fuster J, Bruix J. Intention-to-Treat analysis of surgical treatment
for early hepatocellular carcinoma: resection versus transplantation. Hepatology.
1999;30(6):1434-40, http://dx.doi.org/10.1002/hep.510300629.
http://dx.doi.org/10.1002/hep.510300629...
). Note that given the limitations of retrospective studies, the robustness of
evidence supporting this finding must be validated following evidenced-based ranking systems (99. Guyatt GH, Oxman AD, Vist G, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al.
GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ.
2008;336(7650):924-6, http://dx.doi.org/10.1136/bmj.39489.470347.AD.
http://dx.doi.org/10.1136/bmj.39489.4703...
). Basing recommendations on the results of liver resection
performed in the 1990s ignores recent improvements in the perioperative care of cirrhotic patients
(1010. Tremosini S, Reig M, De Lope CR, Forner A, Bruix J. Treatment of early
hepatocellular carcinoma: towards personalized therapy. Dig Liver Dis. 2010;42 Suppl:S242-S8,
http://dx.doi.org/10.1016/S1590-8658(10)60512-9.
http://dx.doi.org/10.1016/S1590-8658(10)...
). These recommendations may also limit access to liver
resection for patients who have no or limited access to liver transplantation.
Results of a series evaluating liver resection in patients with hepatocellular carcinoma and cirrhosis.
In conclusion, further well-designed trials are warranted to evaluate the role of significant portal hypertension in predicting liver resection outcomes for HCC patients. Nevertheless, until further well-designed prospective studies are undertaken, the recommendations of the EASL-HCC Clinical Practice Guidelines should remain in place.
REFERENCES
-
1Boleslawski E, Petrovai G, Truant S, Dharancy S, Duhamel A, Salleron J, et al. Hepatic venous pressure gradient in the assessment of portal hypertension before liver resection in patients with cirrhosis. Br J Surg 2012;99(6):855-63, http://dx.doi.org/10.1002/bjs.8753.
» http://dx.doi.org/10.1002/bjs.8753 -
2European Association For The Study Of The Liver; European Organisation For Research And Treatment Of Cancer. EASL-EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol. 2012;56(4):908-43.
-
3Simpson KJ, Finlayson ND. Clinical evaluation of liver disease. Baillieres Clin Gastroenterol 1995;9(4):639-59, http://dx.doi.org/10.1016/0950-3528(95)90054-3.
» http://dx.doi.org/10.1016/0950-3528(95)90054-3 -
4Bruix J, Castells A, Bosch J, Feu F, Garcia-Pagan JC, Visa J, et al. Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal pressure. Gastroentrology. 1996; 111(4):1018-22, http://dx.doi.org/10.1016/S0016-5085(96)70070-7.
» http://dx.doi.org/10.1016/S0016-5085(96)70070-7 -
5Llovet JM, Fuster J, Bruix J. Intention-to-Treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology. 1999;30(6):1434-40, http://dx.doi.org/10.1002/hep.510300629.
» http://dx.doi.org/10.1002/hep.510300629 -
6Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53(3):1020-2, http://dx.doi.org/10.1002/hep.24199.
» http://dx.doi.org/10.1002/hep.24199 -
7Llovet JM, Di Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu AX, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst. 2008;100(10):698-711.
-
8Germani G, Gurusamy K, Garcovich M, Toso C, Fede G, Hemming A, et al. Which matters most: Number of tumors, size of the largest tumor, or total tumor volume? Liver Transpl. 2011;17(suppl 2);S58-S66, http://dx.doi.org/10.1002/lt.22336.
» http://dx.doi.org/10.1002/lt.22336 -
9Guyatt GH, Oxman AD, Vist G, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924-6, http://dx.doi.org/10.1136/bmj.39489.470347.AD.
» http://dx.doi.org/10.1136/bmj.39489.470347.AD -
10Tremosini S, Reig M, De Lope CR, Forner A, Bruix J. Treatment of early hepatocellular carcinoma: towards personalized therapy. Dig Liver Dis. 2010;42 Suppl:S242-S8, http://dx.doi.org/10.1016/S1590-8658(10)60512-9.
» http://dx.doi.org/10.1016/S1590-8658(10)60512-9
-
No potential conflict of interest was reported.
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Publication in this collection
Apr 2013