Volumetric parameters for liver regeneration

There are two different ways to calculate liver volumes. Frequently authors use direct measurements of liver volumes to calculate the FLR, delineating the liver, tumors and FLR contours with semi-automatic softwares¹¹⁵ (Figure 8), using the following formula³⁵:

FLR% = FLR volume divided by the total functional liver volume x 100%

(Functional liver volume = Total liver volume - tumor volume)

The other method of estimating liver volumes is related to the body surface^116,117. This concept of the total estimated liver volume is based on the observation that in adults, without liver disease, liver volume correlates linearly with body size and weight¹¹⁸. For instance, in living donor liver transplantation, the patient's body weight is used to calculate the donor graft volume¹¹⁹. The formula to calculate the total estimated liver volume was established as¹²⁰:

Total estimated liver volume = - 794 + 1267 x BSA

Of notice, this formula was derived and corroborated by studies of the Western population^121,122.

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To measure liver growth on CT different volumetric parameters have been used and published. The main markers are absolute FLR growth, degree of hypertrophy (DH) and kinetic growth rate (KGR). Absolute FLR growth translates the FLR volume increase in relation to its original volume. For example, if patient´s FLR volume initially was 300ml and after PVE 450ml then the absolute FLR growth is 50%. As for DH it describes the increase in the FLR ratio after PVE. If patient´s FLR ratio increased from 20% to 30% after PVE then DH is 10%. KGR is a dynamic type of volumetric assessment. It calculates the DH over days or weeks, from the PVE date up to the CT imaging date after PVE, being commonly published as “% per week”.

Here is a summary of the volumetric parameters used to evaluate PVE effect:

● FLR Absolute growth:

○ (FLR volume after PVE - FLR initial volume / FLR initial volume) x 100%

○ example: (450 - 300 / 300) x 100% = 50%

● Degree of Hypertrophy (DH):

○ FLR ratio after PVE - FLR ratio initially

○ example: 30% - 20% = 10%

● Kinetic Growth Rate (KGR) peer week:

○ DH / number of weeks from PVE to the CT imaging after PVE

○ example: 10 / 4 = 2% per week

As the techniques and indications for PVE have evolved over time, numerous groups have attempted to more accurately predict postoperative outcomes on the basis of PVE-induced imaging volume changes¹¹⁰. Absolute hypertrophy has the advantage of directly measuring the capacity of the FLR to regenerate. Low values for absolute hypertrophy after PVE are associated with PHLF^67,93,148. Also, absolute hypertrophy is not influenced by the atrophy of the non-FLR parenchyma as the FLR ratio (and DH) is, which might lead to a false interpretation of significant hypertrophy if only DH is taken into account¹³⁰. Nevertheless, the FLR ratio, and its increase after PVE (e.g., DH) has traditionally been used as one of the main parameters for decision making in liver surgery^1,3,9. DH, as KGR, is a good predictor of PHLF¹³. KGR is a dynamic volumetric tool, as it can be measured at any time point after PVE. For DH, it is necessary many weeks for it to become apparent (e.g., if measured too early the increase will be minimum). KGR is an early marker of the regenerative capacity of the FLR and may provide additional functional information beyond traditional, static measures of volume.

Shindoh et al showed that KGR has a better predictive value than degree of hypertrophy alone for postoperative outcomes²⁴³. Leung et al found similar results, depicting that KGR as well as the extent of growth correlated with PHLF. However, this latter study found that DH was a superior predictor for high-grade complications when compared to KGR¹³. Nonetheless, KGR rate is still a very useful index, since it is an early marker that may support going forward with the hepatic resection before the customary 4 to 6 weeks after PVE. Besides, in the study by Shindoh et all, patients that achieved a KGR above 2.0 did not presented any signs of PHLF, while 21.6% of patients with KGR bellow this value presented PHLF (p < 0.001). Also, in a comparison of the diagnostic capacity of standardized FLR volume, DH and KGR, of these variables, KGR <2.0% per week showed the highest accuracy (81%), with sensitivity of 100%

and specificity of 71% in predicting PHLF.

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Commonly groups report the use of preoperative PVE when the FLR ratio is less than 25% in patients with normal livers or 30% to 35% in chemotherapy heavily pre-treated patients and 40% in diseased liver (i.e.; cholestatic liver disease, liver fibrosis and cirrhosis)25,62,64,66,93,94,112,125-128 (Figure 8).

Figure 8. Segmentation process in a patient planned for right hemihepatectomy without resection of the middle hepatic vein (MHV) due to colorectal metastases a) Plain axial CT image shows a hypoattenuated metastasis in liver segment 8 (black arrows). b) and c) Detection of the liver outline.

Further metastases are depicted at the level of the proximal MHV in c) (black arrows). d) – f) Detection of the intrahepatic portal vein (in pink) and hepatic vein (in blue). g) – h) Definition of the transection plane (in red). Reproduced with permission¹¹⁴.

Nevertheless, patients with liver cirrhosis will show slower and inferior hepatic regeneration when compared to non-cirrhotic cohorts¹²⁹ and PVE in cirrhotic patients will be used more liberally. Also in this scenario, a recent publication from Japanese and French groups showed that transarterial chemoembolization (TACE) followed by PVE is more effective than PVE alone¹³⁰. Interestingly this study showed that not only TACE followed by PVE induces greater hypertrophy than PVE alone (in line with other publications^131-133), but

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also the overall survival and progression free survival were consistently better in the TACE plus PVE group (60% versus 20% for overall survival at 3 years, p = .01 and 35% versus 0% for progression free survival at 3 years, p < .001) (Figure 9). As for PVE indications, this group uses PVE systematically before right hepatectomies for patients with livers containing severe fibrosis or cirrhosis even if the FLR% ratio is greater than 40%.

Figure 9. Kaplan-Meier survival curves: TACE plus PVE (TACE +) versus PVE alone. (A) Overall survival of patients with PVE alone versus patients with TACE plus PVE. (B) Progression-free survival of patients with PVE alone versus patients with TACE plus PVE. Reproduced with permission¹³⁰.

Regarding Biliary cancer some crucial differences also influence the indications for PVE. Hepatectomy is complex, accompanied by caudate lobectomy, extrahepatic bile duct resection with bilioenteric anastomosis, portal vein resection and even pancreatoduodenectomy^64,134,135. In a large study from Nagoya University 393 patients with biliary cancer were treated from 1991 to 2005. Of these, 279 patients (71%) were submitted to PVE, which accounts for more than two thirds of the total bulk of patients. One of the reasons for the frequent use of PVE is that even patients with FLR > 40%, but with low functional reserve (i.e., plasma disappearance rate of indocyanine green of the FLR < 0.05), were submitted to PVE. In this report patients with small FLR submitted to PVE showed similar survival rate when compared to those patients who underwent a less than 50% resection of the liver without PVE (4.5% versus 3.7%)¹³⁴. Figure 10 exemplifies a decision diagram regarding major hepatectomies and the use of PVE as a preoperative procedure.

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Figure 10: Proposed Decision Tree for Major Hepatectomy in Patients with Normal Liver Parenchyma and Those with Cirrhosis. The cutoff points of 30% volume (Panel A) and 50% volume (Panel B) for the potential liver remnant are based on our current practice and available data. For cirrhotic livers with a rate of retention of indocyanine green (ICG) that is less than 14% at 15 minutes (Panel B) and livers with underlying noncirrhotic diseases such as steatosis or fibrosis, we apply the algorithm for normal liver parenchyma with a higher cutoff point (35 to 40%) for the volume of the potential liver remnant. Reproduced with permission from Clavien et al¹², Copyright Massachusetts Medical Society.