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Towards safer liver resections
Hoekstra, L.T.
Publication date
2012
Link to publication
Citation for published version (APA):
Hoekstra, L. T. (2012). Towards safer liver resections.
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Chapter
General introduction
General introduction
Liver resection is the most effective treatment for primary or metastatic liver tumors.1,2
In patients with malignant hepatic tumors, fewer than 15-20% are suitable for surgical resection. Whereas extended liver resections are increasingly indicated because of advanced tumor in these patients, the extent of liver resection is restricted by the minimum volume of the liver remnant required to provide sufficient postoperative liver function. When patients are considered unresectable because of too small future remnant liver (FRL), neoadjuvant therapy or the combination of resection with local ablative techniques such as RFA may be applied. Alternatively, preoperative portal vein embolization (PVE) is an option to increase FRL volume through induction of regeneration of the hepatocellular mass of the non-embolized FRL.3,4 Following occlusion of the right or left branch of
the portal vein, atrophy of the embolized liver segments occurs, while hypertrophy of the contralateral, non-embolized liver lobe is induced.5,6 Liver regeneration is set off
in the contralateral liver lobe via a complex interaction of cytokines, growth factors and metabolic networks.7 The degree of hypertrophy after PVE is variable, especially in
patients with compromised livers.4 PVE is a relatively new intervention and is mostly used
in specialized centres. Numbers reported in clinical studies are relatively limited for this reason. PVE has shown to reduce the risk of liver failure3 and consequently increases the
number of patients who are able to undergo liver resection.
There is increasing evidence that PVE not only stimulates growth of the FRL but also accelerates tumor proliferation.7 Tumor progression after PVE creates a dilemma in terms
of optimal waiting time until resection.4 Surgery is usually performed 3-6 weeks after PVE
when sufficient increase of the FRL is considered to have occurred to allow a safe liver resection.8-10 Several studies reported tumor growth after PVE in the embolized and
non-embolized liver segments11-14 within the waiting time for resection under the influence
of the above mentioned cytokines and growth factors. In addition, since the liver has a dual blood supply by the portal vein and the hepatic artery, PVE will also result in a compensatory increase in hepatic arterial flow15 which further enhances tumor growth.
The challenge for future use of PVE is to limit the growth of tumor while efficiently inducing hypertrophy of the non-embolized liver lobe. Several strategies can be devised to limit post-PVE tumor progression, as are discussed in this thesis.
The numbers of hepatic resections have increased as tumors initially considered unresectable have become potentially resectable after preoperative or intraoperative interventions. Strategies such as PVE or two-stage resection16 rely heavily on the
tremendous regenerative ability of the normal liver. However, many of the patients who are candidates for resection also have impaired liver function due to fibrosis/cirrhosis, steatosis or chemotherapy induced parenchymal injury. These patients in particular, are at risk when undergoing extensive liver resection and all efforts should be directed to reducing postoperative complications.
General introduction
11
This thesis deals with the available options to perform safer liver resections. In part 1, several clinical questions regarding PVE, are adressed in an experimental model of PVE in the rabbit. Clinical studies mainly focus on liver regeneration markers, and the influence of PVE on tumor growth. In part 2, the aim is to assess complications after liver resection and to discuss methods and surgical approaches to prevent the most common complications.
Outline of the thesis
Part I
Postoperative liver failure is the major cause of mortality and morbidity after liver resection, and develops as a result of insufficient remnant liver function.17 Assessment
of liver function is therefore crucial in the preoperative work-up of patients who require (extensive) liver resection. Chapter 2 describes the physiological basis of the most frequently employed clinical liver function tests.
The extent of liver resection is restricted by the volume of the future remnant liver. Patients are considered resectable when the FRL is larger than 25-30% in patients with normal liver parenchyma, whereas a limit of 40% is taken into account in patients with diseased livers.4,7,18,19 One way to increase the FRL preoperatively is the use of PVE, which
has been clinically introduced in 1990 by Makuuchi et al.20 In chapter 3, the experiences
and outcomes of PVE and extensive resection in predamaged livers in our center are reported.
Although PVE is largely applied worldwide, many questions concerning the hypertrophy response and liver regeneration still need to be elucidated.4 Since liver
regeneration after PVE is variable, we evaluated several possible predictors of liver growth. In chapter 4 and 5, plasma bile salt levels, triglycerides, and ApoA-V were investigated in the prediction of the hypertrophy response after PVE in a rabbit PVE-model, as well as in a series of patients undergoing PVE. Chapter 6 deals with the role of thrombocytes in volumetric regeneration after portal vein embolization in a series of patients undergoing subsequent liver resection.
There is increasing evidence that PVE not only stimulates growth of the FRL but also increases tumor size as a result of cytokines, growth factors and an increased arterial blood supply to the tumor4,7,11,13,14,21-24, but the exact mechanisms of this phenomenon
are largely unknown. Growth of tumor may be accelerated, while micrometastases in the non-embolized remnant liver may also develop or progress. The rate of tumor growth after PVE had been examined in a series of patients in chapter 7.
Another strategy in conjunction with PVE is to selectively embolize the hepatic artery (HAE) branches to the tumor-bearing liver segments prior to PVE. HAE alone does not result in the desired atrophy-hypertrophy response. The combination of HAE and PVE, however, will result in hypertrophy of the non-embolized lobe, at the same time limiting further tumor growth induced by compensatory hyperperfusion of the hepatic artery.
Simultaneous embolization of the portal vein and hepatic artery obviously carries a high risk of parenchymal necrosis as a result of complete occlusion of the dual blood supply.25,26
The risk of necrosis is diminished when the hepatic artery and portal vein are embolized in sequential order. The optimal time-interval between embolization of the portal vein and hepatic artery is, however, unknown. Therefore, the optimal timing of portal vein embolization and transarterial (chemo)embolization is examined in a review presented in chapter 8.
Besides clinical studies that reported tumor growth acceleration after PVE, there is a need for optimization of treatment strategies to prevent tumor progression after portal vein embolization. Experimental studies are necessary to unravel several important clinical questions. We have developed a rabbit model in which PVE can be assessed using the same imaging methods used to evaluate patients after PVE.27 The combination of a VX2
liver tumor in this rabbit model allowed us to investigate tumor growth after PVE in a rabbit VX2 tumor model (chapter 9).
Ascites is a common complication after liver resection.28 It may contribute to liver
failure when large intra-abdominal ascitic fluid collections develop. Because little has been published about this troublesome complication after liver resection, we investigated in chapter 10, the incidence of ascites after hepatectomy with or without preoperative portal vein embolization, in addition to predictive factors for the development of post-resectional ascites.
Part II
Excessive blood loss during transection of the liver parenchyma is associated with adverse postoperative outcomes, which may culminate into liver failure especially when a small liver remnant is involved.29 To combat blood loss during liver resection, various methods
of hepatic inflow or simultaneous in- and outflow occlusion techniques have been introduced. A systematic literature search was conducted to update the effects of liver in- and outflow occlusion techniques during liver resection in chapter 11, focusing on blood loss and hepatic ischemia-reperfusion injury.
Biliary leakage after liver resection continues to be reported.30,31 Management of
bile leakage has changed in recent years, with to date, non-surgical procedures as the preferred treatment. The outcomes of biliary leakage and management were assessed in 381 patients who had undergone liver resection between 2005 and 2011, and the results are presented in chapter 12.
Within the field of liver surgery, the use of laparoscopy has increased substantially in recent years.32 Laparoscopic operations require insufflation of the abdominal cavity
(pneumoperitoneum, PP) with carbon dioxide gas to achieve adequate surgical exposure for instrumentation and surgical manoeuvres. Pneumoperitoneum obviously produces elevated intra-abdominal pressure with continuous compression of intra-abdominal organs which potentially influences hepatic microcirculatory perfusion. The study in chapter 13 was undertaken to investigate the influence of prolonged PP on liver function and hepatic
General introduction
13
microcirculatory parameters in a clinically relevant, porcine model of extended abdominal insufflation.
There is a prominent increase in laparoscopic approaches for primary colorectal carcinoma in recent years. Laparoscopy however, is only used in a selected group of patients with colorectal liver metastases in the Netherlands. There is much discussion in performing colonic and liver resections simultaneously. The aim of the study reported in chapter 14 was to evaluate our initial experiences of combined laparoscopic resection of colorectal cancer and synchronic hepatic metastases.
Staging laparoscopy (SL) has been found useful in determining appropriate treatment in several malignant tumors33-39, but is not regularly performed in patients
with hepatocellular carcinoma (HCC). SL may change treatment strategy, preventing unnecessary open exploration. The aim of the study in chapter 15 was to assess the value and outcomes of diagnostic laparoscopy in the treatment strategy for HCC.
Finally, in chapter 16 the results of the studies performed in this thesis are summarized and discussed.
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General introduction
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