Liver resection offers the only chance of cure in patients with a variety of primary and secondary liver tumors. For breast cancer, the natural history of this condition is poorly defined and the management remains controversial. Most physicians view liver metastases from breast cancer with resignation or attempt palliation with hormones and chemotherapy. Proper patient selection is crucial to ensure favorable long-term results. Although results of hepatic resection for metastatic colorectal cancer have been reported extensively, the experience with liver resection of metastases from breast cancer is limited. In 1991, the first series reporting hepatectomy for breast cancer patients was published.
A large series by Adam et al. reported the experience of 41 French centers regarding liver resection for noncolorectal, nonendocrine liver metastases. Among the 1452 patients who were studied, 454 (32%) were breast cancer patients. Mean age was 52 years (range 27–80 years). Most patients received adjuvant chemotherapy (58%), as few were downstaged by neoadjuvant chemotherapy. Delay between the treatment of the primary breast tumor and metastases was 54 months, with metachronous metastases in more than 90% of cases. There was a single metastasis in 56% of cases and less than three metastases in 84%. Only 8% were nonresectable. Most patients (77% of cases) underwent anatomical major resections (>3 segments). Negative margins were obtained in 82% of cases. Operative mortality was 0.2% during the 2 months following surgery. Fewer than 10% of the patients developed a local or systemic complication. With a median follow-up of 31 months, the overall survival was 41% at 5 years and 22% at 10 years, with a median of 45 months. Five- and 10-year recurrencefree survival rates were 14% and 10%, respectively.
Poor survival was associated with four factors determined by multivariate analysis: time to metastases, extrahepatic location, progression under chemotherapy treatment, and incomplete resection. At the UTMDACC, breast cancer patients who present with isolated synchronous liver metastases are treated initially with systemic chemotherapy. In responders,
hepatic resection is only contemplated if no other disease becomes evident during initial systemic treatment. Most candidates for hepatic resection undergo treatment for metachronous disease and only undergo resection for metastatic disease confined to the liver.
The incidence of HCC is increasing in the worldwide. Surgery in the form of liver resection or transplantation remains the mainstay of curative treatment for HCC, even though selected patients with small tumours may also be cured with ablation. Liver resection and transplantation are not necessarily two binary choices in most patients and, despite all the debates, are often complementary treatment modalities ideally suited to different patient groups. Thus characterisation of patient and tumour characteristics to guide decision making is vital to achieve the best outcome for patients.
1.Anatomical Resection or Not?
The aim of liver resection in patients with HCC and CLD is that it should be curative with resection of tumour vascular territories and also preserve as much liver volume as possible to prevent postoperative liver failure. EASL guidelines recommend anatomical resection of HCC, whereby the lines of resection match the limits of one or more functional segments of the liver. This is based on evidence suggesting superior oncological outcomes in addition to a reduction in the risk of bleeding and biliary fistula. Although there are no randomised data, a meta-analysis including 2000 patients from 12 non-randomised comparative trials did not show any benefit of anatomical compared with non-anatomical resection in 1-, 3- and 5-year survival, recurrence rate, postoperative morbidity or blood loss . It is practice to perform an anatomical resection for tumours >2 cm, and for smaller tumours in anatomically favourable positions, a wedge with adequate margin is often sufficient. Modifying techniques to maximise parenchymal preservation preserving adequate margins are often the key in these patients.
2. Anterior Approach
The anterior approach, as described by Professor Belghiti , has been advocated for large right-sided tumours. This technique involves transection of the liver parenchyma to the IVC without mobilisation of the liver with the theoretical advantage of less tumour seeding. A prospective randomised controlled trial compared the anterior and conventional approach on 120 patients with large (>5 cm) HCCs. The anterior approach group had less blood transfusion requirements and a significantly longer overall survival (68.1 v 22.6 months; p = 0.006).
As in liver resection for other indications, there is no good evidence to indicate that a single method of parenchymal transection, application of fibrin sealants or intermittent inflow occlusion is beneficial in surgery for HCC. There is also no evidence to suggest that using special equipment for liver resection is of any benefit in decreasing the mortality, morbidity, or blood transfusion requirements. Surgeons should use techniques in which they have been trained and can demonstrate acceptable outcomes.
4. Laparoscopic Approach
Laparoscopic HCC resections are gaining popularity as the approach is more widely adopted across centres. It is important that patients for laparoscopic resection are selected based on the technical capabilities of the surgeon and centre, and the proper mentoring takes place during the learning curve. A summary of published metaanalyses concluded that the laparoscopic approach was associated with improved short-term outcomes (blood loss, complication rates and hospital length of stay) without compromising long-term oncological outcomes. It is worth noting that there are no randomised data; however a number of trials are in progress. Furthermore,their analysis suggested that the incidence of postoperative ascites and liver failure is decreased in the selected group of laparoscopic liver resections . A further metaanalysis of cirrhotic patients up to Child-Pugh B undergoing laparoscopic compared with open liver resection for HCC confirmed these perioperative benefits .
5. Robotic Approach
Although still very much in its infancy, the application of robotic surgery to HCC resection can theoretically yield similar advantages in short-term outcomes to the laparoscopic technique. The only comparative study between robotic and open liver resection for HCC included 183 patients undergoing robotic hepatectomy who were compared using propensity scoring with a cohort of 275 open resections. The robotic group required longer operating time (343 vs 220 min), shorter hospital stays (7.5 vs 10.1 days) and lower dosages of postoperative patient-controlled analgesia (350 vs 554 ng/kg). The 3-year disease-free survival of the robotic group was comparable with that of the open group (72.2% vs 58.0%; p = 0.062), as was the 3-year overall survival (92.6 vs 93.7%; p = 0.431). The associated financial costs of robotic surgery still pose a limitation to its adoption, and it is unclear if this approach is associated with any significant advantages over laparoscopic rather than open resection.
6. Associating Liver Partition with Portal Vein Ligation for Staged
ALPPS is still considered an experimental technique in which a first-stage procedure consisting of physical liver splitting and portal vein ligation is followed by a second stage of resection of the HCC and associated liver segments. The advantage seen in colorectal liver metastases is that of rapid hypertrophy for the FLR. There are only limited data describing outcomes of ALPPS for HCC; however an analysis of 35 patients in the international ALPPS registry showed an impressive FLR hypertrophy of 47% following the first stage of the procedure that was associated with a 31% perioperative mortality rate. The majority of these patients were in the intermediate-stage category of the BCLC algorithm. Further evaluation is required prior to routine use of ALPPS for HCC resection, and it is the view of the authors that ALPPS may be a procedure best reserved for carefully selected patients who have bilateral disease.
7. Combined Resection with RFA for Bilobar HCC
For patients with multiple or bilobar HCC in whom resection is contraindicated due to inadequate FLR, combined resection and radiofrequency ablation (RFA) may yield better results than alternative treatments. A single-centre study compared patients with bilobar liver HCCs who underwent resection (n = 89), combination of resection and RFA (n = 114) and TACE (n = 161). The results showed that 1-, 3- and 5-year survival was better in both resection and combined resection, and RFA groups compared with TACE and survival and disease-free survival were comparable between both surgical groups. They concluded that resection combined with RFA provided a chance for cure in patients with bilobar HCC, and provided liver function is preserved, aggressive treatment can improve prognosis.
After the first major hepatic resection, a left hepatic resection, carried out in 1888 by Carl Langenbuch, it took another 20 years before the first right hepatectomy was described by Walter Wendel in 1911. Three years before, in 1908, Hogarth Pringle provided the first description of a technique of vascular control, the portal triad clamping, nowadays known as the Pringle maneuver. Liver surgery has progressed rapidly since then. Modern surgical concepts and techniques, together with advances in anesthesiological care, intensive care medicine, perioperative imaging, and interventional radiology, together with multimodal oncological concepts, have resulted in fundamental changes. Perioperative outcome has improved significantly, and even major hepatic resections can be performed with morbidity and mortality rates of less than 45% and 4% respectively in highvolume liver surgery centers. Many liver surgeries performed routinely in specialized centers today were considered to be high-risk or nonresectable by most surgeons less than 1–2 decades ago.Interestingly, operative blood loss remains the most important predictor of postoperative morbidity and mortality, and therefore vascular control remains one of the most important aspects in liver surgery.
“Bleeding control is achieved by vascular control and optimized and careful parenchymal transection during liver surgery, and these two concepts are cross-linked.”
First described by Pringle in 1908, it has proven effective in decreasing haemorrhage during the resection of the liver tissue. It is frequently used, and it consists in temporarily occluding the hepatic artery and the portal vein, thus limiting the flow of blood into the liver, although this also results in an increased venous pressure in the mesenteric territory. Hemodynamic repercussion during the PM is rare because it only diminishes the venous return in 15% of cases. The cardiovascular system slightly increases the systemic vascular resistance as a compensatory response, thereby limiting the drop in the arterial pressure. Through the administration of crystalloids, it is possible to maintain hemodynamic stability.
In the 1990s, the PM was used continuously for 45 min and even up to an hour because the depth of the potential damage that could occur due to hepatic ischemia was not yet known. During the PM, the lack of oxygen affects all liver cells, especially Kupffer cells which represent the largest fixed macrophage mass. When these cells are deprived of oxygen, they are an endless source of production of the tumour necrosis factor (TNF) and interleukins 1, 6, 8 and 10. IL 6 has been described as the cytokine that best correlates to postoperative complications. In order to mitigate the effects of continuous PM, intermittent clamping of the portal pedicle has been developed. This consists of occluding the pedicle for 15 min, removing the clamps for 5 min, and then starting the manoeuvre again. This intermittent passage of the hepatic tissue through ischemia and reperfusion shows the development of hepatic tolerance to the lack of oxygen with decreased cell damage. Greater ischemic tolerance to this intermittent manoeuvre increases the total time it can be used.
Portal vein Embolizations (PVE) is commonly used in the patients requiring extensive liver resection but have insufficient Future Liver Remanescent (FLR) volume on preoperative testing. The procedure involves occluding portal venous flow to the side of the liver with the lesion thereby redirecting portal flow to the contralateral side, in an attempt to cause hypertrophy and increase the volume of the FLR prior to hepatectomy.
PVE was first described by Kinoshita and later reported by Makuuchi as a technique to facilitate hepatic resection of hilar cholangiocarcinoma. The technique is now widely used by surgeons all over the world to optimize FLR volume before major liver resections.
PVE works because the extrahepatic factors that induce liver hypertrophy are carried primarily by the portal vein and not the hepatic artery. The increase in FLR size seen after PVE is due to both clonal expansion and cellular hypertrophy, and the extent of post-embolization liver growth is generally proportional to the degree of portal flow diversion. The mechanism of liver regeneration after PVE is a complex phenomenon and is not fully understood. Although the exact trigger of liver regeneration remains unknown, several studies have identified periportal inflammation in the embolized liver as an important predictor of liver regeneration.
PVE is technically feasible in 99% of the patients with low risk of complications. Studies have shown the FLR to increase by a median of 40–62% after a median of 34–37 days after PVE, and 72.2–80% of the patients are able to undergo resection as planned. It is generally indicated for patients being considered for right or extended right hepatectomy in the setting of a relatively small FLR. It is rarely required before extended left hepatectomy or left trisectionectomy, since the right posterior section (segments 6 and 7) comprises about 30% of total liver volume.
PVE is usually performed through percutaneous transhepatic access to the portal venous system, but there is considerable variability in technique between centers. The access route can be ipsilateral (portal access at the same side being resected) with retrograde embolization or contralateral (portal access through FLR) with antegrade embolization. The type of approach selected depends on a number of factors including operator preference, anatomic variability, type of resection planned, extent of embolization, and type of embolic agent used. Many authors prefer ipsilateral approach especially for right-sided tumors as this technique allows easy catheterization of segment 4 branches when they must be embolized and also minimizes the theoretic risk of injuring the FLR vasculature or bile ducts through a contralateral approach and potentially making a patient ineligible for surgery.
However, majority of the studies on contralateral PVE show it to be a safe technique with low complication rate. Di Stefano et al. reported a large series of contralateral PVE in 188 patients and described 12 complications (6.4%) only 6 of which could be related to access route and none precluded liver resection. Site of portal vein access can also change depending on the choice of embolic material selected which can include glue, Gelfoam, n-butyl-cyanoacrylate (NBC), different types and sizes of beads, alcohol, and nitinol plus. All agents have similar efficacy and there are no official recommendations for a particular type of agent.
Proponents of PVE believe that there should be very little or no tumor progression during the 4–6 week wait period for regeneration after PVE. Rapid growth of the FLR can be expected within the first 3–4 weeks after PVE and can continue till 6–8 weeks. Results from multiple studies suggest that 8–30% hypertrophy over 2–6 weeks can be expected with slower rates in cirrhotic patients. Most studies comparing outcomes after major hepatectomy with and without preoperative PVE report superior outcomes with PVE. Farges et al. demonstrated significantly less risk of postoperative complications, duration of intensive care unit, and hospital stay in patients with cirrhosis who underwent right hepatectomy after PVE compared to those who did not have preoperative PVE. The authors also reported no benefit of PVE in patients with a normal liver and FLR >30%. Abulkhir et al. reported results from a meta-analysis of 1088 patients undergoing PVE and showed a markedly lower incidence of Post Hepatectomy Liver Failure (PHLF) and death compared to series reporting outcomes after major hepatectomy in patients who did not undergo PVE. All patients had FLR volume increase, and 85% went on to have liver resection after PVE with a PHLF incidence of 2.5% and a surgical mortality of 0.8%. Several studies looking at the effect of systemic neoadjuvant chemotherapy on the degree of hypertrophy after PVE show no significant impact on liver regeneration and growth.
The volumetric response to PVE is also a very important factor in understanding the regenerative capacity of a patient’s liver and when used together with FLR volume can help identify patients at risk of poor postsurgical outcome. Ribero et al. demonstrated that the risk of PHLF was significantly higher not only in patients with FLR ≤ 20% but also in patients with normal liver who demonstrated ≤5% of FLR hypertrophy after PVE. The authors concluded that the degree of hypertrophy >10% in patients with severe underlying liver disease and >5% in patients with normal liver predicts a low risk of PHLF and post-resection mortality. Many authors do not routinely offer resection to patients with borderline FLR who demonstrate ≤5% hypertrophy after PVE.
Careful analysis of outcome based on liver remnant volume stratified by underlying liver disease has led to recommendations regarding the safe limits of resection. The liver remnant to be left after resection is termed the future liver remnant (FLR). For patients with normal underlying liver, complications, extended hospital stay, admission to the intensive care unit, and hepatic insufficiency are rare when the standardized FLR is >20% of the TLV. For patients with tumor-related cholestasis or marked underlying liver disease, a 40% liver remnant is necessary to avoid cholestasis, fluid retention, and liver failure. Among patients who have been treated with preoperative systemic chemotherapy for more than 12 weeks, FLR >30% reduces the rate of postoperative liver insufficiency and subsequent mortality.
When the liver remnant is normal or has only mild disease, the volume of liver remnant can be measured directly and accurately with threedimensional computed tomography (CT) volumetry. However, inaccuracy may arise because the liver to be resected is often diseased, particularly in patients with cirrhosis or biliary obstruction. When multiple or large tumors occupy a large volume of the liver to be resected, subtracting tumor volumes from liver volume further decreases accuracy of CT volumetry. The calculated TLV, which has been derived from the association between body surface area (BSA) and liver size, provides a standard estimate of the TLV. The following formula is used:
TLV (cm3) = –794.41 + 1267.28 × BSA (square meters)
Thus, the standardized FLR (sFLR) volume calculation uses the measured FLR volume from CT volumetry as the numerator and the calculated TLV as the denominator: Standardized FLR (sFLR) = measured FLR volume/TLV Calculating the standardized TLV corrects the actual liver volume to the individual patient’s size and provides an individualized estimate of that patient’s postresection liver function. In the event of an inadequate FLR prior to major hepatectomy, preoperative liver preparation may include portal vein embolization (PVE).
Hepatic resection had an impressive growth over time. It has been widely performed for the treatment of various liver diseases, such as malignant tumors, benign tumors, calculi in the intrahepatic ducts, hydatid disease, and abscesses. Management of hepatic resection is challenging. Despite technical advances and high experience of liver resection of specialized centers, it is still burdened by relatively high rates of postoperative morbidity and mortality. Especially, complex resections are being increasingly performed in high risk and older patient population. Operation on the liver is especially challenging because of its unique anatomic architecture and because of its vital functions. Common post-hepatectomy complications include venous catheter-related infection, pleural effusion, incisional infection, pulmonary atelectasis or infection, ascites, subphrenic infection, urinary tract infection, intraperitoneal hemorrhage, gastrointestinal tract bleeding, biliary tract hemorrhage, coagulation disorders, bile leakage, and liver failure. These problems are closely related to surgical manipulations, anesthesia, preoperative evaluation and preparation, and postoperative observation and management. The safety profile of hepatectomy probably can be improved if the surgeons and medical staff involved have comprehensive knowledge of the expected complications and expertise in their management.
The era of hepatic surgery began with a left lateral hepatic lobectomy performed successfully by Langenbuch in Germany in 1887. Since then, hepatectomy has been widely performed for the treatment of various liver diseases, such as malignant tumors, benign tumors, calculi in the intrahepatic ducts, hydatid disease, and abscesses. Operation on the liver is especially challenging because of its unique anatomic architecture and because of its vital functions. Despite technical advances and high experience of liver resection of specialized centers, it is still burdened by relatively high rates of postoperative morbidity (4.09%-47.7%) and mortality (0.24%-9.7%). This review article focuses on the major postoperative issues after hepatic resection and presents the current management.