Liver and Bile Duct Cancer

Partial hepatectomy.

Surgical excision by partial or total hepatectomy is the most effective and the only potentially curative therapy for HCC. Resectability for any hepatic tumor, including HCC, is dependent on several factors: the patient's ability to undergo a major surgical intervention based on general health criteria, absence of extrahepatic disease, liver disease extent, and favorable anatomic criteria—that is, the ability to achieve a complete resection while leaving behind an adequate liver remnant. Survival after liver resection depends on timely regeneration of the remaining liver, which, in turn, is influenced greatly by the preoperative liver functional status. Underlying hepatic parenchymal disease, specifically fibrosis and cirrhosis, adversely influences surgical outcome in many ways and often is the only determinant that precludes resection. The very hard nature of the liver substance in cirrhosis makes transection of the parenchyma and control of intrahepatic vessels more hazardous than in normal liver and more prone to hemorrhage. More important, the pathophysiologic changes related to portal hypertension, including the development of collateral venous channels and portasystemic shunts or varices, ascites, and hypersplenism, represents an enormous risk for perioperative hemorrhagic events and hepatic failure because of limited regenerative capacity. Portal hypertension, even in the face of relatively well-preserved hepatic synthetic function, is an ominous finding and generally excludes resection as a treatment option. For these reasons, patients with cirrhosis and HCC typically are better served with transplantation if indications regarding tumor size and number are present.

In patients with limited disease and no underlying liver parenchymal disease, the outcomes after resection are good. The operation can be performed with an operative mortality rate of less than 5% in high-volume centers, and 5-year survival may exceed 30%. This subgroup represents, however, a small minority of all patients with HCC; the vast majority have at least some degree of underlying liver disease or frank cirrhosis. The adverse influence of cirrhosis on surgical outcome is well documented, with very high perioperative mortality rates in prior series, up to 10% in some series from high-volume centers. From the same series, cirrhotic patients who survive the operation may have a reasonable 5-year survival rate, approximately 30%. Recent series have shown further improvements in outcome, with perioperative mortality of 1.4% and a 5-year survival rate of 77%. Patients with underlying liver disease who undergo resection are at high risk for recurrent disease, and also the development of new sites of malignancy in the diseased liver remnant and deterioration of liver function resulting in hepatic failure. Indeed, the presence or extent of cirrhosis has been shown to be an independent predictor of reduced survival.

Thus when assessing patients for surgery, careful evaluation of the hepatic functional reserve is equally as important as the disease extent and feasibility of a complete resection. The single most reliable method of assessing hepatic function is the Child-Pugh classification (see Table 77.1 ), which remains the most useful and most widely used in Western series, although the indocyanine green retention rate is commonly used in Asia. A more sensitive assessment of hepatic function is the hepatic vein wedge pressure, a technique that may be particularly useful for identifying patients with Child-Pugh A cirrhosis with occult portal hypertension. The invasive nature and special radiologic expertise required for this study have limited its use.

Most surgeons will consider resection only for patients with Child-Pugh A cirrhosis and in selected patients in the Child-Pugh B category, with major resections considered only in the former group. Few surgeons are willing to perform hepatic resection for patients with Child-Pugh category C, considering the high operative mortality rate and poor survival based on the underlying hepatic dysfunction. Nonetheless, some studies have reported reasonable long-term survival even when a larger tumor size required extended hepatectomy, rather than more limited resection. In general, though, these patients are better served with transplantation if they meet accepted criteria.

HCC has a great propensity for vascular invasion, and the presence of tumor thrombus within the main portal vein or vena cava ( E-Fig. 77.1 and Fig. 77.5 ) is an ominous sign that in the past was considered a contraindication to resection because of the very high risk of occult disseminated disease and the low likelihood of long-term survival. However, more recent studies have suggested that reasonable long-term survival can be achieved in selected patients in the presence of vascular invasion. A review by Roayaie and colleagues confirmed reduced OS after resection of HCC with major vascular involvement, but the results were much better in patients with portal vein tumor thrombus compared with those with hepatic vein involvement.

Multifocal HCC is a sign of more advanced disease but does not necessarily preclude surgical resection or ablation (or both). Five-year survival rates can be expected to be between 20% and 30%. Nonetheless, the presence of multiple tumors is associated with reduced survival after resection compared with resection of solitary tumors. Furthermore, tumor size is a well-known predictor of disease recurrence and survival.

A large analysis of 50 separate reports including nearly 15,000 patients showed a 5-year survival rate of 42%, higher in Asian than in Western patients. In a separate study from two large Asian centers, Li and colleagues reported an OS rate of approximately 40% after resection of large (≥10 cm) HCC, with worse outcome predicted with main portal vein invasion and multifocal disease. One strategy to improve outcome after resection is preoperative portal vein embolization. This technique involves occlusion of the portal vein supplying the portion of the liver targeted for resection, typically the right hemiliver. This procedure results in atrophy of the liver to be resected and hypertrophy of the future liver remnant and theoretically should result in a lower risk of postoperative liver failure. Indeed, a prospective study demonstrated the usefulness of preoperative portal vein embolization in patients undergoing resection of HCC, with significant reductions in postoperative liver failure, overall morbidity, and hospital length of stay. More recently, a technique known as ALPPS (associating liver partitioning with portal vein ligation) has been proposed to replace preoperative portal vein embolization as a means to induce rapid hypertrophy of the future liver remnant. This approach is a two-stage operation. The first stage involves dividing the liver parenchyma and the portal vein supplying the liver to be resected but leaving the specimen in situ, supplied only by hepatic arterial blood flow. In the second operation, the specimen is removed after division of the ipsilateral hepatic artery and hepatic vein, usually performed 1 to 2 weeks after the initial procedure and after ensuring adequate hypertrophy of the future liver remnant. Although ALPPS has been shown to effectively and rapidly effect hypertrophy of the future liver remnant, the high morbidity and mortality related to the procedure remain a major limitation to its widespread adoption.

Total hepatectomy and transplantation.

The Milan criteria—single tumor less than 5 cm in size or no more than three tumors, all less than 3 cm in diameter—became the standard guidelines for hepatic transplantation in patients with hepatic cirrhosis after they were demonstrated to be associated with an actuarial 4-year survival rate of 75% after transplantation. This report refocused attention on liver transplantation for HCC, which was verified in several subsequent reports. Using these criteria, several series have found excellent 5-year survival rates of 70% or greater, with a 15% chance for recurrence.

In comparing the results of transplantation with those of resection, it is important to recognize the inherent selection bias associated with the published reports. First, most patients targeted for transplantation typically have disease that is much more limited than those undergoing resection (smaller tumors, no major vascular invasion, fewer tumors), and therefore a better prognosis. Second, there is additional selection related to selection of patients whose disease has not progressed while on the transplant waiting list. Thus the patients who receive liver transplants are those whose tumors have a less aggressive natural history. This point is demonstrated by an intention-to-treat (ITT) analysis that found “dropout from waiting list” to be the sole survival predictor. This study noted that the 2-year survival rate of patients evaluated for transplantation was reduced from 84% to 54% during two separate time periods in which the wait time increased markedly, so that more patients were excluded from transplantation as a result of progression of disease. Survival was significantly worse for patients on the transplant list than for patients who were the best candidates for resection. A more recent study found that when the waiting list time exceeded 4 months, the differences between resection and hepatic transplantation were not detectable.

The problem of the waiting list is well recognized and has resulted in a number of strategies to improve outcome, the most notable of which is the use of ablative therapy, specifically transarterial chemoembolization (TACE), for patients awaiting transplantation. Use of this strategy probably reduces dropouts from the waiting list, although its impact on long-term outcome is unclear. It is clear, however, that patients who have a response to such treatment before transplantation, even those with tumors exceeding the Milan criteria, appear to have a good prognosis. In a study from the University of California, Los Angeles (UCLA) that included 501 patients, complete pathologic response after locoregional therapy before liver transplantation was associated with lower recurrence and greater OS. In a separate study comparing resection versus transplantation in patients with disease outside of the Milan criteria, response to pretransplant downstaging with TACE was associated with significantly improved survival compared with resection or lack of response. Another factor is the advent of the Model for End-Stage Liver Disease (MELD) for assessing the likelihood of death on the waiting list, and the policy of awarding a greater number of MELD points for patients with transplantable HCC.

Transplantation yields better long-term survival figures when compared directly with resection, but such comparisons are difficult to interpret given the marked differences in patient populations. In a number of recent studies that evaluated outcomes in patients undergoing liver resection with tumors that fit the Milan criteria, the OS rates were comparable with those of transplantation. A more recent analysis comparing treatment modality only in patients with transplant-eligible disease suggested better results with transplantation, although as with all such studies, selection bias cannot be entirely eliminated as a confounding factor As expected, the risk of intrahepatic recurrence in patients undergoing resection was higher than after liver transplantation. To address this problem, a strategy of salvage transplantation in those patients whose tumor recurs after hepatectomy has evolved and may be useful, although it has been shown that not all such patients benefit from such a strategy, which may be best used in the setting of favorable histopathologic findings.

In practice, many obstacles exist to limit the applicability of transplantation to a large number of patients worldwide. The greatest obstacle is the lack of available organs for transplantation. In Asian countries, where the need for donor organs is greater, along with the social and cultural obstacles, livers are in even greater shortage than in the United States. Living donor liver transplantation has therefore emerged as a potential means of filling the gap, although its use is associated with significant donor-related morbidity and mortality and is quite controversial. Because this procedure requires a right hepatectomy in a healthy donor, concerns have arisen about the safety and ethical implications of this procedure. In addition, sporadic reports of deaths in donors have intensified these concerns. In one of the largest series reporting the results of living donor liver transplantation in 71 patients, with approximately 40% a result of HCC, the mean waiting time to transplantation was markedly reduced from 414 (for cadaveric organ transplants) to 83 days (for living related donor transplants), with a recurrence rate of 15%.

Although perioperative morbidity and mortality rates have been as high as 20%, more recent results are more favorable. In fact, a multicenter comparison of resection and transplantation showed lower 90-day mortality for the latter (4.8% for transplantation compared with 10.9% for resection). For patients with liver dysfunction, total hepatectomy with liver transplantation represents the only potentially curative option, because few of these patients can tolerate major hepatectomy. To demonstrate this point, in noncirrhotic HCC, survival is similar after hepatectomy or transplantation, whereas in patients with cirrhotic HCC, survival was significantly improved after transplantation compared with hepatectomy at each TNM stage. The cost associated with transplantation procedure is also a major obstacle.

To summarize, patients with HCC without liver dysfunction should be considered for resection, whereas patients with HCC that arises in the setting of Child-Pugh B or C cirrhosis, and with disease extent meeting the Milan criteria, should be referred for transplantation. Pretransplant response to ablative therapy is associated with improved outcome.

Treatment complications.

After resection, postoperative morbidity occurs in approximately 40% of patients, consisting primarily of transient hepatic insufficiency, intraabdominal abscess or biloma, gastrointestinal bleeding, and cardiopulmonary complications. Postoperative mortality rates range from 3% to 12% in most series. After transplantation, the 90-day mortality rate has been as high as 15% but is lower in more recent series. In the study by Adam and colleagues, operative mortality and major morbidity associated with resection and transplantation were 4.1% and 3.0%, respectively, and 19.1% and 24.7%, respectively.

Follow-up program.

After surgical treatment of HCC, scheduled follow-up evaluations are extremely important to assess for recurrence ( Fig. 77.6 ), which can occur in up to two-thirds of patients after potentially curative resection but is less common after transplantation. Many resection patients with recurrent disease actually have metachronous second primaries that develop in the setting of cirrhosis owing to the fact that the entire liver is diseased and therefore susceptible. These recurrent or new hepatomas can be treated effectively only if discovered early. It is important to emphasize that effective treatments are available for recurrent disease, including transplantation, resection, ablation, and systemic therapy.

First follow-up evaluation after resection of HCC should include an office visit 2 to 3 weeks after hospital discharge. Liver transaminases and AFP are assessed. A return of tumor markers to normal levels postoperatively should dictate a routine follow-up approach of office visits every 3 to 6 months with history and physical examination and measurement of liver function tests and tumor markers. Patients should be asked about symptoms of worsening portal hypertension or liver failure and symptoms of biliary obstruction, including itching or changes in stool or urine color, primarily because a significant proportion of patients die from liver failure, not HCC. Of greatest importance is adequate treatment to prevent the complications of portal hypertension, because it is estimated that up to one-fourth of patients who die after diagnosis of liver cancer succumb to gastrointestinal bleeding from portal hypertension. New-onset right upper quadrant pain or bone pain should prompt investigation by appropriate radiologic examinations. Physical examination should evaluate for new masses, worsening ascites, and jaundice. The follow-up program also should include contrast-enhanced abdominal CT every 6 months, with a chest radiograph obtained yearly. Five years after resection, office visits should be reduced to every 6 months. The follow-up program also must aim to prevent and treat complications of associated etiologic parenchymal disease—for example, HBV and hemochromatosis.