HEPATIC MALIGNANCIES

MULTIDISCIPLINARY APPROACH TO CANCER

0039-6109/00 $15.00

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HEPATIC MALIGNANCIES Jane I. Tsao, MD, Julia DeSanctis, MD, Ricardo L. Rossi, MD, a n d Richard A. Oberfield, MD

The past decade has heralded exciting advances in the diagnosis and treatment of patients with hepatic malignancies. Advances in radiologic technology, such as hardware allowing hgher-quality and more rapid imaging and software capable of complex image reconstruction, have led to a rapid increase in the diagnostic and interventional armamentarium for primary and metastatic hepatic malignancies. The establishment of safe surgical techniques for liver resection and improved perioperative care have lowered the risk for morbidity and mortality of resection for hepatic malignancies to no more than that of other abdominal surgeries.'"O Because the 1990s was a decade of globalization of communication and medical exchange, the expertise of the world's leading hepatic surgeons and oncologists has been made available to all physicians who care for patients with malignant diseases of the liver. ASSESSMENT OF FOCAL HEPATIC LESIONS

Sonography

Sonography is the most commonly used screening modality for the detection of hepatocellular carcinoma (HCC) ~ o r l d w i d e , 'but ~ the sensitivity of sonography for the detection of HCC in the setting of end-stage cirrhosis is only 45%0." The appearance of most focal hepatic lesions on sonography is nonspecific (Fig. 1). The overall sensitivity of sonography for the detection of hepatic lesions is 53% and it is 20% for lesions less than 1 cm in diameter.lo3Although sonography lacks the sensitivity of CT and magnetic resonance (MR) imaging in the

From the Departments of Surgery (JIT) and Radiology (JD), Tufts University School of Medicine; and Departments of General Surgery (JIT), Diagnostic Radiology (JD), and Medical Oncology (RAO), Lahey Clinic Medical Center, Burlington, Massachusetts; and the Department of Surgery, Universidad de Chile, Universidad Catblica, Clinica Alemana, Santiago, Chile (RLR)

SURGICAL CLINICS OF NORTH AMERICA VOLUME 80 * NUMBER 2 APRIL 2000

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Figure 1. Hepatocellular carcinoma. A, On ultrasound, the mass (cursors) is appreciable because of its exophytic location, altering the contour of the liver. Its echotexture, however, is virtually identical to the coarse echotexture of the adjacent cirrhotic liver. The lesion would be difficult to identify if it were in the liver substance. Further, the ultrasound appearance is entirely nonspecific. B, T1-weighted, spin echo MR image. The mass is readily apparent. Further, the imaging features (encapsulation, T1 hyperintensity, and the mosaic pattern) are characteristic of HCC.

classification of hepatic lesions, it retains an important role in the guidance of percutaneous biopsies and in the follow-up of patients with known lesions. CT

CT is well suited for the initial evaluation of patients with known or suspected hepatic malignancy. The introduction of helical CT has made it possi-

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ble to image the liver during one or all three phases of hepatic parenchymal enhancement that occur following bolus injection of intravenous contrast: (1)the hepatic arterial phase (HAP), (2) the portal venous phase (PVP), and (3) the delayed (equilibrium) phase.6 Conventional CT has only one imaging phase, which approximates the PVP. Hepatic neoplasms receive virtually all of their blood supply from the hepatic artery, whereas normal liver parenchyma receives approximately 75% of its blood supply from the portal vein. Because of this differential blood supply between neoplastic and normal liver, most hepatic neoplasms are hypodense and maximally conspicuous during the PVP, when the normal parenchyma is brightly enhanced, but HCC and a subset of hepatic metastases, including renalcell carcinoma, islet-cell tumors, melanoma, sarcoma, and breast cancer, are considered hypervascular because they enhance more prominently than normal liver early after the contrast During the HAP, these hypervascular lesions are conspicuous as hyperdense areas relative to normal parenchyma, enhancement of which is diluted by the dominant contribution of unopacified portal venous blood. These hypervascular lesions tend to be isodense to normal hepatic parenchyma during the PVP, when enhancement of the normal parenchyma is maximal, rendering the lesions less apparent or even entirely con~ealed.~~ The use of biphasic helical CT with imaging of the liver during the HAP and PVP has increased sensitivity for the detection of HCC compared with imaging during the PVP alone. The sensitivity of PVP imaging alone was 67% to 82% compared with 87% to 92% with biphasic helical CT during HAP and PVP.7,18, 38 Biphasic helical CT increases detection of hypervascular metastases relative to PVP imaging but Oliver et aP7 found that unenhanced imaging was better than HAP imaging in identifying lesions not seen in the PVP (28% versus 13% additional lesions; Fig. 2). Because metastases are the most common hepatic malignancy in the Western world, and approximately 90% of hepatic metastases are partially or completely hypova~cular,~~ routine screening for hepatic malignancy is performed in PVP alone. Dual-phase hepatic CT during HAP and PVP incrementally increases detection in patients with suspected HCC7,18, 38 and hypervascular m e t a ~ t a s e s . ~ ~ When hypervascular metastases are suspected, the acquisition of unenhanced images of the liver before biphasic helical CT further improves detection.67 The combination of helical CT and advanced software technology has made possible the reconstruction of three-dimensional CT images. Three-dimensional CT images provide more precise diagnostic information and a realistic virtual image of a tumor's location in the liver. Togo et a199found that three-dimensional CT was 100% accurate in localizing tumors, whereas conventional CT was 75% accurate. The use of three-dimensional CT images has made possible surgical resections confined to the portal unit containing the tumor and allowed maximal liver sparing in patients with poor liver reserve.99 MR Imaging

MR imaging uses inherent soft-tissue contrast and tissue-specific contrast agents to create a highly effective imaging modality for the classification of liver lesions. The sensitivity of MR imaging for the detection of focal hepatic lesions is at least that of biphasic helical CT. In a prospective comparison,106dynamic arterial phase MR imaging was superior to multiple phase helical CT in the detection of HCC less than or equal to 3 cm in diameter. MR imaging also has

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Figure 2. Carcinoid metastasis. A, Unenhanced CT scan. A carcinoid metastasis is present in segment 7 of the liver (arrow). 6,Contrast-enhanced CT scan during the PVP of imaging at the same level as in A. Typically hypervascular, the lesion has enhanced equally to the normal hepatic parenchyma, rendering the metastasis inconspicuous.

a distinct advantage over CT in the setting of fatty liver (Fig. 3). MR imaging can distinguish focal fat from hepatic tumors and can improve detection of hepatic lesions in the setting of diffuse fatty change7O Factors that limit the widespread use of MR as a screening tool for hepatic lesions include the expense of MR, the limited access to MR scanners, and the

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variability of image quality caused by motion artifacts from ascites, peristalsis, respiration, and cardiac activity. MR imaging is ideal when further characterization of lesions detected by another modality is needed. For example, the peripheral nodular enhancement characteristic of hemangioma on dynamic contrast-enhanced CT or MR imaging is not universally demonstrable. On MR imaging, heavily T2-weighted imaging

Figure 3. Metastasis in a fatty liver. A, Unenhanced CT scan. Questionable lesion is the posterior right lobe of the liver. B, T2-weighted spin echo MR image. The metastasis in the posterior right lobe is seen clearly (arrow).

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is more than 90% accurate in differentiating hemangiomas from metastasesz6 (Fig. 4).Following intravenous contrast enhancement, transient rim enhancement on T1-weighted images and peripheral "washout," leaving a hypointense peripheral rim on delayed contrast-enhanced images57(Fig. 5), have been reported to be highly reliable indicators of malignancy. Several new MR contrast agents are under development, including reticulo-

Figure 4. Metastasis versus hemangioma; differentiation with T2-weighted spin echo MR imaging. A, TR 3000rTE 80: the metastasis (arrow) and the hemangioma (arrowhead) are of similar signal intensity. B, TR 3000rTE 160: on this heavily T2-weighted image, the hemangioma remains hyperintense (equivalent to cerebrospinal fluid [arrow]), whereas the metastasis loses signal, distinguishing it from the benign hemangioma.

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Figure 5. Transient rim enhancement and peripheral washout are highly reliable indicators of malignancy. A, Unenhanced T1-weighted gradient echo image demonstrates a hypointense mass (arrow). 6, Thirty seconds after gadolinium administration. Rim enhancement is apparent. Also, other smaller, rim-enhancing metastases have become conspicuous (arrows). C and 0,Five minutes following gadolinium administration. The dominant lesion demonstrates the peripheral washout characteristic of malignancy (arrow).

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endothelial-cell-specific agents and hepatobiliary-specific agents (Fig. 6). Initial results suggest that these agents may make possible noninvasive imaging of the liver with the sensitivity of CT arterial portography (CTAP) but without its false-positive rate. Additional prospective comparison trials are necessary to determine whether these agents compare favorably to CTAP for preoperative staging of hepatic malignancy.

Figure 6. Improved lesion detection with Feridex MR imaging. A, Contrast-enhanced CT scan of a patient with colon metastases. B, MR image after Feridex administration. More lesions are apparent and their conspicuity is improved (arrows).

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Figure 7. CTAP of the patient in Figure 2 at the corresponding level. CTAP detects an additional lesion, not evident at unenhanced or PVP-enhanced CT scan (arrow).

PREOPERATIVE STAGING CT Arterial Portography

For surgical planning, CTAP is accepted as the most sensitive preoperative imaging modality (Fig. 7). Studies evaluating CTAP for the detection of hepatic metastases report sensitivities of 92% to 94%.84, 92 Although Murakami et a158 found helical CTAP to be only 85% sensitive in the detection of hypervascular HCC, when combined with CT hepatic arteriography, the sensitivity increased to 95%. CTAP and CT hepatic arteriography are invasive studies, however, requiring selective arterial catheterization. Because hepatic masses and areas of altered parenchymal perfusion appear as focal hypodense abnormalities on CTAP, the false-positive rate of CTAP is substantial, at 15% to 17%.92,93 Delayed images and an understanding of classic pseudolesions created by perfusion anomalies minimize false-positive diagnoses. Laparoscopy and Laparoscopic lntraoperative Sonography

Diagnostic laparoscopy allows surgeons to inspect for peritoneal metastases and assess the extent of cancer and size of the liver remnant. Intraoperative sonography is sensitive in the detection of additional intrahepatic metastases not seen on preoperative imaging. Lo et aI5Operformed laparoscopy and laparoscopic intraoperative sonography (LIOUS) on 91 patients with HCC immediately before planned laparotomy for liver resection. The procedures added 10 to 120 minutes (median, 30 minutes) to surgical time and avoided laparotomy in 15 of 24

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unresectable patients. Barbot et a15 reported a series of 23 patients in whom laparoscopy and LIOUS predicted unresectability and avoided unnecessary laparotomy in six of eight patients. These studies indicated that laparoscopy and LIOUS altered surgical plans in 16% to 26% of patients and has a predictive value for unresectability of 62% to 75%. Laparoscopy and LIOUS were not sensitive in determining the presence of tumor thrombi in major vasculature, and its accuracy in the detection of adjacent organ invasion was diminished in cases in which tumor was more than 10 cm in diameter.50Laparoscopy may be limited by adhesions and mechanical factors precluding satisfactory inspection and LIOUS. Staging laparoscopy and LIOUS should not replace preoperative noninvasive imaging studies. They are advisable in selected patients to avoid unnecessary laparotomy, especially when preoperative imaging studies are suggestive, but not definitive, for unresectable disease. TREATMENT OPTIONS FOR PATIENTS WITH PRIMARY AND SECONDARY HEPATIC MALIGNANCIES

Surgical resection remains the only potentially curative treatment for hepatic malignancies and is the gold standard against which all other therapies are compared. The normal liver has substantial reserve capacity and regenerative ability and can safely tolerate a 65% to 75% resection. Unfortunately, most primary and secondary hepatic malignancies are unresectable. Approximately 35% of patients with HCC60 and 25% of patients with hepatic metastases have resectable disease at the time of diagnosis. Consequently, nonsurgical local ablative therapy and regional and systemic chemotherapy have a significant role in the treatment of most patients with liver malignancies. The three main categories of local ablative therapies are (1) injectional therapies, of which percutaneous ethanol injection (PEI) is the prototype but also which includes acetic acid and hot-saline injection; (2) cryoablative therapy; and (3) thermal ablative therapies (e.g., radiofrequency ablation, microwave therapy, interstitial laser photocoagulation, and high-intensity focused sonography). Regional therapy includes hepatic artery infusion chemotherapy (HAI) and hepatic artery chemoembolization (HACE). HACE combines the principles of regional chemotherapy and embolization to induce ischemia and tumor necrosis. The most established nonsurgical therapies available for HCC are PEI and HACE. For metastases, HACE and radiofrequency thermoablation have shown benefit. Suggested algorithms for the diagnosis and management of patients with hepatocellular carcinoma and colorectal metastases to the liver are shown in Figures 8 and 9. Although algorithms serve as guidelines, the approach to each patient should be individualized based on comorbid factors, patients' desires, family input, and available techniques. Treatment of Primary Hepatic Malignancy

Hepatocellular carcinoma is one of the most prevalent cancers worldwide. Several milestones in the diagnosis and management of patients with HCC have occurred in the past decade: (1)better screening in susceptible populations, that is, patients with hepatitis B or C infection and patients with alcoholic cirrhosis, using the combination of serum a-fetoprotein (AFP) and liver sonography, has resulted in the diagnosis of smaller, subclinical HCC; (2) vigilant postoperative

HEPATIC MALIGNANCIES Clinically Apparent HCCl HCC Screening (AFP, US, CT)

f

.)

No

\/ 1

]YES

a '

Significant comorbid factors? \

potential for down-

1

No

1) PEI k 2) HACE 3) cry0 4) RF 5) Palliation only (supportive)

NO

YES

Hepatic failurekevere insufficiency

IN0 \

Radlologic Staging (MRI, 3D-CT, CTAP)

1

YES

YES

HCC c 2cm

Child's A or B \

1 \

? Transplant

Supportive

I

Neoadjuvant Therapy (HAI, HACE, XRT, systemic chemo)

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1) PEI f 2) HACE 3) RF 4) Palliation only (supportive)

RESECTABLE DISEASE?

1

SURGICALStaging (Laparoscopy + LlOUS or exploratory laparotomy)

I

-

YES

Extrahepatic Disease?

1 1

No

Palliative chemo vs supportive care

NO

Resectablewith good margin?-

YES RESECT

1) Combined resection 8 cryotherapy or RF 2) Cryotherapy 3) RF

POSTOPERATIVE SURVEILLANCE

Figure 8. Management of HCC. CXR gen.

=

chest radiograph; CEA

=

carcinoembryonic anti-

surveillance and liberal re-resection have expanded the number of patients who benefit from resection and improved their overall survival rate; (3) neoadjuvant cytoreductive measures, such as HACE, HAI, and regional radiotherapy, have been used to increase resectability in patients with initially unresectable lesions because of advanced HCC. Predictors of the Risk for Death Caused by Surgical Complications Selection of patients with HCC for hepatectomy has traditionally been based on the Child-Pugh classification system. The presence of ascites, hypoalbu-

YES

YES

1

Resectabld Liver Met?

Postoperative Surveillance

1

RESECT

YES

1

Resectable with good margin?

Extrahepatic Disease?

+

Surgical Staging (Laparoscopy + LlOUS or exploratory laparotomy) I

Radiologic Staging (MRI. BD-,, CTAP)

/

No

/

Wll Pt. tolerate hepatic resection?

Figure 9. Management of colorectal metastases to the liver. Pt = patient.

NO Wll Pt. tolerate lungand liver resection

-

A

Palliative Rx (Systemic chemo or supportive Rx)

NO

Resectable lung met?

Radiologlc Staging (Dual phase CT abdomen and pelvis, ?CTAP, ?MRI. ?BD-CT)

J

+

I

Consult Liier Surgeon

r

.c

Suspect Liver Mots

-

Consult thoracic surgeon

1

Suspect Lung Mots

*

3) RF

2) Cryotherapy

Cancer Confined to Liver?

PPostop HA1 or HACE

4) Cryotherapy

1) HACE 2) HA1 3) RF

Palliative Chemo or Supportive Rx

?Postop systemic chemo

NO

-

Potential for downstaging (neoadjuvanttherapy) or Increased resectability? (PV embolization)

YES

I-

Neoadjuvant Therapy (HAI. HACE. systemic chemo) Portal Vein Embollzatlon

1) Combined resection 8 cryotherapy or RF

Clinically Apparent Coloroctal Metastasb to Llverl Colorectal Ca Postoperative Survelllance (CW. Colonoscopy, CXR CT CT Abdomen and Pelvis)

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minemia, hyperbilirubinemia, and prolonged prothrombin time is indicative of poor liver function and associated with poor surgical outcome. In Asia, where more than 80% of HCC arises in cirrhotic livers, postoperative liver failure is the leading cause of death following liver resection for HCC. To minimize the risk for death caused by surgical complications, preoperative evaluation of hepatic function is essential. The indocyanine green (ICG) clearance test has been widely used in Asian countries to assess dynamic hepatic function. ICG is a nontoxic dye that is removed and excreted by the liver. Lau et ale prospectively studied 127 patients undergoing hepatectomy for HCC and singled out ICG retention at 15 minutes of more than 14% as the most significant predictor of operative mortality. Shimada et als7reviewed 338 paitients who underwent resection for HCC and found that serum aspartate aminotransferase, blood urea nitrogen, diabetes, and ICG retention were predictors of operative morbidity and mortality. Intraoperative factors, such as blood loss and duration of operation, also contributed to postoperative complications. Noun et aF6retrospectively reviewed 108 Child’s A cirrhotic patients and concluded that serum alanine transferase (ALT) is a predictor of operative morbidity and mortality. Patients with ALT levels of more than 200% of normal had increased operative morbidity, such as ascites, kidney failure, and upper gastrointestinalbleed. Patients with ALT levels of more than 400% of normal had an operative mortality rate of 38% compared to 4% in patients whose ALT levels were 200% of normal. The investigators found that most patients with significantly elevated serum ALT levels had hepatitis C and active hepatitis. They cautioned that cirrhotic patients with ALT levels of more than 200% of normal should undergo only limited resection and that nonsurgical therapy is preferable when larger resection is required. Nagasue et a159found that preoperative HACE was associated with a higher risk for postoperative mortality in patients with Child’s B and C disease.

Hepatic Resection

Tani et a196reported a series of 90 patients who underwent resection for HCC between 1981 and 1994. Cirrhosis was documented in 70% of patients. Serum antihepatitis C was positive in 77%of patients, hepatitis B surface antigen was positive in 19%, and chronic active hepatitis was present in 30%. The hospital mortality rate was 4%. The 5-year and 10-year cumulative survival rates were 38% and 25%, respectively. These survival results were achieved with aggressive management of patients with recurrent HCC. Lise et a147reported on 100 patients with HCC undergoing resection in Italy. Seventy-eight percent of patients had cirrhosis; 68% had Child’s A class, and the remainder had Child’s B. The hospital mortality rate was 7%. The overall 5-year and disease-free survival rates were 38% and 26%, respectively. Tang et a197reviewed 3 decades of experience with HCC in Shanghai and found an increasing incidence of smaller HCC diagnosed in asymptomatic patients undergoing screening with sonography and AFP. They reported a 5-year survival rate of 46% among patients undergoing resection for HCC during 1983 and 1994, a decade during which re-resection for recurrent HCC was done more frequently. Nagasue et a159reviewed the surgical results of patients with Child’s B and C cirrhosis. They reported an overall hospital mortality rate of 14%; a major morbidity rate of 27%; and 5-year overall and disease-free survival rates of 21% and 15%, respectively.

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Hepatic Resection Versus Transplantation

Over the past decade, liver transplantation for patients with large HCC has become obsolete because of poor results, but many surgeons still believe that transplantation is the preferable approach to the treatment of patients with small HCC5'jbecause it completely removes the premalignant cirrhotic liver. Although many centers have reported excellent survival rates after transplantation for small HCC, many tumors were found incidentally at pathologic evaluation of the explanted cirrhotic liver and may represent an earlier stage of cancer. Data from studies comparing transplantation and resection are controversial, partly because of the heterogeneity of patient populations. Otto et a169retrospectively reviewed patients with HCC treated by transplantation (n = 50) and by resection (n = 52). They found that the 3-year survival and recurrence rates were similar among the two groups. Tumor size was the only independent predictor for recurrence in both groups. For tumors less than 5 cm in diameter, vascular infiltration also predicted recurrence in the transplanted group. Otto et aP9 concluded that the theoretic oncologic advantage of liver transplantation compared with liver resection, even for the treatment of small HCC, is questionable. Pichlmayr et a174came to the same conclusion. Liver resection is the treatment of choice for patients with resectable HCC for the following three reasons: (1) the scarcity of donor livers, (2) similar morbidity and mortality rates after resection and transplantation, and (3) similar survival and recurrence rates after resection or transplantation. Liver transplantation, however, retains a role in the treatment of patients with small HCC if resection is impossible because of tumor location or poor hepatic functional capacity.69 Predictors of Long-Term Prognosis

Multivariate analysis of prognosticators has generally shown that Child's class, number of tumors, tumor size, tumor node metastasis (pTNM) stage, venous invasion, preoperative AFP and ALT, and resection margin are independently significant.'" 47, 59, 96 Tani et a196found that solitary HCC less than 4 cm in diameter, absence of intrahepatic metastasis, and a good hepatic functional reserve contributed to improved survival rates. Contrary to other reports, their analysis revealed that portal vein invasion, capsular infiltration, and operative blood loss did not significantly influence survival. Nonami et a16*found that tumor size of more than 2 cm, multiple tumors, surgical margin of less than 1 cm, and Child's C class were independently significant factors of poor survival. This group also concluded that the pTNM staging system is predictive of tumor recurrence, with stage I11 and IVa patients having a significantly higher incidence of tumor recurrence, 60%, than stage I and I1 patients, 40%. They suggested that to allow for better interpretation and comparison of data from different institutions, the results of hepatic resection for HCC should be stratified by pTNM staging and Child's classification of hepatic function. Nagasue et a159analyzed predictors of survival after resection in a hgher-risk group, patients with Child's B and C cirrhosis. Favorable factors for survival were Child's B versus C and a low ALT level before surgery. C h u et all7 investigated prognostic factors based on the pathologic status of the remnant liver. They found that the presence of hepatitis B infection, chronic active hepatitis, hepatocyte dysplasia, and a preoperative bilirubin level of more than 1.5 mg/dL unfavorably affected the disease-free survival time. El-Assal et alZ7devised a scoring system for the prediction of recurrence

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and survival time after curative hepatic resection for HCC using six factors: (1) portal vein invasion, (2) intrahepatic metastasis, (3) hepatic vein invasion, (4) serosal invasion, (5) absence of tumor encapsulation, and (6) presence of capsular invasion. They subdivided patients into three risk groups based on disease-free survival data. The 5-year disease-free survival rate in patients with a score of 0 or 1 was 54%; 2 to 4,12%; and more than 5, 7%. Neoadjuvant Therapy

Despite increased screening for HCC, most HCC diagnosed is large and often multiple. This necessitates therapy to increase resectability. HA1 or HACE, alone or in combination with radioimmunotherapy or regional radiotherapy, has been used as neoadjuvant cytoreductive thera~y.9~ In patients showing response and meeting resection criteria, hepatic resection is carried out to eradicate residual cancer. Tang et a197reported a 5-year survival rate of 62%with this multimodality treatment in 72 patients whose HCC was unresectable at diagnosis. Majno et a151 investigated the effect of HACE on 49 patients undergoing resection and 54 patients undergoing transplantation for HCC. Downstaging or total necrosis of the tumor induced by HACE occurred in 62% of patients and was associated with an improved disease-free survival time in both groups. In the resection group, neoadjuvant HACE was useful to improve the resectability of initially unresectable tumors. Lise et a147 also reported that preoperative HACE significantly prolongs disease-free survival time. Although neoadjuvant therapy may increase the number of patients amenable to resection, clinicians must be cautioned that in patients with moderate to severe liver dysfunction, the use of neoadjuvant HACE significantly increases the risk for postoperative 59 liver Percutaneous Ethanol Injection

Percutaneous ethanol injection (PEI) involves the injection of absolute (95%) ethanol into the HCC by needles placed under imaging guidance (Fig. 10). Diffusion of ethanol into cells induces protein denaturation, resulting in coagulation necrosis and cell death.- Endothelial damage augments tumor killing by inducing local vascular thrombosis and ischemia?" Diffusion of ethanol throughout a targeted HCC is facilitated by its spongelike internal consistency. The encapsulation of HCC and surrounding cirrhotic parenchyma resist diffusion of ethanol outside of the borders of the HCC. The procedure is typically well tolerated with transient, dose-dependent pain and fever.8oMajor complications occur in 2% to 5% of patients who undergo PEI, and procedure-related death is rare.48, 49, 80 Prognostic factors following PEI include size and number of lesions and hepatic functioning. Patients with Child's class A cirrhosis and solitary lesions 3 cm or less in diameter achieved 3-year and 5-year survival rates of 86% and 48%, respe~tively.~~ Nonetheless, favorable survival rates have been reported even in patients with multiple lesions and lesser hepatic functioning. In patients with Child's class B cirrhosis and multiple HCCs, the 3-year and 5-year survival rates were 59% and 0%, re~pectively.~~ In a cohort study, Castells et all4 compared the outcome of patients with solitary HCC less than 4 cm in diameter undergoing PEI versus surgical resection. The two cohorts were similar with respect to age and tumor stage. Preproce-

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Figure 10. Percutaneous ethanol injection (PEI) for HCC. A, HCC in the dome of the liver (surrounded by cursors). Illustration continued on opposite page

dure hepatic functioning was Child’s class A in 30 of 33 surgically treated patients but in only 7 of 30 PEI-treated patients. Survival rates at 4 years did not differ significantly for the two cohorts, at 44% for surgically treated patients and 34% for PEI-treated patients. Hepatic Artery Chemoembolization

Chemoembolization is performed following selective catheterization of the right or left hepatic artery. Protocols vary among centers, but all involve delivery of one or more chemotherapeutic agents (e.g., doxorubicin, cisplatin, and mitomycin C) suspended in water-soluble contrast and iodized oil, which acts as a carrier for the chemotherapeutics and slows blood flow. Particulate embolization, most commonly in the form of a gelatin foam (Gelfoam, UpJohn Co., Kalamazoo, MI) slurry, is performed during the same session. Regardless of the specific protocol, the endpoint following chemoembolization is near-stagnation of blood flow in the arterial distribution of the targeted lesion@). Postembolization syndrome consisting of pain, fever, nausea, vomiting, leukocytosis, and transient elevation of liver enzymes is the rule, but supportive therapy typically suffices. Major complications occur in 3% to 4% of patients and include hepatic failure, hepatic infarction, hepatic abscess, tumor rupture, hepatic arterial occlusion, and nontarget embolizatian.2°,73, 91 Postprocedural hospital admission may range from 2 to 5 days. The efficacy of HACE is controversial, made more difficult by the heterogeneity of the chemoembolization protocols with respect to variables such as the use of Lipiodol, the choice of chemotherapeutic agent, the use of repeated treatments, and the heterogeneity of the patient populations being studied.

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Figure 10 (Continued). B, Appearance during CT-guided PEL Note markedly low density of the ethanol. C, At ultrasound performed immediately after PEI, the ethanol in the treated lesion is hyperechoic (arrow).

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Prospective, randomized, controlled studies are lacking, and results from different investigators are, in some instances, conflicting. In fact, ChungZoargues that prognostic factors related to hepatic function and tumor variables are the most important determinants of survival and, as a result, comparison of survival rates among different studies, with their different patient populations, is not meaningful.20The preponderance of data, however, supports HACE as a useful treatment modality for patients with inoperable HCC. In sizable series, survival rates at 3 years have ranged from 13% to 40%.11,29, 34, 83, lo5, Io7 Although some investigators3Ihave found no survival benefit of HACE over symptom treatment, two European groupsll, 83 demonstrated a survival benefit for patients with unresectable HCC treated with HACE versus those not treated. The 3-year survival rates of treated patients were 26% to 27% versus 3% to 5% for the untreated patients.”,83 Because HACE cannot achieve the survival rate of patients undergoing surgical resection for HCC, it should be reserved for patients with unresectable HCC?9,8zHACE should not be performed in patients with predominant or extensive extrahepatic disease. Because HACE, unlike PEI, causes some damage to the hepatic parenchyma not involved with tumor, significant baseline liver dysfunction is a contraindication. The constellation of more than 50% replacement of the liver by tumor, a lactate dehydrogenase level of more than 425 IU/ L, an aspartate aminotransferase level of more than 100 IU/L, and a total bilirubin level of 2 mg/dL or more has been shown to correspond to a high risk for acute hepatic failure following HACE.” Refractory ascites and difficult-tocontrol encephalopathy are also associated with a greater risk for postprocedural hepatic failure.” Biliary obstruction with intrahepatic ductal dilatation is a contraindication to HACE because of an associated high risk for biliary necrosis.19 Portal vein occlusion is a relative contraindication because HACE can be performed safely in the setting of portal vein occlusion provided that well-formed portal venous collaterals with hepatopetal flow and preserved liver function are adueved.” Combined Percutaneous Ethanol Injection and Hepatic Artery Chemoembolization

Several studies have demonstrated the efficacy of combined PEI and HACE for the treatment of patients with unresectable HCC, especially in patients with multiple and large (> 3 cm) lesions?, 45, 95 In a prospective study, Lencioni et ale treated 86 patients with Child’s class A or B cirrhosis using a single session of HACE followed by PEI. On follow-up CT and MR imaging, a complete response was achieved in 82% of patients and a partial response was achieved in the remainder. The overall survival rate at 3 years was 69%. Allgaier et a13compared the efficacy of PEI and HACE alone and in combination in 132 patients with inoperable HCC. The median survival time was 25 months for patients treated with combined PEI and HACE compared with 18 months and 8 months for patients treated with PEI or HACE alone, respectively3 Cryotherapy

Cryoablation causes nonspecific tissue necrosis as a result of freezing and microvascular thrombosis. LIOUS is used to guide the cryoprobe to the liver lesion. The procedure is safe and carries risks and complication rates similar

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to surgical resection.', Io9 Complications of cryotherapy include myoglobinuria, coagulopathy, acute tubular necrosis, hypothermia, and hemorrhage from cracked liver parenchyma. Cryotherapy has been used for localized and unresectable HCC and for the management of patients with positive margins and residual disease following resection. Although palliation is achieved, no enhancement of survival has resulted. No randomized trials comparing cryotherapy alone or with other treatments have been published. Most investigators agree that cryotherapy combined with resection or with HA1 or PEI increases the likelihood of eradicating tumor in patients with unresectable liver malignancies.lM,lW Zhou and Tanglog performed resection of frozen tumor (i.e., cryoresection) in 72 patients and found in this subgroup of resectable patients a 5-year survival rate of 60%. Longer follow-up and randomized trials are needed to demonstrate survival benefit. Systemic Chemotherapy

Systemic chemotherapy for HCC is generally for palliation. Single agents, such as doxorubicin and 5-fluorouracil (5-FU) with leucovorin, have often been used, with response rates of 10% to 20%. Newer agents, such as irinotecan,68 and combinations, such as doxorubicin, 5-FU, cisplatin, and i n t e r f e r ~ n have ,~~ shown some activity. Additional clinical trials are needed to explore the usefulness of the new antitumor drugs. Tamoxifen has been explored in view of the presence of estrogen receptors in approximately 30% of HCC, with evidence of both benefit and no benefit.", 88 Regional Chemotherapy by Hepatic Artery Infusion

In view of the ineffectiveness of systemic therapy for HCC, HA1 chemotherapy was devised to provide higher concentrations of drugs directly to the liver. Regional drug delivery to the liver is accomplished by a subcutaneous port or pump connected to a catheter positioned selectively in the hepatic artery. Drugs such as floxuridine, mitomycin, doxorubicin, and interferon have been used, with response rates of 40% or more," 9* 13, 71 but no randomized studies have shown survival advantage by this treatment modality for HCC. HA1 has been used with other modalities, such as radiotherapy and cryotherapy, suggesting lo9Clinical trials using HAI-~isplatin~~ and gene therapy77are in progress. FOLLOW-UP STRATEGIES

Recurrence of HCC in the liver remnant is the rule after surgical resection and other treatment modalities, occurring in approximately 60% of patients (range, 50-loo%, depending on length of Whether the recurrence is caused by metastasis (i.e., intrahepatic metastasis) or new foci of HCC (i.e., multicentric occurrence) is often difficult to confirm. Kumada et al4Iinvestigated the patterns of recurrence after initial treatment (i.e., PEI or resection) of HCC in tumors less than 2 cm in diameter. The overall recurrence rate was 24% at 1 year, 65% at 3 years, and 76% at 5 years. Fifty-one percent of patients had intrahepatic metastasis. Most intrahepatic metastasis occurred within the first 3 years after treatment and was associated with the

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degree of tumor differentiation. Forty-nine percent of patients had multicentric occurrence of HCC, which was found throughout the follow-up period and did not cluster around the first 3 years after treatment. The presence of underlying liver disease, such as anti-hepatitis C positive and elevated AFP, was associated with an increased risk for multicentric occurrence. Kumada et a141 found that the prognosis of patients who underwent treatment of multicentric occurrence was superior to that of patients with intrahepatic metastasis. Vigilant postoperative surveillance is critical to the timely detection of HCC recurrence. In a study by Shimada et patients underwent monthly AFP testing, liver sonography, and dynamic CT scanning every 3 months.% In the study by Tang et al;7 patients had AFP checks and liver sonography every 2 or 3 months for 5 to 10 years after resection.97

TREATMENT OF RECURRENT HEPATOCELLULAR CARCINOMA

Tani et a196followed up 90 patients with resected HCC for 1 to 11 years and reported a recurrence rate of 74% (64 of 86 patients). Eighty-eight percent of the recurrence was in the liver, 6% in bone, 5% in lymph nodes, and 2%in lung. In 14 patients, additional treatment was not possible because of poor liver functioning, general weakness, and an advanced state of recurrence. The remaining 50 patients received treatments including HACE (n = 22); HACE and PEI (n = 14); re-resection (n = 6); and irradiation to bone, lymph node, or liver (n = 8). Repeat hepatectomy is the treatment of choice for recurrent HCC in cases in which it is resectable and the patient's liver functioning and general condition allow for surgical treatment.86When repeat hepatectomy is not possible, HACE or PEI alone or in combination are the treatment 86 PEI is well suited for patients with limited hepatic functional reserve and can be applied in repeat sessions with minimal effect on the uninvolved liver parenchyma.49 Cryoablation, alone or in combination with PEI, has also been used for the treatment of recurrent HCC, with approximately 70% of patients showing disease recurrence at 2

HEPATIC METASTASES

Hepatic metastases are the most. common hepatic malignancy in Western countries. This section is limited to the discussion of colorectal metastases to the liver. Liver metastases develop in approximately 65% of patients with colorectal cancer. Approximately 25% of patients with liver metastasis from colorectal cancer have resectable disease at diagnosis. Liver resection is now widely accepted as the only potentially curative treatment of colorectal cancer metastatic to the liver. Similar to the surgical experience with HCC, the trend is toward a decreased operative mortality rate and increased resectability with neoadjuvant measures, as well as a wider acceptance of re-resection for recurrent disease after initial liver resection. Some groups have been aggressive with resection of not only multiple and bilobar liver metastases but also pulmonary metastases.1o

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Factors That Govern Patient Selection for Liver Resection

Thorough preoperative and intraoperative staging are mandatory to avoid surgery that may not benefit patients. Taylor et a19sused the following parameters for patient selection: (1) complete removal of all hepatic metastases is anticipated, (2) primary disease is completely controlled, (3) no extrahepatic disease is identified on preoperative staging, (4)less than five liver metastases are present, (5) 1 cm of clear resection margin is expected upon surgery, and (6) liver resection will be tolerated. Preoperative and intraoperative staging evaluation should include most, if not all, of the following: (1)sonography of the liver, (2) chest radiography and chest CT, (3) CT of the abdomen and pelvis, (4) colonoscopy, (5) CT angioportography, (6) intraoperative bimanual liver palpation, (7) LIOUS, and (8) portal and celiac lymph node biopsy. LIOUS should be routine before liver resection for colorectal metastases. Routine LIOUS should result in increased tumor-free resection margins and decreased missed synchronous liver lesions. For a subset of patients with a large hepatic metastasis and a small remnant of spared liver, hepatic resection may still be possible after selective portal vein embolization of the cancer-bearing portion of the liver. This intervention induces atrophy of the embolized portion of the liver and compensatory hypertrophy of the unembolized liver remnant. Several centers in Japan and Europe have successfully applied this technique to extend the safe application of hepatectomy to patients with cancers otherwise unresectable because of size.lO, 23 Results of Resection of Colorectal Metastases to the Liver

Colorectal metastases usually occur in noncirrhotic livers, contrary to HCC; liver resection in this setting is safer, and the risk for postoperative liver failure is less than in cirrhotic livers. Operative mortality for resection of liver metastases ranges from 0% to 5%.28,32, 36 The 5-year survival ranges from 20% to 50% depending on length of follow-up and patient selection. Jamison et a135reported the results of 280 patients who underwent resection for colorectal metastases with a median follow-up of 11 years. The patients achieved 5-year and 10-year overall survival rates of 27% and 20%, respectively. Only two patients who were disease-free and alive at 5-year follow-up developed recurrence by 10-year follow-up. This Mayo Clinic group concluded that liver resection can be curative of colorectal liver metastases in some patients. Adjuvant Chemotherapy

No randomized trials have studied adjuvant systemic chemotherapy after hepatic resection for metastatic colorectal cancer. Retrospective studies are inconclusive. Despite this, postresection adjuvant 5-FU-based chemotherapy is often offered to patients who have never received chemotherapy. HA1 has been used as adjuvant treatment to prevent recurrence. It was hoped that this would be more effective than systemic chemotherapy. One nonrandomized study using HA1 5-FU for 6 months after hepatic resection produced fewer recurrences than were expected.u Another nonrandomized study used 5-FU, doxorubicin or epirubicin, and mitomycin C, with suggestion of improved survival rates.63The only randomized trial to date comparing HA1 versus no HA1 after resection indicated no survival advantage for HA1 but did

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increase median time to failure from 8.7 to 30.7 months in patients given HA1 chemotherapy after resection compared with resection only.1o1 Predictors of Long-Term Prognosis

Conflicting data exist in the literature regarding prognostic indicators for survival after liver resection for colorectal metastases. Investigators have looked at multiple parameters, such as age, gender, synchronous or metachronous metastases, interval to metastasis, stage of primary colon cancer, intraoperative transfusion at liver resection, size of liver metastases, carcinoembryonic antigen level, number of tumor nodules, bilobar distribution, type of liver resection, and presence of extrahepatic disease. No definitive factors have been consistently identified that can unequivocally predict survival except for surgical margin and presence of extrahepatic disease and perhaps number of tumor nodules?,28, 35, 36, 65, 98 Surgical margin is potentially controllable in the hands of surgeons. Thoughtful surgical planning should be aimed at achieving resection margins that are microscopically free of viable cancer cells. To achieve this, preoperative and intraoperative imaging studies and neoadjuvant and adjuvant interventions should be maximally used as indicated. Neoadjuvant Chemotherapy for Initially Unresectable Liver Metastases

Bismuth et all0reported on a series of 53 patients with liver metastases that were initially unresectable because of location (n = 8), size (n = 8), multinodularity (n = 24), or presence of extrahepatic disease (n = 13). These patients were given neoadjuvant systemic 5-FU-based chemotherapy. The mean time needed to downstage the disease to resectability was approximately 8 months. These surgeons aggressively resected pulmonary metastases in a staged protocol. Portal vein embolization was used, when indicated, to induce hypertrophy of the future remnant liver and to improve resectability. Adjuvant systemic chemotherapy was given for 6 months postoperatively. Cryotherapy was used as an adjunct ablative modality to liver resection to treat residual tumor or to freeze the raw surface of the resection when the margin was less than 1 cm. These aggressive surgeons, with liberality in resection of pulmonary metastases and repeat liver resections, achieved an amazing 5-year overall survival rate of 40%, and a 36% disease-free survival rate at a mean follow-up of 42 months. The success of this team of surgeons and oncologists from France underscores the importance of a multidisciplinary approach to the management of patients' hepatic malignancies. Cryotherapy

Indications for cryotherapy ablation include treatment of unresectable liver metastases, destruction of residual bilobar disease following resection, and treatment of the involved margins after 37, Io2 Cryotherapy may be safely combined with surgical resection and with neoadjuvant chemotherapy. Repeat cryotherapy for recurrent metastases has also been shown to be feasible and safe.*O2 Hewitt et a133reported on 20 patients with bilobar disease treated by cryo-

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therapy; 17 patients also received adjuvant HAI. Significant tumor destruction, as evidenced by a decrease in carcinoembryonic antigen level, occurred in all patients. Weaver et a P 2reported on 136 patients with unresectable liver metastases treated by cryotherapy. A total of 90 patients underwent neoadjuvant chemotherapy, and 55 patients had bilobar disease. Their series achieved a median survival time of 30 months. Disease recurred in 78% of patients, and 82% of recurrence developed in the liver. Most reports regarding cryotherapy for liver metastases have had short follow-up and no control arm', 21, 25, Io8 so were not able to show definitive survival benefit. Korpan40 reported a prospective, randomized series on cryosurgery for hepatic metastases. Patients were randomized into two groups, half receiving cryosurgery and half receiving conventional surgery. These investigators further stratified the cryosurgery group as cryodestruction (22%), cryoresection (32%), and cryoextirpation (46%). They reported 5-year and 10-year survival rates of 44% and 19%, respectively, in the cryosurgery group and 36% and 8%, respectively, in the conventional surgery group. The 10-year disease-free survival rate was 14% and 5%, respectively, for the two groups. This study seems to suggest a survival advantage for the cryosurgery group.

Radiofrequency Ablation

The relative ineffectiveness of PEI for the treatment of hepatic metastasess has driven the search for other in situ ablative therapies for this indication. The most promising of these techniques is radiofrequency (RF) ablation. The RF probe@)is positioned withm the lesion with CT or sonography guidance. The probe is attached to a generator, and the emitted RF energy causes thermally induced coagulation necrosis.3O Rapid advances in probe technology from monopolar to multiprobe arrays to cooled-tip electrodes have increased the achievable diameter of coagulation necr0sis.8~, Solbiati et alas reported a series of 29 patients with 44 hepatic metastases with diameters of 1 cm to 5 cm who were treated with RF ablation using cooledtip electrodes. Technical success with the destruction of all visible tumor was achieved in 91% of lesions. The disease-free survival rate was 50% at 1-year follow-up and the overall survival rate was 94% at 1-year follow-up and 89% at 18 months. Additional studies are necessary to validate the efficacy of RF ablation, but early investigation suggests that it may offer much greater success in treatment of hepatic metastases than have previously available in situ ablative techniques.

Hepatic Artery Chemoembolization

HACE has commonly been used in the treatment of hepatic metastases from colorectal cancer, usually in patients who failed systemic chemotherapy but who have stable or absent extrahepatic disease.73Spence et a194treated 40 patients with colorectal metastases to the liver with a mixture of 5-FU, mitomycin C, ethiodol, and gelatin foam embolization and achieved lesion reduction in 63% of patients, a median time to disease progression in responders of 7 months, and a median survival time of 14 months compared with the approximately 11.5-month anticipated survival time without therapy.94

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Regional Hepatic Artery Infusion Chemotherapy

For more than 30 years, HA1 chemotherapy has been used for the treatment of metastatic hepatic colorectal cancer. Response rates have varied from 50% to 80%, with improved survival in uncontrolled studies. Floxuridine given in continuous infusion into the hepatic artery allows for a higher dose over a longer period of time, enhancing the hepatic extraction of the drug, minimizing systemic toxicity, and allowing maximal tumor-cell death. Numerous studies have compared HA1 and systemic chemotherapy. Although the magnitude of tumor response was significant with HAI, its effect on survival was unclear. A meta-analysis of seven randomized trials comparing HA1 and IV 5-FU-based ~hemotherapy~~ supported the much higher tumor response rates for HA1 compared with systemic chemotherapy, but the effect on survival was less clear. Individual trials comparing HA1 with systemic chemotherapy were too small to detect plausible survival benefits. In their analyses, HA1 was confirmed to be superior to no treatment (some patients are left untreated until symptoms occur). Such a policy of watchful waiting has been shown to be inferior to systemic ~hemotherapy.~~ A meta-analysis of the published literature concluded that HA1 chemotherapy conferred a modest survival benefit over systemic chemotherapy. Systemic Chemotherapy

For many years, 5-FU was the standard chemotherapy agent used for advanced colorectal liver cancer, with response rates of approximately 20% to 30%. In recent years, 5-FU modulation with leucovorin has shown improved response rates and has emerged as the standard treatment. Many clinical trials pursuing the optimal doses and methods of administration for these drugs have been carried out. The Meta-analysis Group in Cancer showed that continuous 5FU therapy had a statistically significant higher response rate than did bolus, with improved overall survival.” Surveillance for Recurrent Disease

Following liver resection for colorectal metastases, approximately 75% of patients develop recurrent disease, and approximately 20% to 40% of patients with recurrent disease have disease confined to the liver. The question of whether recurrent liver metastasis comes from lesions that are undetected during initial liver resection or whether they represent metastatic spread by the portal vein, bile duct, hepatic vein, or lymphatic system of the liver remains unanswered. The high rate of recurrent disease underscores the need for surveillance protocols for these patients. Bismuth et all0 followed a vigilant surveillance protocol for patients at high risk for disease recurrence: complete physical examination, carcinoembryonic antigen, and liver sonography, and CT every 3 months. Repeat Liver Resection for Colorectal Metastases to the Liver

Selected patients with recurrent disease confined to the liver, adequate liver reserve, limited extent of disease, and acceptable comorbid factors could be

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candidates for repeat liver resection with curative intent. Repeat hepatic resection has been safely performed in experienced hands.” 76, 79 These reports have shown surgical morbidity and mortality and long-term survival rates to be similar to those of first-time liver resections. Adam et a12 reported a 5-year overall survival rate of 41% and a disease-free survival rate of 26% among 64 patients who underwent repeat hepatic resection. Some patients had resection of pulmonary metastasis. Over the past decade, repeat hepatic resection for recurrent colorectal metastases has gained wider acceptance as the frontline treatment in selected patients.

SUMMARY

The battle against malignancies of the liver is far from over, although tremendous strides have been made in the past decade, such as improved diagnostic capabilities, safe surgical resection, availability of safe nonsurgical ablative modalities, multimodality therapy, and aggressive approach to recurrent disease. Even after the best attempts at curative treatment, recurrence of primary and secondary malignancies of the liver continues to be the cause of demise for more than 70% of treated patients. The battle continues in the laboratories, where investigations are focused on delineating the pathophysiology of cancer on the molecular and genetic levels and mapping the patterns of cancer emergence and spread. The new millennium holds promise for formulating therapies that may improve disease-free survival for patients with malignancies of the liver.

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