Epidemiology and Etiology

In the United States, there were an estimated 22,620 new cases of primary liver cancer diagnosed and 18,160 deaths in 2009.¹ The worldwide incidence of primary liver cancer is much more significant, with an estimated 1 million patients diagnosed annually.² Hepatocellular carcinoma (HCC) represents approximately 70% to 85% of the cases. The incidence of HCC has been steadily increasing in the United States with a 75% increase during the past decade.³ The most common cause of HCC worldwide is hepatitis B, with other major causes including hepatitis C, alcoholism, and primary biliary cirrhosis. In addition, HCC has been linked with genetic hemochromatosis, hereditary tyrosinemia, α1-antitrypsin deficiency, aflatoxins, and possibly a promotional relation with alcohol. There is an estimated 0.5% annual risk of developing HCC in chronic hepatitis B patients and 5% in chronic hepatitis C patients.

Primary tumors of the bile ducts, also called cholangiocarcinomas, can be divided into intrahepatic (IHCC) or extrahepatic (EHCC) tumors (including hilar and distal bile duct tumors), and excludes tumors of the ampulla of Vater and gallbladder (see Fig. 39-2). HCCs and IHCCs are often grouped together as primary liver tumors, whereas EHCC and gallbladder tumors are treated as separate tumors of the biliary tree. The incidence and mortality from IHCC has been increasing during the last three decades.⁴ A host of predisposing factors have been proposed for bile duct tumors; the most widely accepted associations are with liver flukes, ulcerative colitis associated with primary sclerosing cholangitis, and congenital biliary cysts.

Pathologic Conditions

Histologically, early HCCs are generally well differentiated but can eventually show poor differentiation with marked pleomorphism. The only widely agreed-on HCC subcategory is the fibrolamellar type, which tends to occur in younger populations with less pre-existing liver disease and is associated with better outcome. The World Health Organization histologic classification⁵ recognizes several HCC variants, including childhood, spindle cell, clear cell, combined, carcinosarcoma, and sclerosis; these subcategories are used more, less, or not at all at varying institutions.

IHCCs are primarily adenocarcinomas, and are therefore difficult to distinguish from metastatic lesions from other primary sites involving the liver. There are no pathognomonic immunohistochemical stains distinguishing cholangiocarcinomas, although cytokeratin-7 positivity is often found. Special stains that help in the diagnosis to distinguish IHCC versus HCC include alpha-fetoprotein (AFP), which is positive in 35% to 75% of hepatomas and almost never in IHCC tumors; and CA19-9 or Ca-50, which is positive in 80% to 90% of cholangiocarcinomas and very rarely in hepatomas.⁶

Clinical Presentation

The presentation of primary liver tumors is often insidious, and clinical symptoms generally herald advanced disease. Patients often complain of antecedent malaise, anorexia, and occasionally abdominal pain. Signs include fever of unknown origin, night sweats, hepatomegaly, or a right-upper-quadrant mass, evidence of portal vein obstruction, bruits, ascites, splenomegaly, weight loss, or findings attributable to metastatic disease. In cirrhotic patients, in whom HCC is more common, unexplained weight loss can be a warning sign and some patients present in florid hepatic failure. Jaundice is less common in patients with primary liver tumors and may be associated with very advanced disease caused by biliary obstruction or hepatic failure resulting from extensive parenchymal destruction. Screening of high-risk patients with ultrasonography and measurement of AFP levels can help to detect small asymptomatic lesions, although the effect of early detection on survival is still unclear.^7,8

Diagnostic Studies

The list of imaging studies designed to evaluate local disease is headed by ultrasonography, which, by virtue of its low cost, sensitivity, noninvasive property, and relative simplicity of use, has been effective as both a screening and a diagnostic tool for primary liver tumors. It is useful in determining the number and size of lesions (lesions as small as 1 cm are detectable),⁷ ductal status, and vessel patency. Contrast-enhanced computed tomography (CT) scans have a somewhat higher sensitivity than ultrasonography (68% versus 60%) based on a pooled analysis of imaging studies for detecting HCC,⁹ with even higher sensitivity using triple-phase helical CT scans (arterial, portal venous, and delayed phases) of 89%.¹⁰ HCC tend to be hypervascular and are therefore best seen on the arterial phase, but appear hypodense or even isodense relative to liver parenchyma during the portal venous phase. IHCC tend to be hypodense during the portal venous phase and often hyperattenuated on delayed images. Peripheral contrast enhancement can also be seen in arterial or portal phase imaging.¹¹ Fig. 39-3 shows an example of HCC and IHCC as seen on CT scan.

FIGURE 39-3 • Example of hepatocellular carcinoma in a cirrhotic liver (A-C). The mass (short arrow) is not well visualized on a non-contrast CT scan (A). However, late arterial phase (B) and portal venous phase (C) CT images show a round circumscribed lesion with classic arterial enhancement (long arrow) followed by washout and capsule (double arrows) on portal venous phase. In contrast, an intrahepatic cholangiocarcinoma can be visualized on non-contrast CT (D) as an irregular left lateral lobe lesion (short arrow), which demonstrates peripheral arterial enhancement (long arrow) on late arterial phase CT (E), followed by central heterogeneous fill-in on (double arrow) venous phase CT (F). There is no evidence in this case of peripheral biliary dilatation, and only suggestion of capsular retraction, two features that may help further diagnose intrahepatic cholangiocarcinoma.

(Courtesy Richard Do, MD, Department of Radiology, Memorial Sloan-Kettering Cancer Center.)

CT can also be valuable in evaluating disease beyond the liver and in both the detection of vessel invasion and the identification of vascular variants. Cirrhosis can seriously complicate the picture when evaluating the primary tumor on CT. Recent data suggest that contrast-enhanced magnetic resonance imaging (MRI) is the most sensitive technique for detecting liver nodules, particularly in the setting of cirrhosis; dynamic hepatic arterial-phase contrast material–enhanced imaging is essential with both CT and MRI for visualization of small hepatic nodules in a background of cirrhosis.^9,12–16 On MRI, IHCC can look very similar to metastatic colorectal cancer, but is often accompanied by intrahepatic biliary dilatation.¹⁷ Magnetic resonance cholangiopancreatography (MRCP) is a newer technique to noninvasively visualize the intrahepatic and extrahepatic bile ducts and the pancreatic duct to determine the extent of disease and potential resectability.

Positron emission tomography (PET) scans using fluorine-18–2-fluoro-2-deoxy-d-glucose (F-18 FDG) have not been routinely used for HCC because of the variable FDG avidity of these tumors; however, they appear to be of more benefit for IHCC, particularly for identifying extrahepatic metastatic lesions.¹⁸ Other metastatic studies for both HCC and IHCC include chest CT and bone scan. Of note, IHCC should be regarded as a diagnosis of exclusion because most adenocarcinomas involving the liver are from metastatic disease; thus a work-up to identify a primary site should be performed in the setting of a biopsy-proven adenocarcinoma involving the liver.

A complete laboratory workup for any patient with a primary liver tumor includes the AFP assessment; a complete blood count; liver-function tests, including measurement of the transaminases, alkaline phosphatase, and lactate dehydrogenase; prothrombin time (PT) and partial thromboplastin times (PTT); glucose; cholesterol; albumin; and calcium. Hepatitis B and C serologies should be assessed. Amounts of carcinoembryonic antigen and the glycoprotein CA-19 can be elevated in HCC or even benign disease, but marked elevations are associated more often with cholangiocarcinomas. Elevated alkaline phosphatase without elevated transaminases can also be seen with IHCC.

The benchmark laboratory study for detection and evaluation of treatment response is the serum AFP; it is elevated in 70% to 80% of all HCC patients. This rate is lower (≅30%) in the United States and Europe¹⁹ and in patients with fibrolamellar histologic findings. Overall, AFP, when used with a conventional cutoff point of 500 ng/mL, has a sensitivity of 50% and a specificity of 90% in detecting HCC in a patient with pre-existing liver disease.²⁰ Higher levels are associated with poorer differentiation and shortened survival times.

Histologic confirmation of a hepatic tumor can be obtained through fine-needle aspiration, core biopsy, or open biopsy or resection. For centrally located IHCCs, tissue diagnosis may be a challenge. Endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiogram may be performed to obtain brushings for confirmation of a primary bile duct tumor. Some practitioners also obtain tissue from adjacent liver to determine the extent of coexistent hepatic disease. In patients with underlying liver disease, these procedures can be technically difficult to perform because of coagulopathies and tumor hypervascularity. In the absence of an elevated AFP, it is generally considered crucial to obtain a tissue diagnosis given the large differential and wide range of treatment options and prognoses. However, for tumors larger than 3 cm, with elevated AFP and clinical and radiographic findings suggesting HCC, the false-positive rate for diagnosis of HCC has been shown to be as low as 3%.²¹

Staging

Several staging systems have been proposed for HCC. Many clinicians categorize tumors as being (1) localized, (2) in liver only but in more than one lobe, or (3) metastatic. Okuda and colleagues¹³ incorporate tumor size (percentage of liver), ascites, and albumin (<3 g/dL) and bilirubin (>3 mg/dL) levels. The tumor-node-metastasis (TNM) staging system for both HCC and IHCC, as developed by the American Joint Committee on Cancer (AJCC), is presented in Table 39-1.

Therapeutic Modalities

Epidemiology and Etiology

EHCC, or cholangiocarcinoma of the extrahepatic bile ducts, refers to malignancies of the extrahepatic biliary tree, commencing from the biliary confluence (hilum) extending to the common hepatic duct. There are approximately 4500 new cases per year in the United States, with the peak incidence in the eighth decade of life.^63,64 EHCC is slightly more common in men, but the exact ratio varies from study to study. A host of predisposing factors have been proposed, as outlined in Table 39-2. The most widely accepted associations are with liver flukes, ulcerative colitis, and congenital (choledochal) biliary cysts. The most common risk factor in the West is primary sclerosing cholangitis, an inflammatory condition often associated with ulcerative colitis.

Table 39-2 Carcinoma of the Bile Duct: Proposed Causal Factors and Associations

Pathologic Conditions

More than 90% of EHCC are adenocarcinomas of varying differentiations. Subclassifications include papillary, nodular, and sclerosing. The World Health Organization histologic classification⁵ describes three grades and six variations of adenocarcinomas (papillary, intestinal type, mucinous, clear cell, signet ring, and adenosquamous). The remaining 10% of bile duct lesions include squamous cell, mucoepidermoid, granular cell, small cell, adenosquamous carcinoma, leiomyosarcoma, rhabdomyosarcoma, cystadenocarcinoma, carcinoid, Kaposi sarcoma, angiosarcoma, melanoma, and lymphoma.

Clinical Presentation

Initial signs and symptoms include jaundice, pruritus, right upper quadrant or epigastric pain, anorexia, weight loss, nausea, fever, hepatomegaly, and a right upper quadrant mass (Table 39-3). In end-stage disease, patients may have a periumbilical mass, massive ascites and limb edema, a rectal shelf, or supraclavicular lymphadenopathy. When initially diagnosed, EHCC tumors usually appear relatively small and circumscribed; patients rarely present with signs of overt metastatic disease. The bile duct tree is variably involved; 40% to 60% involve the hilus (upper third; Klatskin tumors), 10% to 15% involve the middle third, and 15% to 25% are in the distal third.^64,65 Less than 10% of patients present with multifocal or diffuse involvement of the biliary tree.^64–66 Although prognosis has historically been considered worse for hilar cholangiocarcinoma than for distal tumors, this is thought to represent the relatively later presentation and failure to institute effective therapy. Recent studies suggest that location in the biliary tree has no effect on survival, provided that complete resection can be performed.⁶⁵ Approximately 30% of patients have lymph node involvement at presentation^65,67; the lymph nodes are a frequent site of recurrence owing to the extensive lymphatics in the bile duct submucosa. Intrahepatic involvement is extremely common at the time of failure, but is usually contiguous with the bile duct lesion itself. Metastases appear in the peritoneum, distant liver, bones, thoracic lymph nodes, and surgical or drain incisions^65,68; but often, lethal local recurrence develops before systemic spread is clinically manifested.

Table 39-3 Carcinoma of the Bile Duct: Signs and Symptoms

Surgery

The primary curative modality for EHCC tumors is surgery. However, resectability rates are low and tumor location can be a critical factor in resectability, applicable surgical procedure, and survival. As preoperative diagnostic expertise increases, the ensuing ability to safely perform complete resections grows as patient selection improves, particularly with Klatskin tumors.^64,72 Contraindications to “curative” surgical resection include hepatic duct involvement up to secondary biliary radicles bilaterally, encasement or occlusion of the main portal vein proximal to its bifurcation, atrophy of one hepatic lobe with encasement of the contralateral portal venous branch or with contralateral involvement of secondary biliary radicles, distant metastases (peritoneum, liver, lung), and significant medical comorbidities.⁶⁵ EHCC resections demand considerable skill and experience on the part of the surgeon. Klatskin tumors can require lobectomy. Distal bile duct tumors are often treated with a Whipple procedure (pancreaticoduodenectomy). The primary goal of palliative procedures is to improve the quality of life through resolution of jaundice and pruritus, prevention of infection, and improvement in pain. Options include palliative debulking, external or internal stent placement, and bypass operations, including hepaticojejunostomies for proximal disease. Palliative procedures are accompanied by high 30-day mortality rates and short survivals with inconsistent improvements in quality of life.

Survival rates after any surgical resection, even curative ones, are low. Median survivals after gross total resection and palliative surgery have been remarkably consistent during the past decade, with values of 17 to 42 months versus 7 to 10 months.^64,66,72,73 Likewise, Boerma,⁷⁴ in an analysis of more than 1000 patients treated worldwide, found a mean survival of 21 versus 11 months.

During the past 20 years, increasing extended hepatic resections, especially for patients with hilar cholangiocarcinoma, has led to an increase in the percentage of negative margin resections, and an observed improvement in survival in some series.⁶⁵ Memorial Sloan-Kettering reported on 225 patients presenting with hilar cholangiocarcinomas. Of these patients, 65 had unresectable disease; 160 patients underwent exploration with curative intent; and 80 patients underwent resection: 62 (78%) had a concomitant hepatic resection and 62 (78%) had an R₀ resection (negative histologic margins).⁷⁵

Wide variations in morbidity and mortality are seen because of variabilities in tumor site, disease extension, medical condition, referral patterns, and institutional expertise. The mortality and morbidity rates after curative resection, however, are relatively high when compared with liver resections performed for other indications. Even in large referral centers, mortality rates can be up to 5% to 10%. Postoperative complication rates are also high (39% at Johns Hopkins,⁷⁶ 25% at the University of California–Los Angeles⁷⁷), and can include wound infection, liver or subphrenic abscess, cholangitis, pulmonary embolus, gastrointestinal hemorrhage, and small bowel obstruction.

Local recurrence is the most common site of failure and cause of mortality: after potentially curative resections, the local failure rate was 59% in the study by Kopelson and associates⁷⁸ and 53% in the study by Cameron and associates.⁷⁶

Liver transplantation has been performed at several centers.^79,80 Meyer and colleagues⁸⁰ reported their experience with 207 patients with unresectable cholangiocarcinomas treated with liver transplantation. The 2- and 5-year survival rates were 48% and 23%, respectively. The Mayo Clinic recently published their results with neoadjuvant chemoradiotherapy followed by orthotopic liver transplantation. Of 148 patients enrolled on the protocol, 90 completed treatemnt. Overall, 1-, 3-, and 5-year patient survival was 82%, 63%, and 55%, respectively; 1-, 3-, and 5-year survival after orthotopic liver transplantation was 90%, 80%, and 71%.⁷⁹ However, the reported high incidence of recurrence both in the allograft and in distant organs after transplant for EHCC suggests that this should not be considered a standard treatment option.^65,80

Chemotherapy

The use of chemotherapy has been described in multiple, small, single-institution studies. A pooled analysis of 112 trial arms and 2810 patients evaluating the activity of systemic chemotherapy in advanced biliary tract cancers was recently published.⁸¹ The pooled response rate (complete response or partial response) with all chemotherapy agents was 22.6% and the pooled tumor control rate (complete response, partial response, or stable disease) was 57.3%. Gemcitabine and platinum compounds exhibited the highest activity with response rates of 25% and 30%, respectively. Combinations of chemotherapy seems to be more effective than single agents in the palliative setting. For those patients with completely resected disease, there does not appear to be a role for adjuvant chemotherapy; however, phase III trials are needed to further evaluate the role of adjuvant chemotherapy.⁸² An ongoing intergroup study is examining the role of adjvuant gemcitabine and capecitabine followed by RT and capecitabine after resection of EHCCs.

Radiation Therapy

Historically, the use of external-beam RT was largely limited to unresectable, recurrent, or gross residual disease treated in the pre-CT era, and this led to the conclusion that extrahepatic bile duct carcinomas were radioresistant. There is, however, no evidence that bile duct tumor cells have an inherent radioresistance, but rather that the doses of radiation generally administered have been limited by the surrounding structures. Indeed, some recent reports indicate that radiation limited to relatively small fields but reaching higher dose levels, combined with more modern surgical approaches and techniques, may have a positive effect on outcome.^67,68,76 Generally, this improvement has been found to be most marked in the setting of minimal residual disease,⁶⁷ although occasionally an advantage is seen in unresectable patients treated with stents and radiation.⁷⁶

The indications for postoperative RT are not yet clear. Patients with negative resection margins are rarely referred for consideration of RT, although the available data suggests isolated local-regional recurrence rates of up to 60% after curative resection. Investigators at the University of Michigan published their retrospective experience with adjuvant RT after a potentially curative resection in 81 patients with localized EHCC.⁸³ With a median follow-up time of 1.2 years, the median overall survival and progression-free survival were 14.7 and 11 months, respectively. Complete resection (R₀) was the only predictive factor significantly associated with increases in both overall and progression-free survival and there was no difference in outcomes between R₁ and R₂ resections. The first site of failure was locoregional in more than two-thirds of patients. Clearly, local failure plays a significant role in many EHCC deaths, and this is a persistent problem after surgery with or without irradiation, and after irradiation alone.^67,68

Prognostic factors that may assist in determining which patients might benefit from adjuvant therapy include age younger than 65 and small tumor size.⁶⁶ The degree of differentiation, lymph node involvement, local invasiveness, and papillary characteristics may also serve as prognosticators. All of these factors must be weighed with the demands of upper quadrant irradiation, the patient’s overall medical status, and the significant quality-of-life issues raised by this disease. As always, by far the most important prognosticator for survival is the extent of resection.

Short-term morbidity associated with standard external-beam RT includes nausea, vomiting, malaise, fatigue, or weight loss, and many patients with in-dwelling catheters have intermittent fevers. Long-term post-RT complications, particularly duodenal, have been reported in the literature at rates that seem to vary with survival times, and are discussed in greater detail in later sections. Efforts to minimize the dose to nearby radiosensitive structures, and hence to minimize complications, may include brachytherapy in combination with external-beam therapy (potentially using the new technology of high-dose-rate brachytherapy), intraoperative RT, higher linear energy transfer modalities, radioprotectors, and the increasing use of CT-based conformal planning systems.

Brachytherapy has been used at numerous institutions. Overall, there appears to be a small trend toward improved survival with its use as a boost.⁶⁵ The potential advantages are clear: the area is reasonably accessible via stents placed during surgery or by the interventional radiologist; a high dose can be limited to a few surrounding centimeters; and the risk of serious short-term toxicity is low, although most series report rates of cholangitis of 30% to 50%. Dose distributions can be quite satisfactory with the use of iridium-192 (¹⁹²Ir) catheters. Ideally, an external-beam dose designed to eradicate microscopic disease (i.e., 45 to 50 Gy) is given first, followed by seed placement designed to give an additional high dose to the site of gross or highly suspect disease. Doses ranging from 15 to 100 Gy have been administered using iodine-192 (¹⁹²I), iodine-131 (¹³¹I), and ¹⁹⁸Au. Dose is usually prescribed at 0.5 to 1 cm from the radiation sources.

Long-term complications secondary to the high doses and use of stents are common, and include stricture, bowel obstruction, and bleeding. In addition, the rapid dose falloff means that some of the high-risk area may well lie outside the high-dose area, so brachytherapy should only be used in conjunction with external-beam RT; no study has shown that brachytherapy alone has anything but the briefest of palliative effects. Reports of high-dose-rate brachytherapy are just beginning to appear in the literature.⁸⁴

Intraoperative RT has been used on EHCCs at several institutions. After promising preliminary work in Japan, a RTOG protocol (85-06) gave 14 to 22 Gy as intraoperative RT before 45 to 50 Gy external beam to eight evaluable patients with unresectable, unresected, or recurrent tumors. Two patients were alive (one with no evidence of disease) at the time of publication with a median follow-up of 10.5 months.⁸⁵ In their study of 15 patients, Busse and co-workers⁸⁶ had a median survival of 14 months with a 50% local control rate using 5 to 20 Gy. In the study by Buskirk and co-workers,⁶⁹ the only long-term survivors had either intraoperative RT or a brachytherapy boost. All of these reports involve the use of both intraoperative and external-beam RT, because the use of the intraoperative RT alone (or brachytherapy alone) has not been shown to have a durable effect. Intraoperative electron doses of 15 to 25 Gy have been given, again before external-beam treatments of approximately 45 to 50 Gy. Buskirk and colleagues⁶⁹ leave transhepatic catheters in place after this procedure.

Epidemiology and Etiology

Gallbladder cancer is the sixth most common cancer of the gastrointestinal tract. It is estimated that gallbladder cancer was diagnosed in 9760 patients in the United States in 2009, of whom 3370 will die of their disease.¹ Gallbladder cancer is found almost three times more often in women than in men. High incidences are also seen in American Indians and Americans of Mexican origin.⁸⁷ The incidence of gallbladder cancer increases steadily with age, and reaches its maximum in the seventh decade,⁸⁸ with a median age of occurrence of invasive carcinoma of 73 years. During the past several decades, the incidence of gallbladder cancer in Canada, the United Kingdom, and the United States has stabilized or declined; this trend appears to be linked to the rising number of cholecystectomies. Of note, gallbladder cancer is found in approximately 1% of all routine cholecystectomy specimens, and it is estimated that one fewer death from gallbladder cancer occurs for about every 100 cholecystectomies done during the preceding year.⁸⁹

Although the cause of gallbladder cancer is unknown, a number of risk factors have been proposed, based on epidemiologic data. The most important risk factor for gallbladder cancer is a history of gallstone disease. Of patients with gallbladder cancer, more than 75% have cholelithiasis. Overall, the risk of developing gallbladder cancer is approximately 4 to 5 times higher in patients with gallstones than in patients without gallstones.⁹⁰ However, in autopsy series, gallbladder cancer is found in only 1% to 3% of patients with gallstones.⁹¹

Other variables associated with elevated gallbladder cancer risk include an elevated body mass index, high total energy intake, high carbohydrate intake,⁹² and anomalous junction of the pancreaticobiliary ducts.^93,94 Patients who suffer from Mirizzi syndrome (a rare complication of long-standing cholelithiasis, defined as obstructive jaundice caused by external compression of the common hepatic duct by an impacted stone in the gallbladder neck) may be at significant risk of developing a gallbladder cancer.⁹⁵ Increasing gallstone size has also been implicated in increasing risk for gallbladder cancer.⁹⁶ Other risk factors include infection with typhoid,⁹⁷ ulcerative colitis (relative risk [RR] 5-10),⁹⁸ porcelain gallbladder (RR 14),⁹⁹ and family history of gallbladder cancer (RR 3).¹⁰⁰

Pathologic Conditions

Multiple genetic changes are associated with development of gallbladder cancer. It is known that many gallbladder cancers are the endpoint of a sequence that starts with dysplasia, then carcinoma in situ, followed lastly by development of frank invasive cancer. This sequence of events is thought to occur during a period of 10 to 15 years. However, in contrast to colonic lesions, based on genetic analysis, adenomas are not thought to be the precursor lesions to gallbladder carcinomas in the majority of cases.^101–106

Classification of primary cancers of the gallbladder is provided in Table 39-5. More than 95% of gallbladder cancers are carcinomas. Sarcomas and other unspecified histologic findings occur less than 2% of the time.^107–113 Overall, the stage of disease appears to be the most reliable predictor of outcome, regardless of histologic stage or grade.¹¹²

Table 39-5 Gallbladder Cancer: Distribution by Histologic Finding*

NOS, Not otherwise specified; NR, not reported; OS, overall survival.

* Data from references 81, 104, and 106–109.

Clinical Presentation

Carcinoma of the gallbladder occurs rarely, and clinical symptoms often mimic benign gallbladder disease until invasion of surrounding structures causes increasingly severe symptoms. The most frequent presenting symptom is right-upper-quadrant abdominal pain. In advanced disease, jaundice, anorexia, weight loss, nausea and vomiting, and a palpable right-upper-quadrant mass (Courvoisier sign) may be found. Physical examination findings in advanced disease also can include a periumbilical mass (Sister Mary Joseph node), hepatomegaly, a rectal shelf (Blumer shelf, resulting from peritoneal seeding), or supraclavicular lymphadenopathy. Because of the vague symptoms with which it presents, carcinoma of the gallbladder is extremely difficult to diagnose early, and a high index of suspicion is recommended, especially for patients older than 70 years of age who present with recent weight loss and prolonged right-upper-quadrant pain. In the majority of patients at presentation, resection is made impossible by virtue of local invasion of the liver, biliary ducts, and adjacent structures.^114–116

Laboratory evaluation should include a complete blood count, screening profile, and liver-function tests. A high alkaline phosphatase with minimal rise in bilirubin can be found with limited obstruction of the intrahepatic bile ducts. Many patients with advanced disease have anemia, hypoalbuminemia, and abnormal liver-function tests.¹¹⁴ If the index of suspicion is high, serum carcinoembryonic antigen or CA19-9 can be considered.^117,118

Diagnostic Studies

Ultrasound and CT scan are often the first studies obtained in evaluation of a patient with jaundice or right-upper-quadrant pain or both. These studies may reveal dilated intrahepatic bile ducts, a mass replacing the normal gallbladder, diffuse or focal thickening of the gallbladder wall, or a polypoid mass within the gallbladder lumen. Often, adjacent organ invasion (e.g., the liver) is seen. Because most patients present with advanced disease, it is important to evaluate for periportal and peripancreatic lymphadenopathy, hematogenous metastases, and peritoneal carcinomatosis.¹¹⁹ CT identifies 60% to 80% of primary tumors.¹²⁰ Advances in MRI may offer more detailed information than either CT scan or ultrasound, and can be used to identify the level of obstruction and the site of underlying tumor in neoplastic pancreaticobiliary duct obstruction.^121,122 Endoscopic or percutaneous cholangiograms may be used for evaluation of obstructive jaundice, or in cases in which vague symptoms and abnormal blood work prompt further workup and other imaging modalities are nondiagnostic. A correct preoperative diagnosis is made in fewer than 50% of cases, depending on location and stage of tumor.¹²³ If lesions are not considered amenable to surgical resection, bile cytologic examination can be obtained via ERCP without violating the tumor or risking peritoneal or incisional seeding, with sensitivity in diagnosis of cancer of the gallbladder of up to 90%.^124,125 If ERCP is unsuccessful, percutaneous fine-needle aspiration is recommended instead of core needle biopsy, because of the decreased risk of needle-tract seeding. The accuracy of this approach is up to 90%, with a negligible false-negative rate.^125,126

Staging

The AJCC/International Union Against Cancer staging system for gallbladder cancer is provided in Table 39-6¹²⁷; the TNM stage has been found to be a strong predictor of patient outcome in many series. The risk of lymph node metastases increases with increasing depth of tumor invasion. Tsukada et al.¹²⁸ reviewed their experience with 106 patients with gallbladder cancer treated with radical surgery and found that lymph node metastases were present in 0% of T₁ tumors, 48% of T₂ tumors, 72% of T₃ tumors, and 80% of T₄ tumors.¹²⁸

Overall, according to Surveillance, Epidemiology, and End Results data, 25% of gallbladder cancers are “localized” at diagnosis, and 40% have abdominal or distant metastases.^114,129

Therapeutic Modalities

Overall, the curative resection rates for gallbladder cancer range from 10% to 30%.¹³⁰ Outcome in gallbladder cancer is closely related to tumor stage. According to a National Cancer Database report based on information collected from hospital registries across the United States from 1989 to 1995, the 5-year survival rates for patients with stage 0, I, II, III, and IV tumors were 60%, 39%, 15%, 5%, and 1%, respectively. Overall, 5-year survival was less than 5%, with a median survival of 5 to 8 months. According to this report, many patients diagnosed with gallbladder carcinoma between 1989 and 1995 received no definitive therapeutic intervention because of the advanced stage of disease at presentation.¹³¹

The Role of Adjuvant Radiation Therapy

A review of the literature by Kopelson and Gunderson found that up to 86% of patients with gallbladder cancer treated curatively failed with locoregional disease.^78,146 The use of adjuvant RT has been proposed as a method to decrease local-regional failure. Despite a number of largely retrospective series reporting a benefit to adjuvant RT (Table 39-7), the small number of patients with mixed diagnoses, stages, and treatments make it difficult to draw any significant conclusions.^{134,147–157} Because of the relative rarity of gallbladder cancer, and the difficulty in diagnosis while still locally confined, there are no prospective, randomized studies examining the role of radiation and chemotherapy in this disease. However, given its propensity for local failure, some have suggested that a multimodality approach with effective chemotherapy and RT may provide the best chance for long-term survival. Certainly, the previously mentioned retrospective data, as well as data from gastric and gastroesophageal junction carcinomas¹⁵⁸ suggest that there may be a benefit for chemoradiation in these tumors. Therefore, it may not be unreasonable to recommend adjuvant RT for resected, locally advanced gallbladder cancers, or for unresectable disease. However, it is important to note that, in contrast to bile duct tumors, gallbladder cancers are much more likely to fail distantly in addition to locally, thus implying an even greater need for improvements in systemic therapy: Isolated local/regional local failure was seen in only 15% of gallbladder patients after curative resection in one large series, compared with findings of distant failure in 85%.¹⁵⁹ Based on this limited data, a prospective multi-institutional phase III study would be of significant value; without this information, no standard treatment recommendations can be given, and treatment decisions must be made on a case-by-case basis.

If the gallbladder has been removed, doses of 45 to 50 Gy (1.8- to 2-Gy fractions) are recommended for microscopic disease; areas of residual disease may be boosted to 54 to 60 Gy, if normal tissue tolerance can be respected.

Radiation Therapy for Unresectable Disease

RT has been used as primary treatment for unresectable gallbladder cancers for relief of jaundice (usually after percutaneous transhepatic biliary drainage has been established) and pain.^159–162 It has also been used to prolong stent patency, with rare long-term survivors.^163–164 Further trials are needed to define the best local and systemic therapies in this population.^165–172

Role of Chemotherapy

The role of chemotherapy in management of gallbladder cancer has not been well defined. Multiple agents have been tried, including 5-FU, adriamycin, l-(2-chloroethyl-3-4-methylcyclohexyl)-l-nitrosourea (methyl-CCNU), irinotecan, mitomycin C, and cisplatin, with few objective responses.^{91,166–167,173} The Eastern Cooperative Oncology Group conducted a prospective three-arm randomized trial comparing oral 5-FU, oral 5-FU and streptozocin, and oral 5-FU and methyl-CCNU. There was no significant difference among treatments with respect to response or survival.¹⁶⁵ Hepatic arterial infusion with 5-FU–based chemotherapy has been used, with mixed results.^168,169 Early experience with gemcitabine suggests promising response rates.^170–172 Further prospective trials are needed to assess the role of chemotherapy in gallbladder carcinoma.

Local Treatment Options

Surgical resection is the treatment of choice for isolated liver metastases. Unfortunately, only a minority of patients with liver metastases are candidates for surgery, secondary to patient or tumor-related factors such as size, number, and location of the lesions.¹⁷⁷ Local treatments that serve as alternatives to surgery for well-defined liver metastases include hepatic artery infusional, isolated hepatic perfusion chemotherapy, radiofrequency ablation, external-beam RT, or a combination of any of these techniques. Not one of these techniques has been proven to be superior to another. Combination therapies have not yet been demonstrated to be more efficacious than any single modality. The overall treatment of liver metastases must be individualized based on the burden of metastatic disease, status of the primary tumor, previous treatments received by the patient, and performance status and treatment goals of the patient.

Whole-Liver Radiation

Although whole-liver radiation is rarely employed nowadays secondary to minimal efficacy and significant dose-limiting toxicities, whole-liver radiation alone has been used for palliation of liver metastases in the 1980s. Historical RTOG studies have explored various dose and fractionation schemes for palliation, as summarized here:

The RTOG 7609 study was a prospective, nonrandomized trial that evaluated six different whole-liver dose and fractionation schemes in 109 patients with symptomatic liver metastases, ranging from 21 Gy in 7 fractions to 25.6 Gy in 16 fractions.¹⁹⁰ Fifty-five percent of patients reported palliation of pain. No incidences of RILD were reported.²³

Additional RTOG trials have attempted to improve the efficacy of whole-liver radiation with either altered hyperfractionated schedules or misonidazole radiosensitization. Although these trials demonstrated that whole-liver radiation improved quality of life (decreased pain, nausea, fever, and other symptoms), it had no effect on survival.^190–192 In RTOG 8405, sequential groups of patients with hepatic metastases from various sites received hyperfractionated whole-liver radiation with 1.5-Gy fractions twice a day to total doses of 27, 30, and 33 Gy. No improvement was noted in median survival (4 months) between the different dose regimens. However, an increase in the incidence of radiation hepatitis (clinical or biochemical) was noted in patients treated with 33 Gy compared with the lower doses. In this group, a 10% incidence of grade 3 radiation-induced hepatitis was reported at 6 months, leading to closure of study to patient entry.

Finally, RTOG 8003¹⁹¹ was a randomized, controlled trial in which 187 patients were treated with 21 Gy in seven fractions, with or without concurrent misonidazole. Median response rates of 80% and a median survival of 4.2 months were seen in both arms. However, survival rates varied significantly with the site of the primary cancer, the number of liver lesions, and the status of extrahepatic disease. Misonidazole radiosensitization was not found to improve the therapeutic response of whole-liver radiation for liver metastases.

Stereotactic Radiation for Liver Metastases

Stereotactic external-beam radiation is an increasingly attractive modality for patients with a limited number of unresectable liver metastases requiring treatment, adequate normal liver reserve, and tumors smaller than 8 cm, because many of the same patient- and tumor-related factors that exclude surgery as a first-line treatment for isolated liver metastases can also limit the applicability of alternative treatments. In colorectal patients with focal unresectable liver metastases, dose escalation to these lesions have demonstrated improved response rates, symptom control, and survival rates compared with patients treated with lower doses, independent of tumor size.^47,193,194

Several groups have reported results of stereotactic radiation to deliver hypofractionated RT for select liver metastases. The majority of clinical experience with stereotactic radiation for liver metastases has been centered on tumors smaller than 5 cm.^195–200 However, tumors as large as 8 to 10 cm have been successfully treated with lower-dose, hypofractionated regimens.^201,202 Although patients with liver metastases from primary colorectal cancer constitute the majority of those who received stereotactic radiation in many series, patients with metastases from other primary malignancies such as other gastrointestinal tumors, breast cancer, ovarian cancer, bladder cancer, and renal cell cancer are also included. The highlights of select contemporary studies of stereotactic radiation for liver metastases are summarized in Table 39-8. A typical SBRT treatment plan is shown in Fig. 39-5.

FIGURE 39-5 • The axial, sagittal, and coronal views and isodose lines for a large solitary liver metastases treated with focal high-dose radiation.

As early as 1995, a study from Blomgren et al.²⁰¹ reported on 14 patients with 17 metastatic liver lesions (11 colorectal primaries) treated with 7.7 to 45 Gy in 1 to 4 fractions. Reported side effects included transient nausea in the majority of patients in the few hours following treatment, as well as one patient with a history of gastritis who subsequently developed hemorrhagic gastritis after radiation treatment.

In a phase I/II dose-escalation trial, Herfarth et al.¹⁹⁵ from the University of Heidelberg, Germany, investigated the use of stereotactic single-dose RT in 60 liver tumors (41 primary liver and 56 liver metastatic lesions) in 37 patients treated with stereotactic radiation for liver metastases. The dose was escalated from 14 to 26 Gy, with the 80% isodose surrounding the planning target volume. Median tumor size was 10 cm³ (range, 1-132 cm³). All patients tolerated the treatment well without any major side effects. Local control rate was 81% at 18 months after treatment. In a subsequent publication including patients accrued after the phase I/II study was closed, a lower control rate was reported (67% at 18 months), which was explained by a high proportion of patients with colorectal liver metastases in which the local control rate was 45%, compared with 91% for metastases of other tumor types.²⁰³

Other investigators from Germany, Wulf et al.,²⁰⁴ conducted a phase I/II study, including patients with mostly liver metastases and one cholangiocarcinoma, who received 30 Gy in three fractions. A local control rate of 76% and 61% at 1 and 2 years after stereotactic radiation was reported, and the corresponding overall survival rates were 71% and 43%, respectively. No grade 3 or higher toxicities were reported. In an updated publication including some patients treated with a higher dose of 36 to 37.5 Gy in three fractions (65% isodose) or 26 Gy in one fraction (80% isodose), the actuarial local control observed was 92% and 66% at 1 and 2 years, respectively.²⁰⁰ High radiation dose was the only significant factor for local control in a multivariate analysis. No severe acute or late toxicities greater than RTOG/European Organisation for Research and Treatment of Cancer grade 2 were seen. Overall survival at 1 and 2 years was 72% and 32%, respectively, for all patients.

Mendez Romero et al.¹⁹⁸ reported the results of a phase I/II study of 25 patients with 34 liver metastases and 11 HCC tumors. Patients with HCC without cirrhosis and patients with HCCs smaller than 4 cm and cirrhosis received a dose of 37.5 Gy (12.5 Gy in three fractions, prescribed to the 65% isodose) in three fractions. Patients with HCCs 4 cm or larger in the presence of cirrhosis received five 5-Gy or three 10-Gy fractions. With a median follow-up of 12.9 months, actuarial local control was 94% and 82% after 1 and 2 years for the entire group, respectively. Three patients with liver metastases developed acute side effects such as elevated γ-glutamyl transferase (n = 2) and asthenia (n = 1). One patient with liver metastases developed portal hypertension with melena. Another patient with Child-Pugh class B HCC developed liver failure and infection and died within the first month after treatment.

Katz et al.¹⁹⁶ from the University of Rochester reports the results of the largest series of patients with liver metastases treated with stereotactic radiation. Sixty-nine patients with 174 metastatic liver lesions were treated with a median dose of 48 Gy (range 30-55 Gy, in 5-15 fractions).¹⁹⁶ The mean number of metastatic lesions treated was 2.7 cm (range 1-6). With a median follow-up of 14.5 months, 10- and 20-month local control was 76% and 57%, and the overall median survival was 14.5 months. There were no grade 3 or higher toxicities reported.

In more recent studies published during the past few years, Gunven et al.²⁰⁵ from the Karolinska Institute in Sweden reported on seven patients with nine liver metastases who received 20 to 45 Gy in two to five fractions.²⁰⁵ With a lengthy median follow-up time of 117 months, all patients were reported to have survived 5 to 14 years without local recurrence.

Goodman et al.²⁰⁶ recently published the results of a phase I dose-escalation trial of single-fraction stereotactic radiation for liver malignancies. Twenty-six patients, nine of whom had liver metastases and seven of whom had IHCCs or recurrent HCCs, were treated with 18 to 30 Gy. Dose was escalated in 4-Gy increments, with the maximum dose being 30 Gy. No dose-limiting toxicities (defined as grade 3 or higher) were incurred. After a median follow-up of 17 months, the cumulative 1-year local failure rate was 23%. Median survival was 29 months and 2-year actuarial overall survival was 50.4%.

Rusthoven et al.²⁰⁷ from the University of Colorado reported the results of a multi-institutional phase I/II study of stereotactic radiation for liver metastases. In a study of 47 patients with 63 metastatic liver lesions, 49 lesions were assessible for local control. During the phase I aspect of the study, the dose was escalated from 36 to 60 Gy. The dose used in the phase II part of the study was 60 Gy. The median follow-up for the 49 assessible lesions was 16 months. Actuarial local control was 95% at 1 year and 92% at 2 years. For lesions 3 cm or smaller, the local control was 100% at 2 years. Only one patient experienced a grade 3 or higher toxicity.

Lastly, Lee et al.²²² from the Princess Margaret Hospital in Toronto, Canada, published their results following a phase I study of stereotactic radiation for liver metastases. Sixty-eight patients with inoperable liver metastases were treated with stereotactic radiation doses individually prescribed, chosen to maintain the same nominal risk of RILD for three estimated risk levels (5%, 10%, and 20%). Additional patients were treated at the maximal study dose in an expanded cohort. The median stereotactic radiation dose was 41.8 Gy (range 27.7 to 60 Gy). Radiation was delivered in six fractions over 2 weeks. The 1-year local control rate was 71% and the median overall survival was 17.6 months. The highest RILD risk level investigated was safe, with no dose-limiting toxicity. Two grade 3 liver-enzyme changes occurred, but no RILD or other grade 3 to 5 liver toxicity was reported. Six patients (9%) reported acute grade 3 toxicities (two gastritis, two nausea, lethargy, and thrombocytopenia) and one (1%) grade 4 toxicity (thrombocytopenia) was seen.

Dose-Limiting Toxicities of Liver Radiation

The most concerning and dose-limiting toxicity of liver radiation is RILD. RILD is a clinical syndrome of fatigue, elevated liver enzymes (particularly alkaline phosphatase over liver transaminases), tender anicteric hepatomegaly, and ascites. Pathologic changes consist of pronounced hyperemia acutely, then veno-occlusive disease, marked central venous congestion, sparing of large veins, and atrophy of adjacent hepatocytes chronically, similar to changes seen following bone-marrow transplant or high-dose chemotherapy.²⁰⁸ Pathophysiologically, deposition of fibrin within the central veins, transforming growth factor-β²⁰⁹ and tumor necrosis factor-α activation²¹⁰ has been observed, postulating that injury occurs in the endothelial cells rather than hepatocytes.²¹¹ RILD can be seen 2 weeks to 8 months following the completion of radiation, but usually occurs within the first 3 months after treatment.²¹² The treatment for RILD is largely supportive. Although most patients can recover with diuretic and steroid treatment, RILD has the potential to lead to liver failure and death.²¹¹

Other acute toxicities include transient increase in liver enzymes, reactivation of hepatitis B, or a general decline in liver function. Notably, these toxicities are more commonly seen in patients with HCC,²¹³ but are rare in patients with liver metastases, unless a history of prior liver radiation or underlying liver disease is present, which can increase the risk of RILD.

Additional potential late toxicities after liver irradiation include biliary sclerosis, hepatic subcapsular injury, gastrointestinal bleeding, small bowel obstruction, gastric outlet obstruction, and fistula formation, depending on whether or not normal tissues such as esophagus, stomach, duodenum, or large bowel are within the high-dose regions of the radiation treatment.

Liver Tolerance

Traditionally, the efficacy of radiation has been limited by low liver tolerance for whole-liver irradiation. In the early 1970s, it was discovered that, although 18 Gy in eight fractions of 2.23 Gy to the whole liver was tolerable, escalating the dose to 28 Gy in 3.5-Gy fraction sizes resulted in liver toxicity in 8 of 25 treated patients.^214,215 In 1991, Emami et al.²¹⁶ estimated that RILD would occur in 5% of patients who receive 30 to 35 Gy to the whole liver in 1.8-Gy fractions.

Data establishing partial liver tolerances to radiation has been elucidated in a more detailed fashion during the past decade. Historically, the gross, often multicentric nature of the disease has subsequently prevented high-dose partial liver irradiation. Recently, enhanced diagnostic imaging detecting focal liver lesions and the prospective collection of quantitative data on toxicities seen after partial-liver radiation delivered with three-dimensional conformal techniques have allowed a better understanding of partial-liver radiation tolerance, thereby allowing safe dose escalation to parts of the liver. In addition, the advent of three-dimensional conformal external-beam radiation planning, intensity-modulated RT (IMRT), image-guided RT, and enhanced management of breathing motion have allowed for the delivery of higher focal doses of radiation to the liver than what was traditionally permissible in the treatment of intrahepatic malignancies. Studies of dose escalation with fractionated radiation have shown a clear dose response for intrahepatic tumors, including liver metastases,⁴⁹ and patients with unresectable focal liver malignancies treated with higher rather than lower doses of radiation have been found to sustain improved symptoms, response rates, and survivals.^47,193

In 1986, the first quantitative partial liver tolerance analysis of RILD as a function of dose and volume was published, from the Lawrence Berkeley Laboratories,²¹⁷ in which 11 patients were treated with heavy ions for pancreatic or biliary carcinoma. The whole liver received 10 to 24 Gy equivalents (GyEq) and tumor doses ranged from 53.5 to 70 GyEq. One case of RILD was reported. The authors concluded that doses larger than 30 to 35 GyEq should be limited to 30% or less of the liver when 18 GyEq of whole-liver radiation is delivered at 2 GyEq per fraction in addition to primary radiation. In 1991, Emami et al.²¹⁶ also reported on TDs for partial liver, estimating the TDs for 5% (TD 5/5) and 50% (TD 50/5) risk of developing liver toxicity after various total liver doses delivered in 1.8- to 2-Gy fraction sizes. It is important to note that the liver toxicities were ascertained retrospectively in 27 patients in whom dose and volume data were available. Nevertheless, based on his data, Emami estimated that TD 5/5s for one-third, two-third, and whole-liver radiation were 50 Gy, 35 Gy, and 30 Gy and TD 50/5s were 55 Gy, 45 Gy, and 40 Gy.²¹⁶

The most comprehensive experience on partial liver tolerance is the series from the University of Michigan.^23,218 In both series, the Lyman normal tissue complication probability model was used to describe the volume dependence of normal tissue toxicity after radiation. This model assumes a sigmoid relationship between dose of uniform radiation delivered to the volume of liver and the risk of toxicity.²¹⁹ Three parameters are used in the Lyman model: TD50 (the whole-liver dose associated with a 50% risk of developing toxicity), m (describes the steepness of the dose response at TD50), and n (the volume-effect parameter).

In the first report, published in 1992 by Lawrence et al.,²³ 79 patients with liver metastases or primary liver malignancy received prescribed doses based on the dose-volume histograms of normal liver. Radiation was delivered with three-dimensional techniques, using 1.5 to 1.65 Gy twice daily with concurrent intra-arterial 5-fluorodeoxyuridine (FuDR) or bromodeoxyuridine (BuDR). All patients had Childs-Pugh class A liver function and were prospectively followed for the development of RILD. Although FuDR did not appear to increase the radiosensitivity of the liver, the 9 of 79 patients who developed RILD were those who received whole-liver radiation as all or part of their treatment that produced a mean dose greater than or equal to 37 Gy. The risk of complication was greatly overestimated among patients receiving a high-dose partial liver radiation. A larger magnitude for the “volume effect parameter” than that quoted in the literature was found.

In 2002, Dawson et al.²¹⁸ updated the University of Michigan experience in 203 patients with liver malignancies treated with hyperfractionated radiation (37 Gy in 1.5 Gy BID) and FuDR or BuDR. Nineteen patients developed RILD, and it was again found that the volume-effect parameter was higher than previously estimated. Moreover, on multivariate analysis, the mean liver dose, the diagnosis of a primary hepatobiliary carcinoma (as opposed to liver metastases), BuDR chemotherapy, and male gender were found to be statistically significant variables contributing to the development of RILD. Moreover, the tolerance of the liver to radiation for liver metastases was found to be higher than for patients with primary hepatobiliary malignancies. The mean liver dose associated with a 5% risk of developing RILD for patients with liver metastases receiving 1.5 Gy per fraction was 37 Gy, versus 32 Gy for patients with primary liver malignancy. For patients receiving 2 Gy per fraction, the values were 32 Gy and 28 Gy, respectively.

Abiding by certain dosimetric guidelines derived from the studies of high-dose focal radiation to liver metastases may help minimize radiation to the normal surrounding liver parenchyma, and therefore limit the mean dose. Strategies include keeping the mean dose for uninvolved liver to less than 32 Gy in 2 Gy per fraction,²¹⁸ or the total dose for 700 mL of nontumorous liver to less than 15 Gy in three fractions, or ensuring that no greater than 30% of the liver receives 21 Gy in three fractions or 12 Gy in a single fraction.²⁰⁰ It is important to keep in mind that patient-related factors, such as underlying liver disease, that can subsequently compromise normal liver function is also an important predictor of RILD. As mentioned previously, patients with abnormal liver function may develop different types of radiation toxicity²¹³ and may have a different dose-volume relationship for RILD than those characterized in the models by Dawson et al.²¹⁸ Therefore, care must be taken before extrapolating these described tolerances to different patient populations.

Knowledge of bile duct tolerance has thus far been limited by the presence of pre-existing ductal injury, the frequency of recurrent or residual disease, and the use of relatively moderate doses of radiation. However, the increasing use of intraoperative RT and brachytherapy has resulted in a heightened understanding of bile duct tolerance. Kopelson¹⁶⁰ reported asymptomatic biliary fibrosis following external-beam doses of 60 Gy, but this has not been a problem clinically (or perhaps is masked by recurrent disease). Both animal and human data appear to demonstrate minimal risk to the ducts with single intraoperative RT doses less than 20 Gy. Iwasaki and colleagues²²⁰ now keep intraoperative RT doses to less than 20 Gy because of a high incidence of hepatic artery stenosis, obstruction, and aneurysm after doses of 20 to 30 Gy. Buskirk and associates⁶⁹ recommend long-term stent placement as a precaution based on their experience with temporary fibrosis following high brachytherapy doses.

Duodenal and gastric mucosal TD5 values are reported to be 50 Gy. Virtually all practitioners recommend restriction of dose to these structures to less than 55 Gy, and many restrict doses to less than 50 Gy. The TD5 and TD50 values for kidneys are 23 and 28 Gy, respectively.²²¹ The same values for spinal cord injury (myelopathy) are 50 and 60 Gy.

Set-Up and Simulation Procedures

At simulation, patients are generally placed supine; the treatment position should be reproducible, ideally through an immobilization device. For patients undergoing definitive therapy, the arms are placed at the side of the head to allow for lateral beam angles that may be used for three-dimensional conformal or IMRT plans. Intravenous contrast should be used for better tumor and lymph node delineation, and CT images should be obtained from at least 2 cm above the dome of the diaphragm to the bottom of the kidneys. With patients in the treatment position, a liver protocol CT scan (1.25 mm cuts) is performed for high-resolution delineation of the tumor and surrounding structures. Intravenous contrast is administered in a rapid bolus such that either the arterial phase or portal venous phase is obtained when the patient is being coached to hold his or her breath while in expiration. For most hepatic metastases, lesions are best seen in the portal venous phase. They appear as hypointense in relation to the liver parenchyma. IHCCs and hilar cholangiocarcinomas can often be difficult to visualize on CT, but generally are best imaged in the portal venous or delayed phases. Hypervascular tumors, such as HCC and metastatic breast, renal cell, thyroid, and neuroendocrine cancers, may be better imaged in the arterial phase. Review of diagnostic imaging to determine the best phase for delineating the tumor should be performed prior to simulation, and scan timing with respect to the contrast administration should be based on diagnostic radiology algorithms or based on discussion with the diagnostic radiologists. Oral contrast can be given approximately hour before simulation to allow for visualization of the small bowel and stomach.

An FDG-PET scan is often performed at the treatment-planning session so that there is accurate coregistration of the tumor with the areas of hypermetabolic activity. To evaluate the extent of respiratory-related liver tumor motion, a four-dimensional CT scan is also performed, in which CT data (2.5-mm cuts) are acquired synchronously with a respiratory signal, to evaluate temporal changes of the anatomy as a function of the respiratory phase during the imaging. At our center, patients are given an audio-coaching CD to review prior to the set-up procedure to determine a comfortable breathing rhythm.

For patients treated with liver SBRT, implantation of three to five fiducial seeds adjacent to the liver tumor is performed prior to simulation, either by CT guidance by an interventional radiologist or during an open bypass procedure. These seeds are made of 100% gold and are radiographically visualized by kilovoltage x-ray films. The seeds measure 5 mm in length and 1 mm in diameter. Because these seeds can migrate several mm in the first few days after implantation, the simulation is performed at least 5 days after the implantation procedure.

In the palliative setting, a CT without contrast is often adequate and the patient can have his or her arms placed either down or above the head depending on the anticipated field arrangement. For palliative therapy, the most common field arrangements are anteroposterior, obliques, or tangents, depending on the tumor location.

Target Delineation

The tumor volume and nodal regions of concern (porta hepatis, celiac axis) should be defined on the scan. Critical structures to be identified include the kidneys, liver, stomach, duodenum, and spinal cord. In the postoperative setting, preoperative studies are essential to define the location of the primary tumor, such as the hilar cholangiocarcinoma or the gallbladder fossa. Surgical clips can also help to define the preoperative tumor volume. Evaluation of the extent of disease requires review of the operative reports and consultation with the surgeon. In the preoperative or definitive therapy setting, tumor volumes can be ascertained through diagnostic CT scans, ERCP, percutaneous transhepatic cholangiography, MRCP, ultrasound evaluations; physical examination findings should not be overlooked. Doses of 45 to 50 Gy (1.8- to 2-Gy fractions) are recommended for microscopic disease; areas of residual disease may be boosted to 54 to 60 Gy if normal tissue tolerance can be respected.

The tumor volume is delineated on cross-sectional images from the planning helical CT scan in the expiratory phase. Four-dimensional CT scans are reconstructed and tumor motion is evaluated using the GE Advantage workstation. The free-breathing PET-CT information is also fused with the exhalation arterial phase CT scan and is used for confirmation of tumor position and delineation of normal liver and adjacent tissues. For SBRT treatments, only the gross tumor volume plus margin, is treated. For conventionally fractionated RT, the gross tumor volume, as well as the clinical treatment volume, including the areas of subclinical disease and draining lymph nodes, are contoured.

Radiation Plans

The standard fractionation protocol for typical three-dimensional conformal or IMRT plans treating the tumor volume, draining lymph nodes (porta hepatis, pancreaticoduodenal, and celiac), and margin is 1.8 Gy per day, 5 days per week, to a total dose of 45 to 50.4 Gy. With very large tumors, a second, smaller field may have to be designed to preserve normal liver. Thereafter, a cone-down treatment to a volume of tumor bed with a smaller margin is taken to 50 or 56 Gy depending on the dose to the surrounding radiosensitive structures, particularly the stomach and duodenum. A few practitioners use doses as high as 60 Gy if tumor location allows and the patient understands the additional risks. IMRT treatment planning can be invaluable in designing boost fields that minimize normal tissue dose deposition.

Image Guidance and Motion Management

The liver motion is complex because of organ deformation and rotation with respiration. With the more targeted approaches to treating liver lesions, such as IMRT and SBRT, novel methods of accounting for target motion have been developed to improve the accuracy of treatment delivery. Image-guided RT is essential for focal liver irradiation, as the bony landmarks do not precisely represent tumor location because of organ motion. Liver tumors are not visualized on standard megavoltage portal images or even on diagnostic kilovoltage two-dimensional imaging. Even cone-beam CT scans, in which three-dimensional tomographic images are generated on the linear accelerator, may not show the target lesion in the liver because of limitations in resolution and contrast. Thus, fiducial markers have been introduced to help identify the tumor and allow for better visualization and improved set-up for both conventionally fractionated treatments and, more importantly, for SBRT. Gold fiducial markers can be placed as described previously, or postoperative clips can also be used to help evaluate the postoperative bed on kilovoltage images.

Motion management is also necessary to compensate for the variation in target location throughout the respiratory cycle. There are many approaches to motion management, including respiratory gating, abdominal compression, active breathing control, and tumor tracking. Respiratory gating is a technique in which the radiation beam is turned on and off depending on where the tumor is with respect to the respiratory cycle. The beam is generally turned on during expiration, when there is the least amount of motion. Respiratory gating is achieved using software to correlate the motion of the chest wall to the phase of respiration. This technique requires the ability to evaluate the motion of the tumor on a daily basis to evaluate the degree of respiratory motion of the tumor versus the chest-wall motion. Using fluoroscopy, the fiducials can be followed throughout the respiratory cycle to confirm that the treatment beam will be turned on at the appropriate time during the respiratory cycle. Abdominal compression uses an abdominal belt that is inflated and causes compression of the abdominal cavity, limiting the degree of respiratory excursion of the abdominal contents. Active breathing control is a method of breath holding that also limits the ventilatory motion while the beam is on. For patients treated on the CyberKnife, the Synchrony system is used for real-time targeting of tumors. A series of light-emitting diodes are placed on the chest wall and movement is detected by wall-mounted cameras in the treatment room. Using motion-tracking software, the Synchrony system identifies, updates, and then correlates external body surface movement with movement of the internal tumor fiducials. Throughout the procedure, the Synchrony system monitors the target and modifies the correlation model as needed to follow changes in tumor motion.

During the past decade, innovations in target delineation, liver imaging, focal radiation delivery, and motion management have led to a significantly more comprehensive understanding of the treatment of liver metastases with RT. As radiation oncologists continue to explore new technologies that allow safe dose escalation to liver lesions, it is hoped that local control rates will be further improved for patients with liver metastases.