Liver metastases

LIVER METASTASES JAMES H. FOSTER, M.D. JOEL LUNDY, M.D.

0011-3840/81/0300157-00204-$6.50 9 1981, Year Book Medical Publishers, Inc.

TABLE OF CONTENTS EDITOR'S PREFACE .

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INTRODUCTION

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PATHOLOGY OF LIVER METASTASIS . . . . . . . . . . . .

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BIOLOGY OF AND EXPERIMENTAL ATTEMPTS TO CONTROL LIVER METASTASES . . . . . . . . . . . . .

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DETECTION OF LIVER METASTASES . . . . . . . . . . . .

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NATURAL HISTORY AND PROGNOSIS . . . . . . . . . . . .

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TREATMENT

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TECtINIQUE OF LIVER RESECTION FOR METASTATIC TUMOR . . . .

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RECOMMENDATIONS FOR THERAPY IN PATIENTS WITH LIVER METASTASES .

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OWEN H. WANGENSTEEN, M.D. 1909-1981 The Editors and Publisher of CURRENT PROBLEMS IN SURGERY are saddened by the passing of Dr. Wangensteen--surgeofi, investigator, educator, founder of a school of surgery, and one of the founding editors of this journal.

EDITOR'S PREFACE Drs. Foster and L undy ha ve provided a r e m a r k a b l y lucid survey of the problem of hepatic metastases, t hei r intimate biology, t h e i r clinical manifestations, and the rationale for t hei r treatment. The authors include a dispassionate review of the effectiveness of frequently multiplied diagnostic techniques, and of ancillary methods of t r e a t m e n t so often u n d e r t a k e n m o r ~ f r o m the need "to do something" t han from any evidence that" t hey are effective or safe.

graduated from Haverford College in 1950 and Columbia Medical School in 1954. After an internship at Barnes Hospital in St. Louis and a short tour of duty with the Air Force, he completed his residency in surgery in Portland, Oregon, and then joined the staff of Portland Veterans Hospital and the faculty of the University of Oregon. From 1966 to 1978 he served as full-time Director'of Surgery at the Hartford Hospital in Hartford, Connecticut. In 1978 he assumed his present position as Chairman of the Department of Surgery at the University of Connecticut School of Medicine, in Farmington. A member of several regional and national surgical societies, he presently serves as Director of the American Board of Surgery.

is an Associate Professor of Surgery at the University of Connecticut School of Medicine. He attended Hahnemann Medical College in Philadelphia, had a surgical residency at Beth-Israel Hospital in Boston, and served a two-year fellowship at Memorial Sloan-Kettering Cancer Center in'New York. Dr. Lundy's clinical interest is in the area of surgical oncology and his research interests are in tumor biology and modification of host defense mechanisms. 160

INTRODUCTION

THE LIVER provides fertile soil for the growth of embolic metastases from a wide range of primary tumors. Liver involvement often tilts the scales toward death in cases of advanced malignant disease. Therapies effective against localized deposits of metastatic tumor elsewhere are often ineffective against liver secondaries. These and other factors m a k e for a grim prognosis once the diagnosis of metastatic disease of the liver has been established. Progress has been made, however, and in a few instance~, hope for substantial palliation and even an occasional cure can be offered to patients with metastatic cancer in the liver. For most patients, unfortunately, effective therapy is still not available. This monograph describes current knowledge of the incidence and biology of liver metastases and the therapy of patients with this unfortunate complication. Our task is made more difficult by the fact that, with few exceptions, there is a striking dearth of properly controlled therapeutic trials that clearly establish either benefit or lack of benefit for any specific treatment modality over the natural history, of patients with untreated disease. PATHOLOGY OF LIVER METASTASIS The liver is the most common site for blood-borne metastatic disease. In 500 consecutive autopsies of patients who died of cancer at multiple primary sites, Willis found hepatic metastases in 180 (36%) patients. The lung was the second most frequent site (29%). At autopsy, 73% of patients dead of pancreatic carcinoma had liver metastases; the figures for other common carcinomas in Willis' series were as follokvs: bowel, 50%; breast, 49%; stomach, 46%; esophagus, 41%; and uterus, 20%. 97 Blood-borne metastases must reach the liver via the portal vein or the hepatic artery. Tumor emboli are commonly seen in portal venules in autopsy material but are rarely seen in the smaller radicles of the hepatic artery. Although there are some experimental data and a few clinical reports about differential distribution in the liver of venous blood from various parts of the splanchnic bed, the distribution of hepatic metastases in m a n would suggest that this is not an important factor. The fact that most metastases from bowel carcinoma are said to be in the right lobe probably relates more to the use of incorrect terminology for liver anatomy than to poor venous mixing. Although the bulk of liver substance is to the right o.f the falciform ligament, the true anatomic left lobe extends over to the gallbladder and contains nearly as much volume and as many metastases as does the anatomic right lobe. 161

The liver apparently provides very fertile soil for metastatic growth--more fertile than the lung. Willis 97 documented this at autopsy where he found a 48% incidence of liver metastases and a 19% incidence of lung metastasis in 179 cancer patients with primary tumors in the portal venous drainage bed. He found a 31% incidence of liver metastasis and a 40% one of pulmonary metastasis in 276 patients with primary tumors outside the portal bed. This is to be viewed in light of the fact that 100% of the blood passes through the lungs and only 30% through the hepatic artery and portal vein. Although factors such as high carbohydrate content and low oxygenation have been c~ed as reasons for the preferential growth of hepatic metastases, no good evidence exists to credit any single factor. The frequency of gastrointestinal cancer and the large and dual blood supply of the liver must also contribute to this phenomenon. Although normal liver tissue receives most of its nourishment from the portal vein and although spread to the liver is often via the portal vein, the blood supply of hepatic metastases more than 1 mm in diameter is almost entirely provided by the hepatic artery. As the microscopic fossi of embolic tumor lodge and grow, neovascularity is sought from the high pressure arterial system. Bierman et al., 14 Breedis and Young, 15 and many others demonstrated this with radiographic and injection-corrosion techniques. Liver metastases are usually more lightly colored and firmer to palpation than the dark and soft normal liver substance. Scirrhous carcinomas are particularly hard. Central umbilication of surface metastasis is common and probably results from central necrosis of a tumor that is outgrowing its blood supply. Occasionally, large metastases may show central liquefaction or cyst formation, and superimposed infection may result in abscess formation. Calcification is rare in liver metastases. Liver metastases usually grow by concentric growth with extension in all directions in the liver substance. Thus, most are spherical except for those on the surface, which may be hemispherical. Glisson's capsule is a strong, if not absolute, barrier to extension beyond the liver. Liver metastases may attain enormous size, and it is not unusual to see livers weighing up to 5,000 gm (the normal liver weighs 1,500 grams) at autopsy of patients who have had little clinical evidence of decreased hepatic function. The record for size seems to be a 15,110-gm liver filled with metastatic rectal carcinoma. Ocular melanoma is also prone to enormous liver involvement (22 collected cases averaged 6,000 gm of liver at autopsy)27

162

BIOLOGY OF AND EXPERIMENTAL ATTEMPTS TO CONTROL LIVER METASTASES

One of the primary goals of oncologists is to successfully eradicate micrometastases before established metastases are manifested clinically. The objective of this section is to discuss the pathobiology of the metastatic process as it relates to liver metastases, cite some experimental approaches to treatment, and pose some challenges for the future. In 1889, Paget 66 hypothesized the "se~d and soil" concept of metastases. This stated that the microenvironment of one organ might be more conducive to the arrest and subsequent growth of metastases, while another organ might not have fertile soil for the seed to grow. In 1928, Ewing ~3 hypothesized that the distribution of metastases was essentially a random event influenced by purely mechanical factors, i.e., anatomical and hemodynamie factors in the vasculature. New knowledge suggests that the properties of tumor cells themselves may also influence patterns of metastatic spread and proliferation. 26 At what point in primary tumor growth can metastasis occur? Assuming that tumors are monoelonal in origin and that the average cell size is 10 • 10 x 10 ~, after 20 doublings the tumor contains 1,000,000 cells and measures 1 • 1 • 1 mm. This is obviously not a clinically detectable cancer, but it is at this point that the tumor develops neovascularity. Work by Folkman 32 suggests t h a t a glycoprotein he calls a tumor angiogenesis factor (TAF) stimulates this endothelial movement and division. Neovascularity is necessary for continued growth of the primary tumor, and elegant studies in animal models indicate that tumor cell shedding into the bloodstream is not seen until neovascularity develops. 52 In animal models, this occurs as early as five to seven days after implantation of a primary tumor. In patients, if we assume a rapid tumor doubling time o f t e n days, this would occur about seven months from the first doubling. About three months after the tumor had the capacity to metastasize hematogenously, it would be 1 x 1 • 1 cm. in volume and detectable clinically if it were in an accessible area, i.e., the breast. Most h u m a n primary solid tumors do not have such a rapid doubling time, and it is conceivable that a tumor could have the capacity to metastasize two to three years before it was detectable clinically. Many of us were taught in medical school that carcinomas spread primarily by lymphatics while sarcomas spread hematogenously. However, there have been several anatomical studies that indicate that, rather than two separate pathways, these are interlinked systems. Studies by Fisher and Fisher, s~ Wood, 99 and Zeidman and Buss 1~ demonstrated that tumor cells may invade lymphatics directly or gain access to them via blood vessels. 163

Conversely, malignant cells that invade lymphatics can ultimately spread hematogenously via venolymphatic anastomoses or the thoracic duct. Lymphatic channels do not directly bring tumors to the liver. Cancers in the gastrointestinal (GI) tract m a y reach the liver via the portal vein or lymphatics and then the hepatic artery. A lung or breast cancer or sarcoma requires access to arterial circulation to reach the liver. This can be accomplished in several ways. A lung cancer can shed tumor emboli into the pulmonary veins, reach the left heart, and enter the arterial circulation. Breast cancers and sarcomas could metastasize in the above fashion after estabhshmg pulmonary metastases. Liver metastases could be seen in the absence of pulmonary metastases if tumor emboli traversed shunts between pulmonary arteries and veins, thus bypassing the capillaries in the parenchyma of the lung, 12 ultimately being carried by the hepatic artery to the liver. Does the presence of tumor cells in the portal vein (or venous circulation) always lead to metastases? After an extensive review of the literature, Salsbury 75 concluded that the presence or absence of tumor cells in the blood is of little or no prognostic significance. This conclusion is reasonable if one considers the fate of the majority of circulating cancer cells, which is death. Single tumor cells are rapidly destroyed in the blood, b u t if aggregated by homotypic (other tumor cells) or heterotypic (platelets, lymphocytes) cell interaction or by soluble blood components into large emboli, their likelihood of reaching and arresting in a distant capillary bed is enhanced. 25 There are still several host/tumor interactions required before a successful metastasis can be established. Once cells arrest, under certain conditions the adhesion of tumor cells to endothelium m a y lead to vessel wall damage. An accumulation of neutrophils m a y occur and tumor cells m a y pass through the endothelium. Another alternative for this poorly understood aspect of the metastatic process is that platelets may aggregate at the site of tumor cell lodgment and release mediators that increase endothelial permeability. A third possibility is that tumor cells m a y release a chemotactic mediator that attracts other malignant, but not normal, cells to extravascular tissue. If cancer cells have escaped host defenses to this point, they must still proliferate in extravascular tissue. In order for these micrometastases to become established, vascularization is again required and TAF probably plays a major role. Fisher and Fisher 29 emphasized the importance of hormonal influences on the establishment of Walker tumor liver metastases in the rat. Hypophysectomy prior to injection of tumor cells via the portal vein prevented the development of liver metastases. Single hormones such as ACTH, GH, or TSH did not increase metastases, but fresh rat pituitary homogenate did. They 164 9~

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postulated that a specific unknown pituitary factor could be essential for establishment of liver metastases. Is a liver metastasis a random event or a selective process? Experimental data is presented below to support the concept that it is a selective process and that only a unique subpopulation of tumor cells from the primary possess this lethal capacity. Work by Fidler 24 indicates that labeled B-16 murine melanoma cells given intravenously initially arrest in the lung. By 24 hours, only 1% of these cells survive in host organs and by day 14 less than 0.1% survive to produce~ metastases, i.e., only a select subpopulation of cells can escape host defense mechanisms and proliferate. In m a n y experimental tumor systems, selective patterns of homing and subsequent growth into metastases have been demonstrated. The intrinsic properties of tumor cells may be responsible for a significant part of this phenomenon. Kinsey, 5~ using the Cloudman melanoma model, and Sugarbaker et al., 84 using a murine fibrosarcoma model, demonstrated that these tumors would selectively metastasize to subcutaneously implanted fragments of lung tissue, but to no other control tissue. Brunson et al. 16 have recently cloned out murine melanoma lines, one of which selectively metastasizes to brain and the other of which to adrenal or ovary. 16 By a series of elegant experiments in an animal tumor system, Kripke et al. 54 have shown that cells cloned out with selective metastatic properties preexisted in the original tumor and did not arise during the metastatic process by adaptation to local environment conditions. A similar heterogeneity of primary tumor cell populations has also been seen with regard to susceptibility to cytotoxic drugs, immunologic properties, hormone receptors, and growth rates. 43' so, 76. 80 Two unique factors that m a y influence the patient's clinical course: tumor cell dormancy and the metastasis of metastases. The reappearance of overt tumors in patients years after successful therapy of primary cancer is certainly not uncommon. This long delay prior to development of clinically detectable metastases suggests that in such patients host defense mechanisms, immune or otherwise, have controlled micrometastatic foci of t u m o r following initial treatment. Fisher and Fisher 28 developed the first experimental model of tumor dormancy in 1959. They injected rats via the portal vein with 50 Walker-256 carcinosarcoma cells and found no tumor growth in the liver after five months. If three months after injection the rats were subjected to repeated laparotomy and liver massage at seven-day intervals, all of them developed tumors within a few weeks. The Walker t u m o r is not immunogenic and it seems unlikely that host immune mechanisms played a vital role. Sugarbak~er, s5 using a highly immunogenic 3 - 4 benzpyrene sarcoma, could not 165

demonstrate activation of dormant liver metastases. In this tumor system either host immunity plays a vital role in preventing the growth of dormant tumor cells or there might be a difference in growth kinetics between the Walker tumor and the benzpyrene sarcoma that makes one more selective for establishing dormancy. In our laboratory, we have cloned a population of tumor cells from a 3-methylcholanthrene fibrosarcoma that can establish dormancy and be activated to grow by stress (a major surgical procedure) or b y , d r u g therapy (thiopental, a t u m o r promoter). 91 Both surgical stress and thiopental have been associated with the generation of suppressor cell activity that impairs host immune responses, ss" 94 Simpson-Herren et al. ~9 have published studies on the kinetics of t u m o r micrometastases following surgical removal of the prim a r y lesion. They found that the presence of a subcutaneous Lewis lung tumor suppressed the growth of lung metastases. Surgical excision of the primary resulted in an increase in growth rate of the metastases that persisted for at least two weeks after the excision and had a slight, but consistent, adverse effect on life span. 7~ The above results from an animal model serve as one basis for starting adjuvant chemotherapy early, i.e., at a time when the micrometastases are actively dividing and before the tumor burden exceeds the capacity of chemotherapy and host defense mechanisms to eradicate it. The old question of whether metastases metastasize cannot be answered absolutely, b u t studies on liver metastases strongly suggest that they do. There is considerable evidence in m a n that intrahepatic spread occurs via the portal vein. Microscopic studies show that the portal vein is the vascular compartment most commonly invaded by liver metastatic growth, and satellite formation close to a large liver metastasis is common with both primary and secondary ~umors of the liver. This suggests that tumor cells have broken off into a portal radicle and have reseeded close to the initial lesion. This m a y result in localized regional groupings of metastases, a factor that might contribute favorably to the possibility of cure by resection (see below). Liver metastases probably spread to the lung by invasion of the hepatic vein or the inferior vena cava. In Willis '97 autopsy series of 88 patients with primary tumors of portal bed origin without liver metastases, only eight had pulmonary metastases, while of 86 patients with primary tumors of the portal bed who had liver metastases, 27 also had pulmonary metastases. Pulmonary spread of splanchnic bed tumors can occur through the thoracic duct and other nonportal venous tributaries, but the most important source of pulmonary metastases in patients with splanchnic bed primary carcinomas is probably secondary disease in the liver. Several studies have shown a significant survival among se166

lected patients after resection of pulmonary or liver metastases. If metastases metastasize, how much risk is incurred by an observation period, before these patients are accepted for resection of metastatic disease? Experimental studies in animal models have certainly shown that pulmonary metastases can shed viable tumor cells into the circulation. Hoover and Ketcham47 made mice whose primary tumors had developed pulmonary metastases and had been amputated parabiotic with normal syngeneic~artners. Metastases were demonstrated in the nontumor-bearing partners despite their development of passive immunity. Immunizing the nontumor-bearing partners prior to joining into parabiosis was not protective against the development of metastases. Clearly, these cells selectively had the capacity to escape immunologic destruction. This is a clear-cut experimental example of the metastasis of metastases. On the basis of this fund of experimental data and clinical observations, how might we interrupt the metastatic process? The ideal situation is where there is early detection of the primary tumor. The series of minimal breast cancer patients with a ten-year survival of 95% of W~nebo et al. 92 reflects the fact that, when the micrometastatic tumor burden is low (probably less than 108 cells based on experimental data), the host immune system is capable of destroying the small number of residual tumor cells following removal of the primary lesion. In the future, therefore, improved techniques for early detection of primary cancers may be the most vital step in aborting the metastatic process. Should patients with Dukes C colon cancers who are at high risk of developing liver metastases have therapy aimed at potential metastases? It is likely that the micrometastatic burden in these patients with more advanced primary cancers is high, and host immune defenses may not be adequate to eradicate residual tumor cells. After removal of the primary lesion, micrometastases that may have been in a resting phase theoretically go into a phase of active growth. Hence adjuvant chemotherapy may be indicated. A high cell kill should reduce the tumor burden to a point where host immune defenses, alone or with the aid of immunotherapy, might ultimately control t h e metastatic process. However, chemotherapeutic agents on the whole have been disappointing, and, to date, the majority of well-controlled studies do not show any benefit from adjuvant chemotherapy for patients with advanced GI tract cancers. The challenge here obviously is to develop more effective chemotherapeutic agents. If we are to use immunotherapy effectively, residual tumor burden must be quite small. We must develop a better understanding of how to use immunopotentiating drugs effectively. 167

And we have to understand better the host immune response to be able to manipulate it favorably. There are some unique experimental approaches that deal with altering various aspects of the metastatic process in favor of the host. Alfonso et al. 3 injected Walker cells into the portal vein of rats and infused radioactive gold intraportally or systemically. When such gold was given soon after injection, significantly fewer tumors were seen in gold-t[eated rats than in controls or rats given 'gSAu two weeks after tumor infusion. A 400 ~Ci dose provided substantial local radiation to the liver for nine days without measurable toxicity. 3 Anticoagulant drugs such as warfarin have effectively decreased distant spread of spontaneously metastasizing animal tumors. In contrast, heparin has not. Hilgard 45 feels that the effects of warfarin are not related to the anticoagulant effect, but more to vitamin K antagonism. Vitamin K-dependent protein synthesis may play a role in the initiation and/or control of the metastatic process. Tranexamic acid is believed by some investigators to inhibit either fibrinolysis (which might decrease tumor cell shedding) or tumor angiogenesis and thus prevent the development of neovascularity. 69 If tumor angiogenesis factor is a tumor-specific product that acts only on tumor cells, purification of this biologic substance and development of a monoclonal antibody could be one method of attacking the metastatic process. We know very little about the biology of the dormant tumor cell. What factors determine whether dormancy concludes in growth or eradication? Can therapy either eradicate dormant cells or prolong the dormant state? Might some anticancer therapies actually promote the proliferation of dormant cells? What biologic markers allow us to select patients who will be benefited by surgical resection of hepatic metastases? We presently do a very careful workup to be sure that the primary tumor is controlled and that no other distant metastatic disease is present. We might use a period of observation to determine rapidity of growth or a trial of chemotherapy before embarking on resection. Certainly, some groups have suggested that the tumor-doubling time of lung metastases is an excellent indicator of who will benefit from resection. Patients with a tumor-doubling time of more than 40 days had a 50% five-year survival rate after resection of limited pulmonary metastases. 46 In the future our therapy will probably be based on a better understanding of the heterogeneity of tumor cells involved in the metastatic process and on a fuller understanding of drug susceptibility, immunogenicity, intrinsic growth characteristics, and other factors that will permit effective multimodal therapy. 168

DETECTION OF LIVER METASTASES

Liver metastases are found either at the time of diagnosis and treatment of the primary tumor or, with slowly growing tumors, after an interval that may reach several years. HISTORY AND PHYSICALEXAMINATION Most early and small metastatic deposits in the liver do not produce symptoms. Liver pain is caused by rapid distention and stretching of Glisson's capsule. Thus, unless necrosis and hemorrhage occur, pain is an infrequent, usually late, and often preterminal sign. There may be a history of anorexia or early satiety, and the chronic weight loss and asthenia of advanced carcinomatosis may reflect gradual liver failure as well as competition for the essentials of life by the voracious appetite of a rapidly growing tumor. True infarction of a liver metastasis is rare, but central necrosis with or without hemorrhage is reasonably common with rapid growth and may lead to pain that is often transient. Rapid growth of bulky disease may produce unremitting pain, which usually is localized in the right upper quadrant of the abdomen or epigastrium and which occasionally radiates to the right shoulder. Ascites may occur without peritoneal spread if there is postsinusoidal obstruction of hepatic venous outflow. Portal hypertension with splenomegaly and bleeding varices may also occasionally be seen. Hepatomegaly is common, but again is a late sign. Livers containing several hundred grams of metastatic tumor may still hide underneath the rib margin. With deep inspiration discrete nodules may be palpable. They are usually nontender. Central umbilication of a nodule is almost pathognomonic of metastatic disease. Bruits may occasionally be heard over primary and secondary tumors, but this sign seldom if ever has any prognostic significance. Jaundice is a very late sign and has an ominous prognostic significance. Rarely does secondary liver disease cause intrahepatic obstruction of bile ducts that can be relieved to afford the patient significant palliation. Still, in a patient with rapidly progressive jaundice without other constitutional symptoms, this possibility should be searched for with ultrasonography o r cholangiography. BLOOD TESTS Of those tests commonly, done to assay liver function, the alkaline phosphatase, serum glutamic oxaloacetic transaminase (SGOT), and Bromsulphalein retention (BSP) tests are most of169

TABLE 1.--ABNORMALITIESIN DIAGNOSTIC TESTS IN PATIENTS WITtt RESECTABLE LIVER METASTASES*

TEST Alkaline phosphatase SGOT BSP Bilirubin (>2mg/100 ml) CEA Radionuclide scan Arteriogram

METASTASES FROM OTHER COLORECTAL PRIMARY PRIMARIESt SOURCESt 38/82 17/61 12/20 0/64 1/1 26/34 19/21

16/28 12/27 6/10 0/22 -19/20 7/7

*Adapted from Foster J.H., Berman hi.: Solid liver tumors, in Major Problems in Clinical Surgery. Philadelphia: W.B. Saunders Co., 1977. tNumerator: Number of patients with abnormal tests; denominator: number of patients who had test performed preoperatively.

ten abnormal with metastatic disease. Table i documents abnormal tests in patients with r~sectable liver metastases, i.e., with early or localized disease. 35 Castagna et al. is studied patients with liver metastases and found elevation of alkaline phosphatase in 58% and of SGOT in 60% of them. The combination of palpable hepatomegaly and increased alkaline phosphatase was associated with a mean patient survival of only 1.4 months in those patients with metastatic colon carcinoma reported by Pettavel and Morgenthaler. v~ The clinician must remember that both alkaline phosphatase and SGOT m a y be elevated in cancer patients without liver metastases. Hence, these and other serum tests must never be used as absolute criteria of liver spread. Although infrequently done, the BSP may be the most sensitive of the common liver function tests in detecting liver secondaries. Carcinoembryonic antigen (CEA) m a y be elevated in patients with metastatic cancer in the liver, b u t this marker m a y of course also be elevated with cancer outside the liver or in patients with a variety of benign conditions. Serial determinations of CEA at one-month to two-month intervals have been recommended for the detection of recurrent cancer. Some propose exploratory laparotomy for patients with two consecutive CEA elevations, even if their preoperative workup has failed to demonstrate a focus of recurrent disease. 22' 60 Theoretically a recurrence in the liver or elsewhere m a y be resectable for cure if found early enough. Whether this plan will prove to be sound remains unestablished.

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ULTRASOUND, SCINTISCANS, COMPUTERIZED TOMOGRAPHY,AND ANGIOORAPHY

Ultrasound is probably most useful in differentiating cystic from solid lesions of the liver and for demonstrating dilated biliary ducts. Most metastases from the common solid tumors are echo-dense when compared with surrounding normal liver tissue and will be demonstrable with echography. Perhaps the test most often used to lo0~k for liver metastases is the radionuclide scintiscan. Technetium-99m sulfur colloid is picked up by the normal reticuloendothelial system. Almost all benign and malignant primary and secondary liver tumors fail to pick up this nuclide and therefore appear as "cold" lesions in contrast to normal liver tissue. Unfortunately, the bulk of normal liver tissue may obscure smaller lesions and, particularly in the right lobe, lesions less than 2 cm in diameter are usually not detectable. Radionuclide scans are notoriously unreliable in differentiating between multiple small metastatic lesions and diffuse nonmalignant liver disease. Cedermark et al. '9 noted only a random correlation of scintiscan to operative findings when less than 25% of the liver was replaced by tumor. Most primary liver cancers and solid benign tumors are hypervascular. With the exception of leiomyosarcomas, some melanomas and metastatic endocrine tumors, most metastatic lesions are hypovascular. ~-Camera assessment of the initial passage of radiocolloid through the liver may permit differentiation of the highly vascular from the hypovascular lesion, both of which may have similar images on the static scintiscanY Some liver metastases also take up gallium (68GA) and thus produce an image of a "hot" lesion. 4 Computerized tomography is probably more accurate than either ultrasound or radionuclide scintiscans in defining the number, size, location, and natur~ of most solid liver tumors. Contrast enhancement is thought to be valuable by some, but Moss et al. 61 in studying 61 patients found lesions without enhancement in most patients and in eight actually "lost" lesions that had been evident on precontrast films. Selective arteriography is probably the most accurate aid to the diagnosis of metastatic liver disease, but is also the most invasive, expensive, and dangerous. It can demonstrate large and small lesions and can differentiate hypervascular from hypovascular tumors. Cavernous hemangiomas and simple cysts of the liver may provide confusing images on radionuclide scans or ultrasonograms; angiography can be of great help in this differential diagnosis. The late venous phase of arteriography may be more valuable than the earlier arterial phase in picking up small avascular metastatic lesions. In addition to finding metastatic deposits, selective arteriog171

raphy shows vascular abnormalities consistent with cirrhosis and defines the vascular anatomy of arterial inflow to the liver should future resection be contemplated. How should the clinician choose between these alternative diagnostic techniques, or should he use them all? When metastatic disease is being looked for, ultrasound and radionuclide scintiscans should probably be used first because they are less invasive and less expensive. A negative scan and echogram combined with a normal SGOT and alkaline~phosphatase in a patient without hepatomegaly provide strong evidence against liver metastasis. If an apparently solitary lesion is found and resection is being contemplated, selective arteriography should be done to look for other smaller lesions and to detail vascular anatomy. BIOPSY AND OPERATIVE DETECTION

Thin-needle biopsy can be done with safety under radiographic or ultrasonic control if laparotomy has been ruled out. But if the possibility of resection of liver metastases remains, or if laparotomy will be need6d for some other reason, the tests mentioned above need not be done. Far and away the most accurate test for the presence of liver metastases is provided by the hands of the surgeon. Two hands in opposition on either side of the liver can find the vast majority of metastatic deposits, even deep within the substance of the right lobe. Pack and Ariel ~4studied the autopsies of 100 patients who died in the postoperative period while still hospitalized after resection of their primary tumors. All of the patients had primary carcinomas of the GI tract and all of their livers had been judged by the surgeon to be free of metastasis at the time of primary tumor resection. Only five of these 100 patients had metastatic disease in the liver at autopsy and only two of these unrecognized metastases were evident macroscopically, even after multiple sectionings of the liver. 84 Goligher 4~ studied 31 autopsies performed in the postoperative period of 790 patients whose livers were judged to be negative at the time of resection of their primary carcinoma: five were found to have liver metastases. Ozarda and Pickren ~ did autopsies on 150 patients with liver metastases from a wide variety of extrahepatic primary cancers and found that nodules were evident on the surface of the liver in 134 (90%) of them. Thus, in the preoperative evaluation of any patient with a primary intra-abdominal tumor, the surgeon should ask himself if preoperative demonstration of liver metastases in this particular circumstance would make any difference in management. If the answer to that questiomis clearly yes, then a careful search for evidence of liver involvement should be made. More often, the answer will be no, and in 172

that circumstance an early approach to laparotomy is recommended. Needle biopsy is dangerous with hemangioma, some of the primary hypervascular tumors, and echinococcal disease. It may be nondiagnostic with adenoma, focal nodular hyperplasia, and hemangioma. But if the preoperative workup has clearly established nonresectability of a primary intra-abdominal cancer, a needle biopsy procedure should be done if it will make a difference in management. Cytologic examination of touch preparations of the tissue core from a percutaneous needle biopsy sample of aspirated fluid may increase the yield of positive diagnoses of cancer. Laparoscopy may afford a compromise between needle biopsy and laparotomy. It certainly can assist in the effectiveness of needle biopsy. Lightdale et al. s6 reported confirmation of diagnosis by needle biopsy in 60 of 65 patients under laparoscopic control. Previous attempts at "blind" percutaneous needle biopsy were negative in 23 of the same 65 patients. NATURAL HISTORY AND PROGNOSIS

Before treatment options are considered, it is important to look at the survival data on patients with liver metastases who receive no treatment. Any therapy may bring with it increased morbidity and mortality, some lessening of host resistance, and an increase in cost. We know of no reports of the comparison of any particular therapy with untreated control patients with secondary liver cancer in a prospective randomized fashion. The TABLE

PRIMARY TLrMOR

2.--NATURAL HISTORY OF PATIENTS WITH UNTREATED LIVER METASTASES

REFERENCE

NO. OF PATIENTS

STAGE

MEAN SURVIVAL (MO.)

56 177 269 43 353 15 11 87 12 41 30 68 23 54

All stages All stages All stages All stages All stages Solitary Localized Widespread Minimal Moderate Widespread All stages All stages All stages

6.5 5 13 8 9 16.7 10.6 3.1 21.5 6.9 1.4 2.4 6 6

Colon and Rectum

Abrams and Lerner 1 Jaffe et al? 9 Cady et al. 17 Flanagan and Foster sl Pestana et al. 6s Wood et al. z~176 PettaveI and Morgenthaler7~ Pancreas Stomach Breast

Bengmark et al. 1~ Bengrnark and Hafstrom 1~ Bengmark et al? 3

173

only available data about the survival of untreated patients have been obtained retrospectively. Table 2 lists some of these data. The most important factor to consider is the extent of liver involvement. Patients with solitary or limited metastases will survive longer than those with multiple or extensive metastases no m a t t e r what therapy is or is not en~ployed. Wood et al. I~176 reported a 5.7% one-year survival rate when both lobes of the liver contained metastatic disease from colorectal primaries, in contrast to 60% survival at one year for patients with solitary untreated metastases. Pettavel and Morgenthaler 71 used hepatomegaly and increased alkaline phosphatase to categorize the extent of liver involvement by colorectal secondaries and found a mean survival of 16 months in 27 patients with neither criterion, in contrast to a mean survival of 1.4 months of 30 patients with bothcriteria. Galante et a l Y reported 11.5% three-year survival of 74 patients who had liver metastases found at the time of resection of their primary colon carcinoma. Four patients in this series lived five years, but they did not have histologic confirmation of liver metastasis. This brings up tl~e important point that all palpable liver nodules in patients with extra-hepatic primary malignancies are not necessarily'metastatic lesions. The more thoroughly one palpates the liver, the more one finds small firm lesions that turn out to be simple cysts, bile duct adenomas, hemangiomas, or other benign lesions. Biopsy confirmation is essential before assigning prognosis. Swinton et al. 8s followed forty-one patients with colorectal liver metastases. Seven lived two years, b u t none survived four years. Bengmark and Hafstrom ~2 found a mean survival of 5.7 months in 38 patients with liver metastases from colorectal primaries; their longest survivor lived only 22 months after bowel resection. Jaffe et al. 49 found a median survival of 75 days and a 7% one-year survival in 390 patients with liver metastases from a variety of primary sites. Patients with solitary liver nodules or colorectal primary did much better than those with bilateral metastases or meta~stases from other primary sites. In all of these series, median survival is shorter than mean survival after the discovery of liver metastases. Most patients who develop liver metastases have them at the time of the diagnosis of the primary carcinoma or within two years thereafter. The vast majority die within two years of the diagnosis of liver involvement. Although there are anecdotal reports of long-term survival after discovery of liver metastases, in most instances further investigation reveals that histologic confirmation is lacking or that the primary tumor was a slow-growing carcinoid or islet cell tumor. Well-documented survival for more than five years 174

after the diagnosis of liver metastases from the common solid tumors is extraordinarily rare. Without treatment specifically aimed at the liver disease it is certainly less than 1%. TREATMENT

The treatment of patients with liver meiastases can be categorized as preventive or "prophylactic" therapy, "palliative" therapy, or potentially "curative" therapy. PROPHYLACTIC THERAPY

When no liver disease is recognized at the time of the initial treatment of patients with primary extrahepatic tumors, the growth of presumably microscopic foci of liver disease may be suppressed or aborted by hormone manipulation in patients with endocrine sensitive tumors (e.g., prostate and breast cancers), augmentation of natural defenses (theoretically ideal for immunotherapy), or use of adjuvant radiotherapy or chemotherapy. A trial of prophylactic radiotherapy using radioactive yttrium spheres in patients with advanced-stage colorectal tumors has been proposed but no results have yet been reported. 42 Although most reports of the use of adjuvant chemotherapy have not shown a significant benefit, two recent studies hold more promise. In a cooperative trial, Woolley et al. T M have shown an advantage that approaches statistical significance with the use of systemic 5-fluorouracil in an ajunctive fashion in patients with colorectal carcinoma. Although the blood supply of liver metastases is almost entirely derived from the hepatic artery, the initial tumor embolism from gastrointestinal carcinomas is presumably seeded through the portal vein. Cognizance of this fact has been taken by Taylor et al., 89 who have infused 5-fluorouracil through the portal vein in a small but well-controlled study of patients with primary gastrointestinal carcinomas who did not have demonstrable liver metastases. The early results of this trial have been encouraging. For the present it would seem reasonable to limit prophylactic adjuvant chemotherapy to patients with primary gastrointestinal carcinomas who can be included in carefully controlled prospective trials. Perhaps in the near future this recommendation can be extended to more patients with aggressive primary tumors who are at high risk for eventual spread to the liver. PALLIATIVE THERAPY

Once a diagnosis of liver metastasis has been established, either at the time of therapy of the primary tumor or after a "dis175

ease-free" interval, several treatment options may be considered, including radiotherapy, systemic or regional chemotherapy, interruption of tumor blood supply, resection, combinations of the above, or no active therapy at all. At the moment, only resection affords a chance for cure for patients with most of the common solid tumors, but the examples of multimodal therapy for certain childhood tumors and the appa2;ent increased efficacy of some of the new chemotherapeutic agents for certain rare adult tumors hold promise for more widespread curative therapy in the future. Unfortunately, at the present time, palliation rather than cure will be the only available goal for most patients with liver metastases. RADIOTHERAPY.--The liver is a very radiosensitive organ, and radiation hepatitis is a severe condition. The chief injury is to the hepatic venules with damage to the central areas of the liver lobule resulting in postsinusoidal obstruction of venous flow, sinusoida ! hypertension leading to ascites, and a resulting BuddChiari-like syndrome. These symptoms may mimic those that occur with fulminant malignant disease, and differentiation may be difficult. Ingold et al. 4s treated 40 patients with external irradiation and noted radiation hepatitis in two of nine patients after 3,000 to 3,500 rad, seven of 18 patients after 3,500 to 4,000 rad, and three of four patients with more than 4,000 rad of whole liver irradiation. Most radiotherapists limit liver radiation to 3,000 rad at low rad/fraction and would reduce that total dose if a rad/fraction as high as 300 per day were used. The kidneys may also be damaged by liver radiation, and Filler et al. 2~ have warned of the dangers of combining radiation with resection and chemotherapy in children. Most metastatic lesions are not sensitive to doses of less than 3,000 rad, but an occasional patient with radio sensitive and symptomatic liver metastases will receive symptomatic benefit from external radiation. Turek-Maischeider and Kazem 9~ reported pain relief after external radiation of liver metastases in ten of 11 patients. Prasad et al., ~s Sherman et al.7 s and others also noted palliation but did not document increased survival. Pain relief is a difficult and unreliable parameter to measure, because it is subjective. In addition, pain from liver metastases is usually due to a rapid change in liver size that is often related to acute necrosis and hemorrhage. Such pain would be expected to subside without therapy in many patients. Early reports of radiotherapy combinecl with the use of the hypoxic cell sensitizer, misonidazole, show no increased toxicity and a high palliative index in 41 patients who had a median survival of five months. ~5 Radiation can also be delivered to the liver by radioisotopes that collect in the liver or by the injection of radiolabeled micro176

spheres into the hepatic arterial supply. Radioactive colloidal gold is picked up by the reticuloendothelial system. It has been used in patients with metastatic lymphoma to the liver, but bone marrow toxicity proved to be excessive, and this has been largely abandoned. 53 Ariel and Padula, Grady, and others have labeled resin spheres with yttrium-90, a strong ~-emitter, and then injected these spheres into the hepatic artery. Radioautographs on animals and autopsied patients suggest that the metastatic tumor receives four times the radiation of surrounding liver tissue by this method. Vasoconstrictive drugs may further increase this differential uptake. Grady 42 noted decrease in liver size in 17 of 25 patients with metastatic disease treated with yttrium spheres alone, and Ariel and Padula 6 noted slightly increased survival (not of statistical significance) in patients treated with spheres and intra-arterial 5-fluorouracil when compared with patients treated with intraarterial 5-fluorouracil alone. Webber et al., 96 Barone et al., 9 Friedman et al. 36 and Herbsman et al. 44 have combined external irradiation with intra-arterial chemotherapy in small groups of patients in uncontrolled studies, but have not yet demonstrated significant prolongation of survival. In summary, radiation therapy has not played an important role in the palliation of patients with liver metastases from the common solid tumors. Combined with resection and/or chemotherapy it may play an important part in the palliation or even cure of patients with embryonal or germ cell tumors. When rapid distention of liver capsule produces localized pain, external radiation in doses of less t h a n 3,000 rad may provide transient symptomatic relief.

CHEMOTHERAPY.--Althoughchemotherapy has been in widespread use for patients with liver metastases for more than two decades, it is still difficult to define its role. Most reports of the results of systemic chemotherapy are discouraging. Schein et al. 77 summarized reports of patients with metastatic colorectal carcinoma and concluded that little impact on survival had been made. Most would agree that no prolongation of survival has been demonstrated and that significant objective response is limited to about 15% of patients after the use of currently available drugs for the common solid tumors. Disappointment with these results prompted Sullivan, 8s Watkins, 95 Ansfield and Ramirez, 5 and many others to try regional perfusion. Large numbers of patients have had 5-fluorouracil, 5floxiuridine, and other agents infused for periods ranging up to ten months through catheters placed in the feeding arteries of the liver at operation or, more commonly in recent years, placed percutaneously by the Seldinger technique. The morbidity and mortality of infusion techniques has been reduced by the lessons 177

of experience in recent years, but the rates of catheter displacem e n t and sepsis, gastrointestinal hemorrhage, and other complications directly related to the catheter remain high. A small chronometric infusion pump has been recommended for ambulatory patients, but even with outpatient therapy the cost remains high, both in patient discomfort and in dollars. What has been accomplished? It has been the subjective impression of most investigators that mtra-arterlal chemotherapy has been much more effective than systemic chemotherapy in t h e treatment of patients with liver metastases. Ansfield and Ramirez s report at least two months of improvement in 55% of 369 patients with liver metastases treated with intra-arterial 5fluorouracil, but the mean survival was only nine months after the initiation of therapy in the overall group of patients. Watkins et al. 95 report objective response of three months or greater in 56% of 108 patients with colorectal secondaries and a median survival of 15 months from the onset of symptoms (not of treatment). Sullivan 86 reports a 58% response in 102 patients with colorectal metastasis for three months or more after the initiation of hepatic artery infusion b u t does not provide overall median or mean survival rates. Petrek and Minton 7~ report an objective response at five to eight weeks after the initiation of intra-arterial therapy in 12 o f 24 patients with colorectal secondaries and in 11 of 27 with other primary tumors 9 They note a median survival of patients with colorectal carcinoma of nine months after the start of infusion therapy, a therapy that lasted a median of eight months. Thus the median patient survival after cessation of intra-arterial infusion in this series was one month. The patients with noncolorectal primaries lived an average of five months after the initiation of hepatic artery infusion. A report from Sweden notes a median survival of nine months and a mean survival of 11.5 months in 15 patients with colorectal metastases. 87 A Swiss report, which included some attempt at staging the degree of liver involvement, presented a more optimistic picture of w h a t hepatic artery infusion might accomplish. 71 In general, however, reported results document mean survivals of less than a year, a survival period that differs little from the natural history of the disease. It has also become clear that infusion must be prolonged over several months rather than weeks in most patients to be effective even in the most favorable "responders." Almost all authors report poorer results in patients with liver secondaries from stomach, pancreas, breast, and lung than in those with colorectal primaries. These results are difficult to put in perspective. There is still no study that clearly demonstrates benefit to treated patients when they are compared with concurrently untreated control patients. Response is usually measured in terms of two or three ly8

months and patients with minimal liver disease are often lumped together with those with extensive disease. Hepatic artery infusion with chemotherapeutic agents is often combined with the use of systemic agents, hepatic artery interruption, or some other treatment. The effects in %esponders" are compared with those in "nonresponders," a practice as difficult to justify as would be the calculation of a baseball player's batting average by comparing his good days with his bad. The most important deficiency of most of these published results involves the almost universal absence of untreated control patients and to the almost equally universal comparison of achieved results with ~'historic" controls often chosen to emphasize the beneficial effects of active treatment. The recent report from the Central Oncology Group is extremely important in that it represents the first properly controlled prospective randomized trial to compare intra-arterial infusion of 5-fluorouracil with systemic 5-fluorouracil therapy in patients with comparable amounts of metastatic colorectal carcinoma. There were no untreated control patients, but the study is important in that it shows no significant difference in response rate, time to progression, duration of response, and survival between patients who received intra-arterial and those who received intravenous chemotherapy. One cannot deny that a dramatic and long-term remission occasionally occurs with systemic or intra-arterial chemotherapy in a patient with liver metastases from the common carcinomas, but the algebraic sum of what we subtract from the many and add to the few is almost certainly negative in 1981. Our goal should be to provide the patient with as many comfortable days at home as possible. Current evidence would suggest that the asymptomatic patient with unresectable liver metastases should not be treated with chemotherapy unless he can be placed in a properly controlled prospective trial. Those experimental trials should continue, but they should be labeled as such and they should include properly matched untreated control patients. If chemotherapy is to be used, a short trial may well separate out those whose tumors are sensitive to currently available agents from the vast majority who are not. Chemotherapy should probably be stopped in the latter group. IMMVNOWnEaAPV.--Theoretically, the ideal place for immunotherapy would be where there is minimal tumor load, a situation that rarely exists with recognized liver metastases. A significant experience with immunotherapy for patients with metastatic liver cancer has not yet been reported. Patt et al. ~ treated 30 patients with a variety of primary and secondary liver tumors with combined intra-arterial infusion of chemotherapeutic agents plus five days of intra-arterial Corynebacterium 179

p a r v u m . There were 16 patients with colorectal secondaries, and

of these, three had a partial response defined as shrinkage of their liver tumors by 50% or more. All of the patients had marked fever and thrombocytopenia; many had hepatomegaly with tenderness. The median response in the patients with colorectal primaries was four months. Toxicity was increased over chemotherapy alone. HEPATIC ARTERY LIGATION.--Markowitz ~9 first recommended arterial ligation in 1952, after it had been established that the great majority of primary and secondary cancers of the liver derive most of their nourishment from the branches of the hepatic artery rather than from the portal vein. At that time it was thought that the hepatic artery could not be ligated safely in man, b u t subsequent experience has shown that this can be done in a majority of patients without long-term adverse consequences. This is possible because of the dual inflow to the liver and the consequent protection of the hepatocyte by the portal venous supply, but it is also due to the amazing ability of the hepatic arterial system to develop collateral circulation from any adjacent vessel. In the 1960s surgeons from Scandinavia and Southeast Asia pioneered the use of hepatic artery ligation for liver tumors. 8' 62. 72 The operation was often followed by a dramatic reduction in the size of liver metastases, but the decrease was always of short duration. As subsequent arteriograms showed reestablishment of arterial circulation, more extensive operations were designed to prevent this, but to no avail. In almost all instances, within a matter of a few weeks after ligation, serial arteriography showed restoration of arterial flow to the metastases and parenchyma of the liver. Hepatic artery ligation is contraindicated when the portal venous inflow is compromised or in patients with cirrhosis. This technique, used alone, has largely been given up, although some investigators still combine ligation with cannulation of the artery for subsequent infusion of chemotherapeutic agents. There are a few anecdotal reports of alleviation of disabling vasomotor symptoms in patients with multiple metastases from a malignant carcinoid tumor after hepatic artery ligation. Hepatic artery ligation or intermittent occlusion of the hepatic artery with balloon catheters combined with chemotherapy in several recent trials yielded no significant benefit. 7"21.5~ HYPERTHERMIA--A few patients with hepatic tumors have been treated with hyperthermia. The technical aspects of heating up tumors to high temperatures without injuring the host are j u s t being developed. Tumor necrosis will result, b u t there are as yet no reports of clinical trials with sufficient follow-up to predict the future of this new modality. 82 18o

CURATIVE THERAPY 9RESECTION OF LIVER M E T A S T A S E S - - T h e l a s t s e v e r a l d e c a d e s

have seen the gradual establishment of a solid place for the resection of pulmonary metastases in certain carefully selected patients. Experience has shown which patient might benefit, and the goal has been a chance for cure, not palliation. A similar trend is now under way for patients with liver m~astases. Undoubtedly this trend was delayed for one overriding reason, and that is that, until comparatively recently, liver resection was a very dangerous operation associated with major blood loss and often followed by a string of postoperative complications. Beginning with the experience of World War II, complemented by the ever-increasing load of civilian liver t r a u m a managed by general surgeons, and pushed forward by the pioneering reports of Lortat-Jacob, Pack, Honjo, and the Quattlebaums, experience with liver resection has grown dramatically in the last two decades. 35 However, the need for elective liver resection is rarely encountered by most general surgeons. A few centers have compiled enough experience with elective resection of liver metastases to report their results. 2' ~3:9s Collective reviews have provided a clearer picture of what m a y be offered. 34 To many, the presence of embolic liver metastases in the liver means that a cancer has spread beyond the hope of cure. Yet attempts to excise deposits have been made for over 100 years. Professor Victor von Bruns of Breslau excised and cauterized a nodule of metastatic cancer from the edge of the right lobe of the liver in the early 1880s. 35 During the next 70 years, however, few followed his example. The experience with resection for metastatic disease in the 1950s and early 1960s reported from the Memorial Hospital in N e w York City and the University of Minnesota was discouraging.~S, G5 Operative mortality rates were high and cures were rare. It is only in the last decade that data have accumulated which are encouraging about the possibility of cure in selected patients with limited metastatic disease in the liver.

Resectability.--The accuracy of the operative evaluation of the extent of liver disease at laparotomy has been discussed abSve. The surgeon can be reasonably certain that careful palpation will detect a large majority of even the smallest liver metastases. Preoperative testing is considerably less reliable, even with the new imaging techniques. How often will a resectable sithation be found? A resectable metastasis is defined here as a metastatic tumor confined to a solitary focus or multiple nodules in one lobe not involving a major vascular trunk. Raven 74 found a resectable situation in 5% of patients with primary carcinoma of the stomach, colon, 181

and rectum. Bengmark and Hafstrom TM noted limited liver disease in nine of 38 patients with colorectal primaries with liver metastases. Jaffe et al. 49 found 56 solitary nodules in 173 patients for whom the location and number of metastatic lesions were stated in their retrospective review. Ozarda and Pickren, 63 who studied autopsies and therefore late cases, found solitary liver metastases in only nine of 150 patients :~Sth liver involvement, b u t in an additional 30 patients there were multiple nodules confined to one lobe. Pettavel and Morgenthaler ~ found resectable liver metastases in 4.5% of all patients with colorectal primaries (or in one fifth of those with liver metastases). Adson and VanHeerden 2 also found resectable liver metastases in 5% of all their patients who underwent operation for primary carcinomas of the colon and rectum. Thus, of the 15% to 30% of patients who will be found to have liver metastases at the time of operation for their primary tumors, about one fourth will have resectable liver disease. How often do liver metastases represent the only remaining focus of malignant disease? This is a difficult question to answer. Of those patients who survived liver resection for metastatic cancer but eventually died of their recurrence in one collected review, about h a l f had more disease in the liver at autopsy and about h a l f did not. ~5 Other questions must be answered before the place of liver resection for metastatic cancer can be defined. Do the size and number of metastatic lesions make a difference? Do patients TABLE 3.--Lvv-ER RESECTION FOR I~IETASTATIC CANCER: REPORTED CASES* PRLMARY CANCER Colon and rectum Wilms' tumor Melanoma Leiomyosarcoma Pancreas Uterus and cervix Stomach Renal Breast Ovary U n k n o w n primary Miscellaneous sarcomas Otherst

PATIENTS 326 15 13 12 7 8 7 5 5 5 4 4 6

OPERATIVE DEATHS 16 2 1 1 1 3 0 0 1 1 1 0 1

*From Foster J.H." Am. J. Surg. 135:389, 1978; and Waneba'H.J., et al.: Am. J. Surg. 135:81, 1978. Used by permission. tIncludes one each: esophagus, lung, neuroblastoma, adrenal, paraganglionoma, perlcytoma. 182

TABLE

4.--SURVIVAL AFTER LIVER RESECTION FOR METASTATIC CANCER RELATED TO P P J ~ R Y T U M O R SITE*

PRIMARY TUMOR

Colon and rectum Wilms' tumor Melanoma Leiomyosarcoma Pancreas Uterus and cervix Stomach Kidney Breast Ovary U n k n o w n primary Sarcomas Others$

OPERATIVE SURVIVORS 284 13 12 11 6 5 7 5 4 3 3 3 5

SURVIVAL'~ 2 YRS 5 YRS 105/217 8/13 2/11 4/9 2/6 1/5 0/7 2/5 0/3 0/2 0/3 1/3 2/4

53/231 4/9 1/11 1/9 1/6 0/5 0/7 1/5 0/2 0/2 0/3 1/3 0/2

DIED OF RECURRENCE AFTER5 YRS

12 0 1 1 1 --0 ---1 --

*Adapted from Foster J.H.: Am. J. Surg. 135:389, 1978; Foster J.H., B e r m a n M.: Solid liver tumors, in Major Problems in Clinical Surgery (Philadelphia: W.B. Saunders Co., 1977); and Wanebo H.J., et al.: Am. J. Surg. 135:81, 1978. tThe numerator of each fraction represents the number of patients alive; the denominator, the number of patients at risk, i.e., those who survived liver resection. $Includes one each: lung, adrenal, neuroblastoma, paraganglionoma, pericytoma.

with a long interval between the resection of their primary tumor and the resection of liver metastases do better? In other words, will a patient with resectable liver metastases found at the time of the resection of the primary tumor do as well after liver resection as the patient whose metastases are found and resected after a disease-free interval? How does the risk of resection compare with the benefits to be achieved and will a larger resection result in a better result? How much influence does the primary site or the stage or grade of the primary tumor have on results after liver resection of metastatic disease? Not all of these questions can be answered definitively, but a start has been made. The data below come from two sources: the experience reported in the literature, and information collected duritag a survey conducted by a series of personal visits to 98 hospitals across the nation, ss Table 3 lists the nature of the patients who were reviewed and documents operative mortality. Table 4 lists survival data in absolute terms. The totals vary from table to table because complete data were not available in every published report. Most of the data relate to the resection of colorectal metastases. A" surprising 48% of patients lived two years and 23% lived five years after liver resection for colorectal secondaries. The experience with other tumors is small and generally un183

T A B L E 5.--SURVIVAL AFTER RESECTION OF COLORECTAL METASTASES: SOLITARY VERSUS MULTIPLE LESIONS* FINDING

SOLITARY

MULTIPLE

Patients at risk 133 56 Operative deaths 3 7 5-Year survivors 40(30%) 7(13@) *Adapted from Foster J.H.: Am. J. Surg. 135:389, 1978; and Wanebo H. J., et al.: Am. J. Surg. 135:81, 1978. favorable. In fact, of those four patients with noncolorectal primaries who survived for five years after liver resection for metastases, three died subsequently of recurrent disease. Only the patient with renal carcinoma reported by Straus and Scanlon s3 in 1956 apparently was cured by the resection of her liver metastases. Autopsy twelve years after liver resection found no tumor in this unusual patient. The overall five-year survival rate after liver resection for colorectal metastases is 23%. Clearly, this remarkably high figure is related to a careful selection of more favorable cases for resection. We shall now look into the various factors t h a t m a y .contribute to proper selection. R i s k Factors.--Number and Size of Metastases.raTable 5 documents the varying survival after liver resection for single and multiple colorectal metastases. Wilson and Adson 9s reported no long-term survivors after the resection of multiple liver metastases in contrast to a 42% five-year survival rate of those with solitary nodules (15 of 36 patients). Wanebo et al. 9s also noted no five-year survivors after resection of multiple nodules. Table 6 documents the influence of the size of the metastatic lesion. Interval Between Resection of Primary Bowel Tumor and Liver Metastasis Resection.--Table 7 lists survival data related to the interval between resection of the primary tumor and the liver TABLE 6.--LrCER RESECTIONFOR ~I[ETASTATIC COLORECTAL CANCER: TUMOR SIZE VERSUS SURVIVAL*

FINDING

0-5 CM

TUMOR SIZE 6 CM AND GREATER

Patients at risk 58 59 Operative deaths 2 5 2-Year survival 28/48(58%) 8/41(19%) 5-Year survival 12/44(27%) 3/40(7.5%) *Adapted from Foster J.H., Berman M.: Solid liver tumors, in Major Problems in Clinical Surgery (Philadelphia: W.B. Saunders Co., 1977). 184

TABLE 7.--LIVE~R'-RESECTIONFOR METASTATIC COLORECTAL CANCER: SURVIVALRELATEDTO INTERVALBETWEEN B O W E L AND LIVER RESECTIONS*

FINDING

SYNCHRONOUS

Patients at Risk Mean Survival (months)t

136 33 641113 (57%) 22/106 (21%)

2-Year Survivalt 5-Year Survivalt

METACIIRONOUS LESS THAN MORE THAN 2 YEARS 2 YEARS 60 26 25/50 (50%) 12/47 (26%)

69 34 19/56 (34%) 10/51 (20%)

*Adapted from Foster J.H.: Am. J. Surg. 135:389, 1978; and Wanebo H.J., et al.: Am. J. Surg. 135:81, 1978. r a f t e r liver resection, excludes operative deaths.

metastases. "Synchronous" refers to liver metastases resected at the same time as the primary tumor or recognized at the time of the resection of the primary tumor and resected within a few weeks. These data pretty much put to rest the older, perhaps reasonable but theoretical, Concept that the patient with a long interval between the recognition and therapy of the primary tumor and the hepatic metastases would do better. Indeed, the overall survival from the date of therapy of the primary tumor may be longer in those with a' long disease-free interval, but there is no statistical difference in survival after liver resection between those patients who have synchronous or metachronous resection of their liver disease.

Operative Magnitude, Risk and Survival.--The operative mortality rate is increased after larger resections, although Adson and VanHeerden's 2 accomplishment of 34 major resections with only two deaths is most commendable. Table 8 relates the type of resection to short and" long-term survival. Although a few surgeons contributing to this collected data may have chosen lobectomy as theoretically a sounder way to provide a wide margin of liver tissue, most major resections were done because TABLE 8.--LIVER RESECTION FOR METASTATIC COLOP,ECTAL CANCER: EXTENT OF OPERATIONVERSUS SURVIVAL* FINDING

Patients at risk Operative deaths 5-Year survivorst

HEPATIC SEGMENTAL LOBECTOMY RESECTION 46 5 (11%} 6/45 (13%)

25 0 5/24 {21%)

WEDGE RESECTION 97 3 (3%) 22/93 (24%)

*From Foster J.H.: Am.'J. Surg. 135:389, 1978. Used by permission.

tExcludes operative deaths, survival after liver resection. 185

the metastatic tumors were large and thus were associated with a worse prognosis. There is no available evidence that documents an advantage to taking a wide margin of normal liver tissue. Simple wedge excision with a margin of at least one centimeter would seem to be preferable when the anatomical circumstances allow. Operative mortality aider resection of liver metastases for colorectal cancer is about 5%. Eight of 158 patients in a collected review 34 and three of 54 patients in two recent reports 2' 93 died during the operation or postoperatively, most aft4r major resection. Although this is a high operative mortality figure (5%), it must be measured against the possibility o f long-term survival and/or cure. Clearly, the patient's risk-versus-benefit ratio for resection of isolated liver metastases is much more favorable t h a n that associated, for instance, with pancreatic or esophageal resection for carcinoma.

Primary Site, and Stage of Tumor.-,With the exception of children with Wilms' tumors, very few patients have been apparently cured b y the resection of liver metastases from a prim a r y site other than the colon a n d rectum. Only one report of a nonendocrine tumor was found with long-term survival and apparent cure, a n d that was the patient with renal carcinoma and metastases mentioned above. Long-term survival (more than 3 years) is veD" rare after resection of metastases from primary tumors whose venous drainage bed was outside of the splanchnic area. There are a few long-term survivors after liver resection for metastatic endocrine tumors b u t these probably reflect the slow-growing nature of their primary disease rather than surgical "cures." The experience w i t h Wilms' tumor is gratifying and m a y prove to be a model for adult tumors in the future when we have better chemotherapeutic agents. Livei~ resection for metastatic T A B L E 9.--LWER RESECTION FOR METASTATIC COLOKECTAL CANCEIh COiON LY~IPH NODE STATUS VERSUS SURVIVAL*

FINDING

Patients 2-Year Survivalt 5-Year Survivalt

MESENTERIC LYMPH NODES NEGATIVE POSITIVE

35 12/26 (46%) 3/23 (13%)

51 15/38 (39%) 8/37 (22%)

*From Foster J.H:, Berman M.: Solid liver tumors, in Major Problems in Clinical Surgery (Philadelphia: W.B. Saunders Co., 1977). Used by permission. rafter liver resection; excludes operative deaths. 186

disease was combined with radiation and chemotherapy in most instances and a few children also had resection of pulmonary metastases. Of 13 who survived liver resection, nine are free of disease from 18 months to seven years after hepatectomyJ ~ Otherwise, success in terms of cure seems to be limited to lesions secondary to large bowel primary cancers. There is no difference in prognosis after liver resection of secondaries from any particular segment of the large bowel, and, surprisingly, there is no statistically significant difference when survival is correlated with the status of the mesenteric lympl~ nodes removed with the colon malignancy (Table 9). 35 TOTAL HEPATECTOMY AND TRANSPLANTATIONFOR METASTATIC CANCER.--The ultimate in liver resection for metastatic disease would be to remove the whole organ a n d r e p l a c e .it with a transplanted liver. This could be done electively in patients who presumably would be in much better condition than those in terminal liver failure who often become candidates for transplantation for benign disease. However, the experience with transplantation for primary liver cancer has been v e r y disappointing and that for metastatic disease has been too limited to allow any conclusions. We were able to find reports of total hepatectomy and transplantation for four patients with metastatic colon carcinoma and one patient with metastatic meningioma. All died within six months of transplantationJ s' 81 The challenge of immunosuppression in patients w i t h malignant disease seems enormous at present, b u t perhaps n e w methods in the future will allow another look at this possibility. ENDOCRINE TUMORS Certain endocrine tumors grow at a very slow rate. Patients may become symptomatic from t h e hormones elaborated by the tumor r a t h e r than from the space-occupying or catabolic effects of the malignant growth. Survival with disease m a y be in terms of decades rather than years, and palliation from hormone-mediated symptoms may represent a more important goal than cure of the cancer. Most patients with the malignant carcinoid syndrome will have diffuse liver metastases not amenable to resection. There are anecdotal reports of palliation after hepatic artery infusion with chemotherapy or after hepatic artery ligation in these patients, b u t symptomatic relief is often short-lived with these methods. There have been at least.44 reported cases of resection of localized liver metastases to control disabling symptoms in patients with malignant carcinoid t u m o r s J 5 When less than 95% of the gross liver disease was resected or when the rate of tumor 187

growth was rapid, little palliation was achieved. However, in a majority of patients good palliation for long periods was accomplished. Careful investigation for resectable liver disease should be carried out when pharmacologic relief is not possible. Palliation of endocrine symptoms from insulinomas and of other endocrine tumors may also be achieved in rare instances when medical measures have failed and when tumor deposits are localized. 3~ TECHNIQUE OF LIVER RESECTION FOR METASTATIC TUMOR Liver resection is more often done by most general surgeons for t r a u m a than for metastatic or primary tumors. Experience has taught us to be more conservative after major injury; resection is usually limited to resectional debridement of devitalized tissue by finger-fracture. There m a y be a major vessel or two to tie, b u t almost all of the smaller vessels have stopped bleeding before the surgeon gets into the belly. Bile leakage is common, so t h a t suction drains are essential to control any fistulas. In the elective situation "the problem is very different. At the exact instant of transection, liver tissue is very soft and very bloody, there are no bloodless planes, and the best t e c h n i q u e s - in terms of patient morbidity and m o r t a l i t y - - a r e those that obtain meticulous control of all small and large vessels and ducts before they are transected. Little or no devitalized tissue should be left, bile fistula is rare, and rubber or plastic drains m a y do more harm than good. There are many techniques by which small and large segFig 1.--Mattress suture wedge excision. Usually, interlocking mattress sutures of heavy absorbable material are ptaced prior to sharp wedge excision of a peripheral tumor, but they also may be placed after tumor excision if required by hemostasis. I,

_ 188

'

Y

ments of liver can be resected. What follows will reveal my current prejudices. The reader is referred to a recent monograph for more detail. 3s The collected data show t h a t wedge excision of metastatic liver cancer is as likely to effect a "cure" as major lobectomy and that the results achieved show no positive correlation with the amount of liver resected or with the width of the resected margin of normal tissue. Thus, the geography of the tumor should dictate the technique of resection. Most small and localized metastases can be safely wedged out. If near the ed~g~ of the liver the time-honored technique of interlocking mattress sutures (Fig 1) is probably not bad enough to abandon. Although we have switched to synthetic absorbable sutures for almost every other indication, we still prefer catgut here, because it slides more easily and thus allows more exact accomplishment of a suture tension t h a t is tight enough to stop bleeding but not tight enough to cut through. More central metastatic lesions should Fig 2.--Note: (1) Left main branch of portal vein is long and curves caudad in plane of fatciform ligament to supply both quadrate lobe and lateral segment of left lobe; (2) right main portal branch is quite short and bifurcates or trifurcates close to junction with main portal vein; (3) portal venous branches come off at right angles from parent trunks; (4) right hepatic venous trunk is often as wide as it is long; (5) middle hepatic vein drains both quadrate lobe (medial segment of left lobe) and lower anterior segment of right lobe; (6) middle and left hepatic veins join to drain together into inferior vena cava in most patients; (7) hepatic veins branch at less than a right angle; (8) most superior branches of left and right hepatic veins are close to surface of liver and are vulnerable during transection of suspensory ligaments; (9) portal and hepatic venous branches interdigitate throughout liver parenchyma, and therefore there are no bloodless planes; (10) middle hepatic vein lies in interlobar plane and is very vulnerable during Iobectomy. The line of transection for Iobectomy must be kept to the right or left of this major trunk.

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be wedged out using the blunt-suction technique described-below. Certain deeply placed and larger solitary lesions should be excised by lobectomy, as should multiple nodules spread widely in one lobe. Lobectomy may be safer and less bloody than a large wedge excision. Most noncirrhotic patients can tolerate either a left or right hepatic Iobectomy with minimal metabolic consequences. The human liver rapidly restores itself to a normal weight and volume by a process of hyperplasia and hypertrophy that is complete within a few months. Figure 2.details the usual anatomy of the major vessels and shows that, although the portal triad structures divide the liver into two discrete lobes, the hepatic venous drainage pays no attention to these anatomical boundaries. There is little argument about the anatomical details of major lobectomies. The difficulties of single segment resections in the right lobe and in the medial segment of the left lobe outweigh their "advantage," since there is really no advantage to saving 200 or 300 gm of an organ that will quickly spring back to its original size. The left lateral segment of the liver can be excised as a wedge excision so long as the line of transection is kept at least 1 cm to the left of the sulcus of the falciform ligament. This will avoid injuring the portal triad supply to the medial segment of the left lobe, which lies directly in the middle of the umbilical fissure. The rest of the technical details of liver resection relate to the general topics of exposure, transection of liver substance, hemostasis and hemostatic agents, the use of clamps, the handling of the raw surface, dead space and drainage, and to details of the control of the major vessels in the liver hilum and near the inferior vena cava. EXPOSURE

Determination of resectability can often be done through an initially small incision that is enlarged as needed. Patients with metastatic lesions usually do not require right thoracic or midsternal extension of their incisions, either of which is easily done if required by a very larg6 metastasis. Posterior lesions can usually be brought up after division of the suspensory coronary ligaments of one lobe or the other. Division of the falciform ligament back to the inferior vena cava allows careful evaluation of this critical area. The caudate lobe is often best evaluated by entering the gastrohepatic ligament, taking care to avoid the commonly anomalous arterial supply to the left lateral segment. TRANSECTION OF LIVER SUBSTANCE

Hilar control of the inflow vessels and bile ducts should precede this step for patients undergoing anatomical lobectomy. 190

Fig 3.--Capsular dissection. After an initial sharp incision through Glisson's capsule, the rest of the capsule is dissected bluntly away from liver parenchyma and then cut so as to completely outline eventual line of transection. This complete capsular incision will guide the plane for subsequent rapid blunt suction transection.

Control of hepatic veins is often be'st left until later (see below). The capsule of the liver should be incised sharply over a short area and then elevated bluntly and transected circumferentially around the liver 1 cm toward the tumor from the proposed line of transection (Fig 3). This will orient the surgeon as he proceeds with transection and may provide an aid to hemostasis later. When capsular incision is complete, and when the anesthesioloFig 4.--Ligation of larger vessels. When blunt suction technique uncovers anterior surface of a large vessel, circumferential dissection is carefully done with a rightangled clamp. The vessel is then tied on both sides before transection.

191

gist has reassured the surgeon about the stability of the patient and the availability of blood for transfusion, the operating team begins to push bluntly through liver tissue. Every small resistance should be clipped with metal clips before transection and the larger vessels should be tied in-continuity (Fig 4). The back of a knife, a blunt-tippe d clamp, or even a finger can do this dissection. I prefer the unsheathed end of an abdominal sucker, which acts nicely as a dissector and keeps the ~field reasonably dry and visible at the same time (Fig 5). Blood' loss will be diminished, time will be saved, and visibility will be maintained if the surgeon dissects and never puts down the sucker while his assistant clips, cuts, and ties. An extra scrub-assistant is often very useful to pass clips during this brief time of rapid transection. The hepatic veins will be encountered last. They are thinwalled and very friable but amenable to gentle circumferential dissection a centimeter or two away from the inferior vena cava if tumor anatomy allows (Fig 6). Even the central plane can be transected within a few moments by this technique applied by a practiced team. With removal of the specimen, raw surface should be gently tamponaded with a gauze compress for a few minutes before any attempt is made at further hemostasis. When this pack is removed only a few clips will be visible (most have withdrawn into liver substance), and the field is usually quite dry. Continual oozing from the low pressure venous system is controlled by another period of tamponade. Significant arterial bleeding should be dealt with by suture control of discrete vessels. Clamps pull off and compound the problem. If bleeding continues and cannot be stopped by discrete control of individual visible vessels, bringing the opposite edges of transected capsule together with small absorbable sutures will often tamponade both venous compartments. Although others~ have sung its praises, our own experi-

Fig 5.--Blunt suction technique. After capsular incision, liver substance is teased away from the more resistant vessels, using a blunt-tipped metal suction tip. Small vessels are best treated with clips and/or ties without application of hemostatic clamps. Illustrated is the inner suction tip of an "abdominal" or Poole sucker, which is used after removal of the multiholed outer sheath.

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,

Flg 6.--Left Iobectomy. After ligation of the major leftvessels at the hilum, blunt dissection will soon find a branch of middle hepatic vein as it lies in central plane. This vein should be presewed after ligation of its branches from quadrate lobe. Its lateral margin sewes as a useful guide for subsequent dissection, and leads the surgeon to the major hepatic trunk or trunks that drain lateral segment of left lobe. At the superior and posterior aspects of this cleavage "planes," dissection should veer to the left to avoid the caudate lobe, inferior vena cava, and risk of compromise to middle hepatic venous drainage.

ence has been that microfibrillar collagen has not been of very much help. Five minutes of patience may serve better than many dollars' worth of hemostatic compounds. Liver clamps are used by some. They are hard to apply centrally and usually are not necessary peripherally. Whether lasers, cryosurgery, and other technical devices will eventually prove to be superior to careful dissection and discrete,control of vessels remains to be shown. The raw surface need not be closed except for hemostasis. Dead space must be filled but this is easily done with adjacent stomach, colon, or omentum. Drains, if used, should be soft and should be removed early unless they produce large amounts of blood or bile. PROXIMAL AND DISTAL CONTROL

The details of dissection of inflow and outflow vessels and ducts that must precede lobectomy are based on a sure knowledge of both extrahepatic and intrahepatic vascular and biliary anatomy. Preoperative arteriography should precede any plan for lobectomy. Arterial anomalies are much more common than anomalies of the portal vein or bile ducts. The bile duct is the most anterior of hilar structures, but the confluence of the right 193

and left hepatic ducts is the most distal, i.e., toward the liver. All of the major hilar bifurcations can be dissected outside of Glisson's capsule. Although at first they m a y appear to be within liver substance, they can be dissected free and surrounded without entering liver substance. Dissection of the bile ducts should begin as high in the hilum as possible so as not to compromise'the blood supply of the common hepatic duct and common bile duct. The hepatic artery is normally surrounded with a dense network of nervous and lymphatic tissue and is best approached with a finger in the foramen of Winslow pushing the palpable artery up into the surgeon's dissecting instrument. The artery branches early. Uncertainty about which branch goes where can be resolved by injection of indigo carmine through a fine needle into the branch in question. The problem with the portal vein is that instead of a single large branch on the right, there m a y be two or even three very large trunks that come off the main portal vein at the point where it gives off the always solitary and therefore easily dissectable left portal branch. For right lobectomy, the safest technique involves surrounding the main portal vein and the proxiFig 7.--The hepatic veins. Note: (1) With diaphragm incised and retroperitoneal attachments of back of right lobe of liver incised, liver has been rolled to the left to expose junction of right hepatic vein and inferior vena cava. (2) This junction may be outside the liver, but usually its inferior and medial edges are within liver substance. Circumferential dissection therefore may be difficult and dangerous. (3) The smaller diagram shows that there may be a few smaller hepatic veins that drain the caudate lobe and medial portion of right superior-posterior segment. These enter the inferior vena cava below the major veins, are variable in number, and rarely are more than 1 cm in diameter. Transection of the most inferior vessels may facilitate right lobectomy; tigation or clipping shouId be done in continuity before transection.

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mal left portal vein before approaching the dangerous branches on the right. Most of the problems during and after hepatic lobectomy are related to blood loss. As in hepatic t r a u m a patients, the most impressive and lethal blood loss usually occurs from the junction of the hepatic veins and the inferior~vena cava at the level of the diaphragm (Fig 7). The suprahepatic infradiaphragmatic inferior vena cava cannot be surrounded because there is no such structure. At the level in question the cava's anterior wall is in the abdomen and its back wall is above the diaphragm. The diaphragm here is a vertical rather than horizontal structure and one simply cannot get around the cava in the abdomen above the liver. In some patients one or more of the major hepatic veins are accessible for circumferential dissection outside liver substance. Ligation of the appropriate branch should in this case follow hilar ligation and precede liver transection. In most patients, however, this junction is at least partially intrahepatic and it is foolish to try to accomplish distal control before transection of liver substance. The intrahepatic hepatic veins are very thin-walled, friable, and subject to injury w i t h ' a t t e m p t s at blunt dissection. Once lacerated, emergency control is difficult. If, because of hemorrhage, caval control is necessary, the suprarenal inferior vena cava is quickly found and easily surrounded behind the second portion of the duodenum after a Kocher maneuver, the suprahepatic inferior vena cava is only accessible within the pericardium. A small hole can be made in the diaphragm about one inch anterior to the anterior surface of the subdiaphragmatic cava, the pericardium entered, and then the inferior vena cava surrounded with a blunt-tipped right-angle clamp. Most liver resections can be done with minimal blood loss and very low operative mortality and without serious metabolic consequences. Attention to the details of technique and management are of critical importance in reducing the risk to the patient, b u t no unusual skills or expensive tools need be used. Elective liver resection for metastatic tumor can be done using techniques familiar to surgeons for many decades and should be accomplished in a controlled and deliberate fashion in a normotensive and normothermic patient. RECOMMENDATIONS FOR THERAPY IN PATIENTS WITH LIVER METASTASES Most patients with liver metastases do not have symptoms directly related to the tumor in the liver, although many eventually succumb to the metabolic effects of liver replacement. Because neither chemotherapy nor radiation therapy has been shown to prolong survival for patients with liver metastases 195

from most of the common solid tumors, the asymptomatic patient should not be treated unless he can be part of a carefully controlled prospective therapeutic trial, a trial which should include a no-treatment arm. Exceptions to this generalization would be provided by patients ~ i t h tumors shown to be unusually sensitive to hormone manipulation, chemotherapy, or radiotherapy. Patients with persistent pain from liver metastases m a y be considered for chemotherapy or local radiation. There would seem to be no place for the intra-arterial infusion of chemotherapeutic agents for hepatic metastases of common cancers until some more compelling evidence exists which would justify the increased morbidity and cost of this technique. Fortunately, symptoms from liver involvement usually come late in the course of the patient with an extrahepatic primary tumor, and, of those methods of exitus of the cancer patient, liver failure is not the worst. Liver resection for metastatic disease should be strongly considered in three circumstances, all of which, unfortunately, are quite uncommon: First, in the child with embryonal cancer (e.g., Wilms' tumor), where chemotherapy, radiation, and resection can complement each other and where the possibility of cure is very great. Second, in those patients with hormone-mediated symptoms from metastatic endocrine tumors in whom the vast bulk of a tumor can be resected without risking the life of the patient. And third (but most commonly), in those patients with solitary or localized metastases from colorectal cancers who show no evidence of recurrence or persistence of their primary disease except in the liver. In this last instance, selection of the appropriate patient and timing of liver resection in relation to the colon resection are very important. Factors ,such as the size and number of liver metastases should be considered, b u t whether or not the mesenteric lymph nodes were involved with cancer and the length of the interval between bowel resection and the discovery of liver metastases seem to bear little relationship to "curability" after liver resection. Very old and poor-risk patients should probably never undergo large hepatic resections, but they m a y be candidates for local wedge resection of small and solitary metastatic lesions. In younger patients, attempts at resection of even very large but solitary lesions, or multiple small lesions in one lobe, might be attempted if the patient and the surgeon understand the risks and the potential benefits involved and if a careful search has shown no other evidence of persistent or recurrent disease. W h a t should the surgeon do if he stumbles unexpectedly on a liver metastasis at the time of colon resection? First, he should carefully document the extent and nature of the liver involve196

ment. If the incision is in the lower belly, he m a y not be able to see the liver clearly, b u t he can feel it with one or both hands and search carefully for small and large nodules. Unresectability is quickly established in most instances with discovery of bilobar disease and biopsy proof of its nature. Percutaneous needle biopsy under manual intraperitoneal control is often a safer procedure than biopsy through a misplaced incision. Frozen section diagnosis is important because the liver lesion m a y be something other than a metastasis. Resectability is more difficult to establish. The surgeon must be sure t h a t the metastatic disease is solitary or localized and does not involve the inferior vena cava and major hilar vessels and ducts. If a resectable lesion is found in the liver, a very careful search of the retroperitoneum for nodal disease must be made. If all is negative; if the primary tumor has come out easily and completely; if the liver lesion is solitary, accessible, and peripheral; if the incision allows, and if the patient's condition and the surgeon's vigor and experience are up to it, wedge excision should be done at the conclusion of the colon operation. In some instances, wedge biopsy of a small lesion on the liver edge should be excisional and not incisional, and if a margin of 2 to 3 mm of normal liver tissue has been taken, no further excision need be done. In most instances, all of the above conditions are not met, and it is better to delay liver resection until another day. Delay allows more careful study of the primary disease, a better look for other metastatic foci, more thorough discussion between patient and surgeon (and perhaps consultants) about the options and risks, and better preparation of the patient for operation. If the planned delay is to be of more than two or three weeks, a baseline liver scan should be obtained for future comparison and a plan drawn up for the next few months. Although no scientific evidence can be offered in defense of this thesis, it does not seem unreasonable to delay for two to four months. This period should allow the aggressive, fast-growing, and widely metastasizing tumor a chance to declare its nature and thus save the patient the pain and suffering of another operation. If however, serial studies show little or no growth of the liver disease and no spread of the t u m o r elsewhere, liver resection should be recommended as the patient's only chance for permanent cure. Hepatic angiography should precede any major liver resection. We end this monograph with a plea for thorough evaluation at the time of bowel surgery. Because of a long-time interest in this problem, we have had referred to us a number of patients said to have solitary liver metastasis found at the time of colon resection. Exploration, often within a few days or weeks of the bowel operation, has more often than not shown multiple foci of metastatic cancer, often with several lesions of about the same 197

size. A few more seconds of careful exploration of all surfaces of the liver or a bet t er appreciation of the proximity of the metastasis to th e inferior vena cava would have spared the pat i ent a second operation. T h e r e is no biochemical test or any imaging technique t h a t can come close to t he ability of the hands and eyes of a skilled surgeon in evaluating t h e extent and n a t u r e of neoplastic invasion of the h u m a n liver. BIBLIOGRAPHY 1. Abrams M.S., Lerner H.J.: Survival of patients at Pennsylvania Hospital with hepatic metastases from carcinoma of the colon and rectum. Dis. Colon Rectum 14(6):431, 1971. 2. Adson M.A., VanHeerden J.A.: Major hepatic resections for metastatic colorectal cancer. Ann. Surg. 191:576, 1980. 3. Alfonso A.A., Hasson A., Gardner B., et al.: Prevention of hepatic metastases by intravenous radioactive gold. Cancer Res. 38:2740, 1978. 4. Alpert E., Ferrucci J., Athanasoulis C., et al.: Primary hepatic tumor. Gastroenterology 74:759, 1978. 5. Ansfield F.J., Ramirez G.: The clinical results of 5-fluorouracil intrahepatic arterial infusion in 528 patients with metastatic cancer to the liver. Prog. Clin. Cancer 7:201, 1978. 6. Ariel I.M., Padula G.: Treatment of symptomatic metastatic cancer to the liver from primary colon and rectal cancer by the intra-arterial administration of chemotherapy and radioactive isotopes. Prog. Clin. Cancer 7:247, 1978. 7. Aronsen K.F., Hellekant C., Holmberg J., et al.: Controlled blocking of hepatic artery flow with enzymatically degradable microspheres combined with oncolytic drugs. Eur. Surg. Res. 11(2):99, 1979. 8. Balasegaram M.: Complete hepatic dearterialization for primary carcinoma of the liver. Am. J. Surg. 124:340, 1972. 9. Barone R.M., Byfield J.E., Frankel S.: Combined infusional 5-fluorouracil and radiation therapy for the treatment of metastatic carcinoma of the colon to the liver. Dis. Colon Rectum 22(6):376, 1979. 10. Bengmark S., Domellof L., Hafstrom L.: The natural history of primary and secondary malignant tumors of the liver: III. Prognosis for patients with hepatic metastases from pancreatic carcinOma. Digestion 3:56, 1970. 11. Bengmark S., Hafstrom L.: The natural history of primary and secondary malignant tumors of the liver: II. The prognosis for patients with hepatic metastases from gastric carcinoma. Digestion 2:179, 1969. 12. Bengmark S., Hafstrom L.: The natural history of primary and secondary malignant tumors of the liver: I. The prognosis for patients with hepatic metastases from colonic ~and rectal carcinoma by laparotomy. Cancer 23:198, 1969. 13. Bengmark S., Hafstrom L., Olsson A.: The natural history of primary and secondary liver tumors: V. The prognosis for conventionally treated patients with liver metastases from breast cancer. Digestion 6:321, 1972. 14. Bierman H.R., et al.: Studies on the blood supply of tumors in man: III. Vascular patterns of the liver by hepatic arteriography in vivo. J. Natl. CancerInst. 12:107, 1951. 15. Breedis C., Young G.: The blood supply of neoplasms in the liver. Am. J. Pathol. 30:969, 1954. 16. Brunson K.E., Beattie G., Nicolson G.L.: Selection and altered properties of brain-colonizing metastatic melanoma. Nature 272:543, 1978. 17. Cady B., Monson D.O., Swinton N.W.: Survival of patients after colonic resection for carcinoma with simultaneous liver metastases. Surg. Gynecol. Obstet. 131:697, 1970. 198

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