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SURGICAL RESECTION FOR COLORECTAL HEPATIC METASTASES GENE F. COPPA, M.D. Associate Professor of Clinical Surgery New York University School of Medicine New York, New York

K NOWLEDGE OF THE DYNAMICS of metastatic disease remains limited. Spread of such solid tumors as colorectal carcinoma continues to be discussed in general terms. Little clinical progress has been made in halting spread by nonsurgical methods. The liver is a common site for blood-borne metastases, and colorectal cancer cells may reach the liver via the portal system or venous lymphatic communications. Hepatic metastases from adenocarcinoma may be classified as synchronous or metachronous, based on the timing of clinical discovery. Hepatic metastases occur in about 50% of patients with colorectal cancer, and approximately 25% of patients with colorectal tumors have hepatic metasases at initial presentation. ' Therefore, about 20,000 new patients are discovered each year with hepatic metastases from primary colorectal cancer. These lesions may be resectable in 10 to 20% of patients.2 Based on cumulative series, 25% of patients with resected hepatic metastases will be five year survivors.3,4

NATURAL HISTORY The dismal fate of untreated patients with liver metastases from colorectal cancer has been well documented.5 Median survival approximates nine months for unselected patients representing all types and stages of hepatic metastases. The two-year survival is only 10%, and there were no five-year survivors in histologically proved colorectal hepatic recurrence. Recent studies3,6 of a select group of patients not treated by resection revealed median survival of 21 months for solitary lesions and 15 months for multiple unilobar lesions. Five-year survival in these two groups was 3% and 0% respectively. The disappointing response of metastatic hepatic colorectal adenocarcinoma to chemotherapy has led to exploration of other types of therapy for this common and frequently fatal complication of colorectal cancer. Address for reprint requests: 530 First Avenue, New York, New York 10016.

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DETECTION

Four groups of patients have detectable hepatic metastases: Those with extensive, bilateral, clinically obvious disease; those with metastases detected preoperatively by history, physical examination, or blood chemistry with number, location, size, and resectability then determined by radiographic techniques; asymptomatic patients with normal laboratory data in whom metastases are discovered only at surgical exploration; and those without initially detectable disease in whom hepatic metastases are discovered during the postoperative period. Patients with synchronous metastases are in the first three groups. The search for metachronous metastases in patients in the fourth group is part of regular careful postoperative evaluation. Historical information and physical findings should be followed by carcinoembryonic antigen determination and liver function tests. Serum lactic dehydrogenase has been reported to have the highest predictive accuracy, 92%, in patients with clinically occult metastases.7 The CEA, carcinoembryonic antigen, is a fetal antigen present in small quantities in many cells and in normal serum. Once thought specific for carcinoma of the colon, it is known to be elevated in the serum of smokers and in some nonmalignant processes as well as in cancers in sites other than the colon, such as stomach and pancreas. The prognostic significance of preoperative CEA levels in colorectal cancer are neither specific nor statistically relevant for patients with hepatic metastases. 8,9 Elevated or normal CEA values cannot be utilized as a reliable diagnostic indicator of the presence or absence of hepatic metastases. After curative colorectal resection, preoperatively elevated CEA levels usually return to the normal range. Subsequent progressive continuous postoperative CEA elevation suggests recurrent disease, especially in the liver. Further pursuit of any abnormalities includes isotopic scanning and computed tomography. At present, no individual procedure or combination of procedures reaches 100% accuracy. Computed tomography of the liver is reported to be slightly more accurate than isotopic scanning, concurring with operative findings in 85% of patients. 10 Computed tomography has slightly lower false positive and false negative rates. Hepatic artery angiography is an additional procedure particularly useful if diagnostic scans are inconclusive. RESULTS OF CURATIVE SURGICAL RESECTION

Since 1972 45 hepatic resections have been performed in 42 patients for colorectal metastases at New York University Medical Center. Perioperative evaluation and screening were performed as described earlier. Bull. N.Y. Acad. Med.

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TABLE I. TUMOR CHARACTERISTICS AND PATTERN OF INVOLVEMENT 42 PATIENTS -45 RESECTIONS Original site of carcinoma No. Left colon 21 Rectum 11 Right colon 8 Transverse colon 2 Characteristic 1) Synchronous 20 Metachronous 25 Original Dukes Class B 10 Original Dukes Class C 15 2) Solitary 33 Multiple 12 3) Unilateral 41 Bilateral 4

The mean age of the patients studied was 60.5 years (range 35-78 years). The sex ratio was 25 men to 17 women. Characteristics of the primary lesion and pattern of hepatic involvement are listed in Table I. Twenty-one patients had primary tumors of the left colon and 11 of the rectum. In 20 patients metastases were discovered at the time of the primary lesion; 25 lesions were discovered after the original colorectal lesion had been treated. In the latter group, the mean period from initial colon resection was 37 months (range 10-96 months); 10 of these colorectal carcinomas were classified as Dukes' class B, and 15 Dukes' class C. Solitary hepatic tumors were found in 33 patients; eight additional patients had multiple metastases with unilobar involvment and four patients had bilobar metastases. Wedge resection was performed in 21 patients, right hepatic lobectomy in 15, left hepatic lobectomy in one, and right trisegmentectomy in eight. (Table II). We previously studied the postoperative response of albumin, coagulation factors, and bile production in patients requiring major hepatic resection. I1 Preoperative serum albumin levels were maintained in these patients by exogenous infusion. Serum levels decreased to less than 3.0 mg/dl when infusion ceased. Serial evaluation of coagulation factors proved a valuable guide to normalization of hepatic function. Elevation in serum bilirubin levels occurred in each patient with major resection, reaching peak levels on postoperative day seven. Decrease in serum bilirubin correlated with an elevation in hepatic bile production as evidenced by an increase in bile duct drainage and decrease in extrahepatic drainage. Table III lists the major complications. Four patients developed subphrenic abscesses, one associated with a prolonged biliary fistula which closed sponVol. 66, No. 3, May-June 1990

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TABLE II. TYPE OF HEPATIC RESECTION No. 21

Type Wedge resection Right Left Bilateral Right lobectomy Right trisegmentectomy Left lobectomy

12 4 4 15 8 I

TABLE III. POSTOPERATIVE COMPLICATIONS

45 hepatic resections Complication Subphrenic abscess Respiratory Wound infection Biliary fistula Death

Number 4 2 1 1 2

taneously. Two patients died during postoperative hospitalization and are excluded from survival data. The operative mortality rate was 4%. The crude yearly survival and mean survival for these patients is presented in Table IV. No differences in survival were detected when comparing the time of discovery of metastatic disease (synchronous vs. metachronous), the number of lesions resected (solitary vs. multiple) or the type of resection (lobectomy vs. wedge). The five-year survival was 22% and the mean duration of survival for all patients is 33 months. DISCUSSION As many as 10 to 20% or as few as 5% of all patients with hepatic colorectal metastases are candidates for resection.3,12 The possibility of five-year survival (20 to 30%) and palliative improvement justify the pursuit and surgical therapy of these lesions. 13 This surgery may be performed with acceptable mortality, 4 to 7%, and a five-year salvage rate of 17 to 27% (Table V). No other therapeutic procedure has equal results for the treatment of histologically proved metastatic hepatic adenocarcinoma from the colon or rectum. The surgery, particularly major resection, requires precise preoperative work-up; a detailed knowledge of the anatomy of the liver; close monitoring; availability of blood, albumin, and clotting elements including fresh frozen plasma; and surgical skill and judgment. It is mandatory to identify the location, number, and extent of hepatic metastases when resection of synchronous or metachronous lesions is considBull. N.Y. Acad. Med.

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TABLE IV. SURVIVAL RESULTS FOR HEPATIC RESECTION OF COLORECTAL METASTASES Overall Mean Lobe Wedge Meta Syn No. No. Survival (%) pts. (%) (%) mos. I year(%) 100 91 93 100 97 34 37 2 year(%) 66 71 69 69 67 30 40 3 year(%) 41 45 50 31 44 25 42 4 year(%) 33 30 45 18 32 22 44 S year(%) 9 43 33 11 22 18 49 Mean (mos.) 26.9 36.5 38 25.4 33

TABLE V. HEPATIC RESECTION FOR METASTATIC COLORECTAL CANCER SURVIVAL AND OPERATIVE COMPLICATIONS (COLLECTIVE REVIEW) Survival Operative Complications Patients 2 yr. 3 yr. 5 yr. mortality morbidity Author (no.) (%) (%) (%) (%) (%) Foster'2 284* 48 22 5 Wagner'3 141 61 46 25 4 Fortner'4 75 71 57 7 23 42 Coppa 67 44 22 4 17 Bengmark23 39 5 Muhe24 38** 20 Tomas-de la Vega25 38 41 33 20 7 31 August26 33 72 0 53t 27 Morrow27 29 27 6 19 Cady28 23 65 43 30 Thompson29 19 17 5 Kortz30 16 67 54 29 5 43 Taylor3l 16 42 *Collected review to 1978

**Mixed primary cancers t4-year survival

ered. Careful preoperative evaluation and operative exploration should assess the resectability of the primary lesion for cure and the presence of extrahepatic metastases.

INDICATIONS FOR HEPATIC RESECTION All pathological stages of the underlying colorectal disease may be resected secondarily. The presence of a cancer with penetration of perirectal fat and nodal involvement (Dukes' class C, C2), blood vessel involvement, or poor cellular differentiation does not necessarily contraindicate hepatic resection. Thus, hepatic resection is indicated for treating patients with the following types of lesion: solitary hepatic metastases without evidence of malignant disease elsewhere, metastases discovered synchronously with the primary Vol. 66, No. 3, May-June 1990

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colorectal tumor or metachronously, 12 and removal may require wedge excision, lobectomy, or an extended segmentectomy; and multiple lesions confined to one lobe. These patients require major hepatic resection.3,15 As imaging and rectal adenocarcinoma markers improve diagnostic efficiency, indications for hepatic resection should become more precise. There seems to be no difference in survival between synchronous and metachronous lesions, or between wedge or lobar resection. 12 However, small lesions that can be removed by simple wedge excision have less perioperative morbidity and mortality.3

CONTRAINDICATIONS TO HEPATIC RESECTION Certain patients are not candidates for resection either because of clinical status or the nature of the hepatic metastases. Examples are: poor-risk patients with a limited outlook due to intercurrent disease; patients with residual local tumor, for example, in the pelvis; patients with disseminated disease, in lung, brain, or bone; patients with limited hepatic function or reserve, particularly with cirrhosis; patients with uncorrectable coagulopathy; and patients with extensive multilobar hepatic metastases. 14 INTRAOPERATIVE AND POSTOPERATIVE MANAGEMENT

Thorough and precise knowledge of the anatomy of the liver accompanied by advances in anesthetic techniques has allowed hepatic resection to be performed safely. 16,17 Most major resections can be performed with blood loss of 1,500 to 2,500 ml. Intraoperative replacement should include fresh frozen plasma in addition to blood. Careful attention to such metabolic factors as splanchnic fluid sequestration, glucose metabolism, and albumin requirements also contributes to low perioperative morbidity and mortality. Splanchnic fluid sequestration accounts for a decrease in plasma volume as well as in red blood cell volume. This occurs during the operation and is maximal in the first four to eight hours postoperatively. The extent of hepatic parenchyma resected correlates with the amount of fluid resuscitation needed. If less than 30% is resected and only maintenance fluids are infused, moderate hypovolemia occurs. Above 30% resection, transfusions are necessary, and shock will occur if additional blood is not administered in patients with greater than 60% hepatic resection. Pulmonary artery monitoring has been a significant advance in management and should be utilized intraoperatively and postoperatively for at least 24 hours. Increased demand for exogenous glucose is due to hypoglycemia produced by hepatic resection and Bull. N.Y. Acad. Med.

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also correlates with the extent of resection. At least 50 gm of glucose is required in the first 24 hours. Frequent monitoring of urine (every four to six hours) and serum glucose (every two hours) and administration of 10 to 25% dextrose through a central venous catheter is required. Preoperative intravenous hyperalimentation and an increase in endogenous insulin may cause potentiation of the hypoglycemia. On rare occasins, hypoglycemia may persist three weeks after the operation. Maintenance of preoperative serum albumin levels also requires exogenous administration. Decrease in hepatic albumin production produces hypoalbuminemia in these patients. Estimates of initial albumin requirements are based on preoperative values and extent of hepatic resection. Hypoalbuminemia may continue and requires postoperative replacement. Other responses include electrolyte imbalance, particularly dilutional hyponatremia and metabolic alkalosis, requiring restriction of sodium and supplementation of potassium. Nutritional factors must be maintained. Serial evaluation of coagulation factors proves important not only to maintain clotting indices but to guide normalization of hepatic function. The prothrombin time, a measure of the extrinsic system in the blood coagulation cascade, is nonspecific and does not reflect individual changes in coagulation profile. An immediate increase on the first postoperative day is followed by a rapid return to normal. The response of factors VII, V, and II and fibrinogen (factor I) varies. An immediate median decrease from preoperative values of all these factors is present on the first postoperative day. Factor II, the proenzyme prothrombin, correlates closely to clinical and biochemical return of hepatic function. Despite these abnormalities in coagulation profile, clinical evidence of bleeding usually does not appear. Administration of fresh frozen plasma or fibrinogen is reserved for patients with coagulation factors less than 30% of preoperative levels, or in patients with evidence of bleeding. Bile production is measured through T-tube drainage. Usually a very small amount is noted in the first few days and is associated with a clinical and chemical rise in the bilirubin. The median serum bilirubin level peaks on postoperative day seven. Decrease in serum bilirubin correlates with an elevation in hepatic bile production as evidenced by an increase in bile duct drainage. External drainage catheters provide a secondary path for bile drainage, particularly from small biliary radicles. Several hundred milliliters of bilious and serosanginous drainage may be expected during the first four to seven days postoperatively. The median volume of extrahepatic drainage declines over this same period of time. Vol. 66, No. 3, May-June 1990

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POSTOPERATIVE CONSIDERATIONS

Morbidity. Subphrenic abscess, wound infection, biliary fistula, hemorrhage, renal failure with or without hepatic failure, and coagulopathy are all reported problems that may occur in the postoperative period in approximately 20-30% of patients (Table V). Mortality. Death usually occurs because of deterioration of liver function as evidenced by rising bilirubin and persistent depression of coagulation factors. Cirrhosis has been an associated factor. 18 Regeneration. The liver has an extraordinary capacity to regenerate. Several investigators report a normal volume of liver tissue approximately 6 months after major hepatic resection. 19 There is an enlargement in the liver remnant with growth of the arterial vasculature, the bile ducts, the portal system, and the liver parenchyma. Angiographic information suggests that regeneration starts immediately after resection and liver function is normal in a matter of weeks.20 Arterial supply keeps pace with the enlarging liver mainly by stretching of the blood vessels. It has been thought that growth controlling (hepatotrophic) factors are responsible for this extraordinary regenerative capacity of the liver.21 However, these hormones in the portal blood have not been accurately identified. Research also suggests that they may be of splanchnic origin.22 SUMMARY

Hepatic resection of metastatic disease due to primary colorectal cancer provides a relatively safe and reliable method to control this otherwise fatal disease. At New York University 45 hepatic resections have been performed in 42 patients over the last fifteen years. Preoperative screening was performed by liver chemistry and intraoperative exploration in synchronous lesions and by liver chemistry, carcinoembryonic antigen, and computed tomography in metachronous lesions. Careful monitoring of fluid management, glucose utilization, and albumin requirements are essential for low postoperative morbidity and mortality. In major hepatic resections, changes in coagulation profile correlate with normalization of hepatic function as evidenced by decrease in serum bilirubin levels and increase bile production. The incidence of major operative morbidity was 17%; operative mortality was 4%. Hepatic resection gives the greatest possibility of extended survival, in our patients providing a 22% crude five year survival rate and a mean duration of survival of 33 months. Bull. N.Y. Acad. Med.

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REFERENCES 1. Blumgart L.H. and Allison, D.J.: Resec- 12. Foster, J.H. and Lundy, J.: Liver metastases. Curr. Prob. Surg. 18:161-202, tion and embolization in the manage1981. ment of secondary hepatic tumors. 13. Wagner, J.S., Adson, M.A., Van HeerWorld. J. Surg. 6:32-45, 1982. den, J.A., et al.: The natural history of 2. Grage, T.B., Vassilopoulous, P.P., hepatic metastases from colorectal canShingleton, W.W., et al.: Results of a cer. Ann. Surg. 199:502-08, 1984. prospective study of hepatic artery infusion with 5-fluorouracil versus intra- 14. Fortner, J.G., Silva, J.S., Golbey, R.B., et al.: Multivariate analysis of a venous 5-fluorouracil in patients with personal series of 247 consecutive pahepatic metastases from colorectal cantients with liver metastases from colorcer. Surgery 86:550-55, 1979. ectal cancer I: Treatment by hepatic 3. Adson, M.A. and Van Heerden, J.A.: resection. Ann. Surg. 199:306-16, 1983. Major hepatic resection for metastatic colorectal cancer. Ann. Surg. 191:576-83, 15. Wilson, S.M. and Adson, M.A.: Surgical treatment of hepatic metatasis from 1980. recurrent cancer. Arch. Surg. 111:330-34, 4. Foster, J.H. and Berman, M.M.: Solid 1976. Liver Tumors. Philadelphia, W.B. Saun16. Lortat-Jacob, J.L. and Robert, H.G.: ders Co., 1977. Hepatectomie droite reglee. Presse 5. Pestana, C., Reitemeyer, R.J., Moertel, Med. 60:549, 1952. C.G., et al.: The natural history of carcinoma of the colon and rectum. Am. J. 17. Goldsmith, N.A. and Woodburne, R.T.: The surgical anatomy pertaining to liver Surg. 108:826-29, 1964. resections. Surg. Gynecol. Obstet. 6. Adson, M.A. and Beart, R.W.: Elective 105:310-18, 1957. hepatic resections. Surg. Clin. North 18. Kanematsu, T., Takenaka, K., MatAm. 57:339-60, 1977. sumata, T., et al.: Limited hepatic re7. Ranson, J.H.C., Adams, P.X., and Losection for selected cirrhotic patients calio, S.A.: Preoperative assessment for with primary liver cancer. Ann. Surg. hepatic metastases in carcinoma of the 171:567-74, 1971. colon and rectum. Surg. Gynecol. Ob19. Aronsen, K.F., Erickson, B., Nossli, stet. 137:435-38, 1973. B., et al.: Evaluation of hepatic regener8. Woolmark, N., Fisher, B., Wiegand, ation by scintillation scanning, cholanH.S., and Henry, R.S.: The prognostic giography and angiography in man. significance of preoperative carcinoAnn. Surg. 171:567-74, 1971. embryonic antigen levels in colorectal 20. Karp, W. and Tylen, U.: Angiography cancer. Ann. Surg. 199:375-82, 1984. of the regenerating liver after lobar re9. Steele, G., Ellenberg, S., Ramming, section. Acta Radiol. Diag. 18:571-80, K., et al.: CEA monitoring among 1977. patients in multi-institutional adjuvant GI therapy protocols. Ann. Surg. 21. Terblanche, J., Porter, K.A., Starzl, T.E., et al.: Stimulation of hepatic re196:162-69, 1982. generation after partial hepatectomy by 10. Temple, D.F., Parthasarathy, K.L., infusion of a cytosol extract from regenBakshi, S.P., and Mittelman, A.E.: A erating dog liver. Surg. Gynecol. Obcomparison of isotopic and computstet. 151:538-44, 1980. erized tomographic scanning in the diagnosis of metastasis to the liver in patients 22. Starzl, T.E., Fracavilla, A., Halgrimson, C.G., et al.: The origin, hormonal with adenocarcinoma of the colon. Surg. nature, and action of hepatotrophic subsGynecol. Obstet. 156:205-08, 1983. tances in portal venous blood. Surg. Gy11. Coppa, G.F., Eng, K., Gouge, T.H., et necol. Obstet. 137:179-99, 1973. al.: Hepatic metastases from colorectal cancer. An evaluation of preoperative 23. Bengmark, S.: Progress in the treatment of liver cancer. World J. Surg. 6:1-8, and postoperative factors. Ann. Surg. 1982. 201:65-72, 1985. Vol. 66, No. 3, May-June 1990

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24. Muhe, E.: Resection of liver metastases. hepatic resection for metachronous WorldJ. Surg. 6:210-15, 1982. metastases from colon cancer. Ann. 25. Tomas-de la Vega, Donahue, E.J., Surg. 201:204-09, 1985. Doolas, A., et al.: A ten year experience 29. Thompson, H.H., Tompkins, R.K., with hepatic resection. Surg. Gynecol. Longmire, W.P.: Major hepatic resecObstet. 159:223-28, 1984. tion: a 25 year experience. Ann. Surg. 26. August, D.A., Sugarbaker, P.H. Ottow, 197:375-88, 1983. R.T., et al.: Hepatic resection of colo- 30. Kortz, W.J., Meyers, W.C., Hanks, rectal metastasis. Ann. Surg. 201:210-18, J.B., et al.: Hepatic resection for meta1985. static cancer. Ann. Surg. 199:182-86, 27. Morrow, C.E., Grage, T.B., Suther1984. land, D.E.R., and Najarian, J.S.: Hepa- 31. Taylor, B., Langer, B., Falk, R.E., and tic resection for secondary neoplasms. Ambus, U.: Role of resection in the Surg. 92:610-14, 1982. management of metastases to the liver. 28. Cady, B. and McDermott, W.V.: Major Can. J. Surg. 26:215-17, 1983.

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