Hepatic Resection of Colorectal Metastases - NCBI

Hepatic Resection of Colorectal Metastases Influence of Clinical Factors and Adjuvant Intraperitoneal 5-Fluorouracil via Tenckhoff Catheter on Survival DAVID A. AUGUST, M.D., PAUL H. SUGARBAKER, M.D., REYER T. OTTOW, M.D., FRED J. GIANOLA, PA-C, PHILIP D. SCHNEIDER, M.D., PH.D.

This report analyzes an experience with 33 hepatic resections for metastatic colorectal cancer over a 7-year period and with intraperitoneal 5-FU administered as a postresection adjuvant in 21 of these patients. Particular emphasis is placed on the identification of clinical deterinants of postresection survival. There was no operative mortality in this series. Postoperative complications occurred in 27% of patients, and the incidence of complications correlated with intraoperative blood loss (p = 0.002). Two- and 4-year estimated survivals were 72% and 53%, respectively. Patients with three or fewer metastases resected or with unilobar disease had improved survival when compared with patients having more than three metastases or bilobar disease, respectively (p < 0.05). Disease-free survival was improved in patients with microscopically negative resection margins (p = 0.019). Dukes' stage of the primary lesion, interval between bowel resection and detection of hepatic metastases, method of detection of metastases, preoperative CEA level, and type of operation performed were not predictive of postresection survival. Intraperitoneal 5-FU was well tolerated. There was a trend toward improved survival in patients receiving adjuvant chemotherapy, but this was not statistically significant. It is concluded that the number of metastases resected, the distribution of the metastases, and the technical adequacy of the excision are all predictive of outcome following hepatic resection of colorectal metastases. Encouraging results with the use of intraperitoneal 5-FU as a postresection adjuvant have led to the initiation of a prospective randomized trial investigating this modality at the NCI.

ALTHOUGH ALMOST 100 YEARS have elapsed since n the first reports of elective hepatic resection for benign' and malignant,23 neoplasms, it is only during the past decade that surgical resection of liver tumors has become a widely accepted and utilized therapy. Numerous series from major centers have documented the safety and efficacy of such resections for both primary and secondary liver neoplasms,4-'4 and a recent Reprint requests: Paul H. Sugarbaker, M.D., Head, Colorectal Cancer Section, Surgery Branch, National Cancer Institute, Bldg. 10, Rm. 2B07, Bethesda, MD 20205. Submitted for publication: June 12, 1984.

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From the Surgery Branch, Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

report has demonstrated the feasibility of performing major hepatic resections within community hospitals.'5 In light of these data, hepatic resection is widely accepted as a safe and effective therapy for a variety of liver tumors and as the only available treatment option that offers the potential for cure. It is now important to determine which patients are most likely to benefit from liver resection and to develop adjuvant therapies for those patients not presently cured by clinically complete

resections. This need is particularly evident for patients with hepatic metastases from colorectal cancers. Approximately five per cent of patients with colorectal cancer will have technically resectable hepatic metastases at the time of operation for the primary lesion. 16 An additional five per cent will develop resectable metastases limited to the liver at some time after resection of the primary metastasis.4"7 Thus, of the 130,000 people annually who develop colorectal cancer in the United States,'8 approximately 13,000 will be candidates for resection of hepatic metastases with curative intent. Assuming a 5-year survival rate of roughly 30%,4-'4 it can be estimated that 3900 patients may receive long-term benefit. However, this also means that 9100 patients will potentially undergo a major hepatic resection, with its attendant morbidity and mortality, without apparent benefit. Clearly, both greater selectivity in choosing candidates for hepatic resection and adjuvant therapies to improve postresection survival are needed to reduce the number of patients not benefitting from this therapy. For patients with hepatic metastatic disease from colorectal cancer primaries, several reports have ad-

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HEPATIC RESECTION OF COLORECTAL METASTASES

dressed the importance of clinical determinants as predictors of outcome following liver resection.4-6'81'0"13"14,16 However, the role of such factors as Dukes' stage of the primary lesion, disease-free interval following bowel resection, and number and location of hepatic metastases has not been definitively assessed. Also undecided is the role of adjuvant chemotherapy following hepatic resection. Data from uncontrolled studies have not indicated chemotherapy to be of benefit when given systemically following hepatic resection of colorectal metastases6'8I'0; this is not surprising given the ineffectiveness of presently available chemotherapeutic agents and regimens for the treatment of colon cancer. If currently available chemotherapeutic agents are to be used successfully as adjuvants following liver resection for colorectal metastases, it is likely that innovative methods of drug administration will be necessary. Intraperitoneal instillation of 5-fluorouracil (5-FU) via Tenckhoff catheter, one alternative, is safe and feasible'9 and achieves portal vein levels unattainable via systemic infusion.20 This report describes the National Cancer Institute (NCI) experience with 33 liver resections for hepatic metastases arising from colon and rectum cancers between January 1976 and January 1983. Particular emphasis is placed on the analysis of factors potentially predictive of outcome following resection. Also reported are the results of a pilot study that included 21 of these 33 patients investigating the use of intraperitoneal 5-FU as a postresection adjuvant. Patients and Methods

Seventy-seven patients with suspected liver metastases from colorectal cancers were seen by the Surgery Branch of the NCI between January 1980 and January 1983 (Table 1). Evaluation included physical examination, liver function tests, CEA, barium enema, chest x-ray, whole lung tomography, bone scan, liver/spleen scan, and abdominal CT scan. When these studies indicated potentially resectable disease, selective angiography with venous phase films was performed. Forty-seven patients were thought to be resectable for cure. Forty-six of these patients underwent exploratory laparotomy (one patient refused surgery) and 33 were resected of all gross disease. Reasons for unresectability included liver involvement judged too extensive to permit resection (six patients), a technically unresectable porta hepatis lesion (one patient), presence of a metastatic pelvic peritoneal implant (one patient), and presence of metastases in lymph nodes draining the liver (five patients). Of the 33 patients resected of all gross disease, three were excluded from this analysis because metastatic disease at another site (lungs, two; lymph node, one) was simultaneously resected. The 33 patients reported here are comprised of

TABLE 1. Resectability 77 patients with suspected colorectal hepatic metastases evaluated at the NCI, 1980-1983. 47 patients thought resectable for cure after preoperative evaluation. 46 patients explored. 33 patients resected of all evident disease. 29-Disease resected limited to liver. 4-Disease resected from liver and one other site (lungs, 2; lymph node, 1; local recurrence, 1). 13 patients found unresectable at laparotomy. 6-Liver involvement too extensive. 1 -Unresectable porta hepatis lesion. 1-Pelvic implant. 5-Lymphatic metastases in nodes draining the liver. 3 additional patients underwent hepatic resection, 1976-1979.

the remaining 30 resected patients and the 3 additional patients who underwent hepatic resection at the NCI between 1976 and 1979. Patients

The group included 23 men and ten women ranging in age from 17 to 74 years (median, 57 years). Median follow-up was 20 months (range, 6-83 months) and was complete in all patients. The stage, grade, and location of the primary tumors are summarized in Table 2; all were adenocarcinomas of the colon or rectum. The primary tumors were classified according to their Dukes' stage, Astler-Coller modification.21 One patient had a Dukes' B 1 primary, 14 and Dukes' B2 tumors, 2 had Dukes' Cl colon lesions, and 16 had Dukes' C2 primaries. In 3 patients, the pathologist classified the tumor TABLE 2. Primary Tumors

Type Dukes' Stage* A Bl B2

Cl C2 Differentiation Well Moderate Poor

Mucinous Location Ascending Transverse

Descending Sigmoid Rectum

Disease-free interval Synchronous 1-6 months 7-24 months >24 months * Astler-Coller

Modification.2'

No.

0 1 14 2 16 3 22 5 3 7 4 3 12 7

15 2 10 6

AUGUST AND OTHERS

212 TABLE 3. Operations Performed

No. Wedge resection

Left Right Left and right Lobectomy Left Left with right wedge Right Right with left wedge Right trisegmentectomy with left lateral wedge

20 2 7 11 12 2 I 6 3 I

as well-differentiated, in 22 moderately well-differentiated, and in five poorly differentiated; three patients had mucin-producing tumors. Seven tumors were located in the ascending colon, four in the transverse colon, three in the descending colon, 12 in the sigmoid colon, and seven in the rectum. Fifteen patients had their hepatic metastases noted at the time of initial colon resection. In the remaining 18 patients, the disease-free interval ranged from 2 to 90 months (median, 16 months). The operative procedures performed are summarized in Table 3. Twenty patients underwent wedge resections, 11 of which involved excisions in both lobes of the liver. Twelve lobectomies were performed (left, three; right, nine), four of which also involved contralateral wedge resection. A single right trisegmentectomy with wedge excision from the left lateral segment was performed.

Chemotherapy Twenty-one patients received intraperitoneal 5-FU as an adjuvant following hepatic resection. Twelve patients did not receive chemotherapy. Five were resected prior to initiation of the 5-FU study, three refused chemotherapy, two had postresection infectious complications preventing administration of chemotherapy, and two were considered to have medical contraindications. The chemotherapy was administered using a Tenckhoff catheter implanted at the time of hepatic resection. Catheter patency was maintained in the perioperative period by continuous exchange dialysis with 1.5% Inpersol (Abbott) supplemented with 4 meq/L of potassium and 500 U/L of heparin until the dialysate return was clear. Oneliter Inpersol exchanges were then made at increasing intervals until a single daily exchange was achieved. This daily irrigation was discontinued at the time of discharge, and the patient was instructed in sterile dressing care of the catheter exit site. Catheters could be removed and reinserted as an outpatient procedure if necessary. All catheters were removed at the completion of chemotherapy.

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Chemotherapy was initiated 10-74 days (median, 34 days) after resection and was given on days 1 through 5 of a 28-day cycle. For the initial cycle, 1040 mg of 5-FU was given in 2 L of Inpersol daily; this daily dose was escalated by 65-130 mg increments with subsequent cycles to a maximum of 1820 mg or until limited by toxicity (usually fatigue or abdominal pain). Treatment was continued for a total of 12 cycles unless toxicity or tumor recurrence indicated earlier cessation. The 21 patients received an average of 9.4 cycles of chemotherapy (range, 2-12), receiving a mean of 6820 mg (range, 4775-8255) of 5-FU per cycle.

Follow-up and Analysis Following resection, patients were seen regularly in clinic. Blood for CEA assay and liver function tests was drawn monthly. Radiologic studies obtained routinely at 3-6-month intervals included chest x-ray, full lung tomograms, liver/spleen scan, and abdominal CT scan. Follow-up was complete in all patients. Time to recurrence and survival data were estimated and plotted using the Kaplan-Meier product-limit method.22 The MantelHaenszel test23 was used to compare outcome between different groups of patients unless otherwise indicated. All p-values cited are two-tailed.

Results

Resectability Forty-seven of 77 patients evaluated (61%) were felt to have technically resectable disease limited to the liver

following preoperative evaluation. Of the 46 patients actually explored, 33 (72%) were resected of all gross disease. Four (12%) of these patients were found to have tumor involvement at the margin upon pathologic examination of the resected liver specimen. The positive margin patients all had multiple metastases (four, five, eight, and nine, respectively) and three had bilobar disease.

Morbidity and Blood Loss There were no intraoperative or in-hospital deaths following either exploration or liver resection. Median time to discharge following resection was 14 days (range, 8-52 days). Seven major and two minor postoperative complications occurred affecting 9 of 33 patients (27%) (Table 4). Intraoperative blood loss as estimated by the anesthesiologist ranged from 350 ml to 16,000 ml (median, 3000 ml). The occurence of postoperative complications correlated with intraoperative blood loss (Fig. 1). Of 11 patients whose blood loss was greater than 4000 ml, 5

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(45%) experienced major complications. Only 2 of 22 patients (9%) with blood loss less than 4000 ml experienced a major postoperative complication. Estimated blood loss in patients with complications averaged 4600 ml, versus 2600 ml in patients without complications (p = 0.002, Wilcoxon Rank Order Test).

Laboratory and Radiologic Studies Preoperative and postoperative CEA levels were available in 30 and 32 patients, respectively. Three of the four positive-margin patients had a CEA level less than 5.0 mg/ml measured within 5 weeks of operation. All three patients with CEA levels persistently greater than 5.0 ng/ml after surgery eventually developed recurrent disease. Preoperatively, CT scans (in most cases contrast enhanced using intravenous Ethiodized Oil Emulsion 13) were used to estimate the number of hepatic metastases present. In 17 of 33 patients (52%), the number of metastases suspected before surgery equalled the number found in the pathologic specimen. In eight patients one unsuspected metastasis was found, in six patients more than one, and in two patients fewer metastases were found than were suspected (the other suspected metastases being hemangiomata). Survival For all patients, median survival was 38 months, with estimated 2-year and 4-year survival of 72% and 53%, respectively (Fig. 2A). The corresponding statistics for the 29 negative-margin patients were 40 month median survival with 2- and 4-year survival of 80% and 55%, respectively. Median disease-free survival for all patients (Fig. 2B) was 13 months, resulting in a 25-month interval between median time to recurrence and median time to death. At present, 13 patients are free of disease with follow-up ranging from 6 to 83 months. Of the 20 patients who have developed recurrent disease, the liver was the first site of recurrence in 1 1; five other patients developed hepatic recurrences subsequent to the discovery of other sites of recurrent disease. Thirteen of 20 recurrences (65%) were evident within 1 year of resection, and 19 of 20 (95%) occurred within 2 years. All were evident within 30 months. The number of metastases resected and the distribution of metastases (unilobar versus bilobar) were predictive of survival. The status of the microscopic margins of the resected specimen was predictive of disease-free survival (Table 5). Median survival in patients with three or fewer metastases was significantly longer than in those with four or more metastases (44 months vs. 20 months, p = 0.028)

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TABLE 4. Postoperative Complications No.

Major Subphrenic fluid collection requiring drainage Culture positive Culture negative Pelvic abcess Bacterial peritonitis Dehiscence of repair of unintentional enterotomy Thoracic wound dehiscence Minor Prolonged ileus Superficial wound infection

3 2 1 1 1 I I

1 1

(Fig. 3). Only one of ten patients with more than three metastases resected is currently disease-free (at 19 months following right lobectomy for five metastases), whereas 6 of 12 patients with two or three metastases and six of 16j

10T

0

9 54 months vs. 23 months; p = 0.001) (Fig. 4). This remained true when patients with solitary metastases were excluded from the analysis (p = 0.053). All four patients with positive microscopic margins following resection developed recurrent disease within 1 year, but all survived beyond 2 years. Median diseasefree survival in the positive margin patients was 7 months versus 16 months in negative margin patients (p = 0.019). The Dukes' stage of the primary lesion, the interval between bowel resection and detection of hepatic metastases, the method of detection of hepatic metastases

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and

Chemotherapy As part of a pilot study, 21 of the patients undergoing hepatic resection received intraperitoneal 5-FU via Tenckhoff catheter as a postresection adjuvant therapy. Seven patients were given a full 12 cycles of therapy, receiving an average of 7170 mg of 5-FU per cycle. Five

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FIG. 2. Estimated survival distribution of all patients undergoing hepatic resection. A, top. Survival (median, 38 months). B, bottom. Disease-free survival (median, 13 months). (Tic marks represent followup time in patients who have not failed). 11 patients with solitary metastases resected are currently disease-free (minimum follow-up, 6 months). Patients with three or fewer metastases resected had estimated 2and 4-year survivals of 86% and 59%, respectively. There

All patients, positive margins One to three metastases Four or more metastases

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FIG. 3. Estimated survival distribution of patients according to number of metastases resected. Patients with one to three metastases fared better than those with four or more (median survival, 44 months vs. 20 months; p = 0.028).

5-FU (average, 6344 mg/cycle), their therapy being terminated prior to completion of 12 cycles because of abdominal pain (two patients), disabling fatigue (one patient), nausea (one patient), or bacterial peritonitis (one patient). In nine patients chemotherapy was terminated because of documented tumor recurrence. Adverse reactions were experienced by most patients during chemotherapy (Table 6). None were life-threatening and all responded to appropriate conservative management and minor dose reduction (approximately 10%). There were two Tenckhoff catheter-related problems; in one patient diaphragmatic irritation was relieved by replacing and repositioning the catheter, and in one patient bacterial peritonitis was treated by removing the catheter and stopping chemotherapy after 11.2 cycles. Overall, there was no difference in survival between patients who received intraperitoneal 5-FU and those who did not. However, patients receiving chemotherapy had an average of 3.7 metastases resected, whereas those not receiving chemotherapy had only 2.2 metastases removed; all four patients with greater than 5 metastases resected were in the chemotherapy group. When only patients with five or fewer metastases were compared, the patients receiving intraperitoneal 5-FU appeared to fare better, but follow-up is limited (median, 24 months for the no adjuvant group and 18 months in the 5-FU

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MONTHS POST-RESECTION

FIG. 4. Estimated survival distribution of patients according to distribution of metastases. Patients with unilobar disease survived longer than those with bilobar disease (median survival >54 months vs. 23 months; p = 0.001).

group) (Fig. 5). Ten of the 12 patients (73%) who received adjuvant therapy and six of the eight patients (63%) who did not receive adjuvant therapy who developed recurrent disease had the liver as a site of tumor regrowth.

Discussion These results support the growing acceptance of liver resection as a primary therapy for treatment of metastatic colorectal cancer in the liver. The low morbidity (27%) and zero mortality experienced in these 33 patients attest to the safety of this approach and are in agreement with the 4-20% operative4'14 and 15-50% morbidity6'8,-""3 reported by others. The 38-month meTABLE 6. Adverse Effects from Intraperitoneal 5-FU

Patients Abdominal pain Leukopenia Fatigue Nausea Pulmonary embolus Pancreatitis Congestive heart failure

4 4 3

2 1 1 1

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AUGUST AND OTHERS

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survival observed in patients undergo ing hepatic resection confirms the survival benefit co)nferred by surgery. Patients with unresected colorectal Ihepatic metastases have a median survival of 6-12.5 nnonths,24-27 and even when attempts are made to selec,t favorable prognosis patients or patients with surgicall)y resectable disease not operated upon, median surviva Ll is in the range of only 14-24 months.25-28 The correlation of high intraoperative bloc d loss with the occurrence of postoperative complicatic ins (Fig. 1) emphasizes the technically exacting requiremLents of safe liver surgery. The patient and the surgeon are rewarded by controlled resection with good hemostasis The difference observed between survival (disease-free survival estimates (Fig. 2) highlights the ca ution with which published survival statistics (includingg our own) must be evaluated. As in the study by Fort-ner et al.,6 95% of recurrences seen in this series we re evident within 24 months. However, many of the: se patients with disease are alive to be included in an analysis of 3-year survival. Three- or even 5-year surviv;al does not equate with cure. Five to ten per cent of all cancerrelated deaths will occur more than 5 years after resection, meaning that approximately 25% of 5-yeair survivors eventually succumb to their cancer.4 Clearly, long-term follow-up is essential to achieve a better undlerstanding of the role of resection of hepatic metastases. dian

Thorough preoperative evaluation was effectively utilized to define the subgroup of patients with surgically resectable disease. In this referral population, 60% were thought to be resectable for cure following preoperative evaluation; 72% of these patients ultimately had all gross disease excised (Table 1). These figures compare favorably with 25-30% resectability figures quoted for less stringently screened patients.6"6 CT scanning with the use of Ethiodized Oil Emulsion 132930 as a contrast agent was particularly helpful in defining the number of lesions and their relationship to portal and hepatic venous

I

Ann. Surg. * February 1985

structures.

It is noteworthy that five of 11 patients (45%) found unresectable at laparotomy were unresectable because of the presence of isolated lymphatic metastases in the hepatic and celiac nodes that drain the liver. These patients have been described elsewhere3' and are thought to represent the occurrence of lymphatic "remetastasis" from established hepatic metastases. These findings emphasize the need for thorough intraoperative exploration of these nodal groups to avoid undertaking a major liver resection in the face of disseminated disease. They also highlight the importance of early detection of liver metastases prior to their "remetastasis" so that dissemination does not preclude curative surgical excision. In this study patients whose hepatic metastases were detected by CEA elevations (and thus possibly at an earlier stage) did not fare better following resection than those diagnosed otherwise. Nevertheless, careful CEA monitoring following resection of the primary tumor can be expected to increase the proportion of patients who are candidates for potentially curvative hepatic resections by detecting disease before it has the opportunity to disseminate further. Only the number of metastases resected and the distribution of the metastases within the liver (unilobar vs. bilobar) were found to be predictive of survival (Figs. 3 and 4). The microscopic status of the resection margins was predictive of disease-free survival. Foster and Lundy'6 and Wilson and Adson28 observed improved survival in patients with fewer metastasess, but neither group enumerated multiple metastases. In agreement with our study, Cady and McDermott found patients with one, two, or three metastases to have an equivalent prognosis but those with four or more to fare worse.'4 Fortner et al.6 did not find this factor important after accounting for stage of liver disease, but this may be explained by the possibility that some of their multiple metastasis patients had positive margins (Stage II disease) and thus by their analysis would have done poorly because of stage of disease rather than number of metastases. They too failed to enumerate metastases in their analysis.

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Distribution of metastases were found to be a discriminating variable by Foster and Berman,4 in concurrence with the findings reported here. The observation of a poor prognosis for patients left with microscopic disease following resection is supported by Rajpal et al.'° and is also suggested by Fortner et al.6 The observations that the type of operation performed (wedge resection vs. lobectomy) and that the preoperative CEA level are not prognostic indicators are in general agreement with other published reports.6"6 Although Duke's stage of the primary lesion was not an important prognostic factor in this series, some have found this to be a discriminating indicator5 6; others have not.9" 6 Similar disagreement surrounds the observation made here that interval between colectomy and diagnosis of hepatic metastases does not predict ultimate outcome. Attiyeh et al.5 and Morrow et al.9 found that patients with synchronous metastases fared worse than those resected metachronously, but others68" 3",6 disagree. These discrepancies are probably due to the relatively small numbers of patients with colorectal metastases in all of these series. Unfortunately, differences in the manner in which data are reported prevent meaningful combination of the patients in these series to create a larger data base with which to address these issues. Intraperitoneal 5-FU given as an adjuvant following resection may improve survival in patients with five or fewer metastases (Fig. 5). The data are not statistically significant, but the favorable trend has led to the institution of a randomized trial. This finding contrasts with prior experiences with either systemic6'8'0 or regional infusion6 adjuvant chemotherapy following liver resection for colorectal metastases. Chemotherapy-associated complications were minor and easily managed. Intraperitoneal administration of chemotherapy offers a number of theoretic advantages over systemic delivery. It permits the achievement of hepatic 5-FU levels unattainable by systemic administration because of limited peritoneal transport of the drug and high fractional drug clearance by the liver.'9'20'32'33 Prolonged intraperitoneal administration of 5-FU using an indwelling Tenckhoff catheter has been shown to be safe and practical.'9'33 Following hepatic resection, intraperitoneal drug administration avoids potential difficulties confronted when regional vascular infusion is considered. It eliminates the need for an intravascular catheter following a major operative procedure associated with a 15% of greater incidence of postoperative infection. Thus, it can also be used in the "clean-contaminated" situation following synchronous bowel reaction and liver resection. Use of the intraperitoneal route for drug delivery circumvents the need for an intravascular prosthesis with its associated

217

risk of thrombosis. Vascular occlusion secondary to thrombosis in either the hepatic artery or portal vein could be devastating to the liver remaining following resection.6 Maintenance of adequate perfusion is crucial to postresection hepatic regeneration. The chemotherapy and no adjuvant therapy groups analyzed here were not randomized. Patients not receiving chemotherapy were operated upon prior to the institution of the adjuvant study, experienced postoperative complications that precluded administration of intraperitoneal chemotherapy, had medical contraindications to receiving chemotherapy, or refused treatment with chemotherapy. All of these factors may have introduced bias into the chemotherapy/no adjuvant comparison. A prospective, randomized trial is currently in progress to evaluate definitively the efficacy of intraperitoneal 5-FU as an adjuvant following hepatic resection for colorectal metastases. This study has helped better to define factors that can be used to limit the performance of hepatic resections to those patients that may truly benefit from the procedure. It has also identified intraperitoneal 5-FU as a promising agent for adjuvant use following liver resection. Further such studies are needed to improve the care of patients with hepatic metastases from colorectal cancers.

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30:267-283. 4. Foster JH, Berman MMt Solid liver tumors. In Ebert P, ed. Major Problems in Clinical Surgery. Philadelphia: WB Saunders, 1977; 1-342. 5. Attiyeh FF, Wanebo HJ, Stearns MW. Hepatic resection for metastasis from colorectal cancer. Dis Colon Rectum 1978; 21:160-162. 6. Fortner JG, Silva JS, Golbey RB, et al. Multivariate analysis of a personal series of 247 consecutive patients with liver metastases from colorectal cancer. I. Treatment by hepatic resection. Ann Surg 1984; 199:306-316. 7. Adson MA, van Heerden JA. Major hepatic resections for metastatic colorectal cancer. Ann Surg 1980; 191:576-583. 8. Bengmark S, Hafstrom L, Jeppsson B, et al. Metastatic disease in the liver from colorectal cancer: an appraisal of liver surgery. World J Surg 1982; 6:61-65. 9. Morrow CE, Grage TB, Sutherland DER, et al. Hepatic resection for secondary neoplasms. Surgery 1982; 92:610-614. 10. Rajpal S, Dasmahapatra KS, Ledesma EJ, et al. Extensive resections of isolated metastasis from carcinoma of the colon and rectum. Surg Gynecol Obstet 1982; 155:813-816. 11. Iwatsuki S, Shaw BW, Starzl TE. Experience with 150 liver resections. Ann Surg 1983; 197:247-253.

Ann. Surg. * February 1985 AUGUST AND OTHERS 218 12. Thompson HH, Tompkins RK, Longmire WP. Major hepatic metastases from colorectal cancer. Scand J Gastroenteral 1975; 10:221-223. resection: a 25-year experience. Ann Surg 1983; 197:375-388. 25. Goslin R, Steele G, Zamcheck N, et al. Factors influencing survival 13. Kortz WJ, Meyers WC, Hanks JB, et al. Hepatic resection for in patients with hepatic metastases from adenocarcinoma of metastatic cancer. Ann Surg 1984; 199:182-186. 14. Cady B, McDermott WV. Major hepatic resection for metachronous the colon or rectum. Dis Colon Rectum 1982; 25:749-754. 26. Lahr CJ, Soong S-J, Cloud G, et al. A multifactorial analysis of metastases from colon cancer (submitted). 15. Nims TA. Resection of the liver for metastatic cancer. Surg prognostic factors in patients with liver metastases from colorectal carcinoam. J Clin Oncol 1983; 1:720-726. Gynecol Obstet 1984; 158:46-48. 27. Wood CB, Gillis CS, Blumgart LH. A retrospective study of the 16. Foster JM, Lundy J. Liver metastases. Curr Probi Surg 1981; natural history of patients with liver metastases from colorectal 18: 157-202. cancer. Clin Oncol 1976; 2:285-288. 17. Adson MA. Hepatic metastases in perspective. AJR 1983; 140:69528. Wilson SM, Adson MA. Surgical treatment of hepatic metastases 700. from colorectal cancers. Arch Surg 1976; 111:330-334. 18. Cancer Statistics. In Ca-A Cancer Journal for Clinicians. Am 29. Vermess M, Doppman JL, Sugarbaker PH, et al. Computed Cancer Soc 1984; 34:7-23. tomography of the liver and spleen with intravenous lipoid 19. Jenkins J, Sugarbaker PH, Gianola FJ et al. Technical considerations contrast material: review of 60 examinations. AJR 1982; in the use of intraperitoneal chemotherapy administered by 138:1063-1071. Tenckhoff catheter. Surg Gynecol Obstet 1982; 154:858-864. 30. Miller DL, Rosenbaum RC, Sugarbaker PH, et al. Detection of 20. Speyer JL, Sugarbaker PH, Collins JM, et al. Portal levels and hepatic metastases: comparison of EOE-13 computed tomoghepatic clearance of 5-fluorouracil after intraperitoneal adminraphy and scintigraphy. AJR 1983; 141:931-935. istration in humans. Cancer Res 1981; 41:1916-1922. 31. August DA, Sugarbaker PH, Schneider PD. Lymphatic dissemi21. Astler, VB, Coller FA. The prognostic significance of direct extension nation of hepatic metastases: implications for the follow-up and of carcinoma of the colon and rectum. Ann Surg 1954; 139:846treatment of patients with colorectal cancer. Cancer, in press. 852. 32. Dedrick RL, Myers CE, Bungay PM, et al. Pharmacokinetic 22. Kaplan EL, Meier F. Nonparametric estimation from incomplete rationale for peritoneal drug administration in the treatment of observations. J Am Stat Assoc 1958; 53:457-481. ovarian cancer. Cancer Treat Rep 1978; 62: 1-11. 23. Mantel N. Evaluation of survival data and two new rank order 33. Speyer JL, Myers CE. The use of peritoneal dialysis for delivery statistics arising in its consideration. Cancer Chemother Rep of chemotherapy to intraperitoneal malignancies. In Mathe G, 1966; 50:163-170. Muggia F, eds. Recent Results in Cancer Research. Berlin: 24. Baden H, Anderson B. Survival of patients with untreated liver Springer-Verlag, 1980; 264-269.