A Prospective Evaluation of Hepatic Resection for Colorectal Carcinoma Metastases to the Liver: Gastrointestinal Tumor Study Group Protocol 6584 By Glenn Steele, Jr, Ronald Bleday, Robert J. Mayer, Anne Lindblad, Nicholas Petrelli, and Donald Weaver We report here the results of the first multiinstitutional prospective evaluation of patients considered to have potentially resectable hepatic metastases from colorectal carcinoma. One hundred fifty-six patients were enrolled from 15 institutions. Six patients were subsequently excluded. One hundred fifty patients underwent surgery and are evaluable for analysis (median follow-up time, 3.1 years; range, 4 months to 5.1 years). Curative resection could be performed on 46% of patients (69 of 150), noncurative resection on 12% (18 of 150), while 42% were found to be unresectable (63 of 150). Thirty-day surgical mortality and morbidity rates in patients with attempted resection were 2.7% and 13%, respectively. The curative resection group was observed to have an improved median survival (37.1 months) compared with the noncurative resection group (21.2 months) and the unresectable group (16.5 months) (P < .01). Computed tomo-
IT
HAS LONG been assumed, 1' 2 and recently confirmed in prospective multiinstitutional trials,3'4 that liver cancer recurrence after resection of primary colorectal cancer remains the major anatomic site of treatment failure. Although metastasis from colorectal cancer has classically been assumed to foreshadow death within 4 to 6 months, 57 recent retrospective surveys have shown a far more variable natural history in selected patients with or without treatment.8 ' 9 Recent advances in our understanding of the surgical anatomy of the liver and, particularly, new technical approaches that have been developed for hepatic transplantation t ,"' have allowed a more surgically aggressive approach for both primary and secondary liver tumors. Thus, many more patients have recently undergone attempts at surgically curing their liver tumors, especially patients with metastases from colorectal cancer. From reviewing most recent single-institution series," it is clear that a certain subset of patients with liver-only metastases from colon and rectal cancer can be cured by surgical resection. What remains uncertain is the true denominator (ie, how many patients had to be operated on before some were identified as resectable), what the morbidity of such aggressive surgery is, particu-
graphic (CT) scan was a poor predictor for resectability, and age was not a contraindication to curative resection. Preoperative carcinoembryonic antigen (CEA) values were also a poor predictor for resectability. However, the median CEA value 61 to 180 days postsurgery was significantly higher in unresectable patients compared with median CEA levels in noncuratively and curatively resected groups (P < .01). Our results imply that curative resection leads to an increase in median survival. Noncurative resection provides no benefit to asymptomatic patients, since unresectable and noncurative resection groups have similar life expectancies. Longer follow-up will be needed to demonstrate the ultimate impact of curative resection on survival. J Clin Oncol 9:71105-1112. o 1991 by American Society of Clinical Oncology.
larly in hospitals that may not specialize in liver surgery, and, most important, what the contribution of biologic selection is to the survival as opposed to the impact of surgery itself. This final question cannot be answered by anything less than a formal prospective trial in which surgically staged patients are randomized between those who undergo resection for cure of their liver metastases and those who have no resection. In lieu of performing such a trial (which, although intellectually appealing, will never be acceptable to either surgeon or patient), the Gastrointestinal Tumor Study Group initiated a trial in 1984, addressing the following issues: 1. Could a reasonable number of patients with liver metastases diagnosed at the time of or
following resection of primary colorectal can-
From the Departmentof Surgery, New England Deaconess Hospital; Dana-FarberCancer Institute, Boston, MA; The EMMES Corporation,Potomac, MD; Roswell ParkMemorial Institute,Buffalo, NY and Wayne State University, Detroit,MI. Address reprintrequests to Glenn Steele, Jr,MD, 110 Francis St, 3-A, Boston, MA 02215. SubmittedJuly 24, 1990; accepted December 26, 1990. ©1991 by American Society of Clinical Oncology. 0732-183X/91/0907-0005$3.00/0
Journalof Clinical Oncology, Vol 9, No 7 (July), 1991: pp 1105-1112
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cer be accrued to a multiinstitutional surgical trial? The answer to this question would be an important first step for planning any subsequent prospective randomized testing of the efficacy of systemic or regional therapy after resection of hepatic metastases. How many patients predicted to have surgically resectable liver metastases would be found at surgery to have additional unsuspected liver metastases precluding resection or previously unsuspected extrahepatic recurrence contraindicating any regional therapy (ie, how accurate is preoperative staging)? What are the important prognostic variables in this group of patients with liver-only or liver-predominant colon and rectal carcinoma recurrence? What is the surgical morbidity and mortality when evaluated in a multiinstitutional group setting? What is the survival expectation among patients who had their liver metastases resected for cure when compared with patients undergoing resection but found at surgery or afterward to have residual cancer at surgical margins, and to patients operated on but found to have unresectable liver metastases? MATERIALS AND METHODS
This study was opened to patient accrual in July 1984. Patients having primary colon or rectal adenocarcinomas with synchronous or metachronous hepatic metastases were eligible for entry. Patients were to be registered before surgical exploration for attempted excision of liver metastases. If the liver resection took place at the time of excision of the primary tumor, registration could occur after resection. Patients must have had no other active malignant processes and no suspicion of extrahepatic disease, with the exception of the primary in the case of a synchronous lesion. Required preoperative staging included either a computed tomography (CT) or magnetic resonance imaging of the abdomen and pelvis or a liver/spleen technitium-99 sulphur colloid scan, a chest radiograph, and a barium enema or colonoscopy. Patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible as were those with prothrombin time within 3 seconds of control, hemoglobin 2 10 g/dL, hematocrit > 30%, and pe3 ripheral leukocyte count > 4,000/mm . All patients signed the consent form before registration. Follow-up was designed according to the study parameters listed in Table 1. Patients were classified into three groups based on surgical outcome: curative resection, noncurative resection, and unresectable. To be considered resected for cure, all patients must have had noninvasive tests and intraoperative staging that excluded all metastatic disease such as peripor-
Table 1. Study Parameters Every Every 6 Months 3 Months for 2 Yeors Presurgery for 2 Yers* Then Yearly*
History and physical Height Weight Performance status
x x x
x
ECOGt x x Hemoglobin, WBC, x x platelets Creatinine or BUN x x Total bilirubin x x SGOT x x x x Alkaline phosphatase x x Serum albumin Total protein x Chest x-ray Posteroanterior and lateral* Bone scan (optional-addendum 1, 10/84) Prothrombin time x x x x Carcinoembryonic antigen x CT of abdomen and pelvis x Liver/spleen scan§ Barium enema or x colonscopy
x
x x
*Follow-up study parameters were required for surgically resected patients only. of ECOG performance status: 0, fully active, without symptoms or restrictions; 1, fully ambulatory, not in bed at all during the day, able to carry out light activities and sedentary duties but may be symptomatic; 2, ambulatory, in bed less than 50% of waking hours; 3, in bed more than 50% of waking hours, capable of personal self-care; and 4, completely disabled, totally confined to bed or chair. tIf further study was necessary, a pulmonary tomogram or chest CT scan was required. §lf abdominal CT scan was not available, otherwise optional.
"tDefinitions
tal, mesenteric, or periaortic nodal involvement. Local or regional recurrence was also a contraindication to curative liver resection. Patients resected with curative intent must
have had all of the tumor surgically resected whether it was uni- or bilobar, and margins free of tumor as established by pathologic examination. Cryosurgery was considered curative if intraoperative ultrasound showed no evidence of residual untreated disease and good evidence of adequate freezing margins." Patients undergoing liver resection but who were found to have involvement of tumor margins or extrahepatic disease sites other than their colonic or rectal primary were designated as noncurative resections. Patients who did not undergo a liver resection because their liver metastases were considered anatomically unresectable or because of the presence of extrahepatic disease comprised the unresectable group. StatisticalAnalysis Survival and disease-free survival distributions were estimated according to the product-limit method of Kaplan and
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1107
HEPATIC RESECTION/COLORECTAL CARCINOMA Meier, 14 and comparisons were made assuming Cox's proportional hazards model.15 X2 tests were used to test the differences in baseline patient characteristics, and logistic regression techniques were used to assess the ability of selected characteristics to predict surgical outcome. Differences between pre- and postcarcinoembryonic antigen (postCEA) values for curatively resected and unresectable patients were tested using the Wilcoxon test. RESULTS
A total of 156 patients were registered onto this study between July 1984 and May 1988. Six patients were excluded from all analyses: one patient was lost to follow-up after registration but before surgery, one patient had known extrahepatic metastases prior to surgery, one patient had a primary hepatocellular carcinoma, and three patients (2%) were free of liver disease at laparotomy. One of these latter three patients had recurrent colon cancer in the omentum, which was interpreted incorrectly by preoperative CT as a liver lesion; one had a space-occupying lesion on a preoperative liver/spleen scan but was found to be free of disease at laparotomy; and the third patient had a small liver nodule resected but found subsequently on pathologic examination to be benign. Eight patients with synchronous liver metastasis (five curative, two unresectable, and one noncurative resection) were registered after surgery but are included in all analyses, as is one patient who entered the study with an ECOG performance status of 2. Patient Characteristics Forty-six percent of patients (69 of 150) were resected and classified as curative, 42% (63 of 150) were unresectable, and 12% (18 of 150) of patients underwent a "noncurative" liver resection. Two patients underwent a synchronous resection of the primary tumor and liver lesions, and both resulted in a curative resection classification. A summary of patient characteristics in Table 2 illustrates that over half of the patients were men (61%), and the majority of patients (85%) entered the study with an ECOG performance status score of 0. In the curative resection group, 70% of the patients were older than 60 years of age compared with only 41% in the group in which no resection was possible (P < .05). Overall unilobar right lobe involvement was more common than left lobe involvement (43% v 13%, respectively), with 44% having both lobes involved. In the unresectable
Table 2. Selected Characteristics by Operative Outcome
Characteristic Sex (%) Male Female Age (years) (%) 70 Initial performance status score (ECOG) (%) 0 1 2 Lobes involved (%) Left Right Left and right Diagnosis coincident with primary (%) Median preoperative laboratory results Alkaline phosphatase Bilirubin
Curative Noncurative No Resection Resection Resection Total (n = 69) (n = 18) (n = 63) (n = 150)
61 39
61 39
62 38
61 39
9 22 51 19
22 28 17 33
27 32 30 11
18 27 38 17
88 12 0
78 22 0
84 14 2
85 14 1
17 67 16
22 61 17
6 11 83
13 43 44
17
22
36
25
117.0 .6
105.0 .6
101.0 .6
86.0 .6
group, 83% were found to have both left and right lobe involvement at laparotomy, while bilobar involvement was reported in only 16% and 17% of the patients undergoing curative and noncurative resections, respectively. Preoperative serum alkaline phosphatase values were observed to be higher for the unresectable group as opposed to the curative group, although not significantly different. Preoperative bilirubin values were comparable across groups, and the median time from colon resection to liver exploration was observed to be longer (although not significantly) for patients undergoing a resection compared with those not resected (P = .16). The type of resection by surgical outcome (curative v noncurative) is detailed in Table 3. Overall, 30% of patients underwent a formal right-lobe resection, 10% a formal left-lobe resection, and 37% a wedge resection. Of the 63 patients not resected, 68% (43 of 63) were found to be anatomically unresectable and 32% (20 of 63) were found to have extrahepatic disease. Supplemental data regarding perioperative, operative, and postoperative information on all study patients were requested. One hundred forty-two reports from eligible patients were returned. In the preoperative work-up, CT scans failed to show
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Table 3. Surgical Characteristics by Operative Outcome
Characteristic
%Curative Resection (n = 69)
% Noncurative Resection (n = 18)
% Total (n = 87)
33 10 38
17 11 33
30 10 37
3
6
3
7 1 7
6 0 28
7 1 11
Resection Right lobectomy Left lobectomy Wedge Lobectomy and opposite lobe wedge Extended right (trisegmentectomy) Extended left Other
any involvement in 7% (10 of 139) of patients. Five of these 10 were found to have disease in both lobes at laparotomy. Overall, CT scan results underestimated the number of lobes involved in 33% of patients (46 of 139) and overestimated involvement in 4% (five of 139). Extrahepatic disease was found in 12% (17 of 144) of patients with a negative preoperative CT scan. Arteriography was performed in 82% (115 of 141) of patients. This procedure was successful in identifying lesions not otherwise identified by CT or liver scan in 11% (13 of 115) of patients. Arteriography was not only used to identify occult disease, but also to delineate the anatomy of the hepatic vasculature. Use of intraoperative ultrasound, cryosurgery, cavitron (an ultrasonic liver dissection/suction device), as well as other operative details are summarized for each of the surgical outcomes in Table 4. Overall, 23% of the patients had an intraoperative ultrasound performed, and 8% had cryosurgery. Nine percent of patients in the curative resection group underwent surgery with use of the cavitron. Curatively resected patients required a few extra days of hospitalization, but this was not statistically significantly different from that of the overall group of patients. Operative results indicated a total of 61 of 129 (47%) patients had a solitary liver lesion. Solitary Table 4. Summary by Surgical Outcome Curative Noncurative No Resection Resection Resection 1 (n = 58) (n = 8) (n = 66)
Intraoperative ultrasound (%) Cryosurgery (%) Cavitron (%) Median units of blood Median days hospitalized
Total (n = 142)
18 11 9 3.0
26 22 0 4.0
28 0 0 0
23 8 4 1
17.0
14.0
13.5
15.5
lesions were significantly more common among curatively resected patients than among others (P < .01). Sixty-seven percent of patients resected for cure (43 of 65) had a solitary lesion compared with 35% (six of 17) of noncuratively resected and 26% (12 of 47) of unresected patients. Almost half of the unresected patients (45%, 21 of 47) were found to have more than three lesions, while only 6% (four of 65) and 17% (three of 17) of the curatively resected and noncuratively resected patients had more than three lesions. Within the curatively resected group, the median survival of patients who were found to have only one lesion at surgery is 3.3 years and is 2.8 years for patients with more than one lesion. Disease-free survival for patients with one lesion and more than one lesion is 2.7 years and 1 year, respectively. Although patients with only one lesion were observed to have improved survival and disease-free survival compared with those patients with more than one lesion, these differences were not statistically significant (P > .2). Surgical Complications Nineteen of the 142 patients (13%) had operative complications (Table 5). Four patients were reported to have had an abscess. Seven patients Table 5. Surgical Complications Patient No.
Surgical Outcome
60 85 88 94 105
Curative Curative Curative Curative Curative Curative Curative Curative
126 130 131
Curative Curative Curative
133 11 28
Curative Noncurative Noncurative
97
Noncurative
115 1 3
Noncurative No resection No resection
6
No resection
30 38 46
Description of Complication Hepatic vein tear during resection Abscess, rehospitalized day 28 Intraabdominal hemorrhage Intravascular coagulation Abscess Abdominal wound dehiscence Bacteremia, rehospitalized day 14 Adhesions, small bowel obstruction, rehospitalized day 26 Renal failure, hypotension Biloma Biliary-cutaneous fistula, rehospitalized day 10 Abscess, rehospitalized day 27 Hepatitis, esophagitis, pneumonia Pulmonary embolism, rehospitalized day 30 Respiratory arrest 10th day postoperative Abscess, biloma Pleural effusion Myocardial infarction 2 weeks postoperative Stricture of common hepatic duct, rehospitalized day 19
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required rehospitalization 10 days, 14 days, 19 days, 26 days, 27 days, 28 days, and 30 days after discharge. Two bilomas were reported, one in a patient who also had an abscess. Eighteen percent of patients undergoing a curative resection (12 of 66) and 22% (four of 18) of patients with a noncurative resection were reported to have a surgical complication, whereas only 5% (three of 58) of the unresectable patients were reported to have had complications.
-J
Recurrences In all, 43 (49%) patients in the resected groups experienced disease recurrence (35 curative, eight noncurative). An additional five resected patients (two curative, three noncurative) were reported to have died of disease although supportive documentation has yet to be submitted. Of the 43 documented recurrences, 32 (74%) have involved the liver, with four of these involving both liver and lungs. Eleven patients (26%) have recurred at extrahepatic sites including lung (five), bone (one), colon/rectum (one), biliary bed (one), spleen (one), lymph nodes (one), and pelvis/uterus (one). The 1-year and 2-year probability of recurrence in the curative resection group is estimated to be 26% and 51%, respectively. Survival Follow-up is available on 150 patients. A total of 107 deaths has been reported including 38 of 69 (55%) of the curatively resected group, 14 of 18 (78%) of the noncuratively resected patients, and 55 of 63 (87%) of the unresectable group. Four of these deaths occurred within the 30-day postoperative period because of hemorrhage, intravascular coagulopathy, renal failure, and pulmonary thromboembolism, yielding a 30-day surgical mortality of 2.7%. Median survival of the entire cohort is estimated to be 26.1 months. Median survival times for patients receiving curative and noncurative resections, and those receiving no resection are estimated to be 37.1, 21.2, and 16.5 months, respectively. The median survival time of curatively resected patients is significantly different (P < .01) from that for the patients in the noncuratively resected and the unresected groups. Neither statistically nor clinically interesting differences in the survival distributions of the latter two groups are observed. Estimated survival distribution for the first 3 years poststudy entry are given in Fig 1. One-year
MONTHS Fig 1. Probability of survival by resection type. (-) tive, (....) noncurotive, (---) nonresected.
Cura-
probability of survival estimates are 91%, 67%, and 68% for the curative resection, noncurative resection, and no resection groups, respectively. The probability of survival and disease-free survival for these patients who were resected with curative intent is shown in Fig 2. CEA Assessment Reports of CEA values for patients both before and after hepatic resection were requested. Values reported were separated into three groups as follows: 30 days or less before surgery (preopera-
-5
4l
MONTHS Fig 2. Probability of (-) survival and (-...) disease-free survival of curatively resected patients.
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tive), 1 day to 60 days postsurgery, and 61 days to 180 days postsurgery. Values reported for some patients fell outside these ranges and are excluded from further analysis. Figure 3 and Table 6 summarize the information received by surgical outcome. The median preoperative (:< 30 days before surgery) CEA level for curatively resected patients was 36.2 ng/mL; for the noncuratively resected patients, 45.5 ng/mL; and for the unresected patients, 36.0 ng/mL. These values were not significantly different (P > .3). Median CEA values measured up to 60 days postsurgery were observed to be lower than presurgery medians in all three groups; however, serial titers began to increase in the unresected patients 61 to 180 days postoperatively. The median CEA value 61 to 180 days postsurgery for the unresected group was 42.7 ng/mL, significantly higher (P < .01) than the medians of 3.8 ng/mL and 5.0 ng/mL observed in the curatively and noncuratively resected groups, respectively. DISCUSSION
Liver resection for hepatic metastases from colorectal carcinoma is presently the standard treatment for potentially resectable disease. The efficacy of this treatment, however, has never been evaluated in a randomized prospective fashion, since surgeons who diagnose a resectable liver lesion understandably would not submit his or her patient to a "sham" laparotomy. In singleinstitution and multiinstitutional retrospective series,'"617 numerous authors have attempted to com-
Table 6. Summary of CEA Assessments by Surgical Outcome Surgical Outcome
Prehepatic resection (!30 days) Median CEA (ng/mL) Posthepatic resection (>1 day, 60 days,
IT
HAS LONG been assumed, 1' 2 and recently confirmed in prospective multiinstitutional trials,3'4 that liver cancer recurrence after resection of primary colorectal cancer remains the major anatomic site of treatment failure. Although metastasis from colorectal cancer has classically been assumed to foreshadow death within 4 to 6 months, 57 recent retrospective surveys have shown a far more variable natural history in selected patients with or without treatment.8 ' 9 Recent advances in our understanding of the surgical anatomy of the liver and, particularly, new technical approaches that have been developed for hepatic transplantation t ,"' have allowed a more surgically aggressive approach for both primary and secondary liver tumors. Thus, many more patients have recently undergone attempts at surgically curing their liver tumors, especially patients with metastases from colorectal cancer. From reviewing most recent single-institution series," it is clear that a certain subset of patients with liver-only metastases from colon and rectal cancer can be cured by surgical resection. What remains uncertain is the true denominator (ie, how many patients had to be operated on before some were identified as resectable), what the morbidity of such aggressive surgery is, particu-
graphic (CT) scan was a poor predictor for resectability, and age was not a contraindication to curative resection. Preoperative carcinoembryonic antigen (CEA) values were also a poor predictor for resectability. However, the median CEA value 61 to 180 days postsurgery was significantly higher in unresectable patients compared with median CEA levels in noncuratively and curatively resected groups (P < .01). Our results imply that curative resection leads to an increase in median survival. Noncurative resection provides no benefit to asymptomatic patients, since unresectable and noncurative resection groups have similar life expectancies. Longer follow-up will be needed to demonstrate the ultimate impact of curative resection on survival. J Clin Oncol 9:71105-1112. o 1991 by American Society of Clinical Oncology.
larly in hospitals that may not specialize in liver surgery, and, most important, what the contribution of biologic selection is to the survival as opposed to the impact of surgery itself. This final question cannot be answered by anything less than a formal prospective trial in which surgically staged patients are randomized between those who undergo resection for cure of their liver metastases and those who have no resection. In lieu of performing such a trial (which, although intellectually appealing, will never be acceptable to either surgeon or patient), the Gastrointestinal Tumor Study Group initiated a trial in 1984, addressing the following issues: 1. Could a reasonable number of patients with liver metastases diagnosed at the time of or
following resection of primary colorectal can-
From the Departmentof Surgery, New England Deaconess Hospital; Dana-FarberCancer Institute, Boston, MA; The EMMES Corporation,Potomac, MD; Roswell ParkMemorial Institute,Buffalo, NY and Wayne State University, Detroit,MI. Address reprintrequests to Glenn Steele, Jr,MD, 110 Francis St, 3-A, Boston, MA 02215. SubmittedJuly 24, 1990; accepted December 26, 1990. ©1991 by American Society of Clinical Oncology. 0732-183X/91/0907-0005$3.00/0
Journalof Clinical Oncology, Vol 9, No 7 (July), 1991: pp 1105-1112
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cer be accrued to a multiinstitutional surgical trial? The answer to this question would be an important first step for planning any subsequent prospective randomized testing of the efficacy of systemic or regional therapy after resection of hepatic metastases. How many patients predicted to have surgically resectable liver metastases would be found at surgery to have additional unsuspected liver metastases precluding resection or previously unsuspected extrahepatic recurrence contraindicating any regional therapy (ie, how accurate is preoperative staging)? What are the important prognostic variables in this group of patients with liver-only or liver-predominant colon and rectal carcinoma recurrence? What is the surgical morbidity and mortality when evaluated in a multiinstitutional group setting? What is the survival expectation among patients who had their liver metastases resected for cure when compared with patients undergoing resection but found at surgery or afterward to have residual cancer at surgical margins, and to patients operated on but found to have unresectable liver metastases? MATERIALS AND METHODS
This study was opened to patient accrual in July 1984. Patients having primary colon or rectal adenocarcinomas with synchronous or metachronous hepatic metastases were eligible for entry. Patients were to be registered before surgical exploration for attempted excision of liver metastases. If the liver resection took place at the time of excision of the primary tumor, registration could occur after resection. Patients must have had no other active malignant processes and no suspicion of extrahepatic disease, with the exception of the primary in the case of a synchronous lesion. Required preoperative staging included either a computed tomography (CT) or magnetic resonance imaging of the abdomen and pelvis or a liver/spleen technitium-99 sulphur colloid scan, a chest radiograph, and a barium enema or colonoscopy. Patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible as were those with prothrombin time within 3 seconds of control, hemoglobin 2 10 g/dL, hematocrit > 30%, and pe3 ripheral leukocyte count > 4,000/mm . All patients signed the consent form before registration. Follow-up was designed according to the study parameters listed in Table 1. Patients were classified into three groups based on surgical outcome: curative resection, noncurative resection, and unresectable. To be considered resected for cure, all patients must have had noninvasive tests and intraoperative staging that excluded all metastatic disease such as peripor-
Table 1. Study Parameters Every Every 6 Months 3 Months for 2 Yeors Presurgery for 2 Yers* Then Yearly*
History and physical Height Weight Performance status
x x x
x
ECOGt x x Hemoglobin, WBC, x x platelets Creatinine or BUN x x Total bilirubin x x SGOT x x x x Alkaline phosphatase x x Serum albumin Total protein x Chest x-ray Posteroanterior and lateral* Bone scan (optional-addendum 1, 10/84) Prothrombin time x x x x Carcinoembryonic antigen x CT of abdomen and pelvis x Liver/spleen scan§ Barium enema or x colonscopy
x
x x
*Follow-up study parameters were required for surgically resected patients only. of ECOG performance status: 0, fully active, without symptoms or restrictions; 1, fully ambulatory, not in bed at all during the day, able to carry out light activities and sedentary duties but may be symptomatic; 2, ambulatory, in bed less than 50% of waking hours; 3, in bed more than 50% of waking hours, capable of personal self-care; and 4, completely disabled, totally confined to bed or chair. tIf further study was necessary, a pulmonary tomogram or chest CT scan was required. §lf abdominal CT scan was not available, otherwise optional.
"tDefinitions
tal, mesenteric, or periaortic nodal involvement. Local or regional recurrence was also a contraindication to curative liver resection. Patients resected with curative intent must
have had all of the tumor surgically resected whether it was uni- or bilobar, and margins free of tumor as established by pathologic examination. Cryosurgery was considered curative if intraoperative ultrasound showed no evidence of residual untreated disease and good evidence of adequate freezing margins." Patients undergoing liver resection but who were found to have involvement of tumor margins or extrahepatic disease sites other than their colonic or rectal primary were designated as noncurative resections. Patients who did not undergo a liver resection because their liver metastases were considered anatomically unresectable or because of the presence of extrahepatic disease comprised the unresectable group. StatisticalAnalysis Survival and disease-free survival distributions were estimated according to the product-limit method of Kaplan and
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1107
HEPATIC RESECTION/COLORECTAL CARCINOMA Meier, 14 and comparisons were made assuming Cox's proportional hazards model.15 X2 tests were used to test the differences in baseline patient characteristics, and logistic regression techniques were used to assess the ability of selected characteristics to predict surgical outcome. Differences between pre- and postcarcinoembryonic antigen (postCEA) values for curatively resected and unresectable patients were tested using the Wilcoxon test. RESULTS
A total of 156 patients were registered onto this study between July 1984 and May 1988. Six patients were excluded from all analyses: one patient was lost to follow-up after registration but before surgery, one patient had known extrahepatic metastases prior to surgery, one patient had a primary hepatocellular carcinoma, and three patients (2%) were free of liver disease at laparotomy. One of these latter three patients had recurrent colon cancer in the omentum, which was interpreted incorrectly by preoperative CT as a liver lesion; one had a space-occupying lesion on a preoperative liver/spleen scan but was found to be free of disease at laparotomy; and the third patient had a small liver nodule resected but found subsequently on pathologic examination to be benign. Eight patients with synchronous liver metastasis (five curative, two unresectable, and one noncurative resection) were registered after surgery but are included in all analyses, as is one patient who entered the study with an ECOG performance status of 2. Patient Characteristics Forty-six percent of patients (69 of 150) were resected and classified as curative, 42% (63 of 150) were unresectable, and 12% (18 of 150) of patients underwent a "noncurative" liver resection. Two patients underwent a synchronous resection of the primary tumor and liver lesions, and both resulted in a curative resection classification. A summary of patient characteristics in Table 2 illustrates that over half of the patients were men (61%), and the majority of patients (85%) entered the study with an ECOG performance status score of 0. In the curative resection group, 70% of the patients were older than 60 years of age compared with only 41% in the group in which no resection was possible (P < .05). Overall unilobar right lobe involvement was more common than left lobe involvement (43% v 13%, respectively), with 44% having both lobes involved. In the unresectable
Table 2. Selected Characteristics by Operative Outcome
Characteristic Sex (%) Male Female Age (years) (%) 70 Initial performance status score (ECOG) (%) 0 1 2 Lobes involved (%) Left Right Left and right Diagnosis coincident with primary (%) Median preoperative laboratory results Alkaline phosphatase Bilirubin
Curative Noncurative No Resection Resection Resection Total (n = 69) (n = 18) (n = 63) (n = 150)
61 39
61 39
62 38
61 39
9 22 51 19
22 28 17 33
27 32 30 11
18 27 38 17
88 12 0
78 22 0
84 14 2
85 14 1
17 67 16
22 61 17
6 11 83
13 43 44
17
22
36
25
117.0 .6
105.0 .6
101.0 .6
86.0 .6
group, 83% were found to have both left and right lobe involvement at laparotomy, while bilobar involvement was reported in only 16% and 17% of the patients undergoing curative and noncurative resections, respectively. Preoperative serum alkaline phosphatase values were observed to be higher for the unresectable group as opposed to the curative group, although not significantly different. Preoperative bilirubin values were comparable across groups, and the median time from colon resection to liver exploration was observed to be longer (although not significantly) for patients undergoing a resection compared with those not resected (P = .16). The type of resection by surgical outcome (curative v noncurative) is detailed in Table 3. Overall, 30% of patients underwent a formal right-lobe resection, 10% a formal left-lobe resection, and 37% a wedge resection. Of the 63 patients not resected, 68% (43 of 63) were found to be anatomically unresectable and 32% (20 of 63) were found to have extrahepatic disease. Supplemental data regarding perioperative, operative, and postoperative information on all study patients were requested. One hundred forty-two reports from eligible patients were returned. In the preoperative work-up, CT scans failed to show
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Table 3. Surgical Characteristics by Operative Outcome
Characteristic
%Curative Resection (n = 69)
% Noncurative Resection (n = 18)
% Total (n = 87)
33 10 38
17 11 33
30 10 37
3
6
3
7 1 7
6 0 28
7 1 11
Resection Right lobectomy Left lobectomy Wedge Lobectomy and opposite lobe wedge Extended right (trisegmentectomy) Extended left Other
any involvement in 7% (10 of 139) of patients. Five of these 10 were found to have disease in both lobes at laparotomy. Overall, CT scan results underestimated the number of lobes involved in 33% of patients (46 of 139) and overestimated involvement in 4% (five of 139). Extrahepatic disease was found in 12% (17 of 144) of patients with a negative preoperative CT scan. Arteriography was performed in 82% (115 of 141) of patients. This procedure was successful in identifying lesions not otherwise identified by CT or liver scan in 11% (13 of 115) of patients. Arteriography was not only used to identify occult disease, but also to delineate the anatomy of the hepatic vasculature. Use of intraoperative ultrasound, cryosurgery, cavitron (an ultrasonic liver dissection/suction device), as well as other operative details are summarized for each of the surgical outcomes in Table 4. Overall, 23% of the patients had an intraoperative ultrasound performed, and 8% had cryosurgery. Nine percent of patients in the curative resection group underwent surgery with use of the cavitron. Curatively resected patients required a few extra days of hospitalization, but this was not statistically significantly different from that of the overall group of patients. Operative results indicated a total of 61 of 129 (47%) patients had a solitary liver lesion. Solitary Table 4. Summary by Surgical Outcome Curative Noncurative No Resection Resection Resection 1 (n = 58) (n = 8) (n = 66)
Intraoperative ultrasound (%) Cryosurgery (%) Cavitron (%) Median units of blood Median days hospitalized
Total (n = 142)
18 11 9 3.0
26 22 0 4.0
28 0 0 0
23 8 4 1
17.0
14.0
13.5
15.5
lesions were significantly more common among curatively resected patients than among others (P < .01). Sixty-seven percent of patients resected for cure (43 of 65) had a solitary lesion compared with 35% (six of 17) of noncuratively resected and 26% (12 of 47) of unresected patients. Almost half of the unresected patients (45%, 21 of 47) were found to have more than three lesions, while only 6% (four of 65) and 17% (three of 17) of the curatively resected and noncuratively resected patients had more than three lesions. Within the curatively resected group, the median survival of patients who were found to have only one lesion at surgery is 3.3 years and is 2.8 years for patients with more than one lesion. Disease-free survival for patients with one lesion and more than one lesion is 2.7 years and 1 year, respectively. Although patients with only one lesion were observed to have improved survival and disease-free survival compared with those patients with more than one lesion, these differences were not statistically significant (P > .2). Surgical Complications Nineteen of the 142 patients (13%) had operative complications (Table 5). Four patients were reported to have had an abscess. Seven patients Table 5. Surgical Complications Patient No.
Surgical Outcome
60 85 88 94 105
Curative Curative Curative Curative Curative Curative Curative Curative
126 130 131
Curative Curative Curative
133 11 28
Curative Noncurative Noncurative
97
Noncurative
115 1 3
Noncurative No resection No resection
6
No resection
30 38 46
Description of Complication Hepatic vein tear during resection Abscess, rehospitalized day 28 Intraabdominal hemorrhage Intravascular coagulation Abscess Abdominal wound dehiscence Bacteremia, rehospitalized day 14 Adhesions, small bowel obstruction, rehospitalized day 26 Renal failure, hypotension Biloma Biliary-cutaneous fistula, rehospitalized day 10 Abscess, rehospitalized day 27 Hepatitis, esophagitis, pneumonia Pulmonary embolism, rehospitalized day 30 Respiratory arrest 10th day postoperative Abscess, biloma Pleural effusion Myocardial infarction 2 weeks postoperative Stricture of common hepatic duct, rehospitalized day 19
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HEPATIC RESECTION/COLORECTAL CARCINOMA
required rehospitalization 10 days, 14 days, 19 days, 26 days, 27 days, 28 days, and 30 days after discharge. Two bilomas were reported, one in a patient who also had an abscess. Eighteen percent of patients undergoing a curative resection (12 of 66) and 22% (four of 18) of patients with a noncurative resection were reported to have a surgical complication, whereas only 5% (three of 58) of the unresectable patients were reported to have had complications.
-J
Recurrences In all, 43 (49%) patients in the resected groups experienced disease recurrence (35 curative, eight noncurative). An additional five resected patients (two curative, three noncurative) were reported to have died of disease although supportive documentation has yet to be submitted. Of the 43 documented recurrences, 32 (74%) have involved the liver, with four of these involving both liver and lungs. Eleven patients (26%) have recurred at extrahepatic sites including lung (five), bone (one), colon/rectum (one), biliary bed (one), spleen (one), lymph nodes (one), and pelvis/uterus (one). The 1-year and 2-year probability of recurrence in the curative resection group is estimated to be 26% and 51%, respectively. Survival Follow-up is available on 150 patients. A total of 107 deaths has been reported including 38 of 69 (55%) of the curatively resected group, 14 of 18 (78%) of the noncuratively resected patients, and 55 of 63 (87%) of the unresectable group. Four of these deaths occurred within the 30-day postoperative period because of hemorrhage, intravascular coagulopathy, renal failure, and pulmonary thromboembolism, yielding a 30-day surgical mortality of 2.7%. Median survival of the entire cohort is estimated to be 26.1 months. Median survival times for patients receiving curative and noncurative resections, and those receiving no resection are estimated to be 37.1, 21.2, and 16.5 months, respectively. The median survival time of curatively resected patients is significantly different (P < .01) from that for the patients in the noncuratively resected and the unresected groups. Neither statistically nor clinically interesting differences in the survival distributions of the latter two groups are observed. Estimated survival distribution for the first 3 years poststudy entry are given in Fig 1. One-year
MONTHS Fig 1. Probability of survival by resection type. (-) tive, (....) noncurotive, (---) nonresected.
Cura-
probability of survival estimates are 91%, 67%, and 68% for the curative resection, noncurative resection, and no resection groups, respectively. The probability of survival and disease-free survival for these patients who were resected with curative intent is shown in Fig 2. CEA Assessment Reports of CEA values for patients both before and after hepatic resection were requested. Values reported were separated into three groups as follows: 30 days or less before surgery (preopera-
-5
4l
MONTHS Fig 2. Probability of (-) survival and (-...) disease-free survival of curatively resected patients.
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tive), 1 day to 60 days postsurgery, and 61 days to 180 days postsurgery. Values reported for some patients fell outside these ranges and are excluded from further analysis. Figure 3 and Table 6 summarize the information received by surgical outcome. The median preoperative (:< 30 days before surgery) CEA level for curatively resected patients was 36.2 ng/mL; for the noncuratively resected patients, 45.5 ng/mL; and for the unresected patients, 36.0 ng/mL. These values were not significantly different (P > .3). Median CEA values measured up to 60 days postsurgery were observed to be lower than presurgery medians in all three groups; however, serial titers began to increase in the unresected patients 61 to 180 days postoperatively. The median CEA value 61 to 180 days postsurgery for the unresected group was 42.7 ng/mL, significantly higher (P < .01) than the medians of 3.8 ng/mL and 5.0 ng/mL observed in the curatively and noncuratively resected groups, respectively. DISCUSSION
Liver resection for hepatic metastases from colorectal carcinoma is presently the standard treatment for potentially resectable disease. The efficacy of this treatment, however, has never been evaluated in a randomized prospective fashion, since surgeons who diagnose a resectable liver lesion understandably would not submit his or her patient to a "sham" laparotomy. In singleinstitution and multiinstitutional retrospective series,'"617 numerous authors have attempted to com-
Table 6. Summary of CEA Assessments by Surgical Outcome Surgical Outcome
Prehepatic resection (!30 days) Median CEA (ng/mL) Posthepatic resection (>1 day, 60 days,
