Ninety-Six Five-Year Survivors After Liver Resection for Metastatic Colorectal Cancer

Ninety-Six Five-Year Survivors After Liver Resection for Metastatic Colorectal Cancer Michael D’Angelica, MD, Murray F. Brennan, MD, FACS, Joseph G. Fortner, MD, FACS, Alfred M. Cohen, MD, FACS, Leslie H. Blumgart, MD, FRCS, FACS, and Yuman Fong, MD shown that the liver is involved in . 70% of cases (2). Of all patients with colorectal cancer, approximately 50% will experience tumor recurrence within 5 years and 60 –70% of these recurrences will involve the liver. Furthermore, the liver will be either the first or predominant site of failure in 20% of patients (3). Patients with untreated liver metastases have a very poor prognosis and rarely survive 5 years (4 – 6). Systemic chemotherapy is largely ineffective in improving survival for patients with metastatic colorectal cancer (7). Over the last 3 decades, liver resection has been proved to be a safe and potentially curative therapy for selected patients with isolated hepatic colorectal metastases. Five-year survival rates from 20% to 39% are reported, and operative mortality in modern series is consistently reported to be less than 5% (8 –12). Prognostic factors and the predicted 5-year survival of patients undergoing liver resection for colorectal metastases have been extensively studied. Few studies, however, have had long enough followup or sufficient 5-year survivors to allow study of the clinical course of patients more than 5 years after resection of hepatic metastases. The purpose of this study was to analyze prognostic factors and longterm outcomes of actual 5-year survivors after liver resection for colorectal metastases. The authors present the experience of a single institution over a recent period so as to better define the natural history of these patients and to determine factors that might preclude 5year survival or affect outcomes beyond 5 years.

Background: Studies have consistently confirmed the benefit of liver resection for metastatic colorectal cancer. Few reports, however, have a long enough followup or sufficient 5-year survivors to study the clinical course of patients beyond 5 years. Study Design: From July 1985 through December 1991, 456 patients underwent liver resection for colorectal metastases. Ninety-six actual 5-year survivors (21%) were identified and their clinical course retrospectively reviewed. Results: Five-year survivors (n 5 96) were more likely to have a Duke’s B primary colorectal carcinoma, fewer than four metastatic lesions, unilobar disease, and a negative histologic margin when compared with patients not surviving 5 years (n 5 298). Forty-four (46%) of the 96 five-year survivors had a recurrence after hepatectomy. Of these 44, 19 (43%) were rendered disease free after further treatment. Overall, 71 of the 96 five-year survivors were free of disease at last followup. The actuarial 10-year survival of this group was 78%. Conclusions: Patients that are disease free 5 years after liver resection are likely to have been cured by liver resection. Patients should be aggressively followed for recurrence because of the potential for further treatment and longterm survival. ( J Am Coll Surg 1997; 185:554 –559. © 1997 by the American College of Surgeons)

There are 138,000 new cases and 55,000 deaths annually from colorectal cancer in the United States (1). The liver is a common site of involvement in colorectal cancer (2). Autopsy series have

Methods

Received June 20, 1997; Revised August 7, 1997; Accepted August 11, 1997. From the Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York. Presented in part at the 50th Annual Meeting of the Society of Surgical Oncology, March 21–24, 1996, Atlanta, GA. Correspondence address: Yuman Fong, MD, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021.

All patients admitted to the Memorial SloanKettering Cancer Center (MSKCC) for liver surgery for the 6-year period from July 1985 to December 1991 were identified in the Department of Surgery Liver Resection database. Four hundred fifty-six patients were identified who underwent

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D’Angelica et al liver resection for metastatic colorectal cancer. Selection criteria for liver resection were as follows: (1) medical fitness for major laparotomy, (2) no signs on preoperative imaging of disseminated disease, and (3) tumors anatomically confined within the liver such that adequate liver parenchyma could be preserved for recovery. In addition to complete history and physical examination, the preoperative studies during this period consisted of abdominal and pelvic computed tomography, chest x-ray, and colonoscopy. Sixty-two patients were lost to followup, so death earlier than 5 years or survival beyond 5 years could not be documented. Of the remaining 394 patients, 96 patients survived at least 5 years from the time of liver resection and comprise the cohort of patients studied. Data for these patients were extracted from the database, hospital and office charts, and telephone interviews. Variables studied included age, gender, site and stage of primary tumor, disease-free interval, preoperative carcinoembryonic antigen (CEA), type of liver resection, presence or absence of extrahepatic disease, number of metastases, size of largest metastasis, margin status, and presence or absence of bilobar disease. Eleven patients did not have documentation of preoperative CEA, and in nine patients, we could not identify the stage of the primary colorectal lesion. Definitions. Nomenclature for the type of resection is as defined by Goldsmith and Woodburne (13). Extended hepatectomy refers to an extended right or left hepatectomy. Extended right hepatectomy refers to resection of Couinaud’s segments (14) 4, 5, 6, 7, and 8; extended left hepatectomy refers to resection of segments 2, 3, 4, 5, and 8. These types of liver resection are also known as right and left trisegmentectomies. Lobectomy refers to either a left or right hepatic lobectomy. Right lobectomy is resection of segments 5, 6, 7, and 8, whereas left lobectomy is resection of segments 2, 3, and 4. Disease-free interval is defined as the time from resection of the colorectal primary to the time of liver recurrence. Bilobar disease refers to the presence of tumor both to the right and left of the middle hepatic vein. Statistics. For comparison of characteristics between 5-year survivors and non–5-year survivors, chi-square analysis was used. Survival and diseasefree survival were calculated from the time of liver resection by the methods of Kaplan and Meier (15). Patients were censored at the time of loss to followup or at the time of death due to other causes. Univariate analysis for factors associated

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with disease-free survival and overall survival were analyzed by log-rank test (16). All factors with p values # 0.10 by log rank analysis were entered into the Cox proportional hazards model (17) for multivariate analysis. Statistical analysis was performed using the SPSS software package (Statistical Package for Social Science; SPSS, Inc.; version 7, Chicago, IL). Two-sided p values , 0.05 were considered statistically significant. Results

Demographics and followup. Four hundred fifty-six patients underwent liver resection during the 6year study period. Two hundred ninety-eight patients were documented to have died of disease earlier than 5 years after liver resection. Sixty-two patients (14%) were lost to followup, and death earlier than 5 years or survival past 5 years was unknown. Median followup for these 62 patients was 18 months (range, 1–54). A total of 58% (36 of 62) patients had NED (no evidence of disease) when lost to followup. Ninety-six patients were documented to be alive 5 years after liver resection and comprise the study population. Thus, the actual 5-year survival rate was 21%. Of the 96 five-year survivors, there were 52 males (54%) and 44 females (46%). The median age was 59 (range, 32–76). The median followup of the 96 five-year survivors was 75 months (range, 60 –136). Characteristics of primary colorectal tumor and liver metastases. Table 1 summarizes the characteristics of both the primary tumor and the liver metastases analyzed. Disease-free interval, from the time of colorectal resection to presentation with hepatic metastases, ranged from 0 to 138 months, with a median of 15 months. Preoperative CEA ranged from undetectable to 822 ng/mL (median of 11.4; mean of 65 ng/mL). Size of the largest liver metastasis ranged from 0.5 to 17.5 cm and averaged 4.5 cm. The number of metastatic lesions in the liver ranged from 1 to 10 (median of 1; mean of 1.77 lesions). Many recognized poor prognostic factors were present, and even common, in the group of 5-year survivors. Of specific interest is that there were four patients with extrahepatic disease who survived 5 years. The sites of extrahepatic disease were the diaphragm in two, soft tissue in one, and a celiac node in one. The two patients with extrahepatic disease in surrounding soft tissue and in the celiac node are disease free at 75 and 74 months followup, respectively. Four patients with positive margins survived 5 years, but all have ex-

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Table 1. Characteristics of Primary Colorectal Tumor and Liver Metastases Characteristic Primary site (n 5 96) Colon Rectum Stage of primary (n 5 87) Duke’s B Duke’s C Disease-free interval (n 5 96) , 12 mo $ 12 mo Type of resection (n 5 96) Wedge or less Lobectomy Extended Extrahepatic disease (n 5 96) Yes No Preoperative CEA (n 5 85) , 200 ng/mL $ 200 ng/mL Number of lesions (n 5 96) 1 2 3 $4 Bilobar (n 5 96) Yes No Lesion size (n 5 96) , 5 cm $ 5 cm Margin (n 5 96) Positive Negative

n

%

67 29

69.8 30.2

42 45

48.3 51.7

40 56

41.7 58.3

45 41 10

46.9 42.7 10.4

4 92

4.2 95.8

77 8

90.6 9.4

64 15 8 9

66.7 15.6 8.3 9.4

15 81

15.6 84.4

62 34

64.6 35.4

4 92

4.2 95.8

CEA, carcinoembryonic antigen.

perienced recurrence. Nine patients with four or more metastatic lesions survived 5 years, and four of them are disease free at 70, 73, 74, and 113 months’ followup. Comparison of 5-year survivors with non–5-year survivors. The characteristics of actual 5-year survivors (n 5 96) were compared with those of patients documented to have died of disease earlier than 5 years (n 5 298). Five-year survivors were more likely to have a node-negative primary, fewer than four metastatic lesions, unilobar disease, and a negative hepatic histologic margin. Disease-free survival. Figure 1 illustrates the KaplanMeier disease-free survival curve. Actuarial diseasefree survival for the group of actual 5-year survivors at 10 years was 55%. Overall, 44 (46%) patients had recurrence. The rate of tumor recurrence is relatively constant at nearly 10% per year until 5 years after liver resection, after which only two recurrences were documented. The two patients with recurrence after 5 years were both NED before this late recurrence. The sites of recurrence were liver in 16 patients (36%), lung in 15 (34%), colon or rectum in 4 (9%), bone in 4 (9%), and other sites in 4 (9%).

FIG 1. Kaplan-Meier plot of disease-free survival for the 96 five-year survivors. Time to first recurrence is recorded and begins at the time of liver resection. Actuarial 10-year diseasefree survival is 55%.

Of the 44 patients who had recurrence, 19 (43%) were disease free at last followup as a result of further treatment. Further surgical therapies for these 19 patients included 11 hepatic resections (3 wedge resections, 6 segmental resections, 2 lobectomies), 6 lung resections, 1 left hemicolectomy, and 1 pelvic local resection. The median followup from the time of first posthepatectomy recurrence in these 19 patients was 59.8 months (range, 24.8–112.5). The sites of recurrence in these 19 patients were liver in 11, lung in 6, pelvis in 1, and colon in 1. Overall, 71 of the 96 five-year survivors are free of disease at last followup. Table 2 demonstrates univariate and multivariate analysis of prognostic factors for disease-free survival. Female gender, presence of bilobar disease, and positive margins were predictors of recurrence by univariate analysis. By multivariate analysis, female gender was the only independent predictor of recurrence. Disease-specific overall survival. Figure 2 illustrates the Kaplan-Meier disease-specific survival curve. Overall, the actuarial 10-year survival was 78%. Table 3 demonstrates the univariate and multivariate analysis of prognostic factors for diseasespecific survival. Although on univariate analysis, more extensive resection and more than four metastases were negative prognostic factors, on multivariate analysis, no independent prognosticator of survival could be identified. Discussion

Two studies (8, 18) have sufficient followup to comment on the outcomes of patients beyond 5 years after liver resection for colorectal metastases.

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Table 2. Univariate and Multivariate Analysis of Prognostic Factors for Disease-Free Survival n

No. recur

Log rank (p)

Cox (p)

Male Female $ 70 , 70

52 44 15 81

17 27 4 40

0.004* — 0.1 —

0.03† — — —

Colon Rectum B C

67 29 42 45

32 12 21 20

0.4 — 0.6 —

— — — —

, 12 mo $ 12 mo Wedge or less Lobectomy Extended Yes No , 200 $ 200 1–3 $4 Yes No , 5 cm $ 5 cm Positive Negative

40 56 45 41 10 4 92 77 8 87 9 15 81 62 34 4 92

22 22 20 16 8 2 42 35 4 39 5 11 33 28 16 4 40

0.06* — 0.1 — — 0.6 — 0.7 — 0.8 — 0.03* — 1.0 — 0.04* —

0.1 — — — — — — — — — — 0.2 — — — 0.2 —

Factor Patient (n 5 96) Gender Age (y) Primary tumor Primary site (n 5 96) Stage of primary (n 5 87) Liver metastases Disease-free interval (n 5 96) Type of resection (n 5 96) Extrahepatic disease (n 5 96) Preoperative CEA (n 5 85) No. of lesions (n 5 96) Bilobar (n 5 96) Lesion size (n 5 96) Margin (n 5 96)

*Factor entered into Cox proportional hazards model. † p , 0.05. CEA, carcinoembryonic antigen; No. recur, number of patients experiencing recurrence.

Scheele and colleagues (8), in a very large study from Germany, were able to document 5-, 10-, and 20-year survival rates of 33%, 20% and 15%, respectively. Hughes and colleagues (18), in a multiinstitutional study of 100 actual 5-year survivors from 24 institutions, found that many negative prognostic factors were present in these longterm survivors and concluded that the decision to resect hepatic metastases must be individualized. Their study compared the characteristics of 5-year survivors with those of nonsurvivors but did not address the natural longterm history of this patient population. A multiinstitutional study such as this can reflect varying clinical approaches and is subject to bias in reporting of patients. The purpose of our study was to review the characteristics, role of prognostic factors, and natural history of actual 5-year survivors of liver resection for metastatic colorectal cancer. The patients are from a recent and short time interval and from one institution. This uniform population of patients limits the effects of differing treatments, indications, and operative techniques seen in multiinstitutional studies and in series involving broad spans of time. We show that 5-year survival after liver resection for colorectal metastases is possible

despite the presence of poor prognostic factors, and we confirm the potential curative nature of this treatment. A 5-year actuarial survival rate of 20 –39% for patients undergoing liver resection for metastatic

FIG 2. Kaplan-Meier plot of overall disease-specific survival for the 96 five-year survivors. Time begins at the time of liver resection. Actuarial 10-year overall disease-specific survival is 78%.

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Table 3. Univariate and Multivariate Analysis of Prognostic Factors for Disease-specific Overall Survival n

No. DOD

Male Female $ 70 , 70

52 44 15 81

5 7 3 9

0.2 — 0.3 —

— — — —

Colon Rectum B C

67 29 42 45

10 2 8 3

0.3 — 0.06* —

— — 0.1 —

, 12 mo $ 12 mo Wedge or less Lobectomy Extended Yes No , 200 $ 200 1–3 $4 Yes No , 5 cm $ 5 cm Positive Negative

40 56 45 41 10 4 92 77 8 87 9 15 81 62 34 4 92

2 10 1 8 3 1 11 9 0 9 3 2 10 7 5 1 11

0.1* — 0.003* — — 0.2 — 0.3 — 0.02* — 0.9 — 0.5 — 0.8 —

0.8 — 0.08 — — — — — — 0.2 — — — — — — —

Factor Patient (n 5 96) Gender Age (y) Primary tumor Primary site (n 5 96) Stage of primary (n 5 87) Liver metastases Disease-free interval (n 5 96) Type of resection (n 5 96) Extrahepatic disease (n 5 96) Preoperative CEA (n 5 85) No. of lesions (n 5 96) Bilobar (n 5 96) Lesion size (n 5 96) Margin (n 5 96)

Log rank (p)

Cox (p)

*Factor entered into Cox proportional hazards model. CEA, carcinoembryonic antigen; No. DOD, number of patients dying of disease.

colorectal cancer is well documented (8 –12). Liver resection has become the standard of care for anatomically resectable disease. Studies of outcomes in patients undergoing liver resection for colorectal metastases have shown age (10), stage of primary (8, 10, 19, 20), disease-free interval (10, 20), extrahepatic disease (8, 10, 11, 19), preoperative CEA (8, 20), number of metastatic lesions (10, 20), bilobar disease (10), metastatic lesion size (8, 20), and microscopic margin (8, 10, 20) to be predictive of outcomes. Excluding extrahepatic disease, these findings are not consistently confirmed in the literature. The only universally accepted relative contraindication to liver resection in these patients is the identification of extrahepatic disease. A very important observation in this study is that some patients with poor prognostic features do survive 5 years. We have shown that 5-year survival is possible even with positive margins and extrahepatic disease. Such poor prognostic factors as age, node-positive primary, diseasefree interval , 12 months, high CEA, . four lesions, large lesions, and bilobar disease were present and prevalent in this group of longterm survivors. None of the factors studied in this report precluded 5-year survival. This observation is in agreement with the study by Hughes and col-

leagues (18), and we agree that the decision to resect hepatic metastases must be individualized. Although there are clearly poor prognostic factors that decrease the likelihood of longterm survival, 5-year survival is possible in all patients with resectable disease. Of all patients who undergo liver resection for metastatic colorectal cancer, approximately 75% will experience recurrence (21). Many studies have addressed management of patients with recurrent disease and demonstrate safety and longterm survival after resecting isolated recurrent disease (22–24). We found that despite a steady interval rate of recurrence in these patients until 5 years after resection, recurrence after 5 years was rare. Only two patients were documented to recur after 5 years. Nineteen of the 44 patients who experienced recurrence were rendered disease free by further treatment, with a median followup of 60 months from the time of recurrence. These findings demonstrate that disease-free survival 5 years after liver resection most likely implies cure. In addition, this study clearly shows that recurrence of disease does not preclude 5-year survival and in many cases is treatable, allowing for further longterm survival. The most common sites of recurrence such as liver, lung, and colon can be

D’Angelica et al amenable to a further surgical approach. This forms the basis for close followup of patients after liver resection for metastatic colorectal cancer. To analyze the role of prognostic factors in actual 5-year survivors, an extensive univariate and multivariate analysis was carried out for diseasefree survival and overall disease-specific survival. This type of analysis must be interpreted with caution because of the highly selected nature of these patients and the limited number of recurrences or deaths occurring. Specifically, the small number of deaths makes analysis of survival difficult even in a large series such as this. Despite these shortcomings, female gender was demonstrated to be an independent predictor of recurrence, but not survival. No independent predictor of survival could be identified. In summary, 5-year survivors of liver resection for colorectal metastases are composed of two distinct groups of patients. The first group is those that are recurrence free at 5 years and are very unlikely to experience further recurrence of disease. These patients can be considered cured by hepatic resection. The second group is those that have experienced recurrences of disease and survive 5 years. These patients showed a potential for further longterm survival, almost half being rendered disease free by further treatment. Patients undergoing liver resection for metastatic colorectal cancer should be aggressively followed for recurrence for up to 5 years because of the potential for longterm survival. References 1. Fong Y, Blumgart LH, Cohen AM. Surgical treatment of colorectal metastases to the liver. CA Cancer J Clin 1995;45: 50 – 62. 2. Pestana C, Retemeier RJ, Moertel CG, et al. The natural history of carcinoma of the colon and rectum. Am J Surg 1964;108:826 – 829. 3. Steele GD, Jr, Ravikumar TS. Resection of hepatic metastases from colorectal cancer. Ann Surg 1989;210:127–138. 4. Cady B, Monson DO, Swinton NW. Survival of patients after colonic resection for carcinoma with simultaneous liver metastases. Surg Gynecol Obstet 1970;131:697–700. 5. Wagner JS, Adson MA, van Heerden JA, et al. The natural history of hepatic metastases from colorectal cancer. Ann Surg 1984;199:502–508.

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