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Originally published as Ann Surg Oncol Early Release 10.1245/ASO.2004.03.085 on February 9, 2004

Annals of Surgical Oncology 11:274-280 (2004)
© 2004 Society of Surgical Oncology
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ORIGINAL ARTICLES

Results of R0 Resection for Colorectal Liver Metastases Associated With Extrahepatic Disease

Dominique Elias, MD, PhD, Lucas Sideris, MD, FRCSC, Marc Pocard, MD, PhD, Jean-Francois Ouellet, MD, FRCSC, Valérie Boige, MD, Philippe Lasser, MD, Jean-Pierre Pignon, MD, PhD and Michel Ducreux, MD

From the Departments of Surgical Oncology (DE, LS, MP, J-FO, PL), Medical Oncology (VB, MD), and Biostatistics and Epidemiology (J-PP), Gustave Roussy Institute, Villejuif, France.

Correspondence: Address correspondence and reprint requests to: Dominique Elias, MD, PhD, Department of Surgery, Division of Surgical Oncology, Gustave Roussy Institute, Rue Camille Desmoulins, 94805, Villejuif CEDEX, France; Fax: 33-1-42-11-52-56; E-mail: elias{at}igr.fr


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Background: Extrahepatic malignant disease has always been considered an absolute contraindication to hepatectomy for colorectal liver metastases. This study reports the long-term outcome and prognostic factors of patients undergoing extrahepatic disease resection simultaneously with hepatectomy for liver metastases.

Methods: From January 1987 to January 2001, 75 patients underwent a complete R0 resection of extrahepatic disease simultaneously with hepatectomy for colorectal liver metastases. They were inscribed in a registry and then prospectively followed up. They represented 25% of the 294 patients who underwent an R0 hepatectomy for colorectal liver metastases during the same period.

Results: The mortality rate was 2.7%, and morbidity was 25%. After a median follow-up of 4.9 years (range, 1.7–13.4 years), the overall 3- and 5-year survival rates were 45% and 28%, respectively. By using a Cox model, there was a significant difference in survival between patients with single versus multiple sites of extrahepatic disease. Also, the presence of more than five liver metastases was a significant parameter.

Conclusions: Extrahepatic disease in colorectal cancer patients with liver metastases should no longer be considered as a contraindication to hepatectomy. However, this intended R0 resection cannot be performed in 50% of laparotomized patients, and negative prognostic factors for surgery include the presence of multiple extrahepatic disease sites or more than five liver metastases.

Key Words: Liver metastases • Colorectal • Extrahepatic disease • Surgery


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Since surgery was first used to treat liver metastases (LM) of colorectal cancer, the presence of extrahepatic disease (metastases) has always been considered a classic contraindication to hepatectomy. This rule was derived from large series published between 1970 and 1990. In these studies, the analysis of subgroups of patients undergoing simultaneous hepatectomy along with extrahepatic disease revealed a very unfavorable prognosis.1–6 However, these subgroups were formed by a very limited number of patients. For instance, there were 37 patients in the multi-institutional registry of Hughes et al.1 In more recent series, this contraindication has usually been respected, and very few patients undergoing LM resection along with extrahepatic disease have been reported. For example, Fong et al.7 reported their results in 43 cases, and their population sometimes included patients with a local involvement of adjacent organs by the LM. Therefore, these studies were not very informative.7–12

This contraindication was also based on the concept that LM represents a regional disease with a better prognosis than that associated with other distal metastases, which are considered disseminated disease. Nevertheless, this concept is inconsistent with recent studies on the pathophysiology of metastases.13

This study reports the long-term outcome of R0 resection of extrahepatic disease simultaneously with hepatectomy. It also identifies the prognostic factors determining which patients will most benefit from this approach.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Patients
This study reports a group of 75 patients who simultaneously underwent the complete (R0) resection of LM along with extrahepatic disease between January 1987 and January 2001. All the data were entered into a registry, and the patients were then prospectively followed up. They represented 25% of the 294 patients who underwent an R0 hepatectomy and 20% of the 376 patients who underwent an R0 to R2 hepatectomy for colorectal LM in our institution during the same period. Meanwhile, 75 other patients with colorectal LM associated with extrahepatic disease had undergone an exploratory laparotomy. Thirty-six (24%) of 150 underwent a hepatectomy associated with resection of the extrahepatic disease, initially with curative intent but resulting in only an R1 to R2 resection. The other 39 (26%) of 150 patients underwent only an exploratory laparotomy or a palliative operation, because of nonresectable disease.

The definition of extrahepatic disease used here excluded patients with primary tumors in situ or with contiguous involvement of adjacent structures by LM. The appellation extrahepatic disease was preferred to extrahepatic metastasis because this series included locoregional recurrences of the primary tumor, which are not true metastases but which are also considered as a contraindication to liver resection.1 The median age was 51.6 years (range, 25–69 years). There were 48 women and 27 men.

Inclusion Criteria
All eligible patients had previously undergone curative surgery for colorectal cancer (colon, 79%; rectum, 21%). They all presented with at least one LM and one site of extrahepatic disease. All patients were considered by a multidisciplinary committee to have resectable disease and were free of surgical contraindications. The last criterion for definitive inclusion was the ability to completely resect all macroscopic tumoral disease at laparotomy.

Preoperative Evaluation
All patients underwent a physical examination; colonoscopy; abdominal ultrasonography; and thoracic, abdominal, and pelvic computed tomography (CT). Other tests were performed if necessary (head CT, bone scintigraphy, and so on). Positron emission tomography and magnetic resonance imaging were not used.

Time of Extrahepatic Disease Diagnosis
In 37 patients, the extrahepatic disease was known before surgery (in 20 of these, additional sites were also discovered at laparotomy). In the remaining 38 patients, the extrahepatic disease was an incidental intraoperative discovery.

Extrahepatic Disease Localization
The distribution of extrahepatic disease is shown in Table 1. This distribution included lung metastases and miscellaneous intra-abdominal localizations, including hepatic hilar lymph nodes and peritoneal carcinomatosis. Peritoneal carcinomatosis was minimal or moderate and always included at least 20 macroscopic tumor nodules. Sugarbaker’s14 mean peritoneal index for carcinomatosis was of 12.4 (the maximum possible index is 39) and involved a mean of 4.6 areas (among a maximum of 13). Local recurrences were abdominal or pelvic sidewall recurrences (not mucosal ones), without any detectable macroscopic or microscopic peritoneal carcinomatosis. To allow statistical comparison of survival curves, all patients were also separated into 2 groups: those with multiple extrahepatic disease sites (including peritoneal carcinomatosis; n = 22; 29.3%) and those with a single site of extrahepatic disease (n = 53; 70.7%; Table 1).


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  		TABLE 1. Extrahepatic disease localization and subgroups used for statistical analysis
 
Surgery
A complete abdominal exploration was performed in every case. After extrahepatic disease identification, the diagnosis was confirmed by frozen-section biopsy. If a safe and complete (R0) resection of all sites of extrahepatic disease was deemed possible, an intraoperative liver ultrasonographic examination was undertaken. When both the extrahepatic disease and LM were considered resectable without risking severe postoperative complications, the extrahepatic disease was resected first, followed by the hepatectomy, according to the technique used in our institution.15–17 No modality of local physical destruction (such as radiofrequency) was used in this series. If suspect lymph nodes were found in the hepatic pedicle during the hepatectomy, a biopsy and frozen-section examination were undertaken. If the results were positive, an en-bloc lymphadenectomy was performed.

In patients with resectable lung metastases, the hepatectomy was performed first. The lung metastases were subsequently resected within 2 months provided that no disease progression had occurred and that the lung metastases were still resectable at that time.

Surgery was considered complete (R0) if the microscopic examination of the tumor margins was negative. In patients with peritoneal carcinomatosis, resection was considered as R0 when the complete removal of peritoneal implants was followed by immediate intraperitoneal chemotherapy, according to protocols that have been described elsewhere.18,19

Chemotherapy
Aside from the standard adjuvant systemic chemotherapy given after resection of stage III colon cancers, 43 patients (57.3%) had also received systemic chemotherapy before hepatectomy. The treatments consisted of 5-fluorouracil and folinic acid, sometimes combined with oxaliplatin or irinotecan. This neoadjuvant chemotherapy was administered when the disease was initially unresectable. Unresectability criteria were based on the number (>6) of lesions when lesions were located in both sides of the liver, a bilateral location of LM when at least one sector of the liver was not respected, and tumor proximity to an inferior or superior central major vascular structure precluding a margin-negative resection. All 43 patients included in this series had presented an objective response, allowing planning of an R0 resection. The median number of LMs was 3 (range, 1–10) for the chemotherapy group and 2 (range, 1–7) for the group without chemotherapy (P = .86). After surgery, systemic chemotherapy was given to all patients who had shown an objective response to preoperative chemotherapy with the same regimen. Systemic chemotherapy was also administered to most patients who did not receive preoperative chemotherapy; only 6 of the 32 remaining patients did not receive any chemotherapy. For 11 patients (14.7%), the surgical procedure consisted of a repeat hepatectomy associated with the resection of extrahepatic disease.

Follow-Up
A physical examination, a CT of the abdomen and pelvis, hepatic ultrasonography, and a seric carcinoembryonic antigen measurement were performed every 3 months for 5 years. A chest x-ray was also performed every 6 months. No patient was lost during follow-up.

Statistics
Data were prospectively recorded in a specific LM database. Survival curves were plotted with the Kaplan-Meier method and were compared by using the log-rank test. The {chi}2 test or Fisher’s exact test, as appropriate, was used for univariate statistical analyses. Multivariate analyses were performed with the Cox regression model. All tests were two sided; any difference was considered significant at P = .05. All deaths within 30 days of surgery or during the postoperative hospital stay were considered postoperative mortality. They were all included in the survival analyses. The median follow-up was calculated according to Schemper and Smith’s method.20 We performed the statistical calculations with SAS 8.01 (SAS Institute Inc., Cary, NC).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
Surgery
The postoperative mortality rate was 2.7% (two patients). Nineteen patients (25%) developed complications, including hemorrhage, biloma, pulmonary effusion that necessitated drainage, transient clinical hepatic insufficiency, and pancreatic or enteric leak. Two patients with complications required surgical treatment.

The mean number of LMs was 3.1 ± 2.1 (mean ± SD) (median, 2; range, 1–11). Twenty-two patients (29.3%) had more than three LMs. These were located in the right liver in 31 (41.3%) patients, in the left liver in 10 (13.3%) patients, and bilaterally in 34 (45.3%) patients. A major hepatectomy (resection of at least 3 Couinaud’s liver segments) was performed in 43 (57.3%) patients. The mean surgical free margin was 7.4 ± 10.6 mm (median, 4 mm; range, 1–90 mm).

Completeness of Surgery
Seventy-five patients underwent an R0 resection and are the subject of this article; 36 underwent only an R1 to R2 resection. The reasons for the 36 R1 and R2 resections were as follows: (1) in 13 patients, the complete removal of the macroscopically detectable peritoneal carcinomatosis was not followed with immediate intraperitoneal chemotherapy (this is necessary to cure the residual microscopic peritoneal disease)14,18,19; (2) 11 patients among the 22 with synchronous resectable lung metastases did not undergo lung resection after hepatectomy, as initially planned, because of disease progression; and (3) the last 12 patients had an R1 resection because of the hepatectomy or extrahepatic disease resection margins.

Survival and Univariate Analysis of Prognostic Factors
After a median follow-up of 4.9 years (range, 1.7–13.4 years), the 3- and 5-year overall survival rates were 45% and 28%, respectively (Fig. 1; Table 2). The 3- and 5-year disease-free survival rates were both 19%. When considering the 111 patients who underwent an R0, R1, or R2 hepatectomy with an extrahepatic disease resection, their 3- and 5-year survival rates were 38% and 20%, respectively. These rates were only 24% and 7% for the 36 patients who had an R1 or R2 resection. The site of extrahepatic disease had no significant effect on survival (P = .17). In the same way, the following parameters were not statistically significant: sex (P = .49), age younger than 55 years (P = .64), colonic or rectal primary tumor (P = .43), preoperative or intraoperative discovery of the extrahepatic disease (P = .09), and repeat hepatectomy (P = .08). Conversely, the parameters that had a significant effect were as follows (Table 2): more than five LMs (with 0% vs. 48% 3-year overall survival; P = .005), preoperative chemotherapy (26% vs. 63% 3-year survival; P = .004), and the presence of multiple extrahepatic metastatic sites (25% vs. 53% 3-year survival rates; P = .02; Fig. 2).



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  		FIG. 1. Survival of patients with liver metastases and extrahepatic disease who received R0 resection.

 

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  		TABLE 2. Overall survival of 75 patients after simultaneous hepatectomy and extrahepatic disease resection (median follow-up, 4.9 years)
 


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  		FIG. 2. Survival rates for single or multiple sites of extrahepatic disease.

 
Multivariate Analysis of Prognostic Factors
Only two variables proved to be statistically significant negative factors in the Cox model (Table 3): the presence of multiple sites of extrahepatic disease (including peritoneal carcinomatosis; P = .04) and more than five LMs (P = .02).


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  		TABLE 3. Cox model results after inclusion of all significant univariate analysis variables
 
Survival Among Patients Without Extrahepatic Disease
To place these data in context, survival rates were reviewed of the entire population of patients without extrahepatic disease (n = 219) who underwent an R0 hepatectomy for colorectal LM in the same institution during the same time period. The 3- and 5-year survival rates were 56% and 33%, respectively, compared with 45% and 28% among the 75 patients with extrahepatic disease (P = .15; Fig. 3).



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  		FIG. 3. Survival of patients with liver metastases with or without extrahepatic disease who received R0 resection. LM, liver metastases; EHD, extrahepatic disease.

 
Disease Recurrence
After a median follow-up of 4.9 years, 22 (29.3%) of the 75 R0 patients were still free of disease. Fifty-three patients (70.7%) had recurrences at one site (n = 46; 61.3%) or at multiple sites (n = 7; 9.3%). The most common sites of recurrence were the liver (n = 23) and lungs (n = 15). Peritoneal carcinomatosis reappeared in only 6 of the 22 patients treated by resection and intraperitoneal chemotherapy.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
To our knowledge, this is the first study reporting an overall 5-year survival rate of 28% after R0 resection of colorectal LM along with extrahepatic disease. Until now, the presence of extrahepatic disease has been an absolute contraindication to hepatectomy for colorectal LM because the few patients who survived a resection of both diseases in the past presented a 5-year survival rate near 0%. For example, in their multi-institutional series of 859 patients, Hughes et al.1 reported 37 patients who underwent a combined treatment. Their 5-year overall survival was 0%. This dogma was also based on the principle stipulating that LMs are "regional" and carry a better prognosis than extrahepatic disease, which is the reflection of a systemic involvement. Several concepts that invalidate this belief have now evolved. First, it is now known that micrometastases and circulating cancer cells in blood, bone marrow, and lymph nodes are almost always present in advanced-stage cancers.21 Moreover, Sadahiro et al.22 have shown that most cells derived from the primary tumor are not stopped by the liver and enter the systemic circulation. Finally, it is well known that cancer cells are always found in the blood spilled in the surgical field.23,24 Thus, a radical operation is, in some respects, only a cytoreductive operation (a treatment that does not completely eradicate all tumor cells, even if it entirely resects all visible and detectable disease). However, cure can be achieved with the assistance of the patients’ natural immunological defenses, chemotherapy, or both. Surgical tumor burden reduction may provide an immunological benefit, because tumor cells produce immunosuppressive cytokines, precipitate immune complexes, and produce peptidoglycans that interfere with normal defenses.25,26 Furthermore, according to the log-kill hypothesis, each dose of a chemotherapeutic agent kills a constant fraction of cells, rather than a specific number of them.27 Therefore, by reducing the initial tumor volume, one increases the likelihood of chemotherapy to reduce the number of viable tumor cells toward the desired end point of 0.

According to these principles, selected patients presenting LM simultaneously with extrahepatic disease have been treated and studied prospectively. This attitude was possible mostly because the morbidity and mortality after hepatectomies decreased sharply from 10% to 2% during the last decade and because of the progress made in colorectal chemotherapy.28–30 Finally, we now know that major hepatectomies can safely be combined with intestinal resections and anastomoses.15

The first objective of this prospective study was to discern the survival benefit. For these 75 patients, a 5-year survival rate of 28% was reached. It must be underlined that the classic attitude of systemic chemotherapy alone (without surgery) would result in a 0% survival rate.31 Our results showed that resection of extrahepatic disease, including peritoneal carcinomatosis and hepatic hilar lymph nodes, can result in a cure for at least some patients. Therefore, from now on, the presence of extrahepatic disease simultaneously with LM should not be considered an absolute contraindication to surgical resection. We previously reported a series of 111 patients who underwent a simultaneous LM and extrahepatic disease extirpation, but 36 among them finally had only an R1 or R2 resection.32 This article showed that palliative procedures are at least two times more frequent when one operates (with a curative intent) on patients who present with LM plus extrahepatic disease than on patients who present with only isolated LM. The 5-year survival rate of these 111 resected patients was 20%, and completeness of resection was the most potent prognostic factor in the Cox model (P = .007). This potent factor did not allow studying the other prognostic factors clearly. When only R0 resections are considered (as in this study), the negative effect of multiple (vs. single) sites of extrahepatic disease becomes significant (P = .04) in the Cox model.

The second objective of this study was to find reliable preoperative prognostic factors that would help to determine in which subgroups an extrahepatic disease resection could be most beneficial. No difference in outcome was found according to the site of extrahepatic disease, either because of insufficient statistical power (75 patients and 9 sites) or because this variable was not a true prognostic factor. When survival was analyzed according to the number of sites of extrahepatic disease (Table 2), multiple sites (including peritoneal carcinomatosis) were associated with a worse survival than single ones (3-year survival rates of 25% and 53%, respectively; P = .02). Invaded hepatic hilar lymph nodes were not synonymous with rapid death. Indeed, 3 of the 10 such patients in this series were disease free after 5 years, and the 3-year survival rate among these 10 patients was 33% (95% confidence interval, 12%–65%). This has been confirmed in a multicenter retrospective study.33

Preoperative chemotherapy seemed to have a negative effect in our study because it was given only to patients in whom primary resection was not possible (for technical or oncological reasons). These patients were most likely bearing a more extensive cancerous disease. Thus, the decreased survival shown in patients who received preoperative chemotherapy is probably the consequence of an unfavorable selection bias (more advanced initial disease). This bias has also been found by other authors34 and prevents drawing any firm conclusions on the utility of adjuvant or neoadjuvant chemotherapy. Only a prospective randomized trial could answer this question. Nevertheless, these patients’ chemosensitivity allowed us to perform an R0 resection, thus probably improving their prognosis. Despite this, in our study, chemosensitivity could not compensate for the fact that these patients initially sustained a more advanced disease, thereby carrying a more dismal prognosis. Unsurprisingly, the Cox model underlined a high number (>5) of LMs and multiples sites of extrahepatic disease as significant negative prognostic variables, illustrating a simple fact: the fewer tumors one has, the better the prognosis.

Surprisingly, after an R0 resection, there was no significant difference in the 5-year survival rate between the 75 patients with and 219 patients without extrahepatic disease (28% and 33%, respectively). Perhaps a larger cohort would allow demonstration of a significant prognostic effect, but in every case, the presence of extrahepatic disease would be only a secondary prognostic factor and not a primary one, again illustrating that it is better to have fewer tumors than more.

Finally, these results modify the old standards for hepatectomy in colorectal patients. They prove that the concept of treating all macroscopic cancerous disease with surgery and treating the remaining microscopic disease with chemotherapy is a reality. This concept has already been used successfully to cure ovarian cancer,35 advanced breast cancer,36 and peritoneal carcinomatosis.19,37 We thus resume the universal logic of treatment for advanced solid cancers.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
Extrahepatic involvement by colorectal cancer in patients who also have LM should no longer be considered an absolute contraindication to hepatectomy. In this study, it has been demonstrated that simultaneous R0 resection of LM and extrahepatic disease leads to a 5-year survival rate of 28%. However, in 50% of cases, the intended R0 resection cannot be performed, and the presence of more than five LMs simultaneously with extrahepatic disease or the presence of multiple extrahepatic sites should stop the surgeon from proceeding with resection, because it leads to very low cure rates.


   FOOTNOTES
 
R0 resection of colorectal liver metastases, along with extrahepatic disease, permitted obtaining a 3- and 5-year overall survival of 45% and 28%, respectively, after a median follow-up of 4.9 years. Extrahepatic disease in colorectal cancer patients with liver metastases should no longer be considered an absolute contraindication to hepatectomy.

Received for publication March 31, 2003. Accepted for publication November 4, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

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