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Hepatic and Extrahepatic Colorectal Metastases: When Resectable, Their Localization Does Not Matter, But Their Total Number Has a Prognostic Effect

¹ Department of Surgical Oncology, Institut Gustave Roussy, Comprehensive Cancer Center, 39 Rue Camille Desmoulins, 94805 Villejuif Cédex, France
² Department of Medical Statistics, Institut Gustave Roussy, Comprehensive Cancer Center, 39 Rue Camille Desmoulins, 94805 Villejuif Cédex, France
³ Department of Medical Oncology, Institut Gustave Roussy, Comprehensive Cancer Center, 39 Rue Camille Desmoulins, 94805 Villejuif Cédex, France

Correspondence: Address correspondence and reprint requests to: Dominique Elias, MD, PhD; E-mail: elias{at}igr.fr

	ABSTRACT

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Background: The presence of extrahepatic disease (EHD) is considered a contraindication to hepatectomy in patients with colorectal liver metastases. After resection, the prognosis is based more on the total number of resected metastases (located inside and outside the liver) than on the site of these metastases (only inside the liver or not).

Methods: A total of 308 patients with colorectal cancer underwent hepatectomy, and 84 (27%) also underwent resection of miscellaneous EHD. The study was a prospective data registration and retrospective analysis. When considering the total number of resected metastases, each liver metastasis and each EHD location was counted as one lesion. Univariate and multivariate analyses were performed.

Results: The median follow-up was 99 months. The overall 5-year survival rate was 32%. In the multivariate analysis, the total number of metastases (inside or outside the liver) had a greater prognostic value than the criterion "presence or absence of EHD." Considering the total number of resected metastases (whatever their site), 5-year survival rates were 38% (SD: 4%) in the group with one to three metastases, 29% (SD: 5%) in patients with four to six metastases, and 18% (SD: 5%) in patients with more than six metastases (P = .002). A very simple prognostic score based on sex and the total number of metastases is proposed.

Conclusions: EHD, when resectable, is no longer a contraindication to hepatectomy. More importantly, the total number of the metastases, whatever their location, has a stronger prognostic effect than the site of these metastases.

Key Words: Colorectal cancer • Liver metastases • Extrahepatic disease

	INTRODUCTION

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Hepatic resection is traditionally the sole treatment that produces long-term survival in patients with colorectal liver metastases (LM), with a 25% to 40% 5-year survival rate.^1–10 Extrahepatic disease (EHD) has been considered a contraindication to hepatectomy because subgroup analyses of large series published before 1990 showed a very unfavorable prognosis.^1–6 Similarly, lung metastases were rarely resected even when they were technically resectable, and peritoneal carcinomatosis was never considered as potentially curable.^11,12 However, over the last few years, some series reported interesting 5-year survival rates after resection of a high number of LMs,^7,13,14 of multiple lung metastases,^15,16 of EHD synchronous to LM,^13,17–19 and of peritoneal carcinomatosis.^20–23 During the same time, the concept that the prognosis of metastasis is better when it is limited to only one organ is inconsistent with recent studies on circulating tumor cells and the pathophysiology of metastases.²⁴ In contradiction to this concept, we recently reported that the crude overall 5-year survival rate of 75 patients who underwent hepatectomy with resection of EHD was 29%¹⁹; these results imply that EHD does not absolutely contraindicate hepatectomy for colorectal LM. This article deals with the same topic but with a new concept: to base the interpretation of the results of metastasis resection not on the sites, as is the case traditionally, but on the total number—regardless of the number of invaded sites.

	PATIENTS AND METHODS

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Patients
All patients with colorectal LM who underwent hepatectomy, possibly associated with EHD resection, and who had at least 4.5 years of follow-up (except for three foreign patients who were lost to follow-up) were retrospectively selected from a prospective database. The following patient-selection criteria were used: the discovery of EHD on preoperative imaging or at laparotomy was not a contra-indication to hepatectomy if the lesions seemed completely resectable, whatever their site. The resection of EHD was performed during the same session as hepatectomy, with intestinal anastomosis (if necessary) and with immediate intraperitoneal chemotherapy (with or without hyperthermia) in case of peritoneal seeding. The only exceptions were lung metastases, which, if present, were resected 2 months later.

Hepatic resection was attempted irrespective of the number of metastases provided that all detected tumors could be removed completely, with potentially negative surgical margins, and that an acceptable amount of liver parenchyma (more than 33% of the total liver volume) could be preserved. In this study, a negative surgical margin was thought to have been secured when the tumor was not exposed at the cut surface of the liver either macroscopically or microscopically, irrespective of the extent of the margin. If the remaining liver was <33% of the total volume as a result of extensive resection, then preoperative portal vein embolization was conducted to induce compensatory hypertrophy of the remaining liver volume and thereby reduce the risk of postoperative hepatic insufficiency.^25,26

Resection of all detectable intrahepatic and extra-hepatic disease was considered complete according to the surgeon’s judgment, even if the final postoperative pathologic or imaging results indicated an incomplete resection (R1 or R2). This definition of the completeness (radicality) of the resection by the surgeon has the merit of being very close to clinical practice and being easily reproducible. In other words, the surgeon always considered a complete (curative) resection to have been performed, even if in a few cases it was finally incomplete (palliative) after pathologic examination.

Methods
Positron emission tomographic imaging was not used in this study. Intraoperative ultrasonography with a high-resolution probe was used systematically to detect possible occult tumors that were not found on preoperative imaging or by inspection and palpation. Hepatectomy was performed anatomically or nonanatomically under intermittent clamping of the pedicle²⁷ and, during the last years, under intermittent exclusion of the liver without interruption of the vena caval flow.²⁸ EHD was resected with a similar curative intent. These procedures included lymphadenectomies (hepatic or lateroaortic), resection of local recurrences of the primary tumor, and resection of organs (such as the ovary, adrenal glands, or spleen) or parts of organs (e.g., lungs) with metastatic disease. For peritoneal carcinomatosis, a complete cytoreductive operation was performed before the hepatectomy began.^22,23,29,30 It was followed with immediate intraperitoneal chemotherapy with the aim of curing the remaining microscopic peritoneal disease.²³ We used different and successive types of intraperitoneal chemotherapies, always in the setting of prospective trials with signed consent from the patients, with a constant improvement of the technique.^31–33

Systemic chemotherapy was given in all patients either before or after hepatectomy. All patients with EHD detected before surgery received preoperative chemotherapy and, in case of objective response, received it again after hepatectomy unless they had limiting toxicity. Regimens of chemotherapy were based on 5-fluorouracil and leucovorin, and after 1997, oxaliplatin or irinotecan were added to this basic regimen. Eighty three percent of them received at least two lines of chemotherapy. Because of the numerous regimens of chemotherapy used during this long period of time and their miscellaneous combinations before or after hepatectomy, we do not report them in this article.

Follow-up after hepatectomy was as follows: after discharge, patients were seen every 3 months during the first 2 years and every 6 months during the next 3 years. Tumor markers were evaluated if they were increased before hepatectomy, and the most accurate personal imaging studies were performed. Before surgery, each patient underwent an ultrasound examination and a computed tomographic scan of the abdomen, pelvis, and thorax. If LM were not easily imaged, a magnetic resonance imaging study was performed. In case of recurrence, surgery was considered first, followed by chemotherapy.

Survival curves were constructed by the Kaplan-Meier method and were compared by using the log-rank test. The cutoff date for analysis was November 15, 2004. Postoperative deaths were included in these curves. Only three foreign patients were lost to follow-up, and they were excluded from the analysis at the date of the last follow-up. Statistical calculation were performed with SAS version 8.02 (SAS Institute, Inc., Cary, NC). Qualitative variables were compared by ² test, and quantitative variables were compared by Student’s t-test. Univariate analysis was performed with the log-rank test. All significant variables in the univariate analysis were considered for multivariate analysis with a Cox proportional hazard regression model. Statistical significance was defined as P < .05. All statistical tests were two sided. All classic parameters (age, sex, lymph node status of the primary tumor, operation, resection radicality, pathologic characteristics, chemotherapy, and follow-up) were prospectively registered in a specific database. However, the carcinoembryonic antigen level was not measured initially in 37% of cases and was therefore excluded from analysis.

In this study, the number of resected lesions was considered from two different perspectives for comparison. In the classic analysis, survival was considered according to the number of resected LMs, with three groups (one to three LMs, four to six LMs, and more than six LMs). In the nonclassic analysis, survival was considered according to the total number of resected intrahepatic but also extrahepatic metastases, with the same three categories of patients (one to three metastases, four to six metastases, and more than six metastases). For the second analysis, we decided arbitrarily to count one metastasis for each LM, each lung metastasis, each distant invaded lymph node, each local recurrence (whatever its size), each ovary or adrenal gland, or each miscellaneous metastasis. For peritoneal carcinomatosis, we counted one for each peritoneal tumor seeding up to five but kept the maximum of five when there was more numerous tumor seeding. This was decided after a first analysis of the data to keep a balance between the number of metastases according to the different sites of disease.

	RESULTS

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Patient Characteristics
A total of 308 patients underwent operation between January 1, 1987, and January 1, 2000, with 160 men and 148 women (mean age, 57 ± 10 years; median, 58 years; range, 18–86 years). The primary tumor was in the colon in 204 cases and in the rectum in 104 cases. One hundred thirty-seven (45%) were synchronous LMs (i.e., they were discovered at the time of or within 6 months after discovery of the primary tumor). The population included in this study is an extension (more patients and longer follow-up) of previously published series.^17,19

Among these 308 patients who underwent hepatectomy for colorectal LM, 84 (27%) also had synchronous EHDs, which were resected. These EHDs were known before surgery in 55 and were discovered at laparotomy in 29.

The details of these localizations are listed in Fig. 1, as are the number of resected LMs. They included peritoneal carcinomatosis, lung metastases, different sites of distant lymph node metastases (in the hepatic pedicle or in the left lateroaortic zone), local recurrence of the primary tumor, and ovarian and other miscellaneous metastases. Peritoneal carcinomatosis was macroscopically present, resected, and histologically proven in 37 patients. Among them, 15 patients had 1 or 2 peritoneal implants, 10 had 3 to 6 implants, and 12 had more than 10 implants.

View larger version (16K): [in this window] [in a new window]   FIG. 1. Distribution of liver metastases (LMs) and extrahepatic disease (EHD) in the 308 patients. Nb, number.

Mortality and Morbidity
For the 308 patients, mortality until hospital discharge was 3% (n = 10). There was no mortality after lung resection performed 2 months later. Morbidity was 18% (n = 54), including that for lung resections. Mortality and morbidity rates were respectively 3% and 22% for the 84 patients who underwent a hepatectomy with resection of 1 or more EHDs, and they were 3% and 20% for the 224 patients without resection of EHD.

The median follow-up was 99 months (range, 8–205 months). Minimum follow-up was 54 months, except for the three foreign patients who were lost to follow-up.

Causes of Death
A total of 236 patients died. Death was due to the cancer in 197 cases (83%), to iatrogenic reasons (including postoperative deaths) in 26 cases, to non-tumor causes in 8 cases, and to unknown causes in 5 cases.

The 5-year overall survival of the 308 patients was 32% (95% confidence interval 3%), and median survival was 38 months (confidence interval, 36–43 months). For patients without EHD, the 5-year survival was 34%—significantly (P = .04) higher than the 28% for patients with EHD (Fig. 2). Table 1 shows the survival rates according to different parameters and analyses, which are detailed afterward. The age, lymph node status of the primary tumor, synchronous or metachronous appearance of the LM, largest size of the LM, and free margin had no significant effect on the prognosis, contrary to the sex (P = .01), in favor of women, and to the completeness of the resection (P < .001).

View larger version (11K): [in this window] [in a new window]   FIG. 2. Overall survival rates of patients with and without extrahepatic disease (EHD).

View larger version (24K): [in this window] [in a new window]   FIG. 3. Overall survival rates of the 308 patients according to the number of metastases in three groups. (A) According to the number of liver metastases (classic analysis); (B) according to the total number of metastases (liver metastases + extrahepatic disease; nonclassic analysis).

View larger version (18K): [in this window] [in a new window]   FIG. 4. Overall survival rates when the total number of metastases (liver metastases + extrahepatic disease [-EHD]) is (A) one to three, (B) four to six, and (C) greater than six in the group of patients without EHD and in the group of patients with EHD.

	DISCUSSION

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For the first time, this study shows that for metastatic colorectal tumors, when they are resectable, the total number of metastases, whatever their locations, is a more important prognostic factor than the site of the metastases. Therefore, it seems that one LM associated with one EHD has almost the same prognostic value as two isolated LMs.

Also, the liver as the first site of extension no longer seems to be a privileged site for resection of metastases but is, rather, similar to any other site. This was recently underlined for peritoneal carcinomatosis, for which the prognostic effect of complete cytoreductive surgery is great^29,34 and for which the combination of complete resection with intraperitoneal chemohyperthermia results in curing of 20% to 40% of patients.^20–23 These results are close to those obtained 10 years earlier with hepatectomy for LM only.³⁵

Therefore, in our study, the site of metastases was not a preponderant prognostic factor, provided that they were completely resectable. We considered the completeness of resection according to the surgeon’s macroscopic judgment, which seems to be the most useful and applicable in a clinical approach. This is why some of our patients who were postoperatively staged as uncompletely resected were kept in our analysis and had very classically a low prognosis.

After complete resection of metastases, whatever their site, it is their number that seems to be the most important prognostic factor. The effect of the number of metastases was reported earlier for LMs,^1–10 lung metastases,^15,16 and peritoneal carcinomatosis.^20–23 In this study, the number of resected metastases was also preponderant, but any type of localization seems equivalent if the metastases are adequately treated.

It is important to underline that these results concern a selected population for which we estimated that all the metastases, whatever their site, but always including LMs, could be resected and also for which the surgeon considered that a complete resection was performed. These results are also supported because equal or similar mortality and morbidity rates were observed in the group of patients who underwent hepatectomy only (3% and 20%, respectively) and in the group of patients who underwent hepatectomy associated with EHL resection (3% and 22%, respectively).

Times are changing, and so are therapeutic concepts. Traditionally it was considered that only a local treatment, such as surgery, could cure a cancer with local extension. Over the last 20 years, we have learned that micrometastases and circulating cancer cells in blood, bone marrow, and lymph nodes are always present in advanced-stage cancer.³⁵ Moreover, it was shown that most cells derived from the primary tumor are not stopped by the liver and enter the systemic circulation.³⁷

Thus, traditional radical surgery is, strictly speaking, only a cytoreductive surgery (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 patient’s 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 peptides that interfere with normal defenses.^38,39 Furthermore, according to the log-kill hypothesis, each dose of chemotherapeutic agent kills a constant fraction of cells, rather than a specific number of cells.⁴⁰ Therefore, reducing the initial tumor volume increases the likelihood that chemotherapy will reduce the number of viable tumor cells toward the desired end point (zero). Reducing the total tumor volume also substantially diminishes the risk for development of drug resistance, which increases directly with the number of cancer cells and the treatment duration.⁴⁰

Recently, it was proven that systemic chemotherapy could cure microscopic disease in colorectal cancer, mainly as adjuvant treatment after operation of the primary tumor.^41,42 In fact, with the last generation of drugs, this principle has increased application for metastatic stages. For example, it is now clear that a complete cytoreductive operation treating macroscopic peritoneal carcinomatosis, followed by immediate intraperitoneal chemotherapy treating the remaining microscopic peritoneal disease, is able to cure some patients^20–23 and results in survival rates similar to those obtained with hepatectomy.³⁵ In the same way, we showed in this study that the complete resection of metastases, whatever their sites, is the first step to a curative intent, in association with more and more efficient chemotherapy. The principle of complete resection of metastases, whatever their localization, becomes more important than the localization of the metastases in only one organ. Also, it was reported that patients whose metastatic disease did not progress while they were receiving neoadjuvant chemotherapy experienced improved survival after liver resection compared with patients who did not receive chemotherapy.^18,43

The logical application of this principle is, in the future, to rapidly test the chemosensitivity of the patients first, when tumor targets are in place, then to completely resect the metastases (when feasible), and then to continue efficient chemotherapy after resection. In this view, surgery and chemotherapy have the same importance for curing. It is their association that is essential: their combination is efficient and potentially able to cure, but one without the other is unable to cure.

In conclusion, to treat macroscopic and microscopic tumor compounds in a different way (but in a combined approach), complete resection of colorectal metastases is more important than the sites of these metastases. Therefore, extrahepatic metastases are no longer a contraindication to hepatectomy. The total number of resected metastases, whatever their site, retains a strong prognostic effect.

Received for publication January 19, 2005. Accepted for publication June 28, 2005.

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