10.1245/s10434-006-9215-5
Annals of Surgical Oncology 14:786-794 (2007)
© 2007 Society of Surgical Oncology
Clinicopathological Features and Prognosis in Resectable Synchronous and Metachronous Colorectal Liver Metastasis
Ming-Shian Tsai, MD1,3,
Yen-Hao Su, MD2,
Ming-Chih Ho, MD2,
Jin-Tung Liang, MD, PhD1,
Tzu-Ping Chen, MS4,
Hong-Shiee Lai, MD, PhD2 and
Po-Huang Lee, MD, PhD2
1 Division of Colorectal Surgery, Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, No. 7, Chung-Shan South Road, Taipei, Taiwan
2 Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
3 Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan
4 Institute of Health and Welfare Policy, National Yang-Ming University, Taipei, Taiwan
Correspondence: Address correspondence and reprint requests to: Jin-Tung Liang, MD, PhD; E-mail: jintung{at}ha.mc.ntu.edu.tw
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ABSTRACT
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Introduction: Hepatic resection may offer long-term survival for patients with colorectal metastases. However, controversies exist regarding the prognostic factors. Herein, the impact of synchronicity of liver metastasis on patient clinicopathological features and prognosis was evaluated.
Methods: One hundred and fifty-five patients who underwent hepatectomy for colon cancer metastasis, from 1995 to 2004, were enrolled in this study. Patients were divided into two groups: synchronous and metachronous colorectal liver metastasis. Patient demographics, the nature of the primary and metastatic tumors, surgery-related complications, and long-term outcome were analyzed.
Results: Patients included in the synchronous group tended to be younger than those in the metachronous group. Compared to the metachronous group, patients in the synchronous group showed more metastases (P = 0.008) and bilobarly distributed metastases (P = 0.016). Bile leakage was the most common surgical complication. The estimated 5-year disease-free and overall survival rates were 16.8 and 41.1%, respectively. Univariate analysis indicated that synchronous metastases, advanced stage of the primary tumor, bilobar distribution of the metastases, more than three metastases, and colonic versus rectal location of the primary tumor were prognostic factors of shorter disease-free survival, but not overall survival. Multivariate analysis revealed that synchronous metastases and the advanced stage of the primary tumor were indicators for a worse disease-free survival.
Conclusion: The synchronous presence of primary colon cancer and liver metastasis may indicate a more disseminated disease status and is associated with a shorter disease-free survival than metachronous metastasis. These patients may need more careful monitoring and aggressive chemotherapy following curative resection.
Key Words: Colorectal cancer • Metastases • Liver resection • Prognosis
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INTRODUCTION
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Presently, hepatic resection is regarded as a potentially curative treatment for patients with colorectal liver metastasis,1 since it is able to offer a reasonable chance of long-term survival.2 Nevertheless, a significant proportion of patients still experience recurrence after hepatectomy. Several investigators have reported the prognostic factors affecting survival and recurrence,2–8 despite some controversies exist regarding these results. Sugihara et al.6 indicated that patients with metachronous tumors showed a significantly improved prognosis compared to those with synchronous lesions, while none of the other factors affected the prognosis. However, few studies compared the clinicopathological data between the two groups, which we believe, may represent two different categories of colorectal cancer. Currently, little is known about the characteristics of the primary tumor, the metastatic tumor and the clinical course after hepatectomy, in these two distinct categories.
To assess the surgical and long-term outcome, a consecutive series of patients at our institution undergoing potentially curative hepatectomy for colorectal cancer and associated liver metastasis, were reviewed. The present study aimed to compare tumor nature, treatment-related complications and long-term outcome between patients with synchronous and metachronous colorectal liver metastasis. In addition, the influences of other prognostic factors reported in the literature were examined.
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METHODS
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Patient Population
This retrospective review included patients who underwent hepatic resection for metastatic colorectal cancer at the National Taiwan University Hospital between January 1995 and December 2004. All patients had to fulfill the following criteria to be considered a candidate for hepatic resection with intent for cure: (1) no signs of extrahepatic metastases found in preoperative studies (chest roentgenography, abdominal ultrasonography and computed tomography of the abdomen and pelvis); (2) hepatic metastases were such that an adequate sized, well-vascularized hepatic remnant would remain after resection; (3) the patient was medically fit for major hepatic resection. Only patients whose metastases were resectable on presentation were included, and those patients receiving neoadjuvant chemotherapy were excluded.
The patient population was divided into two groups based on time frame when the hepatic metastases were discovered. The synchronous metastasis group was defined as when the metastases were observed before or during resection of the primary colorectal cancer. The metachronous metastasis group was defined as when the metastases were noted at least 1 year after resection of the primary colorectal cancer. The definitions for synchronous and metachronous metastasis (interval >12 months) have also been addressed in several previous studies.1,8
Surgical Management
Before hepatic resection, patients underwent full abdominal exploration to exclude extrahepatic metastasis of colorectal cancer. In all cases of synchronous metastases, resections of the primary and metastatic tumors were performed simultaneously. Colorectal surgeons performed the resection of colorectal cancer, and subsequently, surgeons from our hepatobiliary service performed the liver resections. In the majority of patients, intraoperative ultrasound (IOUS) was used for localization of the tumor and identification of vascular and biliary structures.
Liver resections were performed using the clamp-ligation technique or the Cavitron ultrasonic surgical aspirator (CUSA). The portal inflow was isolated and occluded before parenchymal transection for right lobar resections, if necessary.
Adjuvant Chemotherapy and Patient Follow-up
All patients in the present study received chemotherapy following hepatectomy, although no standard regimen was applied throughout the study period. A postoperative follow-up was conducted at least once every 3–4 months during the first two postoperative years, which included a physical examination, serum carcinoembryonic antigen survey and abdominal ultrasonography. Chest roentgenography, a bone scan, colonoscopy and a CT scan of the abdomen and pelvis were performed annually or when there was suspicion of recurrence.
Data Collection
Data were retrieved from each patient’s medical records, and included demographic information, characteristics of the primary and metastatic tumor, surgical information, and hospital course. The death of any patient within 30 days of hepatic resection or at any time after 30 days was considered a surgical death, if it occurred during the same hospitalization period as the hepatectomy. Long-term outcome was obtained through clinical follow-up and contact with the patient, in addition to family members if necessary.
Statistical Analysis
The continuous data were presented as the mean ± standard error of the mean (SEM). The Student’s t-test was used to analyze the continuous variables. The Pearson Chi-Square or the Fisher exact test was used for univariate analysis. Survival and disease-free survival rates were estimated using the Kaplan-Meier method. The log-rank test was used to calculate any significant difference between the subgroups by univariate analysis. The Cox regression analyses were performed to assess the independent prognostic significance of different factors. P < 0.05 was considered significant.
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RESULTS
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Patient Characteristics and Follow-up
One hundred and fifty-five patients underwent curative resection for metastatic colorectal cancer during the period of this study. Ninety-seven (62.6%) patients demonstrated synchronous hepatic metastases, while 58 (37.4%) patients comprised the metachronous metastasis group. In the metachronous group, the interval between resection of the primary tumor and the diagnosis of liver metastasis was 21.1 ± 2.8 months (range, 12.0–120.0 months). The patient’s demographic data and medical comorbidities are summarized in Table 1
. The mean age was higher in the metachronous group than in the synchronous group (63.1 years versus 58.6 years, P = 0.027). Except for age, there was no significant difference in demographics and concomitant medical diseases between the synchronous and metachronous groups (Table 1).
Herein, the follow-up duration ranged from 1 to 156 months, with the mean being 28.5 ± 2.0 months. One hundred and forty-three (92.3%) out of the 155 patients were subjected to follow-up for more than 6 months following hepatectomy.
Characteristics of the Primary Tumor
The primary tumor was located on the right-sided colon in 33 (21.3%) patients, on the left-sided colon in 85 (54.8%) patients, and on the rectum in 37 (23.9%) patients. The mean size of the primary tumor was 4.77 ± 0.14 cm in the present study, while the tumor invaded through the serosa or adjacent organs in 134 (86.5%) patients. One hundred and seven (68.4%) patients showed metastasis to the regional lymph node(s).
No significant difference between the synchronous and metachronous groups in terms of tumor location, tumor size, tumor staging, tumor grading and metastasis to regional lymph nodes was observed (Table 2).
Characteristics of the Metastatic Tumor
The maximal diameter of the largest metastasis was 3.85 ± 0.20 cm, and the mean number of metastases was 2.0 ± 0.2. The hepatic metastases were located in the right lobe of the liver in 87 (56.1%) patients, in the left lobe in 30 (19.4%) patients, and in both lobes in 38 (24.5%) patients.
Significant differences between the synchronous and metachronous groups with respect to the number and bilobar distribution of hepatic metastases were detected (Table 3). The metastatic tumor tended to be smaller in patients included in the synchronous group compared to those in the metachronous group. The difference detected, however, was not statistically significant.
Surgical Methods, Results and Complications
Surgical methods employed were similar in both groups (Table 4). Nonanatomical wedge resection of the metastases was the most frequent method used, which was performed in more than one half of all patients. Lobectomy was the second most common surgical method, and was performed in approximately one-third of all patients. The nearest section margin from the metastases was more than 1.0 cm in 86 (88.7%) patients of the synchronous group and 54 (93.1%) patients of the metachronous group (Table 4). Cancer cell was found on the resection surface in 1(1.0%) patient of the synchronous group.
The incidence of postoperative bile leakage (synchronous 3.1%, metachronous 3.4%) and internal bleeding (synchronous 1.0%, metachronous 1.7%) were comparable between the two groups. Transient impairment of liver function occurred in three patients in the synchronous group but not in the metachronous group. All three patients recovered following conservative treatment. In one patient, the common bile duct was incidentally transected during the left lobectomy, and thus, hepaticojejunostomy was necessary for reconstruction of the biliary conduit. No surgery-related mortality occurred in the present study.
Disease-free Survival
The estimated 5-year disease-free survival rate for all patients was 16.8% (Table 5). Univariate analysis revealed that long-term disease-free survival in the metachronous group was superior to that in the synchronous group (P = 0.004). The advanced stage of the primary tumor, bilobar distribution of the metastases, more than three metastases present and primary tumor located in colon were prognostic factors of shorter disease-free survival on univariate analysis. The estimated disease-free survival curve based on each factor is shown in Fig. 1.
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FIG. 1. Comparison of the disease-free survival of patients undergoing liver resection based on the significant prognostic factors. A Metachronous versus synchronous group; B T2 or T3 primary lesions versus T4 primary lesions; C Unilobar versus bilobar distribution; D number of liver metastases; E location of primary tumor. Kaplan–Meier survival curves were constructed and examined by log-rank test between two groups (*P < 0.05).
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Multivariate analysis indicated that the synchronicity and the primary tumor stage were independent prognostic factors, which influenced disease-free survival (Table 6).
Overall Survival
The estimated 5-year overall survival rate for all patients was 41.1% (Fig. 2A). It was slightly, but not significantly higher in the metachronous group than in the synchronous group (5-year survival, 54.6% versus 34.2%, P = 0.150) (Fig. 2B). None of the evaluated factors in this study significantly contributed to prognosis (Table 5
). There were some, but not significant correlations between prognosis and bilobar distribution of metastases (P = 0.083). In addition, more than three metastases suggested a worse prognosis in comparison with a single metastasis, however, no statistical significance was detected (P = 0.131).
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FIG 2. A The estimated survival curve of our patients. B The estimated survival curve grouped by the synchronicity.
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DISCUSSION
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According to recent reports, the 5-year survival rate for patients with colorectal cancer after hepatectomy is 24–58%,1,2,5,7–16 while previously reported disease-free survival rates ranged from 19 to 28% at 5 years1,5,8,13 (Table 7). In the present study, 41.1% of post-hepatectomy patients survived for more than 5 years and clearly benefited from surgery. Hepatectomy, therefore, provides the possibility of long-term survival, considering that less than 5% of 5-year survival is currently associated with non-surgical care.15,17,18
Unfortunately, a significant number of patients develop recurrence after hepatic resection for colorectal metastasis, which accounts for the majority of patient mortality. Most recurrences are identified during the first 12–18 months post-surgery.19,20 The most common site of recurrence is the liver, occurring on the opposite side of the liver in more than one-third of cases. An improved recognition of the risk factors involved in recurrence may assist in the planning of postoperative follow-up and adjuvant chemotherapy. Univariate analysis of our results showed that synchronous metastasis, more than three metastases, bilobar distribution, an advanced stage of the primary tumor and primary tumor located in the colon instead of the rectum were all risk factors predicting recurrence in patients undergoing hepatectomy for colorectal metastasis. Several previous studies showed similar results (Table 8). However, prognostic factors found in these studies were not the same. Thus, it should be noted that since the selection criteria for hepatectomy differed among these studies, the prognostic factors might also differ.
Several authors have proposed that the more favorable prognosis observed in metachronous metastasis cases than in synchronous metastasis is likely due to the later timing in disease progression when the initial diagnosis was made.2,15 However, there was no significant difference in the primary tumor stage or in the regional lymph node metastasis between the metachronous and synchronous groups (Table 2). Furthermore, in multivariate analysis, the synchronicity and the stage of the primary tumor were two independent prognostic factors in terms of recurrence. This suggested that the difference in prognosis was not merely related to the time of detection in the disease progress. In addition, we found that metastasis in the synchronous group, compared to the metachronous group tended to be multiple and distributed bilobarly. These results suggested that synchronous metastasis might represent a more disseminated disease, compared to metachronous metastasis. The tendency to spread may lead to earlier recurrence and worse prognosis in the synchronous group of patients.
Therefore, we advocate that these patients should receive intense follow-up and adjuvant chemotherapy after liver resection. However, it should be noted that these prognostic factors should not be considered as absolute contraindications of liver resection, since patients with poor prognostic factors may still gain benefit from surgery, which was corroborated in this study. Our results also showed that liver resection for metastasis of colorectal cancer was a safe procedure with no surgery-related mortality and acceptable morbidities.
Positive section margins have been proposed a factor of unfavorable prognosis.1 Nevertheless, few reports indicated that the distance of safety margin had significant impact on the prognosis, provided the metastatic tumor can be removed completely (Table 8). It has been proposed that, with respect to the operative approach, a clear margin of 1 cm or more should be aimed at.2 However, if the size or location of metastases do not allow a 1-cm margin, resection may still be performed, making every surgical effort to ensure a complete rim of unaffected tissue.
Interestingly, the location of the primary tumor is prognostic of disease-free survival by univariate but not multivariate analysis. Though a biological explanation of these findings is not clear at present, it is suggested that colon cancer and rectal cancer have different processes of carcinogenesis. Konishi et al.21 report that cancers that arise in the distal colon and rectum begin as adenomatous polyps whereas a de novo pathway is more important in lesions that arise in the proximal colon. Another compelling difference is that the familial forms of colorectal cancer, familial polyposis syndrome (FAP) and hereditary nonpolyposis coli (HNPCC), arise first in different sections of the colon (FAP: rectum and distal colon, HNPCC: proximal colon).22 Our results suggest that colon and rectal cancer cells may behave differently not only in the early stage of carcinogenesis but also after distant metastasis. A further basic investigation is therefore needed to elucidate the underlying cellular and molecular mechanisms.
Although the metachronous group demonstrated a better prognosis than the synchronous group in terms of recurrence, there was no difference in overall survival between the two groups. On reviewing the literature, a favorable trend in improved overall survival over time, but not disease free survival, was observed. At 5 years, the actual survival rate increased from approximately 25% in the 1980s to more than 50% following the year 2000 (Table 8). A number of possible explanations for the observed trend in improved outcome can be considered. Advances in imaging have contributed to the improvement in both the early detection of recurrence and long-term outcome.23–26 The application of IOUS, for example, can provide a more accurate identification of otherwise occult intrahepatic tumors, which were then either resected or excluded as a complete resection. Herein, we performed IOUS in both the synchronous and metachronous groups. However, the uncontrolled nature of this study limited the ability to draw conclusions regarding the beneficial role of IOUS.
Improvements in surgical techniques are likely to contribute to improved overall outcome. Herein, the surgical morbidity rate was acceptable while no surgical mortality occurred. Innovations in surgical technology, such as mechanical staplers and hemostatic devices, and the use of intraoperative strategies using vascular control and low central venous pressure, have resulted in a definite improvement in short-term outcomes. Several studies have reported trends in decreasing mortality and shorter periods of hospitalization despite the increasing number of liver resections.4,27 Moreover, safer techniques of hepatic resection have enabled surgeons to consider a repeat hepatectomy for colorectal metastases in an increasing number of patients with recurrence, if the recurrence is confined to the liver. Reported mortality and morbidity rates after a repeat hepatectomy are similar to those reported after an initial hepatectomy.3,28 Provided repeat resection is feasible, 5-year survival is comparable with that observed for patients following a single resection.3 Patients showing recurrence after the first resection may, therefore, achieve long-term survival if repeat hepatectomy is regarded potentially curative and feasible.
Systemic chemotherapy is being used with increasing frequency in combination with surgical resection, either following resection or as neoadjuvant chemotherapy. Newer agents and drug combinations demonstrating increasing response rates in advanced disease and increasing survival in the adjuvant setting have fueled this enthusiasm. All patients in this study received chemotherapy following hepatectomy, although indications for chemotherapy, the choice of agents, and the timing of therapy relative to liver resection varied considerably throughout the study period. Advances in postoperative therapy, following resection of metastases, may prolong survival in patients with recurrence. This may partly explain our results where a difference in disease-free survival but not overall survival between the synchronous and metachronous groups was observed.
Several other treatment modalities for colorectal liver metastasis have emerged in the past few years. Hepatic artery infusion of chemotherapy, radiofrequency ablation therapy, and other destructive therapies all assist in prolonging patient survival. However, none of these procedures were performed for patients included in the present study. Their impact on treatment outcome deserves further investigation.
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CONCLUSION
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In summary, synchronicity and primary tumor stage represent two prognostic factors of recurrence after hepatectomy for colorectal liver metastases. We believe that synchronous metastasis may represent a more disseminated disease than metachronous metastasis. However, no different overall survival between the synchronous and metachronous groups was detected, which may be due to improved management following recurrence.
Received for publication April 19, 2006.
Accepted for publication July 31, 2006.
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ABSTRACT
INTRODUCTION
