0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Article |

Simplified Staging System for Predicting the Prognosis of Patients With Resectable Liver Metastasis:  Development and Validation FREE

Masami Minagawa, MD, PhD; Junji Yamamoto, MD, PhD; Tomoo Kosuge, MD, PhD; Yutaka Matsuyama, PhD; Shin-ichi Miyagawa, MD, PhD; Masatoshi Makuuchi, MD, PhD
[+] Author Affiliations

Author Affiliations: Departments of Hepato-Biliary-Pancreatic Surgery and Artificial Organ and Transplantation, Graduate School of Medicine (Drs Minagawa and Makuuchi), and Department of Biostatistics, School of Health Science and Nursing (Dr Matsuyama), University of Tokyo, and Department of Gastrointestinal Surgery, Cancer Institute Hospital (Dr Yamamoto), and Department of Surgery, National Cancer Center (Dr Kosuge), Tokyo, Japan; and First Department of Surgery, Shinshu University, Matsumoto, Japan (Dr Miyagawa).


Arch Surg. 2007;142(3):269-276. doi:10.1001/archsurg.142.3.269.
Text Size: A A A
Published online

Hypothesis  Although several staging systems for colorectal liver metastasis have been proposed, simple and generally accepted staging systems are not available for this disease. We hypothesized that more detailed analysis of primary colorectal cancer may make it possible to develop a simple staging system and that its stratification ability may be demonstrated by validation against data from unrelated patients.

Design  Retrospective analysis of prospectively documented data, development of a stage, and validation against an unrelated cohort.

Setting  Four tertiary referral centers.

Patients  Twenty-two clinicopathologic factors were examined in 369 consecutive patients who underwent curative resection for liver metastasis from colorectal cancer (original cohort). Using the independent prognostic factors, a simplified staging system was developed and was validated by data from 229 unrelated patients (validation cohort).

Main Outcome Measures  Kaplan-Meier survival curve analyses between different prognostic groups in the cohorts.

Results  Multivariate analysis revealed several independent prognostic variables, including hepatic lymph node metastasis (relative risk 4.39), 4 or more colorectal lymph node metastases (RR 1.50), carcinoembryonic antigen level of 50 ng/mL or higher (RR 1.29), and multiple hepatic metastases (RR 1.27). Patients with hepatic lymph node metastasis were assigned to stage 4, and the remaining patients were divided according to number of factors: none, stage 1; 1, stage 2; 2 or 3, stage 3. In the original cohort, median survival in stages 1, 2, 3, and 4 was 7.2, 3.5, 2.0, and 1.3 years, respectively. In the validation cohort, these values were 9.6, 4.1, 2.8, and 1.6 years, respectively.

Conclusions  The proposed simplified staging system was easy to use, was highly predictive of patient outcome, and permitted categorization of patients into treatment groups. Although we validated this staging system, further validation and improvements are needed.

Figures in this Article

Liver metastases from colorectal cancer are classified by Union Internationale Contre le Cancer (UICC) staging criteria as stage IV, although the prognosis of patients with this disease varies widely.1 Hepatic resection for colorectal liver metastasis remains the only treatment that has curative potential.2 Many controversies exist about the treatment of liver metastasis, such as the effectiveness of adjuvant chemotherapy, the timing of resection for synchronous metastasis, and the operative indications for multiple metastasis or extrahepatic metastasis. As a result, there is an increasing need for a simple staging system that can reflect the prognosis and permit the stratification of patients for clinical trials.

Several staging systems for colorectal liver metastasis have been proposed. Gennari,35 Fortner,6 and Gayowski7 and their colleagues proposed staging systems based on the size, number, and intrahepatic and extrahepatic extent of metastatic nodules. Cady and Stone8 developed a prognostic scoring system that weighs individual factors. Nordlinger,9 Fong,10 Iwatsuki,11 and Schindl12 and their colleagues developed staging systems by analyzing prognostic factors, but 5 to 7 factors had to be explored to determine the stage.

What are the requirements of a good staging system? First, it should be simple and easy to use. Second, it must provide reliable information on the prognosis of the disease. Third, it should permit the categorization of patients into various treatment groups. Based on these criteria, well-defined and generally accepted staging systems are not available for this disease. The primary goals of this study were to develop a staging system that will fulfill these requirements and to validate its prognostic reliability in an unrelated group of patients.

Between January 1, 1980, and December 31, 2002, 388 patients with hepatic metastasis from colorectal cancer underwent liver resection at the Department of Surgery, National Cancer Center (1980-1990), the First Department of Surgery, Shinshu University (1990-1994), and the Department of Hepato-Biliary-Pancreatic Surgery, University of Tokyo (1994-2002). The last author (M.M.) participated in all of the operations. Nineteen of these resections were not radical because of gross residual disease within or outside the liver, and the remaining 369 patients were included in the original cohort.

Selection criteria for surgery were the possibility of complete removal of all hepatic and extrahepatic lesions and the possibility of preserving at least 40% of the normal hepatic parenchyma. The total number of hepatic metastases, their unilateral or bilateral presentation, and the existence of extrahepatic metastasis were not considered exclusion criteria. No ablative strategies were used along with resection in any of these patients. The treatment policy for synchronous metastasis was simultaneous resection regardless of the number and extent of liver metastasis and the location of the primary cancer.

In all cases, the preoperative diagnostic workup included ultrasonography and plain and contrast-enhanced computed tomography to stage liver involvement and chest radiography, chest computed tomography, barium enema, and colonoscopy to assess the presence or absence of extrahepatic disease. Patients with advanced disease underwent bone scintigraphy or positron emission tomography. Intraoperative bimanual liver palpation and intraoperative ultrasonography (IOUS) were also performed in all patients, and all of the resections were IOUS-guided procedures. The mean duration of follow-up in the original cohort was 4.11 years (range, 1.1 months to 18.8 years).

The validation cohort consisted of 229 patients with colorectal liver metastases who underwent curative hepatic resections by colleagues of the last author (M.M.): 77 at the National Cancer Center between January 1, 1991, and December 31, 1997 (M.M. moved to Shinshu University in 1990), and 152 at Cancer Institute Hospital between January 1, 1997, and December 31, 2003. The selection criteria for hepatectomy and the preoperative and intraoperative diagnostic workup in these groups were comparable with those of the original cohort. The mean duration of follow-up in the validation cohort was 3.95 years (range, 2.5 months to 13.5 years). This retrospective study was approved by the institutional review boards in the respective institutions.

Survival time was calculated from the date of hepatic resection to death or censored date. Patients who died of colorectal cancer were treated as event observations, and patients who died of unrelated causes and were alive at the last follow-up were treated as censored observations. Survival curves were constructed using the Kaplan-Meier product-limit method and compared using the log-rank test. Significant prognostic factors in a univariate analysis were entered into a Cox proportional hazards model using stepwise selection to identify independent predictors of death. Statistical significance was defined as P<.05. A software program (SAS version 8; SAS Institute Inc, Cary, NC) was used for the statistical analyses.

The 3-, 5-, and 10-year survival of the original cohort were 52%, 38%, and 26%, respectively. There was no in-hospital death. We analyzed the effects of 15 clinicopathologic factors at hepatic resection (Table 1) and 7 at primary colorectal resection (Table 2) on survival after curative hepatic resection. Multiple liver metastases (P<.001), diameter of 5 cm or greater (P = .02), interval between primary cancer and liver resection less than 6 months (P = .04), carcinoembryonic antigen (CEA) level of 50 ng/mL or greater (P<.001), a resection margin less than 5 mm (P = .006), hepatic lymph node metastasis (P<.001), extrahepatic metastasis (P = .03), and extrahepatic invasion (P = .03) showed significant prognostic value for survival in a univariate analysis. Unilateral distribution of metastases was a favorable factor (P<.001), and 148 of 222 patients with unilateral metastasis had a solitary metastasis. Excluding patients with a single metastasis, distribution was not significant in patients with multiple metastases (P = .64) (Table 1). Survival curves stratified by the number of liver metastases are shown in Figure 1A. The prognosis according to the serum CEA level at hepatic resection is shown in Figure 1B. In this article, patients were divided into 2 groups according to the serum CEA level at hepatic resection (≥50 and <50 ng/mL) because the χ2 statistic by the log-rank test reached a maximum (χ2 = 21.8) when the boundary was set at 50 ng/mL.

Place holder to copy figure label and caption
Figure 1.

Kaplan-Meier survival analyses for patients in the original cohort. A, Stratified by the number of liver metastases. Median survival in 156 patients with a single metastasis was 4.8 years (95% confidence interval [CI], 3.3-6.9 years), in 116 patients with 2 to 3 nodules was 2.5 years (95% CI, 2.1-3.8 years), and in 97 patients with 4 or more deposits was 2.3 years (95% CI, 1.9-2.8 years) (1 vs 2-3, P = .003; 1 vs ≥4, P<.001; and 2-3 vs ≥4, P = .33). B, Stratified by the serum level of carcinoembryonic antigen at hepatectomy. Median survival in 234 patients with a level of less than 50 ng/mL was 4.0 years (95% CI, 3.3-5.3 years) and in 124 patients with a level of 50 ng/mL or more was 2.1 years (95% CI, 1.7-2.8 years) (P<.001). C, Stratified by the number of colorectal lymph node metastases. Median survival in 114 patients without lymph node involvement (pN0 by Union Internationale Contre le Cancer classification) was 5.2 years (95% CI, 3.5-7.2 years), in 116 patients with 1 to 3 lymph node metastases (pN1) was 3.7 years (95% CI, 2.8-5.8 years), and in 87 patients with 4 or more lymph node metastases (pN2) was 1.8 years (95% CI, 1.3-2.1 years) (0 vs 1-3, P = .29; and 1-3 vs ≥4, P<.001).

Graphic Jump Location
Table Graphic Jump LocationTable 1. Factors at Hepatic Resection
Table Graphic Jump LocationTable 2. Factors at Resection of Colorectal Cancer

Invasion to the serosa or another organ of primary colorectal cancer (pT4 by UICC classification) (P = .02), number of colorectal lymph node metastases of 4 or more (pN2 by UICC classification) (P<.001), and lymphatic duct involvement by the primary cancer (P = .03) also predicted an adverse outcome (Table 2). Nodal status of the primary cancer and long-term survival are shown in Figure 1C.

MULTIVARIATE ANALYSIS OF OUTCOME

The univariate prognostic factors were entered into a multivariate model to identify independent predictors of long-term survival. Hepatic lymph node metastases had the greatest impact on survival (relative risk, 4.39), followed by 4 or more colorectal lymph node metastases (pN2) (relative risk, 1.50), CEA level of 50 ng/mL or greater (relative risk, 1.29), and multiple metastases (relative risk, 1.27) (Table 3).

Table Graphic Jump LocationTable 3. Multivariate Analysis Using the Cox Proportional Hazards Model
METHOD FOR DETERMINING THE STAGE

Regional lymph node metastasis of the liver was clearly the most influential factor and was associated with a 4.39-fold increase in the likelihood of death if it was positive. Thus, these patients were assigned to stage 4. The other 3 independent prognostic factors (number of lymph node metastases around the primary cancer ≥4, CEA level ≥50 ng/mL, and multiple liver metastases) cannot be considered complete contraindications to resection because each alone was still associated with a sufficiently favorable outcome to justify an aggressive surgical procedure, and the increase in the likelihood of death ranged from 1.27 to 1.50. Therefore, these criteria were used to determine whether some combination could be used to dictate the choice of clinical options. Patients who had none of these 3 factors were assigned to stage 1, those with 1 factor to stage 2, and those with 2 or 3 factors to stage 3 (Figure 2). Survival curves for the original cohort, classified according to this simplified staging system, are shown in Figure 3. This simple staging was found to be highly predictive of the long-term outcome (P<.001) (Figure 3), and the differences in survival between the stages were significant (Table 4). Next, the original cohort was divided into 2 groups—synchronous vs metachronous metastasis—and the prognostic value of this simplified staging system was evaluated in each group. In the 187 patients with synchronous metastasis, 5-year survival for stages 1, 2, 3, and 4 were 65%, 38%, 18%, and 0%, respectively (P<.001). In the 182 patients with metachronous metastasis, 5-year survival for stages 1, 2, 3, and 4 were 54%, 48%, 30%, and 0%, respectively (P<.001).

Place holder to copy figure label and caption
Figure 2.

Algorithm used to determine the stage in this simplified staging system. CEA indicates carcinoembryonic antigen.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Kaplan-Meier survival analysis for patients in the original cohort stratified according to the simplified staging system.

Graphic Jump Location
Table Graphic Jump LocationTable 4. Kaplan-Meier Analysis in the Original and Validation Cohorts
VALIDATION OF THE SIMPLIFIED STAGING SYSTEM

The 3-, 5-, and 10-year survival of the validation cohort were 61%, 44%, and 35%, respectively. Of the 229 patients, 64 were assigned to stage 1, 93 to stage 2, 67 to stage 3, and 5 to stage 4. Median survival time and 5- and 10-year survival rates for each stage are summarized in Table 4. The assigned stage was highly predictive of patient outcome (P<.001) (Figure 4).

Place holder to copy figure label and caption
Figure 4.

Kaplan-Meier survival analysis for patients in the validation cohort stratified according to the simplified staging system.

Graphic Jump Location

In the 1980s, 2 staging systems were developed by Gennari et al35 and Fortner et al.6 These systems were based on the degree and extent of metastatic tumors and not on factors regarding primary colorectal cancer.36 Cady and Stone8 proposed a scoring index based on 4 risk factors: surgical margin, CEA level, disease-free interval, and number of liver nodules. This staging also did not include factors regarding colorectal cancer, although the researchers pointed out that patients with poor differentiation and greater than 5 lymph node metastases in the primary cancer should have a poor prognosis, which would be governed by biological factors.13 Gayowski et al7 proposed a modified TNM staging system based on several factors: unilateral or bilateral, single or multiple, 2 cm or smaller or larger than 2 cm, and vascular or ductal invasion to a major branch. In this system, all metastases with bilateral distribution are considered modified T4. Generally, most patients with a single tumor have a unilateral distribution, and those with multiple nodules have a bilateral distribution. The worse outcome associated with multiple nodules affects the outcome with a bilateral distribution. As we have shown previously,14 the prognosis of patients with multiple tumors did not differ according to the distribution in the liver. In a multicenter study by Nordlinger et al,9 1568 patients who had metastases confined to the liver and who received curative resection were analyzed, and 7 factors were found to be significant in a multivariate analysis: age 60 years or older, size 5 cm or larger, pT4 by UICC classification, pN1 or greater by UICC classification, disease-free interval of less than 2 years, 4 or more nodules, and margins less than 1 cm. Three stages were established based on the number of factors present: 0 to 2, 3 to 4, and 5 to 7. A similar method was used by Fong et al10 and Iwatsuki et al11 in 1999, but cases with a positive margin, extrahepatic disease, or hepatic lymph node metastasis were either excluded or assigned to the highest stage. Patients without these factors were divided according to the number of the following factors: node-positive primary cancer, disease-free interval of less than 12 months, more than 1 hepatic tumor, largest hepatic tumor greater than 5 cm, and CEA level greater than 200 ng/mL by Fong et al10 and 3 or more tumors, tumor size greater than 8 cm, disease-free interval of 30 months or less, and bilateral tumor by Iwatsuki et al.11 These staging systems were based on a multivariate survival analysis and reflected the prognosis but used 7 factors. Thus, all of the factors must be explored to determine the stage, which may make it difficult to use these staging systems.

It is essential for a good staging system to provide reliable information on the prognosis of the disease. To show that a staging system actually reflects the prognosis, it must be verified by validation against data from unrelated patients. The staging system proposed by Fong et al10 was validated by Mann et al15 in Australia. Schindl et al12 developed a prognostic scoring system using Dukes stage, number of metastases, CEA level, alkaline phosphatase level, and albumin level and validated its prognostic reliability in an unrelated group of patients. The robustness of the present staging system was tested by validation against data from patients who were not included in the original cohort. The survival rates of each stage in the validation cohort approximate those in the original cohort, and the P values for stage 1 vs 2 and stage 3 vs 4 are significant. Regarding stage 2 vs 3, it seems reasonable to predict that it will be significant with increasing numbers of patients because the median survival time of each stage is monotonically decreasing with advancing the stage. Consequently, the present staging system may provide reliable information on the prognosis of patients with colorectal liver metastasis.

Extrahepatic extension, such as extrahepatic metastasis, extrahepatic invasion, local recurrence at the primary cancer, and hepatic node metastases, has been analyzed as a whole in most previous studies. Patients with these factors have long been considered to be contraindicated for hepatectomy because of their dismal outcome. However, lung metastases, intraperitoneal dissemination, and local recurrence have gradually gained acceptance for resection in some institutions because a favorable prognosis can be anticipated if the tumors are removed completely.1619

The incidence of macroscopic involvement of hepatic lymph nodes in patients who underwent hepatic resection reported in the literature is 3% to 6%, and 4 of 7 studies2,7,9,11,18,20,21 reported 5-year survival of 0%. In contrast, Elias et al18 showed 5-year survival of 27% in such patients after hepatectomy and lymph node dissection. The rate of microscopic involvement of hepatic lymph nodes has been reported to be 11% to 28%.2228 Although hepatectomy and lymph node dissection were performed in these patients, 5-year survival was reportedly 0% to 5%.24,25,28 Rodgers and McCall29 reviewed 15 studies that gave survival data on node-positive patients: 145 patients received hepatic resection, and only 5 (3.4%) survived 5 years. Based on these findings together with the present results, patients with hepatic lymph node metastasis were assigned to stage 4 in the simplified staging system. We should not operate on patients with hepatic lymph node metastasis.

Although many researchers2,9,14,3034 have noted that primary colorectal cancer affects the prognosis of patients who received hepatectomy for liver metastases, some7,13,20,24,3540 have reported contrary results. This discrepancy may be due to rates of synchronous and metachronous metastasis in each study. As our group41 previously noted, the significant prognostic factors in patients with synchronous metastasis are different from those in patients with metachronous metastasis. In patients with synchronous metastasis, independent prognostic factors were 4 or more lymph node metastases around the colorectal cancer (P<.001) and multiple liver metastases (P = .003), whereas in patients with metachronous metastasis, CEA level (P = .002), 4 or more lymph node metastases around the colorectal cancer (P = .03), and hepatic lymph node metastasis (P = .03) were independently significant.41 Factors associated with colorectal cancer play a more important role in synchronous metastasis. In a study in which most patients have metachronous metastasis, the stage of the primary cancer may not play an important role in the prognosis.

In most studies, the factors of colorectal cancer were represented in terms of Dukes stage. We analyzed it more precisely: patients without mesenteric lymph node metastasis and those with 1 to 3 lymph node metastases had a similar prognosis, and those with 4 or more metastases showed a significantly worse outcome (Figure 1C). Therefore, it is more reasonable to separate patients according to the number of lymph node metastases (≥4 vs 0-3) than Dukes stage (A-B vs C). Moreover, the depth of the wall invasion by colorectal cancer is known to affect the prognosis. A tumor without regional lymph node invasion is classified as Dukes stage A if it invades the muscularis propria or less and as Dukes stage B if it infiltrates the subserosa or more. According to the present analysis on the depth of invasion and prognosis, tumors that perforated the visceral peritoneum or directly invaded other organs or structures (T4 by UICC classification) had a significantly poor outcome after hepatic resection, and no difference in survival was observed between tumors that invaded the submucosa (T1) or muscularis propria (T2) and tumors that invaded through the muscularis propria into the subserosa or into nonperitonealized pericolic or perirectal tissues (T3). A similar result was reported by Kato et al.42 Therefore, it may be more reasonable to separate patients with liver metastasis into T1 to T3 and T4 than Dukes stages A and B-C.

Many studies have demonstrated that the preoperative CEA level has prognostic value. However, little is known about the biological function of CEA, which might act as an adhesion molecule when expressed on the cell surface or as a secreted immune modulator.4347 It has also been noted that the tumor burden may not correlate with CEA levels,48,49 that the prognostic value of a high serum CEA level was comparable with that of the presence of intraperitoneal tumor cells,50 that CEA enhances liver metastasis by functioning as an attachment factor,51 and that an increased posthepatectomy CEA level was independently associated with extrahepatic recurrence.52 Based on these results, the precise function of CEA is not clear: a high serum CEA level may reflect a highly malignant nature of cancer cells, which induces peritoneal dissemination, liver metastasis, and extrahepatic recurrence. In the present series, a CEA level of 50 ng/mL or more was an independent prognostic factor that contributed to the construction of the staging in association with the number of mesenteric lymph node metastases and multiple liver metastases.

Solitary metastasis was a favorable prognostic factor in a multivariate analysis. The prognosis of 97 patients with 4 or more nodules was similar to that of 116 patients with 2 to 3 deposits (Figure 1A). This result may be a consequence of the complete removal of hepatic and extrahepatic metastases and treatment of postresectional recurrence. In the present series, all of the patients underwent careful examination by means of IOUS and IOUS-guided hepatectomy. Makuuchi et al53 first introduced IOUS in 1979. Twenty-five years later, modern diagnostic instruments still cannot replace IOUS regarding its sensitivity in depicting liver nodules.54 Choti et al40 demonstrated that the patient's prognosis after hepatic resection was significantly improved with the use of IOUS. In our experience, approximately 1.5-fold as many nodules are visualized by means of IOUS in patients with 4 or more metastases, and, thus, one third of the nodules cannot be detected even with extracorporeal diagnostic modalities. If these nodules are left in place, the prognosis of patients with 4 or more metastases will be dramatically worsened. These occult nodules in 4 or more metastases may have played an important role in the poor prognosis. Characteristically, liver metastasis, especially 4 or more metastases, can easily lead to recurrent nodules in the remnant liver. The treatment of such recurrences can strongly affect the prognosis. Our choice of treatment for recurrent metastasis is repeated resection, performed immediately and without neoadjuvant chemotherapy. With this treatment, the prognosis of patients with multiple metastases has been remarkably improved.55,56

This simplified staging system is easy to use, is highly predictive of patient outcome and survival, and permits the categorization of patients into various treatment groups. Patients with hepatic lymph node metastasis, who are categorized to stage 4 using the simplified staging system, should be excluded from hepatic resection. Patients in stage 1, 2, or 3 should receive hepatic resection, but it may be appropriate to apply adjuvant chemotherapy to patients with stage 3 disease. Our simplified staging system was validated by data from unrelated patients. However, further verification and refinement by other medical centers are necessary.

Correspondence: Masami Minagawa, MD, PhD, Department of Hepato-Biliary-Pancreatic Surgery, Department of Artificial Organ and Transplantation, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan (minagawa-tky@umin.ac.jp).

Accepted for Publication: January 28, 2006.

Author Contributions:Study concept and design: Minagawa and Makuuchi. Acquisition of data: Minagawa, Yamamoto, Kosuge, and Miyagawa. Analysis and interpretation of data: Minagawa, Matsuyama, and Makuuchi. Drafting of the manuscript: Minagawa. Critical revision of the manuscript for important intellectual content: Minagawa, Yamamoto, Kosuge, Matsuyama, Miyagawa, and Makuuchi. Statistical analysis: Minagawa and Matsuyama. Administrative, technical, and material support: Minagawa and Kosuge. Study supervision: Yamamoto, Kosuge, Miyagawa, and Makuuchi.

Financial Disclosure: None reported.

International Union Against Cancer, TNM Classification of Malignant Tumours. 6th ed. New York, NY Wiley-Liss2002;
Registry of Hepatic Metastases, Resection of the liver for colorectal carcinoma metastases: a multi-institutional study of indications for resection. Surgery 1988;103278- 288
PubMed
Gennari  LDoci  RBozzetti  FVeronesi  U Proposal for a clinical classification of liver metastases. Tumori 1982;68443- 449
PubMed
Gennari  LDoci  RBignami  PBozzetti  F Surgical treatment of hepatic metastases from colorectal cancer. Ann Surg 1986;20349- 54
PubMed Link to Article
Gennari  LDoci  RBozzetti  FBignami  P Proposal for staging liver metastases. Recent Results Cancer Res 1986;10080- 84
PubMed
Fortner  JGSilva  JSGolbey  RBCox  EBMaclean  BJ Multivariate analysis of a personal series of 247 consecutive patients with liver metastases from colorectal cancer, I: treatment by hepatic resection. Ann Surg 1984;199306- 316
PubMed Link to Article
Gayowski  TJIwatsuki  SMadariaga  JR  et al.  Experience in hepatic resection for metastatic colorectal cancer: analysis of clinical and pathologic risk factors. Surgery 1994;116703- 710
PubMed
Cady  BStone  MD The role of surgical resection of liver metastases in colorectal carcinoma. Semin Oncol 1991;18399- 406
PubMed
Nordlinger  BGuiguet  MVaillant  JC  et al.  Surgical resection of colorectal carcinoma metastases to the liver: a prognostic scoring system to improve case selection, based on 1568 patients. Cancer 1996;771254- 1262
PubMed Link to Article
Fong  YFortner  JSun  RLBrennan  MFBlumgart  LH Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999;230309- 318
PubMed Link to Article
Iwatsuki  SDvorchik  IMadariaga  JR  et al.  Hepatic resection for metastatic colorectal adenocarcinoma: a proposal of a prognostic scoring system. J Am Coll Surg 1999;189291- 299
PubMed Link to Article
Schindl  MWigmore  SJCurrie  EJLaengle  FGarden  OJ Prognostic scoring in colorectal cancer liver metastases: development and validation. Arch Surg 2005;140183- 189
PubMed Link to Article
Cady  BJenkins  RLSteele  GD  Jr  et al.  Surgical margin in hepatic resection for colorectal metastasis: a critical and improvable determinant of outcome. Ann Surg 1998;227566- 571
PubMed Link to Article
Minagawa  MMakuuchi  MTorzilli  G  et al.  Extension of the frontiers of surgical indications in the treatment of liver metastases from colorectal cancer: long-term results. Ann Surg 2000;231487- 499
PubMed Link to Article
Mann  CDMetcalfe  MSLeopardi  LNMaddern  GJ The clinical risk score: emerging as a reliable preoperative prognostic index in hepatectomy for colorectal metastases. Arch Surg 2004;1391168- 1172
PubMed Link to Article
Adam  R The importance of visceral metastasectomy in colorectal cancer. Ann Oncol 2000;11 ((suppl 3)) 29- 36
PubMed
Headrick  JRMiller  DLNagorney  DM  et al.  Surgical treatment of hepatic and pulmonary metastases from colon cancer. Ann Thorac Surg 2001;71975- 979
PubMed Link to Article
Elias  DOuellet  JFBellon  N  et al.  Extrahepatic disease does not contraindicate hepatectomy for colorectal liver metastases. Br J Surg 2003;90567- 574
PubMed Link to Article
Sugarbaker  PHJablonski  KA Prognostic features of 51 colorectal and 130 appendiceal cancer patients with peritoneal carcinomatosis treated by cytoreductive surgery and intraperitoneal chemotherapy. Ann Surg 1995;221124- 132
PubMed Link to Article
Jamison  RLDonohue  JHNagorney  DM  et al.  Hepatic resection for metastatic colorectal cancer results in cure for some patients. Arch Surg 1997;132505- 510
PubMed Link to Article
Rosen  CBNagorney  DMTaswell  HF  et al.  Perioperative blood transfusion and determinants of survival after liver resection for metastatic colorectal carcinoma. Ann Surg 1992;216493- 504
PubMed Link to Article
Nakamura  SYokoi  YSuzuki  SBaba  SMuro  H Results of extensive surgery for liver metastases in colorectal carcinoma. Br J Surg 1992;7935- 38
PubMed Link to Article
Elias  DSaric  JJaeck  D  et al.  Prospective study of microscopic lymph node involvement of the hepatic pedicle during curative hepatectomy for colorectal metastases. Br J Surg 1996;83942- 945
PubMed Link to Article
Beckurts  KTHolscher  AHThorban  SBollschweiler  ESiewert  JR Significance of lymph node involvement at the hepatic hilum in the resection of colorectal liver metastases. Br J Surg 1997;841081- 1084
PubMed Link to Article
Kokudo  NSato  TSeki  M  et al.  Hepatic lymph node involvement in resected cases of liver metastases from colorectal cancer. Dis Colon Rectum 1999;421285- 1290
PubMed Link to Article
Jaeck  DNakano  HBachellier  P  et al.  Significance of hepatic pedicle lymph node involvement in patients with colorectal liver metastases: a prospective study. Ann Surg Oncol 2002;9430- 438
PubMed Link to Article
Ercolani  GGrazi  GLRavaioli  M  et al.  The role of lymphadenectomy for liver tumors: further considerations on the appropriateness of treatment strategy. Ann Surg 2004;239202- 209
PubMed Link to Article
Laurent  CSa Cunha  ARullier  E  et al.  Impact of microscopic hepatic lymph node involvement on survival after resection of colorectal liver metastasis. J Am Coll Surg 2004;198884- 891
PubMed Link to Article
Rodgers  MSMcCall  JL Surgery for colorectal liver metastases with hepatic lymph node involvement: a systematic review. Br J Surg 2000;871142- 1155
PubMed Link to Article
Butler  JAttiyeh  FFDaly  JM Hepatic resection for metastasis of the colon and rectum. Surg Gynecol Obstet 1986;162109- 113
PubMed
Iwatsuki  SEsquivel  COGordon  RDStarzl  TE Liver resection for metastatic colorectal cancer. Surgery 1986;100804- 810
PubMed
Doci  RGennari  LBignami  P  et al.  One hundred patients with hepatic metastases from colorectal cancer treated by resection: analysis of prognostic determinants. Br J Surg 1991;78797- 801
PubMed Link to Article
Scheele  JStang  RAltendorf-Hofmann  APaul  M Resection of colorectal liver metastases. World J Surg 1995;1959- 71
PubMed Link to Article
Jaeck  DBachellier  PGuiguet  M  et al.  Long-term survival following resection of colorectal hepatic metastases. Br J Surg 1997;84977- 980
PubMed Link to Article
Pedersen  IKBurcharth  FRoikjaer  OBaden  H Resection of liver metastases from colorectal cancer: indications and results. Dis Colon Rectum 1994;371078- 1082
PubMed Link to Article
Wanebo  HJChu  QDVezeridis  MPSoderberg  C Patient selection for hepatic resection of colorectal metastases. Arch Surg 1996;131322- 329
PubMed Link to Article
Rees  MPlant  GBygrave  S Late results justify resection for multiple hepatic metastases from colorectal cancer. Br J Surg 1997;841136- 1140
PubMed Link to Article
Taylor  MForster  JLanger  B  et al.  A study of prognostic factors for hepatic resection for colorectal metastases. Am J Surg 1997;173467- 471
PubMed Link to Article
Bakalakos  EAKim  JAYoung  DCMartin  EW  Jr Determinants of survival following hepatic resection for metastatic colorectal cancer. World J Surg 1998;22399- 404
PubMed Link to Article
Choti  MASitzmann  JVTiburi  MF  et al.  Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg 2002;235759- 766
PubMed Link to Article
Minagawa  MYamamoto  JMiwa  S  et al.  Selection criteria for simultaneous resection in patients with synchronous liver metastasis. Arch Surg 2006;1411006- 1012
PubMed Link to Article
Kato  TYasui  KHirai  T  et al.  Therapeutic results for hepatic metastasis of colorectal cancer with special reference to effectiveness of hepatectomy: analysis of prognostic factors for 763 cases recorded at 18 institutions. Dis Colon Rectum 2003;46 ((10)) ((suppl)) S22- S31
PubMed
Hammarstrom  S The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues. Semin Cancer Biol 1999;967- 81
PubMed Link to Article
Benchimol  SFuks  AJothy  S  et al.  Carcinoembryonic antigen, a human tumor marker, functions as an intercellular adhesion molecule. Cell 1989;57327- 334
PubMed Link to Article
von Kleist  SMigule  IHalla  B Possible function of CEA as cell-contact inhibitory molecule. Anticancer Res 1995;15 ((5B)) 1889- 1894
PubMed
Kammerer  Rvon Kleist  S The carcinoembryonic antigen (CEA) modulates effector-target cell interaction by binding to activated lymphocytes. Int J Cancer 1996;68457- 463
PubMed Link to Article
Edmiston  KHGangopadhyay  AShoji  Y  et al.  In vivo induction of murine cytokine production by carcinoembryonic antigen. Cancer Res 1997;574432- 4436
PubMed
Mayer  RJGarnick  MBSteele  GD  JrZamcheck  N Carcinoembryonic antigen (CEA) as a monitor of chemotherapy in disseminated colorectal cancer. Cancer 1978;42 ((3)) ((suppl)) 1428- 1433
PubMed Link to Article
Steele  G  JrZamcheck  N The use of carcinoembryonic antigen in the clinical management of patients with colorectal cancer. Cancer Detect Prev 1985;8421- 427
PubMed
Vogel  IFrancksen  HSoeth  E  et al.  The carcinoembryonic antigen and its prognostic impact on immunocytologically detected intraperitoneal colorectal cancer cells. Am J Surg 2001;181188- 193
PubMed Link to Article
Hostetter  RBAugustus  LBMankarious  R  et al.  Carcinoembryonic antigen as a selective enhancer of colorectal cancer metastasis. J Natl Cancer Inst 1990;82380- 385
PubMed Link to Article
Ueno  HMochizuki  HHashiguchi  Y  et al.  Predictors of extrahepatic recurrence after resection of colorectal liver metastases. Br J Surg 2004;91327- 333
PubMed Link to Article
Makuuchi  MHasegawa  HYamazaki  S Intraoperative ultrasonic examination for hepatectomy. Ultrasound Med Biol 1983; ((suppl 2)) 493- 497
PubMed
Sahani  DVKalva  SPTanabe  KK  et al.  Intraoperative US in patients undergoing surgery for liver neoplasms: comparison with MR imaging. Radiology 2004;232810- 814
PubMed Link to Article
Nordlinger  BVaillant  JCGuiguet  M  et al.  Survival benefit of repeat liver resections for recurrent colorectal metastases: 143 cases. J Clin Oncol 1994;121491- 1496
PubMed
Imamura  HSeyama  YKokudo  N  et al.  Single and multiple resections of multiple hepatic metastases of colorectal origin. Surgery 2004;135508- 517
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Kaplan-Meier survival analyses for patients in the original cohort. A, Stratified by the number of liver metastases. Median survival in 156 patients with a single metastasis was 4.8 years (95% confidence interval [CI], 3.3-6.9 years), in 116 patients with 2 to 3 nodules was 2.5 years (95% CI, 2.1-3.8 years), and in 97 patients with 4 or more deposits was 2.3 years (95% CI, 1.9-2.8 years) (1 vs 2-3, P = .003; 1 vs ≥4, P<.001; and 2-3 vs ≥4, P = .33). B, Stratified by the serum level of carcinoembryonic antigen at hepatectomy. Median survival in 234 patients with a level of less than 50 ng/mL was 4.0 years (95% CI, 3.3-5.3 years) and in 124 patients with a level of 50 ng/mL or more was 2.1 years (95% CI, 1.7-2.8 years) (P<.001). C, Stratified by the number of colorectal lymph node metastases. Median survival in 114 patients without lymph node involvement (pN0 by Union Internationale Contre le Cancer classification) was 5.2 years (95% CI, 3.5-7.2 years), in 116 patients with 1 to 3 lymph node metastases (pN1) was 3.7 years (95% CI, 2.8-5.8 years), and in 87 patients with 4 or more lymph node metastases (pN2) was 1.8 years (95% CI, 1.3-2.1 years) (0 vs 1-3, P = .29; and 1-3 vs ≥4, P<.001).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Algorithm used to determine the stage in this simplified staging system. CEA indicates carcinoembryonic antigen.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Kaplan-Meier survival analysis for patients in the original cohort stratified according to the simplified staging system.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Kaplan-Meier survival analysis for patients in the validation cohort stratified according to the simplified staging system.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Factors at Hepatic Resection
Table Graphic Jump LocationTable 2. Factors at Resection of Colorectal Cancer
Table Graphic Jump LocationTable 3. Multivariate Analysis Using the Cox Proportional Hazards Model
Table Graphic Jump LocationTable 4. Kaplan-Meier Analysis in the Original and Validation Cohorts

References

International Union Against Cancer, TNM Classification of Malignant Tumours. 6th ed. New York, NY Wiley-Liss2002;
Registry of Hepatic Metastases, Resection of the liver for colorectal carcinoma metastases: a multi-institutional study of indications for resection. Surgery 1988;103278- 288
PubMed
Gennari  LDoci  RBozzetti  FVeronesi  U Proposal for a clinical classification of liver metastases. Tumori 1982;68443- 449
PubMed
Gennari  LDoci  RBignami  PBozzetti  F Surgical treatment of hepatic metastases from colorectal cancer. Ann Surg 1986;20349- 54
PubMed Link to Article
Gennari  LDoci  RBozzetti  FBignami  P Proposal for staging liver metastases. Recent Results Cancer Res 1986;10080- 84
PubMed
Fortner  JGSilva  JSGolbey  RBCox  EBMaclean  BJ Multivariate analysis of a personal series of 247 consecutive patients with liver metastases from colorectal cancer, I: treatment by hepatic resection. Ann Surg 1984;199306- 316
PubMed Link to Article
Gayowski  TJIwatsuki  SMadariaga  JR  et al.  Experience in hepatic resection for metastatic colorectal cancer: analysis of clinical and pathologic risk factors. Surgery 1994;116703- 710
PubMed
Cady  BStone  MD The role of surgical resection of liver metastases in colorectal carcinoma. Semin Oncol 1991;18399- 406
PubMed
Nordlinger  BGuiguet  MVaillant  JC  et al.  Surgical resection of colorectal carcinoma metastases to the liver: a prognostic scoring system to improve case selection, based on 1568 patients. Cancer 1996;771254- 1262
PubMed Link to Article
Fong  YFortner  JSun  RLBrennan  MFBlumgart  LH Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999;230309- 318
PubMed Link to Article
Iwatsuki  SDvorchik  IMadariaga  JR  et al.  Hepatic resection for metastatic colorectal adenocarcinoma: a proposal of a prognostic scoring system. J Am Coll Surg 1999;189291- 299
PubMed Link to Article
Schindl  MWigmore  SJCurrie  EJLaengle  FGarden  OJ Prognostic scoring in colorectal cancer liver metastases: development and validation. Arch Surg 2005;140183- 189
PubMed Link to Article
Cady  BJenkins  RLSteele  GD  Jr  et al.  Surgical margin in hepatic resection for colorectal metastasis: a critical and improvable determinant of outcome. Ann Surg 1998;227566- 571
PubMed Link to Article
Minagawa  MMakuuchi  MTorzilli  G  et al.  Extension of the frontiers of surgical indications in the treatment of liver metastases from colorectal cancer: long-term results. Ann Surg 2000;231487- 499
PubMed Link to Article
Mann  CDMetcalfe  MSLeopardi  LNMaddern  GJ The clinical risk score: emerging as a reliable preoperative prognostic index in hepatectomy for colorectal metastases. Arch Surg 2004;1391168- 1172
PubMed Link to Article
Adam  R The importance of visceral metastasectomy in colorectal cancer. Ann Oncol 2000;11 ((suppl 3)) 29- 36
PubMed
Headrick  JRMiller  DLNagorney  DM  et al.  Surgical treatment of hepatic and pulmonary metastases from colon cancer. Ann Thorac Surg 2001;71975- 979
PubMed Link to Article
Elias  DOuellet  JFBellon  N  et al.  Extrahepatic disease does not contraindicate hepatectomy for colorectal liver metastases. Br J Surg 2003;90567- 574
PubMed Link to Article
Sugarbaker  PHJablonski  KA Prognostic features of 51 colorectal and 130 appendiceal cancer patients with peritoneal carcinomatosis treated by cytoreductive surgery and intraperitoneal chemotherapy. Ann Surg 1995;221124- 132
PubMed Link to Article
Jamison  RLDonohue  JHNagorney  DM  et al.  Hepatic resection for metastatic colorectal cancer results in cure for some patients. Arch Surg 1997;132505- 510
PubMed Link to Article
Rosen  CBNagorney  DMTaswell  HF  et al.  Perioperative blood transfusion and determinants of survival after liver resection for metastatic colorectal carcinoma. Ann Surg 1992;216493- 504
PubMed Link to Article
Nakamura  SYokoi  YSuzuki  SBaba  SMuro  H Results of extensive surgery for liver metastases in colorectal carcinoma. Br J Surg 1992;7935- 38
PubMed Link to Article
Elias  DSaric  JJaeck  D  et al.  Prospective study of microscopic lymph node involvement of the hepatic pedicle during curative hepatectomy for colorectal metastases. Br J Surg 1996;83942- 945
PubMed Link to Article
Beckurts  KTHolscher  AHThorban  SBollschweiler  ESiewert  JR Significance of lymph node involvement at the hepatic hilum in the resection of colorectal liver metastases. Br J Surg 1997;841081- 1084
PubMed Link to Article
Kokudo  NSato  TSeki  M  et al.  Hepatic lymph node involvement in resected cases of liver metastases from colorectal cancer. Dis Colon Rectum 1999;421285- 1290
PubMed Link to Article
Jaeck  DNakano  HBachellier  P  et al.  Significance of hepatic pedicle lymph node involvement in patients with colorectal liver metastases: a prospective study. Ann Surg Oncol 2002;9430- 438
PubMed Link to Article
Ercolani  GGrazi  GLRavaioli  M  et al.  The role of lymphadenectomy for liver tumors: further considerations on the appropriateness of treatment strategy. Ann Surg 2004;239202- 209
PubMed Link to Article
Laurent  CSa Cunha  ARullier  E  et al.  Impact of microscopic hepatic lymph node involvement on survival after resection of colorectal liver metastasis. J Am Coll Surg 2004;198884- 891
PubMed Link to Article
Rodgers  MSMcCall  JL Surgery for colorectal liver metastases with hepatic lymph node involvement: a systematic review. Br J Surg 2000;871142- 1155
PubMed Link to Article
Butler  JAttiyeh  FFDaly  JM Hepatic resection for metastasis of the colon and rectum. Surg Gynecol Obstet 1986;162109- 113
PubMed
Iwatsuki  SEsquivel  COGordon  RDStarzl  TE Liver resection for metastatic colorectal cancer. Surgery 1986;100804- 810
PubMed
Doci  RGennari  LBignami  P  et al.  One hundred patients with hepatic metastases from colorectal cancer treated by resection: analysis of prognostic determinants. Br J Surg 1991;78797- 801
PubMed Link to Article
Scheele  JStang  RAltendorf-Hofmann  APaul  M Resection of colorectal liver metastases. World J Surg 1995;1959- 71
PubMed Link to Article
Jaeck  DBachellier  PGuiguet  M  et al.  Long-term survival following resection of colorectal hepatic metastases. Br J Surg 1997;84977- 980
PubMed Link to Article
Pedersen  IKBurcharth  FRoikjaer  OBaden  H Resection of liver metastases from colorectal cancer: indications and results. Dis Colon Rectum 1994;371078- 1082
PubMed Link to Article
Wanebo  HJChu  QDVezeridis  MPSoderberg  C Patient selection for hepatic resection of colorectal metastases. Arch Surg 1996;131322- 329
PubMed Link to Article
Rees  MPlant  GBygrave  S Late results justify resection for multiple hepatic metastases from colorectal cancer. Br J Surg 1997;841136- 1140
PubMed Link to Article
Taylor  MForster  JLanger  B  et al.  A study of prognostic factors for hepatic resection for colorectal metastases. Am J Surg 1997;173467- 471
PubMed Link to Article
Bakalakos  EAKim  JAYoung  DCMartin  EW  Jr Determinants of survival following hepatic resection for metastatic colorectal cancer. World J Surg 1998;22399- 404
PubMed Link to Article
Choti  MASitzmann  JVTiburi  MF  et al.  Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg 2002;235759- 766
PubMed Link to Article
Minagawa  MYamamoto  JMiwa  S  et al.  Selection criteria for simultaneous resection in patients with synchronous liver metastasis. Arch Surg 2006;1411006- 1012
PubMed Link to Article
Kato  TYasui  KHirai  T  et al.  Therapeutic results for hepatic metastasis of colorectal cancer with special reference to effectiveness of hepatectomy: analysis of prognostic factors for 763 cases recorded at 18 institutions. Dis Colon Rectum 2003;46 ((10)) ((suppl)) S22- S31
PubMed
Hammarstrom  S The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues. Semin Cancer Biol 1999;967- 81
PubMed Link to Article
Benchimol  SFuks  AJothy  S  et al.  Carcinoembryonic antigen, a human tumor marker, functions as an intercellular adhesion molecule. Cell 1989;57327- 334
PubMed Link to Article
von Kleist  SMigule  IHalla  B Possible function of CEA as cell-contact inhibitory molecule. Anticancer Res 1995;15 ((5B)) 1889- 1894
PubMed
Kammerer  Rvon Kleist  S The carcinoembryonic antigen (CEA) modulates effector-target cell interaction by binding to activated lymphocytes. Int J Cancer 1996;68457- 463
PubMed Link to Article
Edmiston  KHGangopadhyay  AShoji  Y  et al.  In vivo induction of murine cytokine production by carcinoembryonic antigen. Cancer Res 1997;574432- 4436
PubMed
Mayer  RJGarnick  MBSteele  GD  JrZamcheck  N Carcinoembryonic antigen (CEA) as a monitor of chemotherapy in disseminated colorectal cancer. Cancer 1978;42 ((3)) ((suppl)) 1428- 1433
PubMed Link to Article
Steele  G  JrZamcheck  N The use of carcinoembryonic antigen in the clinical management of patients with colorectal cancer. Cancer Detect Prev 1985;8421- 427
PubMed
Vogel  IFrancksen  HSoeth  E  et al.  The carcinoembryonic antigen and its prognostic impact on immunocytologically detected intraperitoneal colorectal cancer cells. Am J Surg 2001;181188- 193
PubMed Link to Article
Hostetter  RBAugustus  LBMankarious  R  et al.  Carcinoembryonic antigen as a selective enhancer of colorectal cancer metastasis. J Natl Cancer Inst 1990;82380- 385
PubMed Link to Article
Ueno  HMochizuki  HHashiguchi  Y  et al.  Predictors of extrahepatic recurrence after resection of colorectal liver metastases. Br J Surg 2004;91327- 333
PubMed Link to Article
Makuuchi  MHasegawa  HYamazaki  S Intraoperative ultrasonic examination for hepatectomy. Ultrasound Med Biol 1983; ((suppl 2)) 493- 497
PubMed
Sahani  DVKalva  SPTanabe  KK  et al.  Intraoperative US in patients undergoing surgery for liver neoplasms: comparison with MR imaging. Radiology 2004;232810- 814
PubMed Link to Article
Nordlinger  BVaillant  JCGuiguet  M  et al.  Survival benefit of repeat liver resections for recurrent colorectal metastases: 143 cases. J Clin Oncol 1994;121491- 1496
PubMed
Imamura  HSeyama  YKokudo  N  et al.  Single and multiple resections of multiple hepatic metastases of colorectal origin. Surgery 2004;135508- 517
PubMed Link to Article

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 37

Related Content

Customize your page view by dragging & repositioning the boxes below.

See Also...
Articles Related By Topic
Related Collections
PubMed Articles