Research
Original Investigation
Effect of Incorporation of Pretreatment Serum Carcinoembryonic Antigen Levels Into AJCC Staging for Colon Cancer on 5-Year Survival Pragatheeshwar Thirunavukarasu, MD; Chetasi Talati, MD; Sumeet Munjal, MD; Kris Attwood, PhD; Stephen B. Edge, MD; Valerie Francescutti, MD, MSc Invited Commentary IMPORTANCE The American Joint Committee on Cancer (AJCC) has proposed the inclusion of
pretreatment serum carcinoembryonic antigen (CEA) levels (C stage) into the conventional TNM staging system of colon cancer. The latter proposal has yet to be widely adopted because of the lack of long-term survival estimates of after C-stage incorporation into AJCC staging. OBJECTIVES To evaluate whether long-term overall and cancer-specific survival is affected by inclusion of C stage into the standard AJCC TNM staging and to study the implications on survival estimates. DESIGN, SETTING, AND PARTICIPANTS We performed a retrospective study of all patients diagnosed as having histologically proven colonic adenocarcinoma from January 1, 2004, through December 31, 2005, from the National Cancer Institute’s Surveillance, Epidemiology, and End Results database. We stratified each AJCC stage as C0 (normal) or C1 (elevated) based on the pretreatment serum CEA level. Median follow-up was 71 months. MAIN OUTCOME AND MEASURES Five-year estimates of overall and disease-specific survival and hazard ratios (HRs) for estimates of risk of overall and disease-specific mortality. RESULTS A total of 16 619 patients were evaluated, and of these, 8878 patients had C0 disease and 7741 had C1 disease. C1 stage was independently associated with a 51% and 59% increased risk of overall (HR, 1.51; 95% CI, 1.44-1.59; P < .001) and disease-specific mortality (HR, 1.59; 95% CI, 1.49-1.69; P < . 001) at a median follow-up of 71 months. Analysis of survival of the AJCC stages subdivided as C0 or C1 revealed a significant worse prognosis of C1 AJCC stages compared with the respective C0 AJCC stages. The magnitude of change in survival was large enough to cause clustering of survival estimates of C1 vs C0 cancers across various AJCC stages. Analysis of patients with stage I, II, and III cancer revealed that node-negative C1 disease was associated with prognosis similar or worse than node-positive C0 disease. CONCLUSIONS AND RELEVANCE Inclusion of C stage into the AJCC TNM staging of colon cancer revealed significant differences dependent on C stage in terms of 5-year survival. C-stage inclusion resulted in substantial change in survival estimates, with C1 status portending a prognosis to certain stages similar to or worse than higher AJCC TNM stages with C0 status. We recommend routine pretreatment CEA testing as standard of care in colon cancer and use of C stage for multimodality treatment planning and risk stratification in prospective studies and randomized clinical trials.
JAMA Surg. doi:10.1001/jamasurg.2015.0871 Published online June 17, 2015.
Author Affiliations: Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York (Thirunavukarasu, Francescutti); Department of Internal Medicine, University of Buffalo, Buffalo, New York (Talati, Munjal); Department of Biostatistics, Roswell Park Cancer Institute, Buffalo, New York (Attwood); Department of Surgery, Baptist Memorial Health Care, Memphis, Tennessee (Edge). Corresponding Author: Valerie Francescutti, MD, MSc, Department of Surgical Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263 (Valerie [email protected]).
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Research Original Investigation
Inclusion of C Stage Into the AJCC Staging of Colon Cancer
C
olon cancer is the fourth most common cancer and the second most common cause of cancer-related mortality in the United States.1 Adequate staging allows for prognostication and formulation of the plan of treatment. The TNM system developed by the American Joint Committee on Cancer (AJCC)2 is the most widely adopted method of staging of all cancers, including colon cancer.3 On the basis of the local extent of the primary tumor (T stage), the extent of regional lymph node involvement (N stage), and the presence or absence of distant metastases (M stage), colon cancer had been broadly classified into 4 overall stages: stage I (primary tumor localized within the subserosa and no regional lymph node involvement), stage II (primary tumor extending beyond the subserosa and without regional node involvement), stage III (any involvement of regional lymph nodes without distant metastases), and stage IV (distant metastases). On the basis of survival data obtained from large population-based studies, the AJCC periodically updates the arrangement of these TNM combinations into the overall stages to refine the prognostic utility of the staging system.4 Although the TNM system of classification describes the anatomical extent of malignant neoplasms and projects a stagederived survival estimate, it likely oversimplifies assessment of the biological potential of the tumor and the overall risk of recurrence and death.5,6 The AJCC has identified the potential limitation of pure anatomical staging in colon cancer.5,7 Nonanatomical prognostic factors related to biological aggressiveness have been increasingly adopted to complement and enhance the value of the AJCC TNM staging of certain cancers, such as histologic grade in sarcoma, mitotic count in melanoma, age in thyroid cancer, and prostate-specific antigen and Gleason score in prostate cancer.2 Using evidence from several studies8-15 that found pretreatment serum carcinoembryonic antigen (CEA) to be a stageindependent risk factor for poor prognosis in colorectal cancer, the Colorectal Working Group of the AJCC, as early as 2000, proposed the inclusion of serum CEA level (C stage) to complement and modify anatomical TNM staging of colon cancer.7 The group considered adding a C stage classified into substages, namely, not assessable (Cx), not elevated (ie, serum CEA level 5 ng/mL) (C1). Overall stages would be expressed as stages I through IV Cx, C0, and C1. Although it has been widely recognized that elevated pretreatment CEA level portends poor prognosis, this proposal has not been adopted into clinical practice or into AJCC staging, primarily because of the lack of validation using long-term outcomes data and the lack of information on the magnitude of effect of C-stage inclusion on the prognosis of each overall AJCC stage (ie, lack of actuarial survival estimates). To address the above limitations, we used the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database to analyze the survival outcomes after inclusion of pretreatment CEA into the AJCC staging as recommended by the Colorectal Working Group. We also aimed to study the association of C stage and N stage with prognosis to assess the magnitude of the effect of an elevated serum CEA level on prognosis compared with regional lymph node involvement. E2
Methods Data Collection and Patient Selection The SEER database includes approximately 26% of the US population.16 Given that these data are deidentified and ethics approval is waived, approval was not sought through our institution and informed consent was not obtained from the study participants. Using SEER*Stat, an online access program provided by the SEER program, we extracted data from January 1, 2004, through December 31, 2005, on all patients diagnosed as having microscopically confirmed colon adenocarcinoma with available pretreatment serum CEA level information. These analyses of the SEER data are only possible recently because SEER did not routinely collect CEA level information for cases diagnosed before 2004. We included data pertaining to the age at diagnosis; sex; race/ethnicity; marital status at diagnosis; location of the colonic primary tumor (ascending colon, hepatic flexure, transverse colon, splenic flexure, descending colon, sigmoid colon, or overlapping site); the International Classification of Diseases for Oncology, Third Edition, histology code; histologic grade; stage; and use of surgical resection. The SEER database coded data on the pretreatment serum CEA level as “test not done,” “positive/elevated,” “negative/normal; within normal limits,” “borderline; undetermined whether positive or negative,” “ordered, but results not in chart,” or “unknown or no information.” A single cutoff value for determining an abnormal elevation of the serum CEA level may be impractical and inappropriate in a large populationbased database because of variation in the absolute serum CEA levels with patient-related factors (such as heavy smoking and liver dysfunction) and assay techniques used by the testing laboratory. The SEER program therefore used the physician’s interpretation of CEA level information in the medical record when available or the reference values provided by the laboratory reporting the result. We assigned stage C0 to patients with a serum CEA level coded as “negative/normal; within normal limits” and C1 to those with a serum CEA level coded as “positive/elevated.” We used the following exclusion criteria: nonadenocarcinomatous histologic findings, lifetime occurrence of another primary malignant neoplasm and patients recorded to have borderline CEA levels, or CEA levels not recorded or not completed. Survival estimates were based on data from the SEER database. Our final cohort consisted of 16 619 unique records, which were then used for statistical analyses. Using the codes CS (collaborative stage) extension and regional nodes positive (in year 2004 or later), detailed T-stage and N-stage information was extracted, and all cancers were staged according to the AJCC Cancer Staging Handbook.2 Further details about the data reporting of follow-up and linkage can be obtained by accessing the SEER Data Management System User Manual (seer .cancer.gov).
Statistical Analyses Patient characteristics were reported as means (SDs) for continuous variables and as relative frequencies for categorical
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Inclusion of C Stage Into the AJCC Staging of Colon Cancer
variables. The survival outcomes, overall survival (OS), and disease-specific survival (DSS) (ie, cancer), were analyzed using the overall AJCC stage and AJCC and C-stage combinations using standard Kaplan-Meier methods. Estimates of 5-year survival rates were obtained for each stage group, with the corresponding 95% CIs. The log-rank test was used to compare survival among the stage groups in a pairwise fashion. The Tukey honestly significant difference was used to adjust for multiple comparisons. Cox regression models were used to obtain hazard ratios (HRs) for comparing risks of overall and disease-specific mortality among the stage groups. In one multivariate regression analysis, we used a novel covariate (NC), which is a combination of each tumor’s N and C stage to study the interaction of these 2 covariates on prognosis. All analyses were conducted using SAS statistical software, version 9.3 (SAS Institute Inc), at P < .05.
Results Comparison of Patients With C0 and C1 Disease Of the entire study cohort (16 619 records), 8878 patients had C0 disease and 7741 patients had C1 disease. Comparison of patient and tumor characteristics between patients with C0 and C1 disease is given in Table 1. Patients with C1 disease more commonly presented at later stages compared with patients with C0 disease. There were 24.0% of C0 patients vs 41.5% of C1 patients presenting with stage IV disease.
Original Investigation Research
ample, overall mortality of patients with stage IIA C0 disease (HR, 1.41; 95% CI, 1.25-1.59) is lower than that of patients with stage I C1 disease (HR, 2.01; 95% CI, 1.68-2.40), and overall mortality of patients with stage IIIA C0 disease (HR, 0.89; 95% CI, 0.68-1.15) is lower than that of patients with stage IA C1 or IIA C1 disease (HR, 2.27; 95% CI, 2.01-2.57). A similar pattern can be observed in DSS outcomes as well. This phenomenon is better illustrated in the Kaplan-Meier curves (Figure), where the curves of patients with C0 disease of certain AJCC stages appear to be grouped or clustered, whereas the curves of patients with C1 disease of the respective AJCC stages appear to be clustered separately.
Interaction of C Stage and N Stage With Colon Cancer Prognosis Next, we analyzed the association of various combinations of N and C stages with prognosis among all patients with nondistant metastatic (stages I, II, and III) colon cancer to understand the interaction of nodal status and CEA status (Table 4). We calculated the hazards for overall and disease-specific mortality separately, along with the respective 95% CIs, for each N-stage and C-stage combination by using the N0 and C0 combination as the reference value to allow comparison of the outcomes among various combinations. We again observed that patients with C1 disease of each nodal stage had a worse prognosis than patients with C0 disease of the respective nodal stage, and the prognosis of patients with C1 disease with lower nodal stages was worse or similar to that of patients with C0 disease of higher nodal stages.
C Stage as a Prognostic Factor in Colon Cancer Multivariate analyses were used to identify factors independently associated with overall and disease-specific mortality at a median follow-up of 71 months (Table 2). C1 stage was a stage-independent poor prognostic factor associated with an increase in overall mortality (HR, 1.51; 95% CI, 1.44-1.59; P < .001) and disease-specific mortality (HR, 1.59; 95% CI, 1.491.69; P < .001).
Prognosis of Colon Cancer After Incorporation of C Stage into TNM Staging We analyzed the implications of the inclusion of C stage into the AJCC staging by calculating the 5-year OS and DSS outcomes for various AJCC and C-stage combinations, such as stages I C0, I C1, IIA C0, IIA C1, and so on (Table 3). We calculated the hazards for overall and disease-specific mortality separately, along with the respective 95% CIs, by using stage I C0 as the reference value to allow comparison of the outcomes among the various stages. We made 2 major observations. First, within each AJCC stage, patients with C1 disease had a worse prognosis compared with patients with C0 disease. For example, prognosis of patients with stage I C1 disease was worse than patients with stage I C0 disease and so on. Second, the magnitude of the difference in survival between patients with C0 and C1 disease within each stage was large enough that the prognosis of patients with C1 disease of lower AJCC stages was similar to or worse than that of patients with C0 disease of higher AJCC stages. This finding can be gleaned by observing the overlap of the 95% CIs. For ex-
Discussion This study analyzed the long-term prognosis of patients with histologically proven colonic adenocarcinoma after the incorporation of information of their pretreatment serum CEA level into the TNM staging system. The SEER database study was limited to those whose conditions were diagnosed after 2003 because SEER did not collect CEA level information until 2004. With the most recent update of the SEER database (2010 submission), long-term follow-up data were available for analysis for patients whose conditions were diagnosed in 2004 and 2005, thus making it possible to conduct such a large-scale study for long-term survival outcomes. A previous study17 evaluated the effect of C stage on anatomical TNM staging for colon cancer, including its effect on prognosis in terms of 2-year overall survival rate and the hazards for overall mortality, using the SEER database. This study revealed that (1) C1 stage was a stage-independent poor prognostic factor associated with a 60% increased risk of overall mortality; (2) prognosis of C1 cancers of lower AJCC stages were similar or worse than the prognosis of C0 cancers of corresponding higher AJCC stages (ie, inclusion of C stage into the TNM staging resulted in a magnitude of effect large enough to cause stage migration); and (3) node-negative C1 cancers were associated with a poorer prognosis than C0 cancers with limited nodal burden (N1 and N2a). Nevertheless, this study was limited because only short-term outcomes were available for
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E3
Research Original Investigation
Inclusion of C Stage Into the AJCC Staging of Colon Cancer
Table 1. Comparison of Patients With C0 and C1 Disease No. (%) of Patients Characteristic Age, mean (SD), y
All (N = 16 619)
C0 Disease (n = 8878)
67.4 (13.8)
67.4 (13.8)
C1 Disease (n = 7741) 67.5 (13.9)
P Value .93
Sex Male
4416 (49.7)
7936 (47.8)
3520 (45.5)
Female
4462 (50.3)
8683 (52.2)
4221 (54.5)
Original Investigation
Effect of Incorporation of Pretreatment Serum Carcinoembryonic Antigen Levels Into AJCC Staging for Colon Cancer on 5-Year Survival Pragatheeshwar Thirunavukarasu, MD; Chetasi Talati, MD; Sumeet Munjal, MD; Kris Attwood, PhD; Stephen B. Edge, MD; Valerie Francescutti, MD, MSc Invited Commentary IMPORTANCE The American Joint Committee on Cancer (AJCC) has proposed the inclusion of
pretreatment serum carcinoembryonic antigen (CEA) levels (C stage) into the conventional TNM staging system of colon cancer. The latter proposal has yet to be widely adopted because of the lack of long-term survival estimates of after C-stage incorporation into AJCC staging. OBJECTIVES To evaluate whether long-term overall and cancer-specific survival is affected by inclusion of C stage into the standard AJCC TNM staging and to study the implications on survival estimates. DESIGN, SETTING, AND PARTICIPANTS We performed a retrospective study of all patients diagnosed as having histologically proven colonic adenocarcinoma from January 1, 2004, through December 31, 2005, from the National Cancer Institute’s Surveillance, Epidemiology, and End Results database. We stratified each AJCC stage as C0 (normal) or C1 (elevated) based on the pretreatment serum CEA level. Median follow-up was 71 months. MAIN OUTCOME AND MEASURES Five-year estimates of overall and disease-specific survival and hazard ratios (HRs) for estimates of risk of overall and disease-specific mortality. RESULTS A total of 16 619 patients were evaluated, and of these, 8878 patients had C0 disease and 7741 had C1 disease. C1 stage was independently associated with a 51% and 59% increased risk of overall (HR, 1.51; 95% CI, 1.44-1.59; P < .001) and disease-specific mortality (HR, 1.59; 95% CI, 1.49-1.69; P < . 001) at a median follow-up of 71 months. Analysis of survival of the AJCC stages subdivided as C0 or C1 revealed a significant worse prognosis of C1 AJCC stages compared with the respective C0 AJCC stages. The magnitude of change in survival was large enough to cause clustering of survival estimates of C1 vs C0 cancers across various AJCC stages. Analysis of patients with stage I, II, and III cancer revealed that node-negative C1 disease was associated with prognosis similar or worse than node-positive C0 disease. CONCLUSIONS AND RELEVANCE Inclusion of C stage into the AJCC TNM staging of colon cancer revealed significant differences dependent on C stage in terms of 5-year survival. C-stage inclusion resulted in substantial change in survival estimates, with C1 status portending a prognosis to certain stages similar to or worse than higher AJCC TNM stages with C0 status. We recommend routine pretreatment CEA testing as standard of care in colon cancer and use of C stage for multimodality treatment planning and risk stratification in prospective studies and randomized clinical trials.
JAMA Surg. doi:10.1001/jamasurg.2015.0871 Published online June 17, 2015.
Author Affiliations: Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York (Thirunavukarasu, Francescutti); Department of Internal Medicine, University of Buffalo, Buffalo, New York (Talati, Munjal); Department of Biostatistics, Roswell Park Cancer Institute, Buffalo, New York (Attwood); Department of Surgery, Baptist Memorial Health Care, Memphis, Tennessee (Edge). Corresponding Author: Valerie Francescutti, MD, MSc, Department of Surgical Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263 (Valerie [email protected]).
(Reprinted) E1
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Downloaded From: http://archsurg.jamanetwork.com/ by a University of Iowa User on 06/21/2015
Research Original Investigation
Inclusion of C Stage Into the AJCC Staging of Colon Cancer
C
olon cancer is the fourth most common cancer and the second most common cause of cancer-related mortality in the United States.1 Adequate staging allows for prognostication and formulation of the plan of treatment. The TNM system developed by the American Joint Committee on Cancer (AJCC)2 is the most widely adopted method of staging of all cancers, including colon cancer.3 On the basis of the local extent of the primary tumor (T stage), the extent of regional lymph node involvement (N stage), and the presence or absence of distant metastases (M stage), colon cancer had been broadly classified into 4 overall stages: stage I (primary tumor localized within the subserosa and no regional lymph node involvement), stage II (primary tumor extending beyond the subserosa and without regional node involvement), stage III (any involvement of regional lymph nodes without distant metastases), and stage IV (distant metastases). On the basis of survival data obtained from large population-based studies, the AJCC periodically updates the arrangement of these TNM combinations into the overall stages to refine the prognostic utility of the staging system.4 Although the TNM system of classification describes the anatomical extent of malignant neoplasms and projects a stagederived survival estimate, it likely oversimplifies assessment of the biological potential of the tumor and the overall risk of recurrence and death.5,6 The AJCC has identified the potential limitation of pure anatomical staging in colon cancer.5,7 Nonanatomical prognostic factors related to biological aggressiveness have been increasingly adopted to complement and enhance the value of the AJCC TNM staging of certain cancers, such as histologic grade in sarcoma, mitotic count in melanoma, age in thyroid cancer, and prostate-specific antigen and Gleason score in prostate cancer.2 Using evidence from several studies8-15 that found pretreatment serum carcinoembryonic antigen (CEA) to be a stageindependent risk factor for poor prognosis in colorectal cancer, the Colorectal Working Group of the AJCC, as early as 2000, proposed the inclusion of serum CEA level (C stage) to complement and modify anatomical TNM staging of colon cancer.7 The group considered adding a C stage classified into substages, namely, not assessable (Cx), not elevated (ie, serum CEA level 5 ng/mL) (C1). Overall stages would be expressed as stages I through IV Cx, C0, and C1. Although it has been widely recognized that elevated pretreatment CEA level portends poor prognosis, this proposal has not been adopted into clinical practice or into AJCC staging, primarily because of the lack of validation using long-term outcomes data and the lack of information on the magnitude of effect of C-stage inclusion on the prognosis of each overall AJCC stage (ie, lack of actuarial survival estimates). To address the above limitations, we used the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database to analyze the survival outcomes after inclusion of pretreatment CEA into the AJCC staging as recommended by the Colorectal Working Group. We also aimed to study the association of C stage and N stage with prognosis to assess the magnitude of the effect of an elevated serum CEA level on prognosis compared with regional lymph node involvement. E2
Methods Data Collection and Patient Selection The SEER database includes approximately 26% of the US population.16 Given that these data are deidentified and ethics approval is waived, approval was not sought through our institution and informed consent was not obtained from the study participants. Using SEER*Stat, an online access program provided by the SEER program, we extracted data from January 1, 2004, through December 31, 2005, on all patients diagnosed as having microscopically confirmed colon adenocarcinoma with available pretreatment serum CEA level information. These analyses of the SEER data are only possible recently because SEER did not routinely collect CEA level information for cases diagnosed before 2004. We included data pertaining to the age at diagnosis; sex; race/ethnicity; marital status at diagnosis; location of the colonic primary tumor (ascending colon, hepatic flexure, transverse colon, splenic flexure, descending colon, sigmoid colon, or overlapping site); the International Classification of Diseases for Oncology, Third Edition, histology code; histologic grade; stage; and use of surgical resection. The SEER database coded data on the pretreatment serum CEA level as “test not done,” “positive/elevated,” “negative/normal; within normal limits,” “borderline; undetermined whether positive or negative,” “ordered, but results not in chart,” or “unknown or no information.” A single cutoff value for determining an abnormal elevation of the serum CEA level may be impractical and inappropriate in a large populationbased database because of variation in the absolute serum CEA levels with patient-related factors (such as heavy smoking and liver dysfunction) and assay techniques used by the testing laboratory. The SEER program therefore used the physician’s interpretation of CEA level information in the medical record when available or the reference values provided by the laboratory reporting the result. We assigned stage C0 to patients with a serum CEA level coded as “negative/normal; within normal limits” and C1 to those with a serum CEA level coded as “positive/elevated.” We used the following exclusion criteria: nonadenocarcinomatous histologic findings, lifetime occurrence of another primary malignant neoplasm and patients recorded to have borderline CEA levels, or CEA levels not recorded or not completed. Survival estimates were based on data from the SEER database. Our final cohort consisted of 16 619 unique records, which were then used for statistical analyses. Using the codes CS (collaborative stage) extension and regional nodes positive (in year 2004 or later), detailed T-stage and N-stage information was extracted, and all cancers were staged according to the AJCC Cancer Staging Handbook.2 Further details about the data reporting of follow-up and linkage can be obtained by accessing the SEER Data Management System User Manual (seer .cancer.gov).
Statistical Analyses Patient characteristics were reported as means (SDs) for continuous variables and as relative frequencies for categorical
JAMA Surgery Published online June 17, 2015 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
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jamasurgery.com
Inclusion of C Stage Into the AJCC Staging of Colon Cancer
variables. The survival outcomes, overall survival (OS), and disease-specific survival (DSS) (ie, cancer), were analyzed using the overall AJCC stage and AJCC and C-stage combinations using standard Kaplan-Meier methods. Estimates of 5-year survival rates were obtained for each stage group, with the corresponding 95% CIs. The log-rank test was used to compare survival among the stage groups in a pairwise fashion. The Tukey honestly significant difference was used to adjust for multiple comparisons. Cox regression models were used to obtain hazard ratios (HRs) for comparing risks of overall and disease-specific mortality among the stage groups. In one multivariate regression analysis, we used a novel covariate (NC), which is a combination of each tumor’s N and C stage to study the interaction of these 2 covariates on prognosis. All analyses were conducted using SAS statistical software, version 9.3 (SAS Institute Inc), at P < .05.
Results Comparison of Patients With C0 and C1 Disease Of the entire study cohort (16 619 records), 8878 patients had C0 disease and 7741 patients had C1 disease. Comparison of patient and tumor characteristics between patients with C0 and C1 disease is given in Table 1. Patients with C1 disease more commonly presented at later stages compared with patients with C0 disease. There were 24.0% of C0 patients vs 41.5% of C1 patients presenting with stage IV disease.
Original Investigation Research
ample, overall mortality of patients with stage IIA C0 disease (HR, 1.41; 95% CI, 1.25-1.59) is lower than that of patients with stage I C1 disease (HR, 2.01; 95% CI, 1.68-2.40), and overall mortality of patients with stage IIIA C0 disease (HR, 0.89; 95% CI, 0.68-1.15) is lower than that of patients with stage IA C1 or IIA C1 disease (HR, 2.27; 95% CI, 2.01-2.57). A similar pattern can be observed in DSS outcomes as well. This phenomenon is better illustrated in the Kaplan-Meier curves (Figure), where the curves of patients with C0 disease of certain AJCC stages appear to be grouped or clustered, whereas the curves of patients with C1 disease of the respective AJCC stages appear to be clustered separately.
Interaction of C Stage and N Stage With Colon Cancer Prognosis Next, we analyzed the association of various combinations of N and C stages with prognosis among all patients with nondistant metastatic (stages I, II, and III) colon cancer to understand the interaction of nodal status and CEA status (Table 4). We calculated the hazards for overall and disease-specific mortality separately, along with the respective 95% CIs, for each N-stage and C-stage combination by using the N0 and C0 combination as the reference value to allow comparison of the outcomes among various combinations. We again observed that patients with C1 disease of each nodal stage had a worse prognosis than patients with C0 disease of the respective nodal stage, and the prognosis of patients with C1 disease with lower nodal stages was worse or similar to that of patients with C0 disease of higher nodal stages.
C Stage as a Prognostic Factor in Colon Cancer Multivariate analyses were used to identify factors independently associated with overall and disease-specific mortality at a median follow-up of 71 months (Table 2). C1 stage was a stage-independent poor prognostic factor associated with an increase in overall mortality (HR, 1.51; 95% CI, 1.44-1.59; P < .001) and disease-specific mortality (HR, 1.59; 95% CI, 1.491.69; P < .001).
Prognosis of Colon Cancer After Incorporation of C Stage into TNM Staging We analyzed the implications of the inclusion of C stage into the AJCC staging by calculating the 5-year OS and DSS outcomes for various AJCC and C-stage combinations, such as stages I C0, I C1, IIA C0, IIA C1, and so on (Table 3). We calculated the hazards for overall and disease-specific mortality separately, along with the respective 95% CIs, by using stage I C0 as the reference value to allow comparison of the outcomes among the various stages. We made 2 major observations. First, within each AJCC stage, patients with C1 disease had a worse prognosis compared with patients with C0 disease. For example, prognosis of patients with stage I C1 disease was worse than patients with stage I C0 disease and so on. Second, the magnitude of the difference in survival between patients with C0 and C1 disease within each stage was large enough that the prognosis of patients with C1 disease of lower AJCC stages was similar to or worse than that of patients with C0 disease of higher AJCC stages. This finding can be gleaned by observing the overlap of the 95% CIs. For ex-
Discussion This study analyzed the long-term prognosis of patients with histologically proven colonic adenocarcinoma after the incorporation of information of their pretreatment serum CEA level into the TNM staging system. The SEER database study was limited to those whose conditions were diagnosed after 2003 because SEER did not collect CEA level information until 2004. With the most recent update of the SEER database (2010 submission), long-term follow-up data were available for analysis for patients whose conditions were diagnosed in 2004 and 2005, thus making it possible to conduct such a large-scale study for long-term survival outcomes. A previous study17 evaluated the effect of C stage on anatomical TNM staging for colon cancer, including its effect on prognosis in terms of 2-year overall survival rate and the hazards for overall mortality, using the SEER database. This study revealed that (1) C1 stage was a stage-independent poor prognostic factor associated with a 60% increased risk of overall mortality; (2) prognosis of C1 cancers of lower AJCC stages were similar or worse than the prognosis of C0 cancers of corresponding higher AJCC stages (ie, inclusion of C stage into the TNM staging resulted in a magnitude of effect large enough to cause stage migration); and (3) node-negative C1 cancers were associated with a poorer prognosis than C0 cancers with limited nodal burden (N1 and N2a). Nevertheless, this study was limited because only short-term outcomes were available for
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E3
Research Original Investigation
Inclusion of C Stage Into the AJCC Staging of Colon Cancer
Table 1. Comparison of Patients With C0 and C1 Disease No. (%) of Patients Characteristic Age, mean (SD), y
All (N = 16 619)
C0 Disease (n = 8878)
67.4 (13.8)
67.4 (13.8)
C1 Disease (n = 7741) 67.5 (13.9)
P Value .93
Sex Male
4416 (49.7)
7936 (47.8)
3520 (45.5)
Female
4462 (50.3)
8683 (52.2)
4221 (54.5)
