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Originally published as JCO Early Release 10.1200/JCO.2004.07.015 on February 9 2004 © 2004 American Society of Clinical Oncology. New Tumor-Node-Metastasis Staging Strategy for Node-Positive (stage III) Rectal Cancer: An AnalysisFrom the Department of General Surgery, and the Department of Biostatistics, Carolinas Medical Center, Charlotte, NC; Cancer Program, American College of Surgeons, Chicago, IL. Address reprint requests to Frederick L. Greene, MD, Department of General Surgery, Carolinas Medical Center, PO Box 32861, Charlotte, NC 28232-2861; e-mail: frederick.greene{at}carolinashealthcare.org
PURPOSE: The tumor-node-metastasis system for staging rectal cancer is based on invasion, number of involved nodes, and metastasis. Nodes are classified as N1 or N2 according to the number involved with metastases. Nodal positivity defines stage III regardless of depth of invasion or number of positive nodes. Our purpose was to analyze overall survival when node-positive patients were stratified into three new subsets. METHODS: We analyzed data entered into the National Cancer Data Base for 5,987 stage III patients with rectal cancer between 1991 and 1993. Survival was calculated using three new subgroups (IIIA: T1/2, N1; IIIB: T3/4, N1; IIIC: any T, N2). Survival following surgery and adjuvant therapy was assessed. The observed survival rates were calculated and compared using the log-rank method. The Cox regression model assessed subgroup differences. RESULTS: Five-year observed survival rates for stage III subcategories were 55.1% in IIIA; 35.3% in IIIB; and 24.5% in IIIC. Stratifying for treatment outcome, stage IIIA patients having surgery alone (n = 278) had poorer observed 5-year survival (39%) than patients treated with surgery and adjuvant chemotherapy or radiation therapy (chemo/XRT; n = 765; 60%). Similar outcomes occurred in IIIB (surgery-alone [n = 726; 21.7%] and chemo/XRT [n = 2,130; 40.9%] groups) and in IIIC (surgery-alone [n = 467; 12.2%] and chemo/XRT [n = 1,621; 28.9%] groups). Differences were significant (P < .0001) in all stages. CONCLUSION: The traditional stage III designation of rectal cancer fails to account for invasion (T1-4) and number of involved nodes (N1, N2). The stratification of stage III patients into three subsets should be used in future analyses of rectal cancer. The effect of postoperative adjuvant therapy was beneficial in all subsets.
Since 1987,1 the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC) have promoted a worldwide taxonomy of cancer staging based on localized tumor characteristics, nodal involvement, and the status of metastatic implants. The group stage in the tumor-node-metastasis (TNM) system is based on a combination of locoregional tumor involvement and the presence of metastases. Traditional strategies2 of TNM system staging of rectal cancer have grouped patients having mesenteric nodal involvement into the stage III category despite variations in depth of tumor penetration of the rectal wall. A recent analysis of medium-sized patient data sets has suggested that stage III colorectal cancer is heterogeneous in survival patterns when differences in T and N categories are considered.3 An analysis of a large data set using patients reported to the National Cancer Data Base (NCDB) has shown the value of stratification of patients with stage III colon cancer.4 To determine the prognostic significance of subgroup stratification in staging patients with node-positive rectal cancer, we analyzed patient data entered into this large national outcomes tumor registry.
The NCDB is a hospital cancer registry–based, national clinical surveillance and outcomes database supported by the American College of Surgeons and the American Cancer Society.5 The NCDB captures information on 70% to 75% of all newly diagnosed cancer cases in the United States annually. Analysis of patients with rectal carcinoma has focused on management trends and population outcomes.6 The database includes demographic information and tumor stage information, including treatment and survival data. It is now possible to obtain 5-, 10-, and 15-years' follow-up on the 6 million cases of cancer accessioned in the NCDB. The data set contains 48,584 cases of adult (> 16 years) rectal cancer reported for the years 1991 through 1993. From this cohort, 5,987 patients with stage III disease were identified. Patients with clinical or pathologic evidence of metastasis were removed from analysis. During this 3-year period, a total of 1,167 hospitals reported cases to the NCDB. Of this total, 383 (32.8%) were community or nonteaching hospitals; 390 (33.4%) were comprehensive community hospitals or minor teaching hospitals; 233 (20%) were academic or research institutions; and the remaining 161 hospitals (13.8%) could not be classified into one of these three groups. The cases included in this study constitute approximately 37% of node-positive (stage III) rectal cancers diagnosed in the United States between 1991 and 1993. This is consistent with previously reported increased hospital participation and reporting patterns to the NCDB.7,8 Cases included in this study were reported as having been staged according to either the Third9 or Fourth10 Editions of the AJCC Manual for Staging of Cancer. These prior editions included an N3 designation under the stage III group. This designation included nodal involvement in any lymph nodes along named vessels or to the highest apical node marked by the surgeon. Beginning with the Fifth Edition of the AJCC Cancer Staging Manual,2 the N3 designation was incorporated into the N1 or N2 categories, indicating the number of nodes harboring tumor. Survival rates were calculated using a proposed strategy dividing traditional stage III patients into three new subgroups: IIIA (T1/2, N1, M0), IIIB (T3/4, N1, M0), and IIIC (any T, N2, M0). Demographic characteristics, including patient age, sex, and ethnicity, as well as survival benefit of surgery and adjuvant chemotherapy and radiation, were assessed. Observed survival rates (deaths from all causes) were calculated by standard actuarial life-table methods compounding survival in 1-month intervals from the date of diagnosis, with death from any cause as the end point. We calculated 95% CIs using the SE of the computed 5-year survival rate to show differences in survival rates.11 A Cox proportional hazards regression model was fitted to test for prognostic contribution of covariates beyond those illustrated through stratified univariate survival calculations.12,13 The primary end point was time of death, measured from the date of first diagnosis. The Cox model accounts for unequal duration of follow-up and censoring of living patients. The SPSS program (SPSS for Windows, Advanced Statistics, release 9.0; SPSS Inc, Chicago, IL) was used for all analyses. A P < .05 was considered statistically significant.
This analysis included 5,987 patients. The total group included 3,504 men (58.5%) and 2,483 women (41.4%). The average age of men was 64.9 years, and the average age of women was 66.6 years; 58.6% of patients were younger than 70 years, and 41.4% were older than 70 years. Non-Hispanic white patients constituted 78.5% (n = 4,698) of the total group; African Americans, 6.4% (n = 383); Hispanics, 2.8% (n = 165); Asian/Pacific Islanders, 1.9% (n = 111); Native Americans, 0.2% (n = 10); and patients of unknown or unspecified ethnic background, 10.2% (n = 620) of the identified cases. All tumors were limited to the anatomic rectum, designated as extending from the anal verge up to 12 cm proximal to the anal verge.14 First-course therapy information was available for all cases included in this study. All patients received a surgical operation that resulted in a pathologic specimen; 44.1% had a wedge or segmental resection; 44% had a total proctectomy; 5.1% underwent a colectomy or proctectomy with an enbloc resection of other organs; 2.6% received a pull through with sphincter preservation; and 4.1% were reported as undergoing resection, not otherwise specified. Eighty-two percent of patients (n = 4,909) received external beam radiation as part of the reported first course of therapy, and additional information describing the dose delivered to patients was not available. First-course chemotherapy was reported to have been administered to 72.1% (n = 4,315) of patients. Reported information was limited to identifying whether single or multiple agent regimens were administered to the patient. Chemotherapy agent, dose, and cycle information is not routinely captured in hospital-based cancer registries. Three distinct subcategories within the traditional TNM system stage III group are identified using the stage group definitions proposed in the sixth Edition of the AJCC Cancer Staging Manual15 and based on analysis of survival data. The IIIA subgroup (n = 1,043) represents patients with T1/2 rectal wall involvement (invasion of submucosa or muscularis propria; Figs 1A and 1B) and N1 nodal involvement (1 to 3 positive regional nodes). This subgroup represents 17.4% of all patients with stage III disease reported. The IIIB subgroup (n = 2,856) includes patients with T3/4 mural involvement (invasion through muscularis propria and subserosa or the contiguous involvement of adjacent structures; Figs 2A and 2B) and N1 regional nodal involvement. The IIIB group represents 47.6% of the stage III cohort. The IIIC subgroup (n = 2,088) is classified as any degree of mural involvement (T1-4) with four or more regional nodes positive (N2). This subgroup represents 34.8% of the stage III group.
The 5-year observed survival rate (Table 1) for stage IIIA (T1/2, N1) patients was 55.1% (95% CI, 55.05 to 55.15). Patients with stage IIIB (T3/4, N1) disease had an observed survival rate of 35.3% (95% CI, 35.27 to 35.33), and the stage IIIC (any T, N2) group faired worse, with a 24.5% (95% CI, 24.47 to 24.53) observed survival rate. The differences in the survival rates were statistically significant among the three subgroups (Fig 3). When each newly designated stage III subgroup is adjusted for age, sex, and ethnicity, the overall differences in calculated relative survival rates remain significant (Table 1).
A multivariate Cox proportional hazards model identified four covariates as being significantly associated with patient outcomes. These covariates, in descending order of associated significance with patient survival are: (1) stage III subgroups; (2) patient age; (3) tumor grade; and (4) first-course treatment modality. Stage III subsets were strong discriminates of survival with hazard ratios of 1.7 and 2.4 for the IIIB and IIIC subsets, respectively, when these patients are compared with those in the IIIA stage group (Table 2). Patient age may be considered a proximal representation of patient comorbid conditions and can affect treatment management decisions.16 Age stratification above and below 70 years showed the importance of stage differentiation (Fig 4). Decreasing tumor differentiation (higher tumor grade) is associated with an increased stage of disease at diagnosis17 (Table 3). Although grade is not included in current TNM system strategies, tumor differentiation is an important indicator of worsening outcome in each subset of the stage III patients (Fig 5). Treatment of stage III rectal cancer showed that a combination of surgical resection followed by radiation and chemotherapy led to overall better outcomes than using only surgical resection (Table 4). Figures 6 and 7 show 5-year survival outcomes for each stage III subgroup stratified by treatment modality (surgery alone [Fig 6] and surgery plus radiation and chemotherapy [Fig 7]). The observed and relative survival of each stage III subset show the positive effect of adjuvant chemotherapy and radiation compared with surgical therapy alone (Table 4). The significant number of patients with rectal cancer treated with surgery alone reflects the time frame of reporting of this patient cohort just after the 1990 National Institutes of Health Consensus Conference publication18 recommending adjuvant multimodality treatment for stage III rectal cancer.
The TNM system was introduced by Pierre Denoix of France in the 1940s19 and has remained an important prognostic indicator for most solid tumors. For colorectal cancer, staging strategies recommended by Cuthbert Dukes20 and modified by Kirklin et al21 and Astler and Coller22 were based on careful analyses of mural involvement and the presence of regional nodal involvement, though the number of regional nodes involved was not considered. Careful pathological assessment of lymph nodes in the colonic mesentery was supported by the work of Gilchrist and David23 in the 1930s and 1940s. They equated node positivity with decreased survival, and recommended that extensive mesenteric resection leads to more complete nodal analysis and potentially better survival. The presence of positive regional nodes has been the descriptor that has stratified patients with rectal cancer into the TNM system stage III group as described by the AJCC and UICC. Prior reports have shared concern regarding the potential "prognostic in-homogeneity" of the traditional stage III designation. Merkel et al3 recently described 1,453 patients comprising two cohorts of colorectal carcinoma from the Erlangen Registry of Colorectal Carcinomas and the German Study Group of Colorectal Carcinoma. These data sets, while spanning from 1978 to 1997, contained only 788 patients with rectal carcinoma. Stage III patients were stratified into T1/2 versus T3 versus T4, with N1/2 held constant. This strategy revealed significant 5-year survival differences based on Kaplan-Meier methodology. More significant survival differences were identified when T1/2, N1 and T3/4, N1 subgroups were compared. In the German cohort of patients, division of N2 patients into T1/2, N2 and T3/4, N2 showed meaningful survival differences. Various permutations of the T and N category are capable of showing survival differences on subgroup analysis of stage III. The present study shows the most robust differentiation among the three groups, with the N2 subgroup deserving a separate delineation from any of the T descriptors. Gunderson et al pooled a number of North American adjuvant studies of rectal cancer.24,25 These patients received postoperative radiation and were randomized to receive adjuvant chemotherapy. The authors showed that overall survival and disease-free survival were dependent on both the T and N categories. Within the N2 group, the T category influenced the 5-year survival. Based on this work, an intermediate risk group (T3, N0; T1-2, N1), a moderately high-risk group (T4, N0; T1-2, N2; T3 N1), and a high-risk group (T3, N2; T4, N1; T4, N2) were described. Although our analysis supports a strategy to divide only the traditional stage III patients, the recommendations of Gunderson et al, indicating that treatment might be individualized according to subset stratification, certainly give further importance to the staging differentiation of the stage III patients. Based on current recommendations of postsurgical adjuvant therapy for patients with node-positive rectal cancer,26 in the present analysis, the advantages of adjuvant chemotherapy and radiation are apparent for each of the proposed subgroups in the traditional stage III group. There is no evidence that any of the subgroups of stage III should be approached differently regarding the need for postsurgical treatment. The role of neoadjuvant therapy cannot be evaluated in this analysis. Although preoperative radiation has shown benefit after total mesorectal excision in terms of a reduced local recurrence rate when compared with total mesorectal excision alone,27 treatment decisions regarding adjuvant radiation may be based on stratification of stage III patients in the future.28 The inherent value of any cancer staging system is its reproducibility and applicability to current methods of pathological assessment. Since the stage III group is defined by the identification and quantification of mesenteric nodes, accuracy of staging is directly proportional to the aggressiveness of surgical resection, and nodal identification in this group of patients. The AJCC15 and the College of American Pathologists29 have recommended examination of at least 12 lymph nodes to assure better identification of stage III patients. While examination of at least 12 to 15 lymph nodes has been recommended for adequate determination of stage III rectal cancer, the finding of any nodal involvement regardless of the number of nodes examined continues to indicate stage III disease. Goldstein30 has shown that nodal metastases in patients with T3 tumors were present in 22% of specimens with fewer than 15 identified nodes compared with 85% in specimens with 15 or greater recovered nodes. Patients without nodal metastases also showed a survival advantage when a greater number of nodes was identified, indicating the positive effect of the greater magnitude of mesenteric resection. Other studies31,32 have suggested additional benchmarks for nodal excision. Although some have supported the concept of "upstaging" patients with stage I or II colorectal cancer using immunohistochemical identification of lymphatic involvement with or without sentinel node assessment,33-35 there is no clear evidence to support that treatment decisions should be based on the "microinvasive" stage III patient.36 The AJCC and UICC continue to recommend that nodal assessment for colorectal cancer should depend on traditional hematoxylin and eosin techniques. To be relevant, however, the TNM system must be dynamic enough to incorporate changes in molecular or genetic identification if supported by outcomes analysis. Recent authors36 have suggested that the current AJCC15 and UICC37 guidelines regarding micrometastasis and isolated tumor cells give license to add immunohistochemical and molecular methods to routine nodal assessment in the management of colorectal cancer. Because of current lack of outcome data, this trend toward "microstaging" should be resisted except under well-defined protocol guidelines. Recommendations for subclassifying traditional stage III patients with rectal cancer into three prognostic groups should be universally applied, and are included in the sixth edition of the AJCC Cancer Staging Manual.15
The authors indicated no potential conflicts of interest.
Presented at the 39th Annual Meeting of the American Society of Clinical Oncology, May 31-June 3, 2003, Chicago, IL. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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18. NIH Consensus Conference: Adjuvant therapy for patients with colon and rectal cancer. JAMA 264:1444-1450, 1990 19. Sobin LH, Wittekind Ch: The history of the TNM system, in: Sobin LH, Wittekind Ch (eds), TNM Classification of Malignant Tumours (ed 5). New York, NY, John Wiley and Sons, 1997, pp 1-4 20. Dukes CE, Bussey HJR: The spread of rectal cancer and its effect on prognosis. Br J Cancer 12:309-312, 1958[Medline] 21. Kirklin JW, Dockerty MD, Waugh JW: The role of the peritoneal reflection in the prognosis of carcinoma of the rectum and sigmoid colon. Surg Gynecol Obstet 88:326, 1949[Medline] 22. Astler VB, Coller FA: The prognostic significance of direct extension of carcinoma of the colon and rectum. Ann Surg 139:846-852, 1954[Medline] 23. Gilchrist RK, David VC: A consideration of pathological factors influencing five year survival in radical resection of the large bowel and rectum for carcinoma. Ann Surg 126:421-438, 1947[Medline] 24. Gunderson LL, Sargent DJ, Tepper JE, et al: Impact of T and N substage on survival and disease relapse in adjuvant rectal cancer: A pooled analysis. Int J Radiat Oncol Biol Phys 54:386-396, 2002[CrossRef][Medline] 25. Gunderson LL, Sargent D, Tepper J, et al: Impact of TN stage and treatment on survival and relapse in adjuvant rectal cancer pooled analysis. Proc Am Soc Clin Oncol 22:251, 2003 (abstr 1008) 26. Benson AB, Choti MA, Cohen AM, et al: NCCN practice guidelines for colorectal cancer. Oncology 14:203-212, 2000[Medline]
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
