doi:10.1016/j.ijrobp.2008.08.065 Int. J. Radiation Oncology Biol. Phys., Vol. 74, No. 3, pp. 796 802, 2009 Copyright Ó 2009 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/09/$ see front matter CLINICAL INVESTIGATION Rectum LYMPH NODE RATIO AS A PROGNOSTIC FACTOR IN PATIENTS WITH STAGE III RECTAL CANCER TREATED WITH TOTAL MESORECTAL EXCISION FOLLOWED BY CHEMORADIOTHERAPY YOUNG SEOK KIM, M.D.,* JONG HOON KIM, M.D., PH.D.,* SANG MIN YOON, M.D.,* EUN KYUNG CHOI, M.D., PH.D.,* SEUNG DO AHN, M.D., PH.D.,* SANG-WOOK LEE, M.D., PH.D.,* JIN CHEON KIM, M.D., PH.D., y CHANG SIK YU, M.D., PH.D., y HEE CHUL KIM, M.D., PH.D., y TAE WON KIM, M.D., PH.D., z AND HEUNG MOON CHANG, M.D., PH.D. z Departments of *Radiation Oncology, y Colon and Rectal Surgery, and z Internal Medicine, Asan Medical Center, University of Ulsan, Seoul, Korea Purpose: To investigate the prognostic impact of lymph node ratio (LNR) on survival in the patients with Stage III rectal cancer. Methods and Materials: We retrospectively reviewed the data of 421 consecutive patients who underwent total mesorectal excision followed by chemoradiotherapy for rectal cancer from 1996 to 2006. The 232 patients with positive lymph nodes (LNs) were divided into four groups according to LNR quartiles: LNR #0.1 (n = 69), #0.2 (n = 49), #0.4 (n = 54), and >0.4 (n = 60). The association between LNR and survival was evaluated by the Kaplan-Meier method and multivariate analysis with covariates of prognostic significance in univariate analysis. Results: The median numbers of examined and positive LNs were 17 and 3, respectively, and the median LNR was 0.20 (range, 0.03 1). There was a strong correlation between the number of positive LNs and LNR (r = 0.724, p < 0.001). After a median follow-up of 53 months (range, 9 138 months), the actuarial overall survival and diseasefree survival rates at 5 years were 69% and 56%, respectively. The ear survival rate decreased as LNR increased (#0.1, 89%; #0.2, 67%; #0.4, 64%; >0.4, 50%; p < 0.001). Lymph node ratio was also a significant prognostic factor on Cox regression analysis (#0.1, hazard ratio [HR] = 1; #0.2, HR = 1.3, p = 0.623; #0.4, HR = 2.4, p = 0.047; >0.4, HR = 3.7, p = 0.005). Lymph node ratio had a prognostic effect on overall survival in subgroups of patients with N1 (p = 0.032) and N2 (p = 0.034) tumors. Conclusion: Lymph node ratio was the most significant predictor of survival in the patients with Stage III rectal cancer who had undergone postoperative chemoradiation. Ó 2009 Elsevier Inc. Rectal cancer, Prognosis, Lymph node. INTRODUCTION Colorectal cancer is the fourth most common malignancy worldwide, accounting for 9.7% of all cancers and with 780,000 new cases detected annually (1). Approximately one third of these tumors are rectal cancers. The most important prognostic factor for colorectal cancer is disease stage. For example, the ear overall survival (OS) rate in patients with Stage II, or node-negative disease, is approximately 80%, declining to 50% in patients with Stage III, or nodepositive disease (2). Lymph node (LN) staging can be subdivided according to the number of positive LNs (N1, Stage IIIA or IIIB, three or fewer positive LNs; N2, Stage IIIC, more than three positive LNs). Both the American Joint Committee on Cancer and the International Union Against Cancer have estimated that the minimum number of LNs required for accurate staging of nodal status is 12. Lymph node yield in a surgical specimen positively correlates with tumor size, number of involved LNs, and examining pathologist (3). Although the number of examined LNs has been shown to be an independent prognostic factor for OS in patients with colorectal cancer, there is no consensus as to the optimal number of LNs that should be examined (4 10). Rather, the ratio of positive LNs to examined LNs, or lymph node ratio (LNR), has been shown to be an important prognostic factor in pancreatic, breast, bladder, and gastric cancers (11 17), as well as in colorectal cancer (18 20). Relatively little is known regarding the correlation between LNR and survival in patients with node-positive rectal Note An online CME test for this article can be taken at http:// asro.astro.org under Continuing Education. Reprint requests to: Jong Hoon Kim, M.D., Department of Radiation Oncology, Asan Medical Center, University of Ulsan, 388-1, PoongNap-Dong, SongPa-Gu, Seoul, Korea. Tel: (+82) 2-3010- 796 4434; Fax: (+82) 2-486-7258; E-mail: jhkim2@amc.seoul.kr Conflict of interest: none. Received May 23, 2008, and in revised form Aug 28, 2008. Accepted for publication Aug 29, 2008.
Prognostic value of LNR in rectal cancer d Y. S. KIM et al. 797 cancer. Because most studies that have addressed this issue included all patients with colorectal cancer, without separating out patients with rectal cancer from those with other colorectal malignancies, the results obtained may be hard to apply to Stage III rectal cancer patients. We therefore reviewed the clinical data from two prospective studies in a single institution to confirm whether LNR has prognostic value for survival in patients with Stage III rectal cancer. METHODS AND MATERIALS Patients Between February 1996 and February 2006, a total of 528 consecutive patients with pathologically proven Stage II and III rectal cancer were enrolled into two prospective randomized clinical trials at Asan Medical Center. Of these, 308 patients were included in a study of the optimal sequence of postoperative chemotherapy and radiotherapy (21), and 220 were included in a study comparing preand postoperative chemoradiotherapy (22). Exact LN status was obtained for 421 of these patients who had undergone postoperative chemoradiation. We excluded the 189 patients without metastatic LN, leaving 232 patients as our study population. Treatment and follow-up evaluation All patients underwent total mesorectal excision (TME), performed by three colorectal surgeons (J.C.K., C.S.Y., and H.C.K.). Postoperative chemoradiation was usually initiated within 4 8 weeks after surgery. The 308 patients in the earlier trial received fluorouracil 375 mg/m 2 /d plus leucovorin 20 mg/m 2 /d (21), for 3 days per 4-week cycle in the first two cycles, concurrent with radiotherapy, and for 5 days in the remaining four cycles. The remaining 113 patients received capecitabine (1,650 mg/m 2 /d) concurrent with radiotherapy and four cycles of fluorouracil/leucovorin, as above (22). Postoperative radiotherapy consisted of 45 50 Gy in 25 fractions delivered to the pelvis using a three- or four-field box technique. History-taking, physical examination including digital rectal examination, complete blood count, carcinoembryonic antigen (CEA), chemistry, and chest X-ray were performed every 3 months for 2 years and repeated every 6 months thereafter. Computed tomography of the abdomen and pelvis was performed every 6 months for 2 years and then every 12 months. Colonoscopic examination was repeated every 12 months. The median follow-up period of the study population was 53 months (range, 9 138 months). Statistical analysis The primary aim of this study was to investigate the prognostic significance of LNR on OS. Secondary endpoints included disease-free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS). Overall survival time was counted from the date of surgery to date of death or last follow-up. Patients were censored in the DFS analysis if they were disease-free at last visit, but death, regardless of final status, was counted as an event in the survival analysis. Local recurrence was defined as any recurrence within the radiation field, and distant metastasis as outside the field. The first site of recurrence was recognized if both local and distant failure occurred together. Statistical analyses were performed using SPSS 12.0 (SPSS, Chicago, IL). The Kaplan-Meier method was used to construct survival curves, and the log rank test was used to compare survival outcome. Multivariate analysis of independent prognostic factors for survival was determined using Cox regression. Chi-squared tests and analysis of Fig. 1. Correlation between lymph node ratio and number of positive lymph nodes (LNs). variance were used to compare between-group patient characteristics according to LNR. All p values were two-sided. RESULTS A total of 4,461 LNs were examined from 232 patients, with a median harvest of 17 LNs per specimen; of these 1,167 LNs (26%) were diagnosed as positive. A strong, positive correlation was observed between metastatic LNs and LNR as a continuous variable (correlation coefficient = 0.724; p<0.001; Fig. 1). In addition, a positive correlation was observed between the numbers of examined and positive LNs (r = 0.429; p<0.001). On the basis of LNR quartiles, the patients were categorized into four groups: LNR #0.1 (n = 69), #0.2 (n = 49), #0.4 (n = 54), and >0.4 (n = 60). Clinical and pathologic characteristics of the patients are summarized in Table 1. Median age was 54 years (range, 22 78 years), and the majority had moderately differentiated T3 tumors of median size 5 cm (range, 1.5 11.2 cm). The median distance from the anal verge to the most distal part of the tumor was 7 cm, and 89 patients (38%) had low-lying tumors, within 5 cm of the anal verge. Sphincter preservation was impossible in one third of these patients. The study population was evenly distributed across the four groups, except for N stage and the number of positive LNs. Patients with higher LNR had a higher number of metastatic LNs and more frequent N2 disease, owing to the strong correlation between LNR and positive LNs; however, the number of examined LNs was not significantly affected by LNR. The CEA level was increased in 67 of the 232 patients (29%) but did not differ significantly among the four LNR groups. Using the Kaplan-Meier method, we performed survival analyses for OS, LRFS, DMFS, and DFS. The ear OS and DFS rates for the 232 patients with Stage III rectal cancer were 69% and 56%, respectively. Distant metastasis was
798 I. J. Radiation Oncology d Biology d Physics Volume 74, Number 3, 2009 Table 1. Patient characteristics Characteristics #0.1 (n = 69) #0.2 (n = 49) #0.4 (n = 54) >0.4 (n = 60) Total (n = 232) Age (years) 56 (33 78) 56 (34 76) 51 (29 72) 53 (22 73) 54 (22 78) Gender Male 45 (65) 26 (53) 31 (57) 20 (50) 132 (57) Female 24 (35) 23 (47) 23 (43) 30 (50) 100 (43) CEA level (ng/ml) 4.3 (0.7 17.6 3.9 (0.1 254) 4.0 (0.6 48) 4.3 (0.6 146) 4.2 (0.1 254) T stage 1 1 (1) 2 (4) 1 (2) 1 (2) 5 (2) 2 12 (17) 2 (4) 1 (2) 1 (2) 16 (7) 3 55 (80) 40 (82) 47 (87) 53 (88) 195 (84) 4 1 (1) 5 (10) 5 (9) 5 (8) 16 (7) N stage* 1 68 (99) 34 (69) 15 (28) 7 (12) 124 (53) 2 1 (1) 15 (31) 39 (72) 53 (88) 108 (47) LNs examined 21 (10 44) 18 (7 43) 16 (4 61) 16 (3 58) 17 (3 61) LNs positive* 1 (1 4) 3 (1 5) 5 (1 16) 9 (2 42) 3 (1 42) Differentiation Well 5 (7) 2 (4) 3 (6) 3 (5) 13 (6) Moderately 58 (84) 41 (84) 39 (72) 35 (58) 173 (75) Poorly 2 (3) 4 (8) 3 (6) 15 (25) 24 (10) Others 4 (6) 2 (4) 9 (17) 7 (12) 22 (9) Tumor size (cm) 5.0 (2.0 8.5) 5.5 (2.5 11.2) 5.0 (2.0 9.0) 5.0 (1.5 10.0) 5.0 (1.5 11.2) Operation APR 14 (20) 18 (37) 16 (30) 26 (43) 74 (32) LAR 54 (78) 30 (61) 38 (70) 33 (55) 155 (67) Others 1 (1) 1 (2) 0 (0) 1 (2) 3 (1) Abbreviations: LNR = lymph node ratio; CEA = carcinoembryonic antigen; LN = lymph node; APR = abdominoperineal resection; LAR = low anterior resection. Values are number (percentage) or median (range). Because of rounding, not all percentages total 100. * Statistically significant (p < 0.001 in both parameters). LNR observed in 87 patients, and local recurrence in 22. The 5- year LRFS and DMFS rates were 89% and 62%, respectively. Overall survival curves among the four LNR groups differed significantly (Fig. 2); the ear OS rates of patients with LNR #0.1, #0.2, #0.4, and >0.4 were 89%, 67%, 64%, and 50%, respectively (p <0.001). In addition, the DFS curves among the four LNR groups differed significantly (Fig. 3); the ear DFS rates of the patients with LNR #0.1, #0.2, #0.4, and >0.4 were 75%, 66%, 50%, and 33%, respectively (p<0.001). There were substantial differences with statistical significance among the four groups in LRFS and DMFS as well. Univariate analysis showed that age, gender, preoperative CEA level, number of harvested LNs, and tumor size did not have a prognostic impact on OS, LRFS, DMFS, and DFS (Table 2). According to the log rank test, however, lower T and N stages, lower LNR, Fig. 2. Overall survival rate according to lymph node ratio. Fig. 3. Disease-free survival rate according to lymph node ratio.
Prognostic value of LNR in rectal cancer d Y. S. KIM et al. 799 Table 2. Univariate analysis according to clinicopathologic factors in 232 patients Characteristics Patients (n) OS LRFS DMFS DFS Total 232 69 89 62 56 Age #54 123 72 88 61 59 >54 109 65 91 62 54 p 0.355 0.615 0.835 0.624 Gender Male 132 74 87 66 60 Female 100 61 93 58 52 p 0.689 0.307 0.178 0.377 CEA level (ng/ml) #6 165 74 90 64 60 >6 67 59 87 55 49 p 0.238 0.450 0.118 0.086 T stage 1 5 80 100 100 80 2 16 89 100 83 83 3 195 71 90 63 57 4 16 18 65 15 15 p <0.001 <0.001 <0.001 <0.001 N stage 1 124 75 93 73 66 2 108 61 85 48 45 p <0.001 0.061 <0.001 <0.001 LN examined #17 115 63 86 56 53 >17 117 76 93 68 67 p 0.241 0.087 0.110 0.093 Differentiation Well 13 83 100 77 77 Moderately 173 73 92 65 59 Poorly 24 48 77 44 40 Others 22 55 79 43 43 p <0.001 0.024 0.001 0.007 Tumor size (cm) #5 117 67 88 59 55 >5 115 70 90 64 58 p 0.423 0.770 0.481 0.552 LNR #0.1 69 89 96 80 75 #0.2 49 67 95 70 66 #0.4 54 64 89 59 50 >0.4 60 50 77 36 33 p <0.001 0.001 <0.001 <0.001 Operation APR 74 56 79 46 42 LAR 155 75 94 69 63 Others 3 67 100 67 67 p 0.017 0.003 0.002 0.005 Abbreviations: OS = overall survival; LRFS = local recurrence-free survival; DMSF = distant metastasis-free survival; DSF = disease-free survival. Other abbreviations as in Table 1. more-differentiated tumors, and lower anterior resection were associated with significantly improved OS, DMFS, and DFS; T stage, grade of differentiation, type of surgery, and LNR had significant prognostic value in LRFS. Cox regression analysis for OS that included the number of positive LNs as a continuous variable and other variables with prognostic significance in univariate analysis showed that the prognostic value of LNR remained, as well as poorly differentiated tumor (Table 3). Compared with the group with LNR #0.1, the hazard ratios of the groups with LNR #0.2, #0.4, and >0.4 were 1.260 (p = 0.623), 2.435 (p = 0.047), and 3.701 (p = 0.005), respectively. Similarly for DFS, when compared with the group having LNR #0.1, the hazard ratios of the groups with LNR #0.2, #0.4, and >0.4 were 1.156 (p = 0.686), 2.017 (p = 0.024), and 3.404 (p < 0.001), respectively. The prognostic value of T stage and LNR remained significant on multivariate analysis for DFS. To determine whether LNR had a prognostic significance on survival in each N stage, we performed survival analyses based on LNR in patients with N1 and N2 tumors, respectively. We
800 I. J. Radiation Oncology d Biology d Physics Volume 74, Number 3, 2009 Table 3. Multivariate analysis for overall survival in 232 patients Factors p HR >95% CI T stage T1 1 Referent T2 0.665 1.735 0.143 21.098 T3 0.395 2.403 0.318 18.153 T4 0.069 7.526 0.852 66.477 N stage N1 1 Referent N2 0.974 1.010 0.538 1.897 LNR #0.1 1 Referent #0.2 0.623 1.260 0.501 3.173 #0.4 0.047 2.435 1.012 5.862 >0.4 0.005 3.701 1.493 9.178 Differentiation Well 1 Referent Moderately 0.274 2.232 0.529 9.412 Poorly 0.042 4.801 1.055 21.843 Operation LAR 1 Referent APR 0.332 1.286 0.774 2.136 Abbreviations: HR = hazard ratio; CI = confidence interval. Other abbreviations as in Table 1. found that LNR had a prognostic impact on OS in both patients with N1 (p = 0.032) and N2 (p = 0.034) tumors (Table 4). Five-year OS was inversely related to LNR for both N1 and N2 except for the group with N1 and LNR >0.4, which consisted of only 7 patients. Similar findings were also observed for DFS. Irrespective of the number of examined LNs, LNR also had a prognostic impact on survival in each subgroup (Table 5). DISCUSSION Postoperative chemoradiotherapy has become a standard treatment in patients with Stage II and III rectal cancer (23, 24). Local control, toxicities, and compliance to treatment favored preoperative chemoradiation although there was no significant difference in OS between pre- and postoperative chemoradiation(25). However, it should be noted that only Table 4. Survival rate by LNR in N1 and N2 disease Factors Patients (n) OS LRFS DMFS DFS N1 LNR #0.1 68 89 96 80 74 LNR #0.2 34 60 93 67 62 LNR #0.4 15 53 73 57 43 LNR >0.4 7 57 100 60 50 p 0.032 0.002 0.232 0.082 N2 LNR #0.1 1 100 100 100 100 LNR #0.2 15 86 100 77 77 LNR #0.4 39 68 95 57 52 LNR >0.4 53 49 74 33 30 p 0.034 0.025 0.005 0.012 Abbreviations as in Tables 1 and 2. Table 5. Survival rate by LNR in patients with #17 and >17 examined LNs Factors Patients (n) OS LRFS DMFS DFS Examined LNs #17 LNR #0.1 27 86 96 64 59 LNR #0.2 22 62 95 65 65 LNR #0.4 29 60 82 72 56 LNR >0.4 37 50 75 33 30 p 0.015 0.058 0.005 0.017 Examined LNs >17 LNR #0.1 42 92 96 92 86 LNR #0.2 27 77 96 74 68 LNR #0.4 25 70 96 41 42 LNR >0.4 23 53 87 42 39 p 0.001 0.044 <0.001 <0.001 Abbreviations as in Tables 1 and 2. half of the patients in the postoperative chemoradiation group received the planned treatment, likely contributing to their inferior clinical outcome. The most important advantage of postoperative treatment is accurate staging, particularly nodal status. We therefore reviewed the clinical data of patients who received adjuvant chemoradiotherapy, not those who received preoperative treatment. We found that the ear OS rate in 232 patients with Stage III rectal cancer was 69% (75% for N1 and 61% for N2 disease), superior to the OS rates reported in earlier randomized trials. A pooled analysis of patients in three North American Phase III trials who received adjuvant chemoradiation for rectal cancer (26) showed that the ear OS rates of patients with N1 and N2 disease were 65% and 52%, respectively. Because we used similar chemotherapy and radiotherapy regimens, the increased survival advantage reported here may have resulted, at least in part, from the surgical technique (TME) used. There have been few clinical evaluations of TME combined with postoperative chemoradiation, although one trial reported that the ear OS rate in patients with Stage II and Stage III tumors was 74% (25). In addition, because all 232 of our patients underwent a uniform TME performed by three colorectal-specialized surgeons at the same hospital, better clinical outcomes in terms of survival and local control could be achieved (27, 28). Although the number of examined LNs did not have a statistical effect on OS (p = 0.121), patients with more than 17 examined LNs showed a trend toward increased LRFS and DFS. A median of 17 LNs harvested per patient, a marker of appropriate surgery and pathologic examination, is thought to result in better LRFS and DFS (8, 29). There was a positive correlation between the numbers of involved and examined LNs (r = 0.429, p< 0.001), in agreement with previous findings showing that LN harvest correlated with tumor size, pathologist s interest, and number of positive LNs (3). The number of involved LNs also strongly correlated with LNR (r = 0.724, p<0.001), with a correlation between higher LNR and higher frequency of N2 disease. However, the number of examined LNs did not differ
Prognostic value of LNR in rectal cancer d Y. S. KIM et al. 801 significantly among the four LNR groups. Increased OS in the patients with more than 17 examined LNs did not reach statistical significance (77% vs. 63%, p = 0.121), which may have been due, at least in part, to the relatively small sample size. Number of examined LNs has been shown to correlate with better survival in patients with Stage III colorectal cancer (5 7); in those trials, 0 to 34% had rectal cancer. In some of these trials, the prognostic value of the number of LNs retrieved could not be assessed separately in patients with rectal cancer (6, 7). In other analyses, the number of examined LNs did not have a significant impact on survival (5, 29). Thus, to date, the impact of LN yield on survival of patients with Stage III rectal cancer has not been clear. Part of the prognostic value of the number of examined LNs is thought to be due to the Will Rogers phenomenon, or stage migration, as observed in stomach and breast cancer as well as in colorectal cancer (30). As demonstrated in reports on stomach cancer, the use of LNR-based staging decreases the incidence of stage migration by 50% (31, 32). LNR was also proven as an independent prognostic factor of both local recurrence and overall survival in the retrospective review of three North Central Cancer Treatment Group trials (20). In this analysis of 673 patients with Stage II/III rectal cancer, patients were categorized according to their LNR: LNR <0.25 (n = 355), #0.5 (n = 153), #0.75 (n = 66), and >0.75 (n = 68). Local recurrence rate increased as LNR increased: 10%, 14%, 34%, and 34%, respectively. Opposite findings were observed in overall survival: 70%, 55%, 39%, and 37%. These trends are in accordance with those of the present study (Table 2). Because TME was performed in every patients and because of more meticulous LN examination in the present study (18% of patients had 4 or fewer nodes examined, and 68% had fewer than 12 in the study by Stocchi et al. [20]), more favorable outcomes in terms of survival and local control could be gained, even when the patients with Stage III disease were assessed. Given the more constant denominator (i.e., the number of examined LNs), LNR may reflect the number of involved LNs, especially in patients who undergo meticulous LN dissection. Moreover, LNR can be influenced by suboptimal LN examination and can complement the drawback of current N staging (i.e., N2 when more than three LNs are involved, regardless of quantity). LNR is thought to have its own prognostic value for survival, besides N staging and the number of dissected LNs. The possible decrease in the incidence of stage migration and the differences in ear OS, LRFS, DMFS, and DFS in patients with each N stage seem to suggest the prognostic importance of LNR. Our study had several important limitations, including its relatively small sample size and its retrospective design. However, there have been few reports on the prognostic value of LNR in patients with Stage III rectal cancer. Moreover, LNR showed prognostic significance on multivariate analysis and in patients with each N stage, and there were noticeable disparities among the LNR groups in both OS and DFS curves. In contrast to postoperative chemoradiotherapy, several studies have shown that preoperative treatment decreased LN yield (33, 34), whereas other studies have reported that preoperative treatment had no effect on LN yield (3, 35). Prospective studies including larger numbers of patients are needed to determine the prognostic value of LNR in patients undergoing neoadjuvant chemoradiation followed by TME. In conclusion, we have shown here that LNR is an important prognostic factor in patients with Stage III rectal cancer who underwent TME followed by chemoradiation and should be considered a stratification factor in future randomized controlled trials. More-intensive or further chemotherapy is indicated for patients with higher LNR, because most treatment failures were distant metastases. REFERENCES 1. Parkin DM, Pisani P, Ferlay J. Global cancer statistics. CA Cancer J Clin 1999;49:33 64. 2. Compton C, Fenoglio-Preiser CM, Pettigrew N, et al. American Joint Committee on Cancer Prognostic Factors Consensus Conference: Colorectal Working Group. Cancer 2000;88:1739 1757. 3. Thorn CC, Woodcock NP, Scott N, et al. What factors affect lymph node yield in surgery for rectal cancer? Colorectal Dis 2004;6:356 361. 4. Berberoglu U. Prognostic significance of total lymph node number in patients with T1-4N0M0 colorectal cancer. Hepatogastroenterology 2004;51:1689 1693. 5. Edler D, Ohrling K, Hallstrom M, et al. The number of analyzed lymph nodes a prognostic factor in colorectal cancer. Acta Oncol 2007;46:975 981. 6. George S, Primrose J, Talbot R, et al. Will Rogers revisited: Prospective observational study of survival of 3592 patients with colorectal cancer according to number of nodes examined by pathologists. Br J Cancer 2006;95: 841 847. 7. Johnson PM, Porter GA, Ricciardi R, et al. Increasing negative lymph node count is independently associated with improved long-term survival in stage IIIB and IIIC colon cancer. J Clin Oncol 2006;24:3570 3575. 8. Sarli L, Bader G, Iusco D, et al. Number of lymph nodes examined and prognosis of TNM stage II colorectal cancer. Eur J Cancer 2005;41:272 279. 9. Tsai HL, Lu CY, Hsieh JS, et al. The prognostic significance of total lymph node harvest in patients with T2-4N0M0 colorectal cancer. J Gastrointest Surg 2007;11:660 665. 10. Yoshimatsu K, Ishibashi K, Umehara A, et al. How many lymph nodes should be examined in Dukes B colorectal cancer? Determination on the basis of cumulative survival rate. Hepatogastroenterology 2005;52:1703 1706. 11. Herr HW. Superiority of ratio based lymph node staging for bladder cancer. J Urol 2003;169:943 945. 12. Marchet A, Mocellin S, Ambrosi A, et al. The ratio between metastatic and examined lymph nodes (N ratio) is an independent prognostic factor in gastric cancer regardless of the type of lymphadenectomy: Results from an Italian multicentric study in 1853 patients. Ann Surg 2007;245:543 552. 13. Pawlik TM, Gleisner AL, Cameron JL, et al. Prognostic relevance of lymph node ratio following pancreaticoduodenectomy for pancreatic cancer. Surgery 2007;141:610 618.
802 I. J. Radiation Oncology d Biology d Physics Volume 74, Number 3, 2009 14. Sierzega M, Popiela T, Kulig J, et al. The ratio of metastatic/ resected lymph nodes is an independent prognostic factor in patients with node-positive pancreatic head cancer. Pancreas 2006;33:240 245. 15. Truong PT, Berthelet E, Lee J, et al. The prognostic significance of the percentage of positive/dissected axillary lymph nodes in breast cancer recurrence and survival in patients with one to three positive axillary lymph nodes. Cancer 2005;103: 2006 2014. 16. van der Wal BC, Butzelaar RM, van der Meij S, et al. Axillary lymph node ratio and total number of removed lymph nodes: Predictors of survival in stage I and II breast cancer. Eur J Surg Oncol 2002;28:481 489. 17. Voordeckers M, Vinh-Hung V, Van de Steene J, et al. The lymph node ratio as prognostic factor in node-positive breast cancer. Radiother Oncol 2004;70:225 230. 18. Berger AC, Sigurdson ER, LeVoyer T, et al. Colon cancer survival is associated with decreasing ratio of metastatic to examined lymph nodes. J Clin Oncol 2005;23:8706 8712. 19. Lee HY, Choi HJ, Park KJ, et al. Prognostic significance of metastatic lymph node ratio in node-positive colon carcinoma. Ann Surg Oncol 2007;14:1712 1717. 20. Stocchi L, Nelson H, Sargent DJ, et al. Impact of surgical and pathologic variables in rectal cancer: A United States community and cooperative group report. J Clin Oncol 2001;19:3895 3902. 21. Lee JH, Lee JH, Ahn JH, et al. Randomized trial of postoperative adjuvant therapy in stage II and III rectal cancer to define the optimal sequence of chemotherapy and radiotherapy: A preliminary report. J Clin Oncol 2002;20:1751 1758. 22. Yoon SM, Kim JH, Kim JC, et al. Comparison of preoperative and postoperative radiotherapy with capecitabine in locally advanced rectal cancer: A preliminary report of a phase III randomized trial (Abstr.). Int J Radiat Oncol Biol Phys 2007; 63(Suppl.):S109. 23. Gastrointestinal Tumor Study Group. Prolongation of the disease-free interval in surgically treated rectal cancer. N Engl J Med 1985;312:1465 1472. 24. Krook JE, Moertel CG, Gunderson LL, et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 1991;324:709 715. 25. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731 1740. 26. 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 2002;54: 386 396. 27. Kockerling F, Reymond MA, Altendorf-Hofmann A, et al. Influence of surgery on metachronous distant metastases and survival in rectal cancer. J Clin Oncol 1998;16:324 329. 28. Porter GA, Soskolne CL, Yakimets WW, et al. Surgeon-related factors and outcome in rectal cancer. Ann Surg 1998;227: 157 167. 29. Tepper JE, O Connell MJ, Niedzwiecki D, et al. Impact of number of nodes retrieved on outcome in patients with rectal cancer. J Clin Oncol 2001;19:157 163. 30. Derwinger K, Carlsson G, Gustavsson B. Stage migration in colorectal cancer related to improved lymph node assessment. Eur J Surg Oncol 2007;33:849 853. 31. Bando E, Yonemura Y, Taniguchi K, et al. Outcome of ratio of lymph node metastasis in gastric carcinoma. Ann Surg Oncol 2002;9:775 784. 32. Inoue K, Nakane Y, Iiyama H, et al. The superiority of ratiobased lymph node staging in gastric carcinoma. Ann Surg Oncol 2002;9:27 34. 33. Marijnen CA, Nagtegaal ID, Klein Kranenbarg E, et al. No downstaging after short-term preoperative radiotherapy in rectal cancer patients. J Clin Oncol 2001;19:1976 1984. 34. Wichmann MW, Muller C, Meyer G, et al. Effect of preoperative radiochemotherapy on lymph node retrieval after resection of rectal cancer. Arch Surg 2002;137:206 210. 35. Kim J, Huynh R, Abraham I, et al. Number of lymph nodes examined and its impact on colorectal cancer staging. Am Surg 2006;72:902 905.