LYMPH NODE RATIO AS A PROGNOSTIC FACTOR IN PATIENTS WITH STAGE III RECTAL CANCER TREATED WITH TOTAL MESORECTAL EXCISION FOLLOWED BY CHEMORADIOTHERAPY

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1 doi: /j.ijrobp Int. J. Radiation Oncology Biol. Phys., Vol. 74, No. 3, pp , 2009 Copyright Ó 2009 Elsevier Inc. Printed in the USA. All rights reserved /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 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, ). 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, 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 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) ; Fax: (+82) ; jhkim2@amc.seoul.kr Conflict of interest: none. Received May 23, 2008, and in revised form Aug 28, Accepted for publication Aug 29, 2008.

2 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 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, 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, years), and the majority had moderately differentiated T3 tumors of median size 5 cm (range, 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

3 798 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 ( ( ) 4.0 (0.6 48) 4.3 ( ) 4.2 ( ) 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 ( ) 5.5 ( ) 5.0 ( ) 5.0 ( ) 5.0 ( ) 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 < 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.

4 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 Age # > p Gender Male Female p CEA level (ng/ml) # > p T stage p <0.001 <0.001 <0.001 <0.001 N stage p < <0.001 <0.001 LN examined # > p Differentiation Well Moderately Poorly Others p < Tumor size (cm) # > p LNR # # # > p < <0.001 <0.001 Operation APR LAR Others p 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 (p = 0.623), (p = 0.047), and (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 (p = 0.686), (p = 0.024), and (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

5 800 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 T T T N stage N1 1 Referent N LNR #0.1 1 Referent # # > Differentiation Well 1 Referent Moderately Poorly Operation LAR 1 Referent APR 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 # LNR # LNR # LNR > p N2 LNR # LNR # LNR # LNR > p 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 # LNR # LNR # LNR > p Examined LNs >17 LNR # LNR # LNR # LNR > p <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

6 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). 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