The impact of lymph node examination on survival of stage II colorectal cancer patients: Are 12 nodes adequate?

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1 Formosan Journal of Surgery (2011) 44, 176e180 Available online at journal homepage: ORIGINAL ARTICLE The impact of lymph node examination on survival of stage II colorectal cancer patients: Are 12 nodes adequate? Yi-Feng Lin a, Yih-Huei Uen b, * a Division of General Surgery, Department of Surgery, Chi-Mei Medical Center, Tainan, Taiwan b Department of Surgery, Chi-Mei Medical Center, Tainan, Taiwan Received 13 December 2010; received in revised form 26 January 2011; accepted 19 June 2011 Available online 18 November 2011 KEYWORDS age; early-stage colorectal adenocarcinoma; lymph node number; survival Summary Objective: Early-stage colorectal cancer without lymph node (LN) metastasis is a disease requiring only surgery, except when it has a high risk. However, inadequate resection or LN examination is often followed by poor prognosis. In this study, we evaluated the adequacy of the number of LNs examined with regard to the survival of patients with stage II colorectal adenocarcinoma. Methods: Between January 2003 and December 2006, patients with stage II colorectal cancer were enrolled in this study. Disease progression, background data, including tumor characteristics, and pathologic factors with an emphasis on the number of LNs examined and nodal status of the number of nodes variously involved were analyzed and correlated with survival. Results: A total of 190 patients were included in our study. Using the receiver-operating characteristic curve and multivariate Cox proportional hazard regression analysis, we found that better overall survival was significantly associated with examination of >15 LNs (HR Z 0.15, p Z 0.001) and T3 stage (HR Z 3.393, p Z 0.024). Conclusions: In this study, patients with stage II colorectal adenocarcinoma who had >15 LNs examined and were stage T3 had a better prognosis. In other words, we believe that examination of 12 LNs is not a sufficient number for evaluation of overall survival of such patients. We should follow-up patients with fewer examined LNs more closely. Copyright ª 2011, Taiwan Surgical Association. Published by Elsevier Taiwan LLC. All rights reserved. * Corresponding author. Department of Surgery, Chi-Mei Medical Center, 901 Chung Hwa Road, Yung Kang City, Tainan, Taiwan address: linyf1977@yahoo.com.tw (Y.-H. Uen) X/$ - see front matter Copyright ª 2011, Taiwan Surgical Association. Published by Elsevier Taiwan LLC. All rights reserved. doi: /j.fjs

2 LN examination for early colon cancer Introduction Colorectal cancer is the second leading cause of cancer deaths in the United States. 1 In Taiwan, it ranks third in cancer deaths but second in incidence. Surgical treatment is the mainstay of curative treatment. Adequate surgery means an en bloc resection of the tumor with a wide safe margin. In addition, lymph node (LN) dissection should be performed along lymphatic drainage. Recently, evaluation of 12 LNs has been mandated to prevent colon cancer understaging. 2,3 As indicated by the National Comprehensive Cancer Network guidelines, adjuvant chemotherapy should not be delivered to patients with node-negative colorectal cancer (including stages I and II) except for patients with a high risk. With this treatment guideline, however, inadequate node assessment will lead to undertreatment and result in poor outcome, particularly for node-negative patients due to a lack of further treatment following an operation. In our study, therefore, we have attempted to find a relation between the number of examined LNs and the survival of patients with node-negative stage II colorectal cancer. 2. Methodology Patients with colorectal cancer who had undergone surgical intervention were enrolled from January 2003 to December 2006 in a referral tertiary medical center in southern Taiwan. This study was approved by the IRB at our hospital. A complete medical history and thorough physical examination were performed for each patient, who also had an abdominal computed tomography scan preoperatively. All patients underwent surgery. We performed radical resection for colorectal cancer with LN dissection. All specimens were carefully checked and reported. Patients with preoperative bowel perforation or obstruction, and those who received preoperative chemotherapy and/or radiotherapy, inadequate surgical treatment or surgical mortality cases were excluded from this study. The correlations between the patients basic data, laboratory data, pathologic results, and survival were evaluated. For the convenience of data analysis, each patient s age and gender were recorded. Preoperative carcinoembryonic antigen (CEA) level was divided into two categories: CEA 5 ng/ml and CEA < 5 ng/ml. Pathologic staging was determined according to the American Joint Committee on Cancer system (sixth edition). Tumor differentiation was classified as moderate and poor. The number of examined LNs, T-stage, lymphovascular invasion (LVI), and adjuvant therapy were also included in this investigation. Overall survival was defined as the length of time from the date of operation to the date of death or the last visit at our outpatient department. Data were expressed as mean standard deviation (SD). Logistic regression and the receiver-operating characteristic (ROC) 4 curve were used for statistics based on the number of examined LNs. The ROC curve is a method used to express the relation and trade-off between sensitivity and specificity. It can be used as an aid to decide where the best cut-off value should be. The univariate and multivariate Cox proportional hazard regression analyses were used to assess statistical significance among all groups. Multivariate Cox proportional hazard regression analysis predicting overall survival was performed. The final model was conducted using the forward stepwise model selection method from the candidate predictors with p < 0.1 in the univariate analysis. Finally, all data were analyzed using SPSS statistical software (SPSS for Windows, Version 16, Table 1 Pertinent patient data Characteristics Patient number (%) Mean age (y) y 84 <65 y 106 Gender Male 106 (55.8) Female 50 (44.2) Mean survival, mo (range) Median follow-up time, mo (range) 65.1 (62.2e68.0) 42.4 (2.4e74.4) Number of examined LNs Mean SD (range) (2e42) >15 77 (41) (59) Tumor location Colon 140 (73.7) Rectum 50 (26.3) Preoperative CEA level 5 ng/ml 63 (33) <5 ng/ml 118 (62) Tumor differentiation Well 24 (12.6) Moderate 140 (73.7) Poor 26 (13.7) T-Stage T3 181 (95) T4 9 (5) Tumor type Adenocarcinoma 185 (97) Mucinous adenocarcinoma 5 (3) Lymphovascular invasion Yes 20 (11) No 170 (89) Postoperative adjuvant chemotherapy Yes 78 (41) No 112 (59) Disease recurrence Yes 37 (21) No 153 (79) Mortality Yes 7 (4) No 173 (96)

3 178 Y.-F. Lin, Y.-H. Uen Figure 1 Receiver-operating characteristic (ROC) curve using LN Z 15 with overall survival cut-off value Z 15, sensitivity Z 47.1%, specificity Z 90.9%. Area under curvature (AUC) Z 0.731, p < SPSS Inc., Chicago, IL, USA). A p value <0.05 was considered statistically significant. 3. Results During the period from January 2003 to December 2006, data for 709 colorectal cancer patients were recorded in a database. For this study, 190 patients with stage II colorectal cancer were selected from the database by exclusion criteria. There were 106 males (55.8%) and 84 females (44.2%). Ages (mean SD) were years (range 29e89 years). Median follow-up time was 42.4 months (2.4e74.4 months). Disease recurrence was noted in 37 patients (21%) and mortality in 7 patients (4%). The average number of examined LNs was There were 77 patients with >15 LNs examined. T3 tumor stage was found in 181 patients and adenocarcinoma was diagnosed in 185 patients. Lymphovascular invasion was found in 20 patients (10.5%). Adjuvant therapy was delivered to 78 patients (Table 1). Using logistic regression and the ROC curve, we found that the number of examined LNs of >15 or <15 was the most meaningful cut-point value for prediction of progress of overall survival [sensitivity Z 47.1%, specificity Z 90.9%, area under curvature (AUC) Z 0.731] (Figure 1). Using univariate Cox proportional hazard regression analysis, for overall survival, we found that age [hazard ratio (HR) Z 2.29, p Z 0.034], number of examined LNs > 15 (HR Z 0.15, p Z 0.001), T3 lesion (HR Z 2.91, p Z 0.046), and administration of adjuvant therapy (HR Z 0.37, p Z 0.019) were significantly associated with a better outcome (Table 2). Moreover, when using multivariate Cox proportional hazard regression analysis, we found that number of examined LNs > 15 (HR Z 0.15, p Z 0.001) and T3 stage (HR Z 0.29, p Z 0.024) were independent factors of a better outcome for overall survival (Table 3). 4. Discussion Accurate LN examination is crucial because nodal status is an important prognostic factor. 5,6 In America, patients with node-negative colon cancer have a 5-year survival of >75%, whereas patients with node-positive disease have a 5-year survival rate of only around 50%. In addition, node metastasis status also affects the further delivery of chemotherapy, which could improve survival by approximately 30% for patients with node-positive disease. 7,8 Patients with stage II colorectal cancer are node-negative, and chemotherapy is not suggested except when the disease is complicated. In this study, for overall survival, the number of examined nodes >15 and T3 stage were factors that indicated Table 2 Univariate Cox proportional hazard regression analysis for overall survival HR 95% CI for HR p Age (y) 65 vs. < Sex Female vs. male Tumor location Rectum vs. colon Preoperative CEA CEA (ng/ml) 5 vs. < Differentiation Well vs. poor Moderate vs. poor LN total >15 vs >12 vs Tumor type Mucinous vs. adenocarcinoma T-stage T4 vs. T LVI Yes vs. no Adjuvant therapy Yes vs. no CEA Z carcinoembryonic antigen; CI Z confidence interval; HR Z hazard ratio; LN Z lymph node; LVI Z lymphovascular invasion. Lower Upper

4 LN examination for early colon cancer 179 Table 3 Multivariate Cox proportional hazard regression analysis conducted using forward stepwise model selection method HR 95% CI for HR p LN total >15 vs T-Stage T4 vs. T Adjuvant therapy Yes vs. No Age (y) 65 vs. < CI Z confidence interval; HR Z hazard ratio; LN Z lymph node. Lower Upper better progress. This result showed that more than the previously suggested number of examined LNs was considered to improve the overall survival of patients with nodenegative colon cancer. Several recent studies have shown that the greater the number of examined nodes, the better the outcome. 9,10 In Taiwan, the situation is similar. Tsai et al 27 found that >18 examined LNs and T-stage are factors for better overall survival. However, T-stage in their study was divided into T2 and T3 þ T4 groups, thus differing from the present study. The larger number of nodes examined may indicate that staging is more accurate, and thus patients will not be undertreated. In other words, fewer nodes examined may potentially have more positive nodes that are either not resected or not included in the specimen. During data analysis, the number of LNs examined (>12 or <12) was also included. The results showed that 12 LNs is also an indicator during univariate analysis (HR Z 0.29, p Z 0.002). However, with the ROC curve, we found that 15 LNs is better than 12 LNs (sensitivity Z 59.2%, specificity Z 75.8%) in predicting prognosis. T-Stage was another independent factor for overall survival in our study. Several published articles have shown that advanced T-stage has a strong likelihood of having positive nodes and approximately 8e12% of T1 tumors and 14% of T2 tumors are node-positive. 11e13 Another explanation is that T4 patients have a poor prognosis when compared with early stage III (T1-2N1M0). 14 Misclassification for such T4 patients would result in micrometastasis without treatment. Several studies have shown that LVI is a strong stageindependent prognostic factor. 15e18 The presence of LVI is associated with an increased risk of regional LN metastasis. 19e21 Lim et al 22 also revealed that LVI is an independent factor for unfavorable prognosis. In our present study, however, no significant difference was associated with the presence of LVI. It may be because our pathologic examination was performed by different pathologists. They used only hematoxylin and eosin (H&E) for staining and fewer slides for diagnosis. Kingston et al 23 found that H&E staining proved less sensitive in identification of LVI. The poorer sensitive stain and fewer slides might have led to a small number of LVI in our patients (10.5%); however, in another study 26.6% T3-stage and 43.5% T4-stage patients were documented. 22 In this study, adjuvant therapy was a significant prognostic factor for overall survival in univariate analysis but failed to show significance in multivariate analysis. This finding is similar to that of a meta-analysis by Gill et al indicating that adjuvant therapy slightly improves diseasefree survival but not overall survival. 24 Adjuvant therapy should be considered in stage II patients with high risk, including inadequately sampled nodes, T4 lesions, perforation, poorly differentiated tumor, lymphovascular or perineural invasion, close-positive, indeterminate or positive margins, and bowel obstruction, which are also known to carry a higher rate of recurrence. 25,26 The limitations in this study include the nature of the retrospective design. In general, the date of death in each case was recorded, but the cause of death was not available in some cases. Thus, in some cases we could not confirm whether the death was disease-related or not. 5. Conclusions This study showed that long-term outcomes expressed by cancer deaths after attempted curative resection for stage II colon cancer were significantly improved by increasing lymph node retrieval and examination. Statistically, our results show that 12 examined LNs is not large enough for prediction of overall survival and suggest that examination of >15 LNs is associated with a significant increase in overall survival. This supports the current clinical practice of harvesting and analyzing as many nodes as possible during surgical resection for pathologic analysis, particularly in stage II patients. Acknowledgments We thank all the participants of our cancer center, and also Ms Chin-Li Lu and Wen-Chun Lin for their statistical analysis. We also thank Dr Jinn-Rung Kuo for kind revision of the article. References 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics. CA Cancer J Clin. 2006;2006(56):106e Scott KW, Grace RH. Detection of lymph node metastases in colorectal carcinoma before and after fat clearance. Br J Surg. 1989;76:1165e Ratto C, Sofo L, Ippoliti M, et al. Accurate lymph-node detection in colorectal specimens resected for cancer is of prognostic significance. Dis Colon Rectum. 1999;42:143e Zweig MH, Campbell G. Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine. Clin Chem. 1993;39:561e Le Voyer TE, Sigurdson ER, Hanlon AL, et al. Colon cancer survival is associated with increasing number of lymph nodes

5 180 Y.-F. Lin, Y.-H. Uen analyzed: a secondary survey of intergroup trial INT J Clin Oncol. 2003;21:2912e Wong JH, Severino R, Honnebier MB, et al. Number of nodes examined and staging accuracy in colorectal carcinoma. J Clin Oncol. 1999;17:2896e Moertel CG, Fleming TR, Macdonald JS, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med. 1990;322:352e Mamounas E, Wieand S, Wolmark N, et al. Comparative efficacy of adjuvant chemotherapy in patients with Dukes B versus Dukes C colon cancer: results from four National surgical adjuvant breast and bowel project adjuvant studies (C-01, C-02, C-03, and C-04). J Clin Oncol. 1999;17:1349e Vather R, Sammour T, Zargar-Shoshtari K, et al. Lymph node examination as a predictor of long-term outcome in Dukes B colon cancer. Int J Colorectal Dis. 2009;24:283e Vather R, Sammour T, Kahokehr A, et al. Lymph node evaluation and long-term survival in stage II and stage III colon cancer: a national study. Ann Surg Oncol. 2009;16:585e Kawamura YJ, Sakuragi M, Togashi K, et al. Distribution of lymph node metastasis in T1 sigmoid colon carcinoma: should we ligate the inferior mesenteric artery? Scand J Gastroenterol. 2005;40:858e Nascimbeni R, Burgart LJ, Nivatvongs S, et al. Risk of lymph node metastasis in T1 carcinoma of the colon and rectum. Dis Colon Rectum. 2002;45:200e Leibl S, Tsybrovskyy O, Denk H. How many lymph nodes are necessary to stage early and advanced adenocarcinoma of the sigmoid colon and upper rectum? Virchows Arch. 2003;443: 133e O Connell JB, Maggard MA, Ko CY. Colon cancer survival rates with the new American Joint Committee on cancer sixth edition staging. J Natl Cancer Inst. 2004;96:1420e Compton C, Fenoglio-Preiser CM, Pettigrew N, et al. American Joint Committee on cancer prognostic factors consensus conference: colorectal working group. Cancer. 2000;88: 1739e Compton CC, Fielding LP, Burgart LJ, et al. Prognostic factors in colorectal cancer. College of American pathologists consensus statement Arch Pathol Lab Med. 2000;124: 979e Losi L, Ponti G, Gregorio CD, et al. Prognostic significance of histological features and biological parameters in stage I (pt1 and pt2) colorectal adenocarcinoma. Pathol Res Pract. 2006; 202:663e Minsky BD, Mies C, Recht A, et al. Resectable adenocarcinoma of the rectosigmoid of rectum II. The influence of blood vessel invasion. Cancer. 1988;61:1417e Coverlizza S, Risio M, Ferrari A, et al. Colorectal adenomas containing invasive carcinoma. Pathologic assessment of lymph node metastatic potential. Cancer. 1989;64:1937e Muller S, Chesner IM, Egan MJ, et al. Significance of venous and lymphatic invasion in malignant polyps of the colon and rectum. Gut. 1989;30:1385e Nivatvongs S, Rojanasakul A, Reiman HM, et al. The risk of lymph node metastasis in colorectal polyps with invasive adenocarcinoma. Dis Colon Rectum. 1991;34:323e Lim SB, Yu CS, Jang SJ, Kim TW, Kim JH, Kim JC. Prognostic significance of lymphovascular invasion in sporadic colorectal cancer. Dis Colon Rectum. 2010;53:377e Kingston EF, Goulding H, Bateman AC. Vascular invasion is underrecognized in colorectal cancer using conventional hematoxylin and eosin staining. Dis Colon Rectum. 2007;50: 1867e Gill S, Loprinzi CL, Sargent DJ, et al. Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much? J Clin Oncol. 2004;22: 1797e Benson AB III, Schrag D, Somerfield MR, et al. American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol. 2004;22: 3408e National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology, Tsai HL, Lu CY, Hsieh JS, et al. The prognostic significance of total lymph node harvest in patients with T2e4N0M0 colorectal cancer. J Gastrointest Surg. 2007;11:660e665.