Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer-related deaths worldwide, because it accounted for approximately 1.4 million new patients and 700 thousand cancer-related deaths in 2012.1 Although adjuvant chemotherapy containing oxaliplatin represented a new era of treatment for nonmetastatic CRC, radical resection of the primary tumor still plays a leading role in the pursuit of a cure.2–6
The principle of colorectal surgery is to resect not only the primary tumor, but also all of the lymphatic, vascular, and neural tissues in the drainage area, without exposure of the remaining tissue to the tumor tissue.7 , 8 To achieve this principle, the concept of complete mesocolic excision (CME) for colon cancer was proposed in Germany. This procedure involves the removal of the intact mesentery, peritoneum, and encasing fascia.9 Meanwhile, extended lymphadenectomy (D3 lymphadenectomy) for CRC, which involves the complete removal of regional lymph tissues in the drainage area, was proposed in Japan.10 Both concepts share a common feature and attach importance to the complete removal of the tumor tissue in the mesentery to prevent local recurrence. We have previously reported the safety and satisfactory long-term outcomes of D3 lymphadenectomy for right- and left-sided CRC,11 , 12 and this procedure is now a standard protocol used by many colorectal surgeons in East Asia.13–17 However, only a few studies have evaluated the detailed survival benefit of D3 lymphadenectomy thus far; as a result, its impact is still not sufficiently clear.18 , 19
Lymphadenectomy for clinically node-negative and node-positive CRC has a different meaning in treatments for nonmetastatic CRC. Lymphadenectomy for clinically node-negative CRC consists of a prophylactic dissection to prevent disease recurrence. In contrast, lymphadenectomy for clinically node-positive CRC is a therapeutic dissection to achieve a cure. One of the most important prognostic factors in nonmetastatic CRC is nodal status20–22; therefore, we assumed that clinical nodal status might be associated with the impact of D3 lymphadenectomy.
The aim of this retrospective case-matched cohort study was to evaluate the survival benefit of D3 lymphadenectomy for clinically node-negative and node-positive CRCs and to provide greater detail to clarify the impact of D3 lymphadenectomy on CRC.
MATERIALS AND METHODS
Details of Japanese D3 Lymphadenectomy
In Japan, the commonly recommended treatment for colon and upper rectal cancer, according to the classification of the Japanese Society for Cancer of the Colon and Rectum (JSCCR), is radical resection of the primary tumor with proximal lymphadenectomy.23 Additional lateral pelvic lymphadenectomy is recommended only for lower rectal cancer, but preoperative chemotherapy or chemoradiotherapy is not recommended. The classification of the JSCCR clearly states the extent of proximal lymphadenectomy (Fig. 1).23 D3 lymphadenectomy is defined as the complete dissection of regional lymph nodes, including pericolic nodes, intermediate nodes, and the main nodes at the root of the supplying artery. Inadequate or omitted dissection of the main node is classified as nonextended lymphadenectomy (D1 or D2 lymphadenectomy). The supplying artery of the cecum, ascending, and transverse colon is the superior mesenteric artery, whereas that of the descending, sigmoid, and rectosigmoid colon, and upper rectum is the inferior mesenteric artery (IMA).
According to the classification of JSCCR, the length of the bowel resection is also defined by the positional relationship between the feeding artery and the tumor and, in general, is shorter than in Western countries23 because the classification of JSCCR considers the rate of lymph node metastasis longitudinally from the tumor.24 The length of the remnant bowel is longer than in Western countries for this reason25; therefore, the retention of blood flow to the remnant bowel is important in D3 lymphadenectomy. In our right hemicolectomy procedure for right-sided colon cancer, the left branch of the middle colic artery is generally preserved for the retention of blood flow, with the complete dissection of regional lymph nodes (Fig. 2A). In our sigmoidectomy procedure or anterior resection for left-sided CRC, the IMA is, in general, resected for complete main node dissection at the root of the IMA (Fig. 2B); however, the preservation of the IMA for the retention of blood flow is acceptable as long as complete main node dissection is performed.
Between January 1988 and December 2007, 2326 consecutive patients underwent resection for solitary nonmetastatic CRC at the Aichi Cancer Center Hospital. Among these patients, 970 were excluded because of lower rectal cancer (n = 466), lateral pelvic lymph node dissection for metastatic lateral lymph nodes (n = 166), palliative resection (n = 312), pilot laparoscopic surgery (n = 13), or inadequate (less than D2) lymphadenectomy (n = 13). Furthermore, 42 patients who underwent D3 lymphadenectomy were excluded because of clinical main node metastasis. Finally, 1314 patients who underwent open radical resection with D2 or D3 lymphadenectomy for cStage I to III CRC were enrolled in the present study. No patient in the study group received preoperative chemotherapy or other preoperative treatment.
The variates of each patient were retrospectively examined based on data from a prospective database. We categorized the patients according to study period as either the former half (1988–1997) or the latter half (1998–2007) to eliminate the influence of the improvement in the quality of diagnostic images, which affected the accuracy of nodal staging. We also categorized the patients by primary tumor site as right- or left-sided tumors, which included the cecum, ascending and transverse colon (supplied by the superior mesenteric artery), and descending, sigmoid, and rectosigmoid colon and upper rectum (supplied by the IMA). Clinical staging according to the Union for International Cancer Control Classification was determined by preoperative imaging procedures in all cases. cT stage was determined by preoperative lower gastrointestinal series or colonoscopy, and cN stage was determined by preoperative computed tomography or abdominal ultrasonography. The follow-up data of each patient were also retrospectively examined from a prospective database. All patients were followed up until death, 10 years after the surgery, or December 2012 when possible. The mean follow-up period of all patients was 92.3 ± 34.5 months.
The extent of proximal lymphadenectomy depended on the decisions of each surgeon; these decisions were made according to preoperative demographics and the clinical staging of patients; therefore, a large bias existed between the populations that underwent D2 and D3 lymphadenectomy. For the adjustment of preoperative demographics and clinical staging of patients, we applied propensity score matching to the study series. Here, 1314 patients were divided into a cN0 series (n = 711, including D2; n = 178 and D3; n = 533) and a cN1/2 series (n = 603, including D2; n = 77 and D3; n = 526). The propensity score was calculated using potential confounders between D2 and D3 lymphadenectomy, as follows: age, sex, study period, primary tumor site, preoperative pathology, cT stage, and cN stage. These were used as covariates in multivariable logistic regression. Patients were matched by using a propensity score matching method with r set at 0.01. Finally, 141 and 63 propensity score-matched pairs were extracted from the cN0 and cN1/2 series.
The means and SDs were calculated for all the collected continuous variates and were compared by using the Student t test. Categorical variates were recorded as numbers and were compared by using the χ2 or Fisher exact test. Survival rates were calculated using the Kaplan-Meier method, and the differences between the curves were compared by using a log-rank test. All tests were 2-sided, and α was set at 0.05. SPSS 24.0 (IBM Corporation, Armonk, NY) was used for all statistical analyses.
D3 Lymphadenectomy for Clinically Node-Negative CRC
The preoperative demographics of all patients and matched patients in the cN0 series are shown in Table 1. Several preoperative covariates differed between the D2 and D3 groups before matching. The mean age was lower (p = 0.009), the tumors were less differentiated according to the preoperative pathology (p = 0.002), and the cT stage was more progressive (p < 0.001) in the D3 group. After propensity score matching was performed, all preoperative covariates were adjusted for balance, and no statistically significant differences were present between the groups after matching.
The postoperative details of all patients and matched patients in the cN0 series are shown in Table 2. After matching, the mean operative time was longer (p = 0.05), and the mean hospital stay was longer (p = 0.01) in the D2 group. The number of examined lymph nodes was also larger (p = 0.008) in the D3 group. No significant differences were observed in the number of metastatic lymph nodes.
The Kaplan-Meier curves of disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) of the matched patients in the cN0 series are shown in Figure 3. Disease-free survival (93.5% vs 93.5%), CSS (97.8% vs 97.1%), and OS (94.2% vs 94.9%) of patients in the D2 and D3 groups at 5 years were all excellent, and no differences were observed between the groups according to the log-rank test.
D3 Lymphadenectomy for Clinically Node-Positive CRC
The preoperative demographics of all patients and matched patients in the cN1/2 series are shown in Table 3. As with the cN0 series, several preoperative covariates differed between the 2 groups before matching. The mean age was lower (p < 0.001), the proportion of right-sided CRC was larger (p = 0.01), and the cT and cN stages were more progressive (p = 0.005 and p = 0.02) in the D3 group. After propensity score matching was applied, all preoperative covariates were adjusted for balance, and no statistically significant differences were present between the groups after matching.
The postoperative details of all patients and matched patients in the cN1/2 series are shown in Table 4. After matching, the mean operative time was longer (p = 0.01), the amount of blood loss tended to be larger, and the mean hospital stay tended to be longer in the D2 group. The number of examined lymph nodes was larger (p = 0.03) in the D3 group. No significant differences were found in the number of metastatic lymph nodes. Two of 63 matched patients in the D3 group were pathologically positive for main node metastasis. A small number of patients in the entire series received postoperative chemotherapy, which reflects the historical background of that time.
The Kaplan-Meier curves of DFS, CSS, and OS of matched patients in the cN1/2 series are shown in Figure 4. Disease-free survival (55.0% vs 76.1%), CSS (79.0% vs 93.3%), and OS (59.8% vs 86.1%) of the patients in the D2 and D3 groups at 5 years were all inferior to those of the patients in the cN0 series. Disease-free survival tended to be higher in the D3 group, and CSS and OS were significantly higher (p = 0.04, p = 0.02 and p = 0.01) in the D3 group than in the D2 group according to the log-rank test.
Details of the primary recurrence site of all patients and matched patients in the cN1/2 series are shown in Table 5. The frequency of local recurrence, including recurrence in the perianastomotic colon, mesenteric and paracolic lymph nodes, and retroperitoneum, was significantly lower (p = 0.04) in the D3 group after matching. No differences were found in the frequency of distant lymph node recurrence or distant recurrence between the groups after matching.
In the present study, D3 lymphadenectomy demonstrated a good inhibitory effect on local recurrence and led to improved DFS, CSS, and OS in patients of the cN1/2 series. Based on these results, the principal objective of D3 lymphadenectomy is assumed to be an inhibitory effect on local recurrence, which would result in an improvement in the long-term outcome. The objective of D3 lymphadenectomy is not only additional main node dissection, but also the complete removal of the regional lymphatic tissues for the prevention of local recurrence, including recurrence in the perianastomotic colon, mesenteric and paracolic lymph nodes, and retroperitoneum, as with CME with central vascular ligation. In Germany, West et al8 also reported a significant improvement in OS in patients with complete CME for pathologically node-positive colon cancer compared with those with incomplete CME. These results reveal that the complete removal of tumor tissues in the mesentery has a large impact on the improvement of the long-term outcome in patients with node-positive CRC.
One of the most important factors that affected the improvement of the long-term prognosis exerted an inhibitory effect on local recurrence; however, in the present study, stage migration due to the difference in the number of examined lymph nodes is also considered to affect the long-term prognosis.20–22 The number of examined lymph nodes in the D3 group was significantly larger, and the number of metastatic lymph nodes in both groups was equivalent in the cN1/2 series. These results reveal that another objective of D3 lymphadenectomy is the accurate staging of lymph node metastasis to predict the long-term prognosis.
In a previous study, Kotake et al18 reported the survival benefit of D3 lymphadenectomy for pT3 and pT4 colon cancers in patients matched from a multi-institutional database of CRC in Japan using a propensity score matching method. However, in their study, the survival benefit of D3 lymphadenectomy was significant but weak. In the present study, the impact of D3 lymphadenectomy on clinically node-positive CRC was larger than that in the study by Kotake et al. The reason for this difference is considered to be related to the correlation between invasion depth and lymph node metastasis. Lymph node metastasis in CRC is generally known to increase with the progression of invasion depth of the primary tumor. The impact of D3 lymphadenectomy for pT3 and pT4 colon cancer seems to be indirect through an increase in lymph node metastasis and seems to be directly exhibited in patients with clinically node-positive CRC.
The importance of the complete removal of the tumor tissue in the mesentery to prevent local recurrence has been accepted; however, evidence for this has not been revealed in either CME or D3 lymphadenectomy. In 2015, Bertelsen et al26 reported a retrospective population-based study of the comparison of CME and conventional surgery in Denmark and revealed the superiority of CME with respect to DFS over conventional colon surgery in patients with stage I to III colon cancer. Herein, we also revealed the benefit of therapeutic D3 lymphadenectomy for clinically node-positive CRC in terms of local control and accurate staging, which contributed to prolonged survival. The high rates of mesocolic plane surgery of European CME with central vascular ligation and Japanese D3 lymphadenectomy have already been reported.25 , 27 As colorectal surgeons, we must keep in mind that the achievement of radical resection of the primary tumor and the tumor tissue in the mesentery using these procedures or others is the most important.
Our study has several limitations that need to be addressed in future research. First, the study period was relatively long, and we could not obtain data on the comorbidities or ASA scores of old cases for calculation of the propensity score, which might have affected the treatment outcome. Second, after propensity score matching was applied, the differences in operative time, blood loss, and hospital stay remained in the cN1/2 series. We cannot clearly explain the reason for this; however, the differences might indicate the presence of other intangible potential confounders that may indirectly affect the long-term prognosis. Third, a small number of patients received postoperative chemotherapy in the cN1/2 series, which reflects the historical background in that time. The impact of D3 lymphadenectomy might be more limited in recent patients who routinely receive postoperative chemotherapy when they are diagnosed with pathologically node-positive CRC. Fourth, although propensity score matching was applied, this study was a retrospective, case-matched cohort study of a small number of patients from a single department. In Japan, where D3 lymphadenectomy is a standard protocol and is performed in general, a large randomized controlled trial is impractical. Further retrospective analysis of a larger number of patients is required to investigate a more detailed survival benefit of D3 lymphadenectomy for CRC.
Extended lymphadenectomy revealed a good inhibitory effect on local recurrence and led to improved DFS, CSS, and OS in the cN1/2 series. These results demonstrate the impact of therapeutic D3 lymphadenectomy on clinically node-positive CRC in terms of local control and accurate staging, which contributed to prolonged survival.
1. Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A, Bray FGlobal patterns and trends in colorectal cancer incidence and mortality. Gut. 2017;66:683–691.
2. André T, Boni C, Mounedji-Boudiaf L, et alMulticenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350:2343–2351.
3. André T, Boni C, Navarro M, et alImproved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009;27:3109–3116.
4. Kuebler JP, Wieand HS, O’Connell MJ, et alOxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 2007;25:2198–2204.
5. Yothers G, O’Connell MJ, Allegra CJ, et alOxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses. J Clin Oncol. 2011;29:3768–3774.
6. Schmoll HJ, Cartwright T, Tabernero J, et alPhase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol. 2007;25:102–109.
7. West NP, Hohenberger W, Weber K, Perrakis A, Finan PJ, Quirke PComplete mesocolic excision with central vascular ligation produces an oncologically superior specimen compared with standard surgery for carcinoma of the colon. J Clin Oncol. 2010;28:272–278.
8. West NP, Morris EJ, Rotimi O, Cairns A, Finan PJ, Quirke PPathology grading of colon cancer surgical resection and its association with survival: a retrospective observational study. Lancet Oncol. 2008;9:857–865.
9. Hohenberger W, Weber K, Matzel K, Papadopoulos T, Merkel SStandardized surgery for colonic cancer: complete mesocolic excision and central ligation–technical notes and outcome. Colorectal Dis. 2009;11:354–364.
10. Okuno KSurgical treatment for digestive cancer. Current issues - colon cancer. Dig Surg. 2007;24:108–114.
11. Kanemitsu Y, Hirai T, Komori K, Kato TSurvival benefit of high ligation of the inferior mesenteric artery in sigmoid colon or rectal cancer surgery. Br J Surg. 2006;93:609–615.
12. Kanemitsu Y, Komori K, Kimura K, Kato TD3 Lymph Node Dissection in Right Hemicolectomy with a No-touch Isolation Technique in Patients With Colon Cancer. Dis Colon Rectum. 2013;56:815–824.
13. Watanabe T, Itabashi M, Shimada Y, et alJapanese Society for Cancer of the Colon and Rectum. Japanese Society for Cancer of the Colon and Rectum (JSCCR) Guidelines 2014 for treatment of colorectal cancer. Int J Clin Oncol. 2015;20:207–239.
14. Lee SD, Lim SBD3 lymphadenectomy using a medial to lateral approach for curable right-sided colon cancer. Int J Colorectal Dis. 2009;24:295–300.
15. Han DP, Lu AG, Feng H, et alLong-term results of laparoscopy-assisted radical right hemicolectomy with D3 lymphadenectomy: clinical analysis with 177 cases. Int J Colorectal Dis. 2013;28:623–629.
16. Liang JT, Lai HS, Huang J, Sun CTLong-term oncologic results of laparoscopic D3 lymphadenectomy with complete mesocolic excision for right-sided colon cancer with clinically positive lymph nodes. Surg Endosc. 2015;29:2394–2401.
17. Xie D, Yu C, Gao C, Osaiweran H, Hu J, Gong JAn optimal approach for laparoscopic D3 lymphadenectomy plus complete mesocolic excision (D3+CME) for right-sided colon cancer. Ann Surg Oncol. 2017;24:1312–1313.
18. Kotake K, Mizuguchi T, Moritani K, et alImpact of D3 lymph node dissection on survival for patients with T3 and T4 colon cancer. Int J Colorectal Dis. 2014;29:847–852.
19. Kotake K, Kobayashi H, Asano M, Ozawa H, Sugihara KInfluence of extent of lymph node dissection on survival for patients with pT2 colon cancer. Int J Colorectal Dis. 2015;30:813–820.
20. Gospodarowicz MK, O’Sullivan B, Sobin LHPrognostic Factors in Cancer. 2006.3rd ed. Hoboken, NJ: John Wiley & Sons, Inc;
21. Chang GJ, Rodriguez-Bigas MA, Skibber JM, Moyer VALymph node evaluation and survival after curative resection of colon cancer: systematic review. J Natl Cancer Inst. 2007;99:433–441.
22. Le Voyer TE, Sigurdson ER, Hanlon AL, et alColon cancer survival is associated with increasing number of lymph nodes analyzed: a secondary survey of intergroup trial INT-0089. J Clin Oncol. 2003;21:2912–2919.
23. Japanese Society for Cancer of the Colon and Rectum. Japanese Classification of Colorectal Carcinoma. 2013.8th ed. Tokyo: Kanehara-& Co, Ltd;
24. Toyota S, Ohta H, Anazawa SRationale for extent of lymph node dissection for right colon cancer. Dis Colon Rectum. 1995;38:705–711.
25. West NP, Kobayashi H, Takahashi K, et alUnderstanding optimal colonic cancer surgery: comparison of Japanese D3 resection and European complete mesocolic excision with central vascular ligation. J Clin Oncol. 2012;30:1763–1769.
26. Bertelsen CA, Neuenschwander AU, Jansen JE, et alDanish Colorectal Cancer Group. Disease-free survival after complete mesocolic excision compared with conventional colon cancer surgery: a retrospective, population-based study. Lancet Oncol. 2015;16:161–168.
27. Kobayashi H, West NP, Takahashi K, et alQuality of surgery for stage III colon cancer: comparison between England, Germany, and Japan. Ann Surg Oncol. 2014;21(suppl 3):S398–S404.