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Distribution of lymph node metastasis is a prognostic index in patients with stage III colon cancer
Distribution of lymph node metastasis is a prognostic index in patients with stage III colon cancer Hirotoshi Kobayashi, MD, Hideki Ueno, MD, Yojiro Hashiguchi, MD, and Hidetaka Mochizuki, MD, Saitama, Japan
Background. In the TNM classification of colorectal carcinoma, N-staging is dependent on the number of metastases; in the Japanese classification system, staging usually has been based on the distribution of metastases (N1, paracolic; N2, along the major vessels; N3, at the root of major vessels). The aim of our study was to examine whether the concept of the distribution of nodal metastasis could improve the TNM classification for colorectal cancer. Methods. We studied the survival rates of 485 and 136 patients with stage III colonic and rectal cancer, respectively, who underwent curative surgery between 1979 and 1998. The patients were categorized into 4 groups: group 1, TNM-N1 classified in J-N1; group 2, TNM-N2 in J-N1; group 3, TNM-N1 in J-N2-3; and group 4, TNM-N2 in J-N2-3. Results. In the colon cancer arm, the 5-year survival rates of the patients in groups 1 to 4 were 74%, 51%, 52%, and 54%, respectively. There was a significant difference in survival rate between groups 1 and 3 ( P = .0002). Thus, in colon cancer, nodal metastasis along the major vessels was a bad prognostic factor, even though the number of nodes that were involved was <4. In the rectum cancer arm, the 5-year survival rates of the patients in each group were 65%, 39%, 60%, and 32%, respectively. Only the number of nodal metastases was an independently significant prognostic variable. Conclusion. This study suggests that adding the concept of nodal distribution to the conventional TNM staging of colon cancer will improve the accuracy in the evaluation of the nodal status. (Surgery 2006;139:516-22.) From the Department of Surgery I, National Defense Medical College, Saitama, Japan
COLORECTAL CANCER IS THE SECOND leading cause of death from cancer in the United States,1 and its frequency is increasing in Japan.2 Several prognostic factors in colorectal cancer have been evaluated.3,4 Nodal involvement is well accepted as one of the most important determinants of prognosis in patients with localized carcinoma of the colon and rectum,5 as acknowledged in the TNM and Dukes classifications of colorectal carcinoma.6,7 The number of involved lymph nodes affects the prognosis in patients with colorectal cancer8 and has been incorporated into the current TNM classification.6 However, in the Japanese
Accepted for publication September 2, 2005. Reprint requests: Hirotoshi Kobayashi, MD, Department of Surgical Oncology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. E-mail: h-kobayashi. [email protected]. 0039-6060/$ - see front matter Ó 2006 Mosby, Inc. All rights reserved. doi:10.1016/j.surg.2005.09.004
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classification of colorectal carcinoma, the staging (N number) is dependent on the distribution rather than on the absolute number of lymph node metastases.9 Both the Japanese and the TNM classifications of lymph node metastasis are considered to provide accurate prognoses of patients with colorectal carcinoma.2 Therefore, we decided to investigate which classification of lymph node metastasis predicts the outcome of patients with colorectal carcinoma more precisely. A recent report suggested that the number of lymph nodes that are retrieved and analyzed on resection for staging colon cancer is, itself, a prognostic variable on outcome.10 Another study indicated that the examination of at least 14 lymph nodes after resection of T2 or T3 carcinoma of the colon and rectum will stage the lymphatic basin accurately.11 Thus, we also investigated the prognostic effect of the number of lymph nodes that were examined to eliminate the risk of downstaging. The present study was designed to examine whether the distribution of nodal involvement is
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Table I. Classification of the patients with stage III disease Criteria for TNM-N1 TNM-N2 nodal involvement (TNM-stage IIIA, IIIB) (TNM-stage IIIC) Japanese-N1 (J-stage IIIa) Japanese-N2, 3 (J-stage IIIb)
Group 1
Group 2
Group 3
Group 4
able to improve the TNM classification for colorectal cancer. PATIENTS AND METHODS Patients. The medical charts of patients with stage III disease with lymph node metastasis who underwent curative operation for colorectal carcinoma at a single institute (the Department of Surgery I, National Defense Medical College, Saitama, Japan) between January 1979 and December 1998 were reviewed. In our institute, the standard practice of nodal dissection involved ligation of the major artery to the region of resection at its origin; for resection of the right colon, this involves the resection of the right colonic artery at its origin from the superior mesenteric artery and, for the left colon, ligation of the inferior mesenteric artery at its origin from the aorta. During this period, total mesorectal excision was performed for the patients with rectal cancer. Patients with T2, T3, and T4 lower rectal cancer underwent total mesorectal excision with lateral node dissection. Lateral node dissection was performed as described previously.12 Patients with familial adenomatous polyposis, cancer family syndrome kindreds, or ulcerative colitis were excluded in this study. Rectal cancer above the peritoneal reflection was analyzed as colon cancer, because these neoplasms do not have a lateral lymphatic drainage and act as colon cancers. Tumor stage was classified according to 2 systems, the TNM6 (TNM-IIIA, IIIB, and IIIC) and the Japanese classification for colorectal carcinoma9 (J-IIIa [J-N1] and IIIb [J-N2, N3]). In the TNM classification, N1 is defined as metastasis in 1 to 3 regional lymph nodes, and N2 is defined as metastasis in $4 regional lymph nodes; TNM IIIA is defined as T1 to T2N1M0; TNM IIIB is defined as T3 to T4N1M0, and TNM IIIC is defined as any TN2M0. The Japanese N1 is defined as lymph node metastasis adjacent to the colon and rectum or along the vascular arcades of marginal arteries; N2 is defined as metastasis along the course of the major vessels that supply the colon and rectum,
and N3 is defined as metastasis near the root of the major vessels. For example, J-N3 in patients with lower rectal cancer is defined as metastasis in lymph nodes along the inferior mesenteric artery proximal to the origin of left colic artery or those along the external iliac artery and common iliac artery. J-N2 in these patients is defined as metastasis in lymph nodes along the inferior mesenteric artery distal to the origin of left colic artery or those along the internal iliac artery. In the present study, to compare the accuracy of these classifications of nodal metastasis in colorectal cancer, patients were categorized into 4 groups: group 1, TNM-N1 classified in J-N1; group 2, TNM-N2 in J-N1; group 3, TNM-N1 in J-N2-3; and group 4, TNM-N2 in J-N2-3 (Table I). In the original text of the Japanese classification of colorectal carcinoma, stage IIIa was defined as T4 (direct invasion), N0, or any TN1. In this study, however, the patients with stage IIIa to T4N0 were excluded. Pathologic examination. All specimens were examined in the following manner: After tumor removal, the excised specimen was opened along the antimesenteric border by the surgeon. The specimen with the mesentery was stretched and pinned to a corkboard. The surgeon identified the lymph nodes, isolated them, and recorded both their number and distribution. The time that was required by the surgeon to complete the examination was approximately 60 minutes. In this study, the surgeons harvested the lymph nodes from the specimen to evaluate the precise location of nodal metastases; we acknowledge that this technique is not the custom in the United States or Europe in most centers. After formalin fixation, the specimens and lymph nodes were examined by the pathologist. Follow-up program. All patients were followed for 5 years after the operation. During the first 3 years, patients with stage III disease were followed every 3 months with clinical assessment and measurement of serum carcinoembryonic antigen and every 6 months with chest x-ray and abdominal ultrasonography or computed tomography. For the remaining 2 years, all tests were performed every 6 months. Colonoscopy was performed 1 year after operation and every 2 years for the next 4 years. Statistical analysis. Statistical analysis was performed with the Statview statistical package (Statview 5.0; Abacus Concepts, Inc, Berkeley, Calif). All data are expressed as the means ± SD. The data concerning age and the number of lymph nodes were analyzed with the Mann-Whitney and KruskalWallis test. The Kaplan-Meier method was used to calculate the actuarial survival of patients. Overall
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survival rates in all groups were compared with the use of the log rank test. A Cox’s proportional hazard regression analysis was performed to determine which concepts of nodal metastasis had an independent effect on postoperative survival. Statistical significance was established at a probability value of <.05 for all results. RESULTS A total of 621 patients with stage III disease (485 patients with colon cancer and 136 patients with rectal cancer) were studied in this analysis. Table II shows the clinical characteristics of the patients in this study. Colon cancer. The overall survival curves of the patients with stage III colon cancer are shown in Fig 1. The 5-year survival rates for TNM-IIIA, IIIB, and IIIC were 87%, 68%, and 52%, respectively (P = .0001; Fig 1, A). The rates for J-IIIa and IIIb were 70% and 53%, respectively (P < .0001; Fig 1, B). Fig 1, C compares the survival of patients with stage III colon cancer according to the distribution of nodal involvement alone, independent of number of lymph nodes that were involved. As nodal involvement beyond N1 occurred, the outcome of the patients worsened (P < .0001). This means that the distribution of lymph node metastasis was also an important prognostic factor. However, there was no significant difference in the prognosis between the patients with J-N2 disease and patients with J-N3 disease. The 5-year survival rates of groups 1, 2, 3, and 4 were 74%, 51%, 52%, and 54%, respectively (P < .0001; Fig 1, D). The overall survival of group 1 (< 4 involved nodes limited to paracolic sites) was better than that of the other groups. In particular, there was a significant difference between the survival rates of group 1 (< 4 involved nodes limited to paracolic sites) and group 3 (< 4 involved nodes, but the involved nodes were distant nodes along the major artery to the colonic segment that was involved; P = .0002). These findings suggest that the prognosis of patients whose lymph node metastases are of paracolic type and of < 4 in number is better than that of other patients with stage III colon cancer with more distant nodes involved. Multivariate analysis disclosed that both location and number of nodal involvement were prognostic variables in colon cancer (Table III). Rectal cancer. Fig 2 shows the survival curves of the patients with rectal cancer in this study. Fig 2, A indicates that the TNM classification provides an excellent prognosis for patients with rectal cancer (P = .0005). The concept of the distribution of nodal involvement, however, was not useful for the
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Table II. Characteristics of the 621 patients with stage III colorectal cancer Variable Gender (n) Male Female Age (y)* Location (n) Cecum Ascending colon Transverse colon Descending colon Sigmoid colon Rectosigmoid junction Rectum above the peritoneal reflection Rectum below the peritoneal reflection pT category (n) T1 T2 T3 T4 Number of dissected lymph nodes* <14 (n) $14 (n) Mean follow-up period (y)* TNM classification (n) Stage IIIA Stage IIIB Stage IIIC Japanese classification (n) Stage IIIa Stage IIIb Group in this study (n) Group 1 Group 2 Group 3 Group 4
Colon (n = 485)
Rectum (n = 136)
251 234 62 ± 12 (21-87)
91 45 60 ± 12 (25-89)
40 52 24 37 154 89 89 136
9 24 306 146 24 ± 16
4 13 105 14 34 ± 21
130 355 6.1 ± 4.2
19 117 5.5 ± 4.2
26 320 139
13 67 56
328 157
68 68
275 53 71 86
49 19 31 37
*Data are given as mean ± SD; data in parentheses indicate range.
prediction of the outcome of treatment for rectal cancer (Fig 2, B). Furthermore, there were no significant differences in the overall survival rates between groups 1 and 3 or between groups 2 and 4 (Fig 2, C). In contrast to colon cancer, multivariate analysis disclosed that only the number of lymph node metastases was an independent prognostic factor in rectal cancer (Table III). Number of dissected lymph nodes. We also evaluated the relation between the number of lymph nodes that were retrieved and the prognosis of patients with colorectal cancer. The numbers of
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Table III. Multivariate analysis on the concept of nodal metastasis of colorectal cancer Concept of nodal metastasis Colon Distribution J-N1 J-N2, 3 Number TNM-N1 TNM-N2 Rectum Distribution J-N1 J-N2, 3 Number TNM-N1 TNM-N2
Hazard ratio (95% CI)
P value
1 1.57 (1.14-2.18) 1 1.43 (1.03-2.00)
.007
1 1.06 (0.68-1.66) 1 2.14 (1.36-3.36)
Not significant
.03
.0009
30 ± 21, and 37 ±21, respectively. There were no significant differences in the number of dissected lymph nodes among the 4 groups, either. However, the number of lymph nodes that were retrieved in the rectum was greater than that retrieved in the colon (P < .0001). Moreover, in the present study, there were no significant differences in prognosis between the patients for whom $14 lymph nodes were retrieved and those patients for whom <14 lymph nodes were retrieved. Among the 4 groups, there were no differences in adjuvant chemotherapy, which has changed over time in our institute for the patients with stage III colorectal cancer. DISCUSSION The present study revealed that both the distribution and the number of lymph node metastases are important prognostic factors in colon cancer. The patients with #3 lymph node metastases and in whom the metastases were adjacent to the colon or along the marginal vessels had better prognosis than the other patients with stage III disease with
retrieved lymph nodes in group 1, 2, 3, and 4 patients with colon cancer were 24 ± 17, 24 ± 12, 22 ± 18, and 26 ±16, respectively. There were no significant differences in the number of dissected lymph nodes among the 4 groups. The numbers of retrieved lymph nodes in group 1, 2, 3, and 4 patients with rectal cancer were 32 ± 22, 37 ± 22,
Fig 1. Survival curves of patients with stage III colon cancer by different pathologic classifications of nodal involvement. A, The TNM staging was found to reflect the prognosis of these patients. B, The Japanese classification, in which the number is based on the location of lymph node metastasis, was also found to reflect the prognosis of these patients. C, The distribution of nodal involvement alone. The 5-year survival rates of the patients with J-N1 (paracolic), J-N2 (intermediate), and J-N3 (near the root of major vessels) were 70%, 56%, and 31%, respectively; nodal distribution also reflected prognosis. D, Groups 1, 2, 3, and 4. The prognosis of group 1 patients was better than that of the other groups. There was no significant difference in the overall survival between groups 2 and 3.
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Fig 2. Survival curves of patients with stage III rectal cancer by different pathologic classifications of nodal involvement. A, TNM staging. The TNM staging reflected the prognosis. B, Japanese classification of colorectal carcinoma. The Japanese classification was less precise compared with the TNM staging. C, Groups 1, 2, 3, and 4. The prognoses of groups 1 and 3 were better than the prognoses of groups 2 and 4. There were no differences in overall survival between groups 1 and 3 or between groups 2 and 4.
colon carcinoma in whom <4 nodes were involved, but in whom the involved nodes were located distant to the paracolic or marginal nodes. However, there were no differences in prognosis between the patients with more distant nodes (ie, J-N2 and J-N3 disease). Thus, we believe that it is important to distinguish patients with J-N1 disease
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from patients with J-N2 or J-N3 disease, who are classified in TNM-N1. In our study, the TNM classification accurately reflected the prognosis of patients with stage III colon cancer. The present TNM staging for node-positive colon cancer is based in large part on the analysis performed by Greene et al.13 In their study, data for patients with stage III colon cancer that are found in the National Cancer Database from 1987 to 1993 were analyzed. The 5-year survival rates were 59.8% for IIIA, 42.0% for IIIB, and 27.3% for IIIC. Those rates in the present study were 87% for IIIA, 68% for IIIB, and 52% for IIIC. Outcomes of the treatment of colon cancer in our institution seem to be better than the outcomes in the nationwide analysis in the United States. The prime reason for this difference might be that the data of the study of Greene et al included data from multicenter institutions that included not only leading hospitals for colorectal cancer but also various other hospitals. On the other hand, O’Connell et al14 demonstrated recently that 5-year, stage-specific survival rates were 83.4% for stage IIIA, 64.1% for stage IIIB, and 44.3% for stage IIIC. Their data are close to ours. In our current study, the TNM staging accurately reflected the prognosis of patients with rectal carcinoma. In the survival curves, there were close similarities between groups 1 and 3 and between groups 2 and 4. In rectal cancer, our data showed that the number of lymph node metastases was found to be a more powerful prognostic determinant than the location of nodal involvement. A potential explanation for these findings may be that, in colon carcinoma, the primary lymphatic drainage occurs along the major vessels to the segment of colon that is involved, and the location of nodal involvement indicates the spread of cancer. Thus, we suggest that the distribution and the number of the retrieved lymph nodes should be recorded at the time of pathologic examination. However, in rectal carcinoma, especially lower rectal cancer, there is a lateral spread of cancer as well as in the mesorectum.15,16 Therefore, the distribution of lymph node metastasis by itself can not predict accurately the outcome of treatment in rectal cancer. Recent reports have shown that the prognosis of colorectal carcinoma is dependent on the number of lymph nodes in the resected specimens.10,11,17-20 Le Voyer et al10 reported that the number of retrieved lymph nodes was, itself, a prognostic variable in outcome of patients with stage II and stage III colon cancer. Tepper et al19 demonstrated that approximately 14 nodes needed to be studied
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to define accurately the nodal status in patients with T3, T4, or node-positive rectal cancer. Therefore, in the present study, the number of retrieved lymph nodes was also investigated to eliminate the risk of down-staging. The mean numbers of retrieved nodes in this study were 24 and 34 in patients with cancer of the colon and rectum, respectively. We consider these figures to be sufficient for estimating the nodal status accurately. There were no significant differences in the number of lymph nodes that were retrieved among the 4 groups in both colon and rectal cancer. Moreover, the present study demonstrated that the number of retrieved lymph nodes, whether it was <14 or not, did not affect the prognosis of the patients with stage III colorectal cancer. Our study suggests, however, that it is important to take into account the optimal area of dissection in colorectal surgery, because there are differences in the numbers of regional lymph nodes. In this study, operations were performed by 7 surgeons. Because there has been standardization of the technique of the dissection in our institute, there were no differences in the number of dissected lymph nodes by surgeons. However, there could be a bias by surgeons, which might give potential limitation to the present study. Since Moertel et al21 reported that postoperative adjuvant treatment with fluorouracil and levamisole reduced the mortality rate by 33% in patients with stage III colon cancer, several trials have established 6 months of treatment with fluorouracil plus leucovorin as the standard adjuvant chemotherapy for stage III colon cancer.22-26 Furthermore, Andre et al27 demonstrated that adding oxaliplatin to a regimen of fluorouracil and leucovorin improved the adjuvant treatment of colon cancer. Recent reports have shown that treatments with new drugs (such as irinotecan, oxaliplatin, and bevacizumab) provided patients with metastatic colorectal cancer with significant survival advantages.28-34 Although new drugs enable us to choose various regimens for colorectal cancer, we must diagnose the stage of patients with colorectal cancer more accurately than ever and select the most appropriate treatment. Because the prognoses of patients of groups 2, 3 and 4 in colon cancer and groups 2 and 4 in rectal cancer were worse than those of other groups, such patients may be indicated for more powerful adjuvant chemotherapy. The distribution and the number of the involved nodes is an important index of the prognosis in patients with colon cancer. These findings may indicate that the addition of the concept of
nodal distribution to the conventional TNM staging of colon cancer will improve the accuracy in the evaluation of the nodal status. In rectal cancer, however, the number of lymph node metastases is a better predictor than the location. The results of the present study may be useful in the treatment of patients with stage III colon cancer and in the improvement of categorization based on nodal involvement. REFERENCES 1. American Cancer Society. Cancer facts & figures 2003. Atlanta: American Cancer Society; 2003. 2. Muto T, Kotake K, Koyama Y. Colorectal cancer statistics in Japan: data from JSCCR registration, 1974-1993. Int J Clin Oncol 2001;6:171-6. 3. Griffin MR, Bergstralh EJ, Coffey RJ, et al. Predictors of survival after curative resection of carcinoma of the colon and rectum. Cancer 1987;60:2318-24. 4. Steinberg SM, Barkin JS, Kaplan RS, Stablein DM. Prognostic indicators of colon tumors: the Gastrointestinal Tumor Study Group experience. Cancer 1986;57:1866-70. 5. Newland RC, Chapuis PH, Pheils MT, MacPherson JG. The relationship of survival to staging and grading of colorectal carcinoma: a prospective study of 503 cases. Cancer 1981; 47:1424-9. 6. Greene FL, Page DL, Fleming ID, et al. American Joint Committee on Cancer staging manual. 6th ed. New York: Springer-Verlag; 2002. 7. Dukes C. The classification of cancer of the rectum. J Pathol 1932;35:323-32. 8. Phillips RK, Hittinger R, Blesovsky L, et al. Large bowel cancer: surgical pathology and its relationship to survival. Br J Surg 1984;71:604-10. 9. Japanese Society for Cancer of the Colon and Rectum. Japanese classification of colorectal carcinoma. 5th ed. Tokyo: Kanehara; 1997. 10. Le Voyer TE, Sigurdson ER, Hanlon AL, et al. Colon cancer survival is associated with increasing number of lymph nodes analyzed: a secondary survey of intergroup trial INT-0089. J Clin Oncol 2003;21:2912-9. 11. Wong JH, Severino R, Honnebier MB, et al. Number of nodes examined and staging accuracy in colorectal carcinoma. J Clin Oncol 1999;17:2896-900. 12. Ueno H, Mochizuki H, Hashiguchi Y, Hase K. Prognostic determinants of patients with lateral nodal involvement by rectal cancer. Ann Surg 2001;234:190-7. 13. Greene FL, Stewart AK, Norton HJ. A new TNM staging strategy for node-positive (stage III) colon cancer: an analysis of 50,042 patients. Ann Surg 2002;236:416-21. 14. 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;96:1420-5. 15. Deddish MR. Abdominopelvic lymph node dissection in cancer of the rectum and distal colon. Cancer 1951;4:1364-6. 16. Sauer I, Bacon HE. Influence of lateral spread of cancer of the rectum on radiability of operation and prognosis. Am J Surg 1951;81:111-20. 17. Swanson RS, Compton CC, Stewart AK, Bland KI. The prognosis of T3N0 colon cancer is dependent on the number of lymph nodes examined. Ann Surg Oncol 2003;10:65-71. 18. Pocard M, Panis Y, Malassagne B, et al. Assessing the effectiveness of mesorectal excision in rectal cancer: prognostic
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19.
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value of the number of lymph nodes found in resected specimens. Dis Colon Rectum 1998;41:839-45. 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;19:157-63. Caplin S, Cerottini JP, Bosman FT, et al. For patients with Dukes’ B (TNM stage II) colorectal carcinoma, examination of six or fewer lymph nodes is related to poor prognosis. Cancer 1998;83:666-72. Moertel CG, Fleming TR, Macdonald JS, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 1990;322:352-8. Wolmark N, Rockette H, Fisher B, et al. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol 1993;11:1879-87. O’Connell MJ, Mailliard JA, Kahn MJ, et al. Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol 1997;15:246-50. Wolmark N, Rockette H, Mamounas E, et al. Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin, and levamisole in patients with Dukes’ B and C carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project C-04. J Clin Oncol 1999;17:3553-9. O’Connell MJ, Laurie JA, Kahn M, et al. Prospectively randomized trial of postoperative adjuvant chemotherapy in patients with high-risk colon cancer. J Clin Oncol 1998; 16:295-300. Zaniboni A. Adjuvant chemotherapy in colorectal cancer with high-dose leucovorin and fluorouracil: impact on
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disease-free survival and overall survival. J Clin Oncol 1997;15:2432-41. Andre T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004;350:2343-51. Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer: Irinotecan Study Group. N Engl J Med 2000;343:905-14. Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000;355:1041-7. Giacchetti S, Perpoint B, Zidani R, et al. Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 2000;18:136-47. Andre T, Bensmaine MA, Louvet C, et al. Multicenter phase II study of bimonthly high-dose leucovorin, fluorouracil infusion, and oxaliplatin for metastatic colorectal cancer resistant to the same leucovorin and fluorouracil regimen. J Clin Oncol 1999;17:3560-8. de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000;18: 2938-47. Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004; 22:23-30. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335-42.
Background. In the TNM classification of colorectal carcinoma, N-staging is dependent on the number of metastases; in the Japanese classification system, staging usually has been based on the distribution of metastases (N1, paracolic; N2, along the major vessels; N3, at the root of major vessels). The aim of our study was to examine whether the concept of the distribution of nodal metastasis could improve the TNM classification for colorectal cancer. Methods. We studied the survival rates of 485 and 136 patients with stage III colonic and rectal cancer, respectively, who underwent curative surgery between 1979 and 1998. The patients were categorized into 4 groups: group 1, TNM-N1 classified in J-N1; group 2, TNM-N2 in J-N1; group 3, TNM-N1 in J-N2-3; and group 4, TNM-N2 in J-N2-3. Results. In the colon cancer arm, the 5-year survival rates of the patients in groups 1 to 4 were 74%, 51%, 52%, and 54%, respectively. There was a significant difference in survival rate between groups 1 and 3 ( P = .0002). Thus, in colon cancer, nodal metastasis along the major vessels was a bad prognostic factor, even though the number of nodes that were involved was <4. In the rectum cancer arm, the 5-year survival rates of the patients in each group were 65%, 39%, 60%, and 32%, respectively. Only the number of nodal metastases was an independently significant prognostic variable. Conclusion. This study suggests that adding the concept of nodal distribution to the conventional TNM staging of colon cancer will improve the accuracy in the evaluation of the nodal status. (Surgery 2006;139:516-22.) From the Department of Surgery I, National Defense Medical College, Saitama, Japan
COLORECTAL CANCER IS THE SECOND leading cause of death from cancer in the United States,1 and its frequency is increasing in Japan.2 Several prognostic factors in colorectal cancer have been evaluated.3,4 Nodal involvement is well accepted as one of the most important determinants of prognosis in patients with localized carcinoma of the colon and rectum,5 as acknowledged in the TNM and Dukes classifications of colorectal carcinoma.6,7 The number of involved lymph nodes affects the prognosis in patients with colorectal cancer8 and has been incorporated into the current TNM classification.6 However, in the Japanese
Accepted for publication September 2, 2005. Reprint requests: Hirotoshi Kobayashi, MD, Department of Surgical Oncology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. E-mail: h-kobayashi. [email protected]. 0039-6060/$ - see front matter Ó 2006 Mosby, Inc. All rights reserved. doi:10.1016/j.surg.2005.09.004
516 SURGERY
classification of colorectal carcinoma, the staging (N number) is dependent on the distribution rather than on the absolute number of lymph node metastases.9 Both the Japanese and the TNM classifications of lymph node metastasis are considered to provide accurate prognoses of patients with colorectal carcinoma.2 Therefore, we decided to investigate which classification of lymph node metastasis predicts the outcome of patients with colorectal carcinoma more precisely. A recent report suggested that the number of lymph nodes that are retrieved and analyzed on resection for staging colon cancer is, itself, a prognostic variable on outcome.10 Another study indicated that the examination of at least 14 lymph nodes after resection of T2 or T3 carcinoma of the colon and rectum will stage the lymphatic basin accurately.11 Thus, we also investigated the prognostic effect of the number of lymph nodes that were examined to eliminate the risk of downstaging. The present study was designed to examine whether the distribution of nodal involvement is
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Table I. Classification of the patients with stage III disease Criteria for TNM-N1 TNM-N2 nodal involvement (TNM-stage IIIA, IIIB) (TNM-stage IIIC) Japanese-N1 (J-stage IIIa) Japanese-N2, 3 (J-stage IIIb)
Group 1
Group 2
Group 3
Group 4
able to improve the TNM classification for colorectal cancer. PATIENTS AND METHODS Patients. The medical charts of patients with stage III disease with lymph node metastasis who underwent curative operation for colorectal carcinoma at a single institute (the Department of Surgery I, National Defense Medical College, Saitama, Japan) between January 1979 and December 1998 were reviewed. In our institute, the standard practice of nodal dissection involved ligation of the major artery to the region of resection at its origin; for resection of the right colon, this involves the resection of the right colonic artery at its origin from the superior mesenteric artery and, for the left colon, ligation of the inferior mesenteric artery at its origin from the aorta. During this period, total mesorectal excision was performed for the patients with rectal cancer. Patients with T2, T3, and T4 lower rectal cancer underwent total mesorectal excision with lateral node dissection. Lateral node dissection was performed as described previously.12 Patients with familial adenomatous polyposis, cancer family syndrome kindreds, or ulcerative colitis were excluded in this study. Rectal cancer above the peritoneal reflection was analyzed as colon cancer, because these neoplasms do not have a lateral lymphatic drainage and act as colon cancers. Tumor stage was classified according to 2 systems, the TNM6 (TNM-IIIA, IIIB, and IIIC) and the Japanese classification for colorectal carcinoma9 (J-IIIa [J-N1] and IIIb [J-N2, N3]). In the TNM classification, N1 is defined as metastasis in 1 to 3 regional lymph nodes, and N2 is defined as metastasis in $4 regional lymph nodes; TNM IIIA is defined as T1 to T2N1M0; TNM IIIB is defined as T3 to T4N1M0, and TNM IIIC is defined as any TN2M0. The Japanese N1 is defined as lymph node metastasis adjacent to the colon and rectum or along the vascular arcades of marginal arteries; N2 is defined as metastasis along the course of the major vessels that supply the colon and rectum,
and N3 is defined as metastasis near the root of the major vessels. For example, J-N3 in patients with lower rectal cancer is defined as metastasis in lymph nodes along the inferior mesenteric artery proximal to the origin of left colic artery or those along the external iliac artery and common iliac artery. J-N2 in these patients is defined as metastasis in lymph nodes along the inferior mesenteric artery distal to the origin of left colic artery or those along the internal iliac artery. In the present study, to compare the accuracy of these classifications of nodal metastasis in colorectal cancer, patients were categorized into 4 groups: group 1, TNM-N1 classified in J-N1; group 2, TNM-N2 in J-N1; group 3, TNM-N1 in J-N2-3; and group 4, TNM-N2 in J-N2-3 (Table I). In the original text of the Japanese classification of colorectal carcinoma, stage IIIa was defined as T4 (direct invasion), N0, or any TN1. In this study, however, the patients with stage IIIa to T4N0 were excluded. Pathologic examination. All specimens were examined in the following manner: After tumor removal, the excised specimen was opened along the antimesenteric border by the surgeon. The specimen with the mesentery was stretched and pinned to a corkboard. The surgeon identified the lymph nodes, isolated them, and recorded both their number and distribution. The time that was required by the surgeon to complete the examination was approximately 60 minutes. In this study, the surgeons harvested the lymph nodes from the specimen to evaluate the precise location of nodal metastases; we acknowledge that this technique is not the custom in the United States or Europe in most centers. After formalin fixation, the specimens and lymph nodes were examined by the pathologist. Follow-up program. All patients were followed for 5 years after the operation. During the first 3 years, patients with stage III disease were followed every 3 months with clinical assessment and measurement of serum carcinoembryonic antigen and every 6 months with chest x-ray and abdominal ultrasonography or computed tomography. For the remaining 2 years, all tests were performed every 6 months. Colonoscopy was performed 1 year after operation and every 2 years for the next 4 years. Statistical analysis. Statistical analysis was performed with the Statview statistical package (Statview 5.0; Abacus Concepts, Inc, Berkeley, Calif). All data are expressed as the means ± SD. The data concerning age and the number of lymph nodes were analyzed with the Mann-Whitney and KruskalWallis test. The Kaplan-Meier method was used to calculate the actuarial survival of patients. Overall
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survival rates in all groups were compared with the use of the log rank test. A Cox’s proportional hazard regression analysis was performed to determine which concepts of nodal metastasis had an independent effect on postoperative survival. Statistical significance was established at a probability value of <.05 for all results. RESULTS A total of 621 patients with stage III disease (485 patients with colon cancer and 136 patients with rectal cancer) were studied in this analysis. Table II shows the clinical characteristics of the patients in this study. Colon cancer. The overall survival curves of the patients with stage III colon cancer are shown in Fig 1. The 5-year survival rates for TNM-IIIA, IIIB, and IIIC were 87%, 68%, and 52%, respectively (P = .0001; Fig 1, A). The rates for J-IIIa and IIIb were 70% and 53%, respectively (P < .0001; Fig 1, B). Fig 1, C compares the survival of patients with stage III colon cancer according to the distribution of nodal involvement alone, independent of number of lymph nodes that were involved. As nodal involvement beyond N1 occurred, the outcome of the patients worsened (P < .0001). This means that the distribution of lymph node metastasis was also an important prognostic factor. However, there was no significant difference in the prognosis between the patients with J-N2 disease and patients with J-N3 disease. The 5-year survival rates of groups 1, 2, 3, and 4 were 74%, 51%, 52%, and 54%, respectively (P < .0001; Fig 1, D). The overall survival of group 1 (< 4 involved nodes limited to paracolic sites) was better than that of the other groups. In particular, there was a significant difference between the survival rates of group 1 (< 4 involved nodes limited to paracolic sites) and group 3 (< 4 involved nodes, but the involved nodes were distant nodes along the major artery to the colonic segment that was involved; P = .0002). These findings suggest that the prognosis of patients whose lymph node metastases are of paracolic type and of < 4 in number is better than that of other patients with stage III colon cancer with more distant nodes involved. Multivariate analysis disclosed that both location and number of nodal involvement were prognostic variables in colon cancer (Table III). Rectal cancer. Fig 2 shows the survival curves of the patients with rectal cancer in this study. Fig 2, A indicates that the TNM classification provides an excellent prognosis for patients with rectal cancer (P = .0005). The concept of the distribution of nodal involvement, however, was not useful for the
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Table II. Characteristics of the 621 patients with stage III colorectal cancer Variable Gender (n) Male Female Age (y)* Location (n) Cecum Ascending colon Transverse colon Descending colon Sigmoid colon Rectosigmoid junction Rectum above the peritoneal reflection Rectum below the peritoneal reflection pT category (n) T1 T2 T3 T4 Number of dissected lymph nodes* <14 (n) $14 (n) Mean follow-up period (y)* TNM classification (n) Stage IIIA Stage IIIB Stage IIIC Japanese classification (n) Stage IIIa Stage IIIb Group in this study (n) Group 1 Group 2 Group 3 Group 4
Colon (n = 485)
Rectum (n = 136)
251 234 62 ± 12 (21-87)
91 45 60 ± 12 (25-89)
40 52 24 37 154 89 89 136
9 24 306 146 24 ± 16
4 13 105 14 34 ± 21
130 355 6.1 ± 4.2
19 117 5.5 ± 4.2
26 320 139
13 67 56
328 157
68 68
275 53 71 86
49 19 31 37
*Data are given as mean ± SD; data in parentheses indicate range.
prediction of the outcome of treatment for rectal cancer (Fig 2, B). Furthermore, there were no significant differences in the overall survival rates between groups 1 and 3 or between groups 2 and 4 (Fig 2, C). In contrast to colon cancer, multivariate analysis disclosed that only the number of lymph node metastases was an independent prognostic factor in rectal cancer (Table III). Number of dissected lymph nodes. We also evaluated the relation between the number of lymph nodes that were retrieved and the prognosis of patients with colorectal cancer. The numbers of
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Table III. Multivariate analysis on the concept of nodal metastasis of colorectal cancer Concept of nodal metastasis Colon Distribution J-N1 J-N2, 3 Number TNM-N1 TNM-N2 Rectum Distribution J-N1 J-N2, 3 Number TNM-N1 TNM-N2
Hazard ratio (95% CI)
P value
1 1.57 (1.14-2.18) 1 1.43 (1.03-2.00)
.007
1 1.06 (0.68-1.66) 1 2.14 (1.36-3.36)
Not significant
.03
.0009
30 ± 21, and 37 ±21, respectively. There were no significant differences in the number of dissected lymph nodes among the 4 groups, either. However, the number of lymph nodes that were retrieved in the rectum was greater than that retrieved in the colon (P < .0001). Moreover, in the present study, there were no significant differences in prognosis between the patients for whom $14 lymph nodes were retrieved and those patients for whom <14 lymph nodes were retrieved. Among the 4 groups, there were no differences in adjuvant chemotherapy, which has changed over time in our institute for the patients with stage III colorectal cancer. DISCUSSION The present study revealed that both the distribution and the number of lymph node metastases are important prognostic factors in colon cancer. The patients with #3 lymph node metastases and in whom the metastases were adjacent to the colon or along the marginal vessels had better prognosis than the other patients with stage III disease with
retrieved lymph nodes in group 1, 2, 3, and 4 patients with colon cancer were 24 ± 17, 24 ± 12, 22 ± 18, and 26 ±16, respectively. There were no significant differences in the number of dissected lymph nodes among the 4 groups. The numbers of retrieved lymph nodes in group 1, 2, 3, and 4 patients with rectal cancer were 32 ± 22, 37 ± 22,
Fig 1. Survival curves of patients with stage III colon cancer by different pathologic classifications of nodal involvement. A, The TNM staging was found to reflect the prognosis of these patients. B, The Japanese classification, in which the number is based on the location of lymph node metastasis, was also found to reflect the prognosis of these patients. C, The distribution of nodal involvement alone. The 5-year survival rates of the patients with J-N1 (paracolic), J-N2 (intermediate), and J-N3 (near the root of major vessels) were 70%, 56%, and 31%, respectively; nodal distribution also reflected prognosis. D, Groups 1, 2, 3, and 4. The prognosis of group 1 patients was better than that of the other groups. There was no significant difference in the overall survival between groups 2 and 3.
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Fig 2. Survival curves of patients with stage III rectal cancer by different pathologic classifications of nodal involvement. A, TNM staging. The TNM staging reflected the prognosis. B, Japanese classification of colorectal carcinoma. The Japanese classification was less precise compared with the TNM staging. C, Groups 1, 2, 3, and 4. The prognoses of groups 1 and 3 were better than the prognoses of groups 2 and 4. There were no differences in overall survival between groups 1 and 3 or between groups 2 and 4.
colon carcinoma in whom <4 nodes were involved, but in whom the involved nodes were located distant to the paracolic or marginal nodes. However, there were no differences in prognosis between the patients with more distant nodes (ie, J-N2 and J-N3 disease). Thus, we believe that it is important to distinguish patients with J-N1 disease
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from patients with J-N2 or J-N3 disease, who are classified in TNM-N1. In our study, the TNM classification accurately reflected the prognosis of patients with stage III colon cancer. The present TNM staging for node-positive colon cancer is based in large part on the analysis performed by Greene et al.13 In their study, data for patients with stage III colon cancer that are found in the National Cancer Database from 1987 to 1993 were analyzed. The 5-year survival rates were 59.8% for IIIA, 42.0% for IIIB, and 27.3% for IIIC. Those rates in the present study were 87% for IIIA, 68% for IIIB, and 52% for IIIC. Outcomes of the treatment of colon cancer in our institution seem to be better than the outcomes in the nationwide analysis in the United States. The prime reason for this difference might be that the data of the study of Greene et al included data from multicenter institutions that included not only leading hospitals for colorectal cancer but also various other hospitals. On the other hand, O’Connell et al14 demonstrated recently that 5-year, stage-specific survival rates were 83.4% for stage IIIA, 64.1% for stage IIIB, and 44.3% for stage IIIC. Their data are close to ours. In our current study, the TNM staging accurately reflected the prognosis of patients with rectal carcinoma. In the survival curves, there were close similarities between groups 1 and 3 and between groups 2 and 4. In rectal cancer, our data showed that the number of lymph node metastases was found to be a more powerful prognostic determinant than the location of nodal involvement. A potential explanation for these findings may be that, in colon carcinoma, the primary lymphatic drainage occurs along the major vessels to the segment of colon that is involved, and the location of nodal involvement indicates the spread of cancer. Thus, we suggest that the distribution and the number of the retrieved lymph nodes should be recorded at the time of pathologic examination. However, in rectal carcinoma, especially lower rectal cancer, there is a lateral spread of cancer as well as in the mesorectum.15,16 Therefore, the distribution of lymph node metastasis by itself can not predict accurately the outcome of treatment in rectal cancer. Recent reports have shown that the prognosis of colorectal carcinoma is dependent on the number of lymph nodes in the resected specimens.10,11,17-20 Le Voyer et al10 reported that the number of retrieved lymph nodes was, itself, a prognostic variable in outcome of patients with stage II and stage III colon cancer. Tepper et al19 demonstrated that approximately 14 nodes needed to be studied
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to define accurately the nodal status in patients with T3, T4, or node-positive rectal cancer. Therefore, in the present study, the number of retrieved lymph nodes was also investigated to eliminate the risk of down-staging. The mean numbers of retrieved nodes in this study were 24 and 34 in patients with cancer of the colon and rectum, respectively. We consider these figures to be sufficient for estimating the nodal status accurately. There were no significant differences in the number of lymph nodes that were retrieved among the 4 groups in both colon and rectal cancer. Moreover, the present study demonstrated that the number of retrieved lymph nodes, whether it was <14 or not, did not affect the prognosis of the patients with stage III colorectal cancer. Our study suggests, however, that it is important to take into account the optimal area of dissection in colorectal surgery, because there are differences in the numbers of regional lymph nodes. In this study, operations were performed by 7 surgeons. Because there has been standardization of the technique of the dissection in our institute, there were no differences in the number of dissected lymph nodes by surgeons. However, there could be a bias by surgeons, which might give potential limitation to the present study. Since Moertel et al21 reported that postoperative adjuvant treatment with fluorouracil and levamisole reduced the mortality rate by 33% in patients with stage III colon cancer, several trials have established 6 months of treatment with fluorouracil plus leucovorin as the standard adjuvant chemotherapy for stage III colon cancer.22-26 Furthermore, Andre et al27 demonstrated that adding oxaliplatin to a regimen of fluorouracil and leucovorin improved the adjuvant treatment of colon cancer. Recent reports have shown that treatments with new drugs (such as irinotecan, oxaliplatin, and bevacizumab) provided patients with metastatic colorectal cancer with significant survival advantages.28-34 Although new drugs enable us to choose various regimens for colorectal cancer, we must diagnose the stage of patients with colorectal cancer more accurately than ever and select the most appropriate treatment. Because the prognoses of patients of groups 2, 3 and 4 in colon cancer and groups 2 and 4 in rectal cancer were worse than those of other groups, such patients may be indicated for more powerful adjuvant chemotherapy. The distribution and the number of the involved nodes is an important index of the prognosis in patients with colon cancer. These findings may indicate that the addition of the concept of
nodal distribution to the conventional TNM staging of colon cancer will improve the accuracy in the evaluation of the nodal status. In rectal cancer, however, the number of lymph node metastases is a better predictor than the location. The results of the present study may be useful in the treatment of patients with stage III colon cancer and in the improvement of categorization based on nodal involvement. REFERENCES 1. American Cancer Society. Cancer facts & figures 2003. Atlanta: American Cancer Society; 2003. 2. Muto T, Kotake K, Koyama Y. Colorectal cancer statistics in Japan: data from JSCCR registration, 1974-1993. Int J Clin Oncol 2001;6:171-6. 3. Griffin MR, Bergstralh EJ, Coffey RJ, et al. Predictors of survival after curative resection of carcinoma of the colon and rectum. Cancer 1987;60:2318-24. 4. Steinberg SM, Barkin JS, Kaplan RS, Stablein DM. Prognostic indicators of colon tumors: the Gastrointestinal Tumor Study Group experience. Cancer 1986;57:1866-70. 5. Newland RC, Chapuis PH, Pheils MT, MacPherson JG. The relationship of survival to staging and grading of colorectal carcinoma: a prospective study of 503 cases. Cancer 1981; 47:1424-9. 6. Greene FL, Page DL, Fleming ID, et al. American Joint Committee on Cancer staging manual. 6th ed. New York: Springer-Verlag; 2002. 7. Dukes C. The classification of cancer of the rectum. J Pathol 1932;35:323-32. 8. Phillips RK, Hittinger R, Blesovsky L, et al. Large bowel cancer: surgical pathology and its relationship to survival. Br J Surg 1984;71:604-10. 9. Japanese Society for Cancer of the Colon and Rectum. Japanese classification of colorectal carcinoma. 5th ed. Tokyo: Kanehara; 1997. 10. Le Voyer TE, Sigurdson ER, Hanlon AL, et al. Colon cancer survival is associated with increasing number of lymph nodes analyzed: a secondary survey of intergroup trial INT-0089. J Clin Oncol 2003;21:2912-9. 11. Wong JH, Severino R, Honnebier MB, et al. Number of nodes examined and staging accuracy in colorectal carcinoma. J Clin Oncol 1999;17:2896-900. 12. Ueno H, Mochizuki H, Hashiguchi Y, Hase K. Prognostic determinants of patients with lateral nodal involvement by rectal cancer. Ann Surg 2001;234:190-7. 13. Greene FL, Stewart AK, Norton HJ. A new TNM staging strategy for node-positive (stage III) colon cancer: an analysis of 50,042 patients. Ann Surg 2002;236:416-21. 14. 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;96:1420-5. 15. Deddish MR. Abdominopelvic lymph node dissection in cancer of the rectum and distal colon. Cancer 1951;4:1364-6. 16. Sauer I, Bacon HE. Influence of lateral spread of cancer of the rectum on radiability of operation and prognosis. Am J Surg 1951;81:111-20. 17. Swanson RS, Compton CC, Stewart AK, Bland KI. The prognosis of T3N0 colon cancer is dependent on the number of lymph nodes examined. Ann Surg Oncol 2003;10:65-71. 18. Pocard M, Panis Y, Malassagne B, et al. Assessing the effectiveness of mesorectal excision in rectal cancer: prognostic
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