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EJSO 35 (2009) 721e727

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The clinical outcome and prognostic factors after multi-visceral resection for advanced colon cancer
S.H. Yun 1, H.R. Yun 1, W.S. Lee, Y.B. Cho, W.Y. Lee, H.K. Chun*
Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Accepted 23 January 2008 Available online 1 April 2008

Abstract Aim: The value of multi-visceral resection (MVR) for treating primary advanced colon cancer inltrating into the neighboring organs had been debated because of the high mortality. Methods: We reviewed 1288 patients who underwent curative resection for pT3e4 colon cancer without distant metastasis from 1994 to 2004. Results: Eighty four patients (6.5%) with colon cancer inltrating into the neighboring organs (cT4) underwent MVR. The accuracy of the intra-operative decision for true invasion (pT4) was 35.7%. Major surgical morbidity occurred in 11 patients of the standard resection group (0.9%) and in 2 patients of the MVR group (2.3%) ( p 0.206). Most of the recurrence was distant metastasis (20 patients, 23.8%). Local recurrence was occurred in ve patients (6.0%). The prognostic factors for recurrence and survival were pathologic tumor invasion ( p 0.033 and p 0.016, respectively) and lymph node metastasis ( p 0.010 and p < 0.001, respectively). Conclusion: Multi-visceral resection was a safe and curative procedure as compared with standard resection for patients with advanced colon cancer. The cause of a poor prognosis in MVR was not local recurrence but distant metastasis. Pathologic tumor invasion and lymph node metastasis were the potential prognostic factors. 2008 Published by Elsevier Ltd.
Keywords: Colon cancer; Multi-visceral resection; Morbidity; Prognosis

Introduction Approximately 5e10% of all patients with colon cancer were found to have locally advanced tumor inltrating into the neighboring organs on the operation eld.1 Until 50 years ago, colorectal cancer with advanced tumor inltrating the neighboring organs was considered to be un-resectable. Yet, multi-visceral resection has recently performed in more than 10% of all the patients with primary colorectal cancer and this is the only real chance for advanced colorectal cancer patients to achieve a cure.2e4 However, it is also well recognized that the extended operation increases the morbidity and mortality.1,4e9 Some investigators have reported that multi-visceral resection shows acceptable morbidity and
* Corresponding author. Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Ilwon-dong 50, Gangnam-gu, Seoul 135-710, Republic of Korea. Tel.: 82 2 3410 3465; fax: 82 2 3410 0040. E-mail address: hokyung.chun@samsung.com (H.K. Chun). 1 S.H. Yun and H.R. Yun equally contributed as rst authors. 0748-7983/$ - see front matter 2008 Published by Elsevier Ltd. doi:10.1016/j.ejso.2008.01.024

mortality rates and the curative operation with extended resection improved the long-term prognosis for locally advanced colorectal cancer.2,5 There is a lack of relevant information concerning multi-visceral resection for advanced colon cancer mainly because of the rarity of this type operation. To evaluate whether such an aggressive surgical approach is justied, this study assessed the morbidity, mortality and the potential prognostic factors for survival and recurrence after performing multi-visceral resection in patients with advanced colon cancer.

Patients and methods We carried out a retrospective analysis of 1288 consecutive patients who underwent radical surgery for pT3epT4 colon cancer without distant metastasis at the Department of Surgery from 1994 to 2004. Eighty-four patients (6.5%) underwent multi-visceral resection because of suspected

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S.H. Yun et al. / EJSO 35 (2009) 721e727

locally advanced colon cancer inltrating into the neighboring organs (cT4), according to the operation records. The types of operation were divided into two groups: the standard resection group (SRG), which included surgery for colon cancer without any resection of other organs or structures, and the multi-visceral resection (MVR) group, which included surgery for colon cancer with en bloc removal of any organ or structure to which the primary tumor was adhered. The potentially curative procedures, such as multi-visceral resection of the tumor and the involved structures, were all carried out with conformation of negative margins and removal of the draining lymph nodes on the condition that there was no evidence of distant metastases. None of the patients received preoperative chemotherapy or radiotherapy. According to the operation records, the MVR group was dened that the operator suspected the tumor had invaded into the neighboring organs and he/she decided on extended resection of the surrounding organs or structures during surgery. By examining the medical records, we investigated such clinicopathological factors as age, gender, the size of tumor, tumor inltration, histologic differentiation, the pathologic lymph node metastasis, lymphatic invasion, venous invasion, perioperative blood transfusion and the organs or structures of the combined resection. The tumors were staged according to the 6th edition of the cancer staging guidelines of the American Joint Committee of Cancer (AJCC).10 The postoperative morbidity and mortality was evaluated based on a review of medical follow-up records in the hospital records and from the out patients clinics data system for at least two years after operations. The clinically important morbidity as major morbidity was dened as more than Claviens classication grade II for the surgical complications. The other complications were dened as minor.11 Operative mortality was dened as death within 30 days subsequent to the surgical procedure. Statistics The differences of complications between the SRG and MVR groups were analyzed by chi-square tests. The survival-rate and disease free survival rate were analyzed by the KaplaneMeier method and they were tested by means of the Cox proportional hazard model for the potential prognostic clinic-pathologic factors. A signicant difference was dened as a p value of <0.05. Follow-up All the patients were followed up according to a standard protocol, including physical examination, liver function tests, carcinoembryonic antigen (CEA) measurement, chest radiography, and abdomino-pelvic computed tomography, and then the patients were followed-up via yearly colonoscopy exams at outpatient clinics.

Results Patient demographics Of the 1288 patients with cT3eT4 colon cancer, 84 patients (6.5%) received multi-visceral resection. There were 43 male patients and 41 female patients. Their mean age was 56.2 years, with a range of 27 w 84 years (Table 1). The median follow up duration was 48.0 months. The most common resected organs in the multi-visceral resection group were the small bowel and urinary bladder. Eighteen patients (21.4%) had 2 resected organs and 6 patients (7.1%) had 3 resected organs. The accuracy of the intra-operative judgment for invasion was 35.7%, according to the true invasion (pT4), as determined by the postoperative pathological examination of the resected tumors and organs (Table 2). Comparison of morbidity between the standard resection group (SRG) and the multi-visceral resection group (MVR) The overall operation related morbidity rate in the SRG was higher (2.8%) than that in the MVR group (13.2%). But if the morbidities were sorted into major and minor according to the Claviens classication with using grade II as the dividing line, then major morbidity (Claviens classication  grade II) occurred in 11 patients in the SRG and 2 patients in the MVR group and the difference was not statistical signicant. Most of the operation related morbidities were minor for the SRG and MVR group (Table 3). There were two cases of postoperative mortality in the SRG and no mortality in the MVR group. The causes of mortalities were acute myocardial infarction (AMI) and acute respiratory distress syndrome (ARDS). Recurrence after multi-visceral resection for advanced colon cancer Recurrences occurred in 23 patients (27.3%). There were 2 patients who had both distant and local recurrence.
Table 1 The clinico-pathologic characteristics of the mutivisceral resection group. n Gender Age (yr) Tumor size (cm) Tumor location Stage Male Female 43 41 56 (27e84) 7.3 (3.0e13.0) 22 62 36 22 17 9 84 51.2% 48.8%

Right colon Left colon T3N0 T3N T4N0 T4N

26.2% 73.8% 42.9% 26.2% 20.2% 10.7%

Total

S.H. Yun et al. / EJSO 35 (2009) 721e727 Table 2 The distribution of the resected organs of the multi-visceral resection group. Organ Small bowel Small bowel only Small bowel/pancreas, spleen Small bowel/spleen Small bowel/uterus or ureter Urinary bladder Abdominal wall Pancreas Pancreas/SMV Pancreas/spleen Pancreas/spleen/stomach/ adrenal gland Ovary or adnexa Uterus Segment of colon Spleen Stomach Duodenum Others* Total *Liver wedge resection. N (%) 26 (31.0) Pathologic invasion 9 True invasion (%) 34.6

723

21 (25.0) 12 (14.3) 6 (7.1)

6 3 2

28.6 25.0 33.3

On univariate analysis, the prognostic factor for recurrence was the lymph node metastasis in the MVR group. But on the multivariate analysis with including factors that had a p value below 0.10, the signicant predictors were true tumor invasion and lymph node metastasis (Table 4). On comparison of the disease free rate according to true invasion and lymph node metastasis, the 2 year disease free survival rates were 88.0%, 77.3%, 58.8% and 48.5% in the pT3N0, pT4N0, pT3N1 w 2 and pT4N1 w 2 patients, respectively (Fig. 1a). Survival in the multi-visceral resection group The 5 year overall survival rate in the MVR group was 62.8%. The signicant prognostic factors for survival were age, lymph node metastasis, lymphatic invasion and venous invasion on univariate analysis. Yet there were signicant differences in survival for true invasion and lymph node metastasis on the multivariate analysis with including the factors that p values were below 0.10 (Table 5). According to true invasion and lymph node metastasis, the 2 year survival rates were 94.4%, 86.4%, 58.8% and 37.5% for the patients with pT3N0, pT4N0, pT3N1 w 2 and pT4N1 w 2 disease, respectively (Fig. 1b). Discussion It was generally believed that primary colorectal cancer that inltrates into the neighboring organs was incurable via operation. Moynihan, in 1926, originally described locally advanced colon cancer and he advocated extended en bloc resection for any involved organs or structures.12 Such a suggestion was reinforced by Sugarbaker, who in 1946, presented the rst large series of extended multivisceral resections for 42 colorectal cancers, and he did this type of surgery with avoid spillage of tumor cell when cutting into the tumor.13 The diverse accuracy for true invasion in advanced colon cancer During exploration, colon cancer occasionally has attachments to the abdominal wall or adjacent organs, but the challenge to the surgeon is clinically distinguish between carcinomatous and inammatory inltration when faced with locally advanced colon cancer. Intra-operative frozen sectioning for the attachment by the primary tumor is not helpful to identify true tumor inltration.14,15 Several previous studies has reported that, 33e84% of the en bloc resected specimens of primary colorectal cancer had histologically proven carcinomatous invasion to the adjacent organs.1e3,5,6,9,16 Because the accuracy of discriminating between true invasion and inammatory adhesion is known to vary, if clinically local invasion is suspected, then multivisceral resection should be performed for achieving a radical curative operation when possible. In the multi-visceral

6 4 4 3 2 1 1 84

(7.1) (4.8) (4.8) (3.6) (2.4) (1.2) (1.2)

1 2 2 3 1 1 0 30

16.6 50.0 50.0 100 50.0 100 0 35.7

Distant metastasis was the main cause of recurrence (20 patients, 23.8%). The common distant metastatic sites were the liver and distant lymph nodes. Local recurrence occurred in 5 patients (6.0%). Local recurrence occurred in 3 patients (5.5%) of the 53 patients who had adhesion without invasion while local recurrence occurred in 2 patients (6.6%) of the 30 patients who had true invasion. This showed that there was similar local failure between mere adhesion and true invasion after curative operation.

Table 3 Comparison of the operation-related morbidity between the standard resection group (SRG) and the multi-visceral resection (MVR) group. MVR (n 84) Op. related morbidity Major (Clavien classication  2) Ileus Gastric ulcer bleeding Enterocutaneous stula Major wound dehiscence Leakage Bleeding Intraabdominal abscess Minor (Clavien classication 1) Minor wound problem Urinary discomfort Ileus n.s, no signicance. 11(13.2%) 2 (2.4%) 1 1 SRG (n 1204) 34 (2.8%) 11 (0.9%) 2 1 1 2 4 1 23 (1.9%) 8 1 14 p value <0.001 n.s

9 (10.8%) 2 7

<0.001

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Table 4 The potential risk factors for recurrence of the multi-visceral resection group (MVR). n Univariate analysis HR Gender Age (yr) Pathologic T stage Pathologic N stage Male Female <55 55 T3 T4 N0 N1 N2 No Yes No Yes Low grade High grade <7 7 No Yes No Yes No Yes 43 41 35 49 54 30 58 18 8 67 17 70 14 62 21 36 48 59 25 79 5 68 15 1 1.42 1 1.87 1 2.04 1 2.53 4.00 1 1.21 1 1.70 1 1.13 1 1.67 1 1.91 1 22.4 1 2.76 95% CI 0.62e3.24 0.77e4.57 0.90e4.63 0.99e6.46 1.27e12.61 0.45e3.28 0.63e4.62 0.42e3.05 0.73e3.80 0.83e4.36 0.01e30306.4 0.64e11.79 n.s n.s n.s n.s n.s n.s p value n.s n.s 0.087* 0.026 0.050 0.017 n.s 1 2.55 1 2.26 5.58 1.08e6.04 1.03e6.65 1.67e18.68 0.033 0.010 0.044 0.005 Multivariate analysis HR 95% CI p value

Lymphatic invasion Venous invasion Histology Tumor size (cm) Obstruction Perforation Transfusion

*p < 0.10, n.s, no signicance. Multivariate analysis was performed with factors that had p values below 0.10. CI, condence interval; HR, hazard ratio.

resection group of our current study, pathological invasion was identied in 30 patients (35.7%) and the most frequently en bloc resected organs were the small bowel and the urinary bladder (31.0% and 23.8%, respectively) in patients with advanced colon cancer. Risk of postoperative morbidity The known morbidity and mortality associated with en bloc resection have been very diverse at 1.4 w 49.1% and 1.2 w 12.0% for colorectal cancer, respectively.1e7,9,16e20 In the case of colon cancer, the known morbidity and mortality associated with en bloc resection are 6 w 37% and 3 w 5%, respectively.1,17,18 Some authors have reported

that multi-visceral resection had more postoperative complications and a poorer prognosis than the standard resection for colorectal cancer.3,4,6 But others have reported that there was no difference in the morbidity and mortality rates between standard and multi-visceral resections.2,5 In our retrospective review of the hospital records and out patients Clinics data system, there was a statistical difference in overall morbidity between standard and multivisceral resections. As the Claviens classication is the standard for determining the clinical importance of morbidity, if we compared the major morbidity according to the Clavien classication (above the grade II), then the major morbidity of MVR seemed to similar with that of the SRG. Minor

Figure 1. Comparison of (a) recurrence and (b) survival for the multi-visceral resection (MVR) group according to the pathologic T and N stage.

S.H. Yun et al. / EJSO 35 (2009) 721e727 Table 5 The potential risk factors for survival of the multi-visceral resection group (MVR). n Univariate analysis HR Gender Age (yr) Pathologic T stage Pathologic N stage Male Female <55 55 T3 T4 N0 N1 N2 No Yes No Yes Low grade High grade <7 7 No Yes No Yes No Yes 43 41 35 49 54 30 58 18 8 67 17 70 14 62 21 36 48 59 25 79 5 68 15 1 1.62 1 2.46 1 1.76 1 2.19 8.23 1 2.43 1 3.34 1 1.25 1 1.01 1 2.03 1 1.21 1 1.96 95% CI 0.76e3.51 1.04e5.84 0.83e2.76 0.87e5.52 3.24e20.96 1.09e5.43 1.49e7.50 0.53e2.97 0.47e2.18 0.95e4.35 0.29e5.13 0.59e6.52 p value n.s 0.039 0.098* <0.001 0.094* <0.001 0.030 0.003 n.s n.s 0.067* n.s n.s n.s 1 2.79 1 2.27 12.7 1.21e6.49 0.91e5.72 4.50e35.88 n.s Multivariate analysis HR 95% CI

725

p value

0.016 <0.001 0.079 <0.001 n.s n.s

Lymphatic invasion Venous invasion Histology Tumor size (cm) Obstruction Perforation Transfusion

*p < 0.10, n.s, no signicance. Multivariate analysis was performed with factors that had p values below 0.10. CI, condence interval; HR, hazard ratio.

morbidity (grade I) was more frequency in the MVR group. There was no case of mortality after MVR in our study, the same as in other studies.3,21,22 If multi-visceral resection is done with prudence and careful radical resection, then we can expect that there will be no difference of the operation related morbidity compared with standard resection. Prognosis in patient with advanced colon cancer after multi-visceral resection The prognosis after multi-visceral resection is still debatable. The overall and local recurrence after colon cancer operation has ranged from 20% to 40% and from 3.1% to 25.6%, respectively.23e27 Some authors have reported that the disease-free survival rate of multi-visceral resection was also similar to that of the standard operation.1,3,27 Others had insisted that the local recurrence that was true invasion to neighboring organ was much higher than that for mere adherent organs when en bloc resection was performed for colon cancer.4,15 In our study, 23 patients (27.3%) had recurrence in multi-visceral resection group. There were two patients who had distant metastasis and local recurrence together. Most of the recurrence was distant metastasis (20 patients, 21.4%). Only ve patients (5.9%) had local recurrence. This very low rate of local recurrence in our study may be attributed to our performing trials of radical resection of the involved neighboring organ. For the 30 pT4 patients, distant recurrence occurred in 11 patients (33.3%) and local recurrence occurred in 2 patients (6.6%). For the 54 pT3

patients, there were 9 patients with distant recurrence (14.8%) and 3 patients with local recurrence (5.5%). It seemed there was similar local recurrence between the patients with true invasion and those with inammatory adhesion. The clinically important prognostic factor for the patients who had true invasion was thought be not local recurrence, but distant metastasis after multi-visceral resection in advanced colon cancer. The crude 5-year survival of the colon cancer patients has been reported to be from 40% to 70%. In our study, the 5 year survival rate of the multi-visceral resection group was lower than that of the standard resection group (62.8% vs. 80.9%, respectively, p < 0.001), the same as the previous studies.1,4,7,20,28,29 But there were some reports that the survival of colorectal cancer patients after multi-visceral resection was very similar to the standard resection when curative surgery was performed.3 Many reports have documented that the potential prognostic factors for recurrence or survival were age, tumor perforation, a large tumor size, pathologic tumor invasion, lymph node metastasis and perioperative transfusion.1,3,4,6,9,14,30e34 There have been some reports that local tumor inltration was not an independent prognostic factor on multivariate analysis.4,7 But in our study, the potential prognosis factors for recurrence and survival were pathologic tumor invasion and lymph node metastasis on multivariate analysis. There was no statistical signicance for recurrence and survival according to age, lymphovascular invasion, the gross tumor features, tumor differentiation

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S.H. Yun et al. / EJSO 35 (2009) 721e727 5. Izbicki JR, Hosch SB, Knoefel WT, Passlick B, Bloechle C, Broelsch CE. Extended resections are benecial for patients with locally advanced colorectal cancer. Dis Colon Rectum 1995;38: 12516. 6. Gall FP, Tonak J, Altendorf A. Multivisceral resections in colorectal cancer. Dis Colon Rectum 1987;30:33741. 7. Rowe VL, Frost DB, Huang S. Extended resection for locally advanced colorectal carcinoma. Ann Surg Oncol 1997;4:1316. 8. Perez RO, Coser RB, Kiss DR, et al. Combined resection of the duodenum and pancreas for locally advanced colon cancer. Curr Surg 2005;62:6137. 9. Eisenberg SB, Kraybill WG, Lopez MJ. Long-term results of surgical resection of locally advanced colorectal carcinoma. Surgery 1990;108: 77985. [discussion 85e86]. 10. Sixth AJCC Cancer Staging Manual 2003. 11. Clavien PA, Sanabria JR, Strasberg SM. Proposed classication of complications of surgery with examples of utility in cholecystectomy. Surgery 1992;111:51826. 12. Moynihan B. Abdominal operations. Philadelphia: WB Saunders; 1926. 19. 13. Sugarbaker ED. Coincident removal of additional structures in resections for carcinoma of the colon and rectum. Ann Surg 1946; 123:103646. 14. Spratt Jr JS, Watson FR, Pratt JL. Characteristics of variants of colorectal carcinoma that do not metastasize to lymph nodes. Dis Colon Rectum 1970;13:2436. 15. Hunter JA, Ryan Jr JA, Schultz P. En bloc resection of colon cancer adherent to other organs. Am J Surg 1987;154:6771. 16. Lopez MJ, Monafo WW. Role of extended resection in the initial treatment of locally advanced colorectal carcinoma. Surgery 1993; 113:36572. 17. Lopez MJ. Multivisceral resections for colorectal cancer. J Surg Oncol 2001;76:15. 18. Gebhardt C, Meyer W, Ruckriegel S, Meier U. Multivisceral resection of advanced colorectal carcinoma. Langenbecks Arch Surg 1999;384: 1949. 19. Bokey EL, Chapuis PH, Fung C, et al. Postoperative morbidity and mortality following resection of the colon and rectum for cancer. Dis Colon Rectum 1995;38:4806. [discussion 6e7]. 20. Kroneman H, Castelein A, Jeekel J. En bloc resection of colon carcinoma adherent to other organs: an efcacious treatment? Dis Colon Rectum 1991;34:7803. 21. Curley SA, Evans DB, Ames FC. Resection for cure of carcinoma of the colon directly invading the duodenum or pancreatic head. J Am Coll Surg 1994;179:58792. 22. Willett CG, Goldberg S, Shellito PC, et al. Does postoperative irradiation play a role in the adjuvant therapy of stage T4 colon cancer? Cancer J Sci Am 1999;5:2427. 23. Sjovall A, Holm T, Singnomklao T, Granath F, Glimelius B, Cedermark B. Colon cancer management and outcome in relation to individual hospitals in a dened population. Br J Surg 2007; 94:4919. 24. Harris GJ, Church JM, Senagore AJ, et al. Factors affecting local recurrence of colonic adenocarcinoma. Dis Colon Rectum 2002;45: 102934. 25. Cass AW, Million RR, Pfaff WW. Patterns of recurrence following surgery alone for adenocarcinoma of the colon and rectum. Cancer 1976; 37:28615. 26. Read TE, Mutch MG, Chang BW, et al. Locoregional recurrence and survival after curative resection of adenocarcinoma of the colon. J Am Coll Surg 2002;195:3340. 27. Obrand DI, Gordon PH. Incidence and patterns of recurrence following curative resection for colorectal carcinoma. Dis Colon Rectum 1997;40:1524. 28. Heslov SF, Frost DB. Extended resection for primary colorectal carcinoma involving adjacent organs or structures. Cancer 1988;62: 163740.

and size, tumor obstruction, tumor perforation and perioperative blood transfusion in our study. Necessity of adjuvant chemotherapy for the patient with MVR There is no denite consensus on the effect of adjuvant therapy for advanced colon cancer. Along with the development of perioperative chemotherapy, adjuvant therapy after complete resection for T4 colon has been recommended,1,22 yet there are opposing points of view.2 Because most of our patients had undergone postoperative chemotherapy, except for the patients who were very old with a poor medical condition or they refused to receive the chemotherapy, we didnt consider chemotherapy in the analyzed factors. More active adjuvant therapy and careful attention will be required during follow up for the patients who have poor prognostic factors (pathologic tumor invasion or lymph node metastasis) after en bloc extended resection for advanced colon cancer. Conclusion Although this study has limitations due to its small size and retrospective review, our results suggest that multivisceral resection can be performed with radical curative resection and the morbidity is tolerable for the patients with locally advanced colon cancer. Distant metastasis, not local recurrence, is the leading cause of treatment failure and the prognostic factors are pathologic tumor invasion and lymph node metastasis for patients who undergo multi-visceral resection for locally advanced colon cancer. Conict of interest We hereby declare that there is no potential or actual personal, nancial or political interest related to this article. Reference
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