International Surgery Treatment outcome of obstructive colorectal cancer with bowel perforation.

Transcription

1 International Surgery Treatment outcome of obstructive colorectal cancer with bowel perforation. --Manuscript Draft-- Manuscript Number: Full Title: Article Type: Keywords: Corresponding Author: INTSURG-D R1 Treatment outcome of obstructive colorectal cancer with bowel perforation. Original Article obstructive colorectal cancer, bowel perforation, APACHEII score, prognosis Keisuke Ihara Dokkyo Medical University Mibu, Tochigi, JAPAN Corresponding Author Secondary Information: Corresponding Author's Institution: Dokkyo Medical University Corresponding Author's Secondary Institution: First Author: Keisuke Ihara First Author Secondary Information: Order of Authors: Keisuke Ihara Satoru Yamaguchi Yosuke Shida Haruka Yokoyama Tsukasa Kubo Hiroto Muroi Hideo Ogata Jun Ito Masanobu Nakajima Kinro Sasaki Takashi Tsuchioka Hiroyuki Kato Order of Authors Secondary Information: Abstract: Objective: We reported the analysis of long and short-term treatment outcomes of patients with bowel perforation caused by obstructive colorectal cancer. Summary of Background Date: From April 00 to March 01, 15 patients with bowel perforation caused by obstructive colorectal cancer underwent emergent surgery in our hospital. Methods: Clinical outcomes were retrospectively analyzed by age, gender, tumor location, time to surgery from diagnosis, operative method, stage, postoperative complication, and preoperative severity score by APACHE II scoring system. We studied outcome of short-term outcomes and long-term prognosis used by overall survival. Results: The median age was 67.6 years. Male to female ratio was 10:5. The mortality rate was 0% and the median of APACHE II score was 15. The survival cases (n=11) showed significantly lower APACHE II score compared with fatal cases (n=4) (p=0.0). The median overall survival was 18.9 months in survival cases except for stage IV case. 5 patients had recurrence and distant metastasis (50%). Conclusion: The APACHE II score may be an useful predictive marker for short-term outcome and determining operative method in patient with perforation caused by Powered by Editorial Manager and ProduXion Manager from Aries Systems Corporation

2 obstructive colorectal cancer. It is necessary to consider that perforation is high risk factor for recurrence and the most of recurrence pattern is peritoneum dissemination. Powered by Editorial Manager and ProduXion Manager from Aries Systems Corporation

3 Title Page Click here to download Title Page Title page.docx Treatment outcome of obstructive colorectal cancer with bowel perforation Keisuke Ihara, M.D., Satoru Yamaguchi, M.D., Ph.D., FACS, Yosuke Shida, M.D., Ph.D., Haruka Yokoyama, M.D., Tsukasa Kubo, M.D., Hiroto Muroi, M.D., Hideo Ogata, M.D., Ph.D., Jun Ito, M.D., Ph.D, Masanobu Nakajima, M.D., Ph.D., FACS, Kinro Sasaki, M.D., Ph.D., Takashi Tsuchioka, M.D., Ph.D., Hiroyuki Kato, M.D., Ph.D., FACS Department of Surgery 1, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi 1-09, Japan Corresponding author: Keisuke Ihara Department of Surgical Oncology, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi 1-09, Japan Tel: ; Fax: k-ihara@dokkyomed.ac.jp Running title: Treatment outcome of obstructive colorectal cancer 1

4 Acknowledgments The authors would like to thank Ozeki H, Ohashi Y, and Yuzawa N for their secretarial assistance. This work was supported in part by JSPS KAKENHI Grant Number

5 Manuscript Click here to download Manuscript MS revise.docx Abstract Objective: To analyze the short and long-term treatment outcomes of patients with bowel perforation caused by obstructive colorectal cancer. Summary of Background Data: From April 00 to March 01, 15 patients with bowel perforation caused by obstructive colorectal cancer underwent emergency surgery at our hospital. Methods: Clinical outcomes were retrospectively analyzed by age, sex, tumor location, tumor stage, preoperative APACHE II severity score, time to surgery from diagnosis, operative method, and postoperative complications. We studied short-term outcomes and long-term prognosis used by overall survival. Results: Ten men and five women, with a median age of 67.6 years were enrolled in the study. The mortality rate was 0% and the median APACHE II score was 15. The 11 patients who survived had significantly lower APACHE II scores than the four fatal cases (P=0.0). Excluding the patient with Stage IV cancer, the median overall survival was 18.9 months. Five patients (50%) had recurrence and distant metastasis. Conclusion: APACHE II score may be a useful predictive marker for short-term outcome and determining operative method in patients with bowel perforation caused by obstructive colorectal cancer. Perforation should be considered as a high-risk factor for cancer recurrence, most of which are peritoneal. 0 Keywords: obstructive colorectal cancer, bowel perforation, APACHEII score, 1

6 prognosis 4

7 Introduction The frequency of bowel perforation caused by obstructive colorectal cancer is reported to be.6% 6.1%. 1 Colorectal perforation causes panperitonitis by outflow of gastrointestinal contents, including many intestinal bacteria, into the abdominal cavity. Colorectal perforation also often causes early-onset septic shock. Patients can develop multiple organ failure if they are not able to receive appropriate treatment. Most cases of bowel perforation related to colorectal cancer occur on the oral side of the tumor because of obstructive colitis. Cases of bowel perforation related to colorectal cancer have been decreased by ostomy, transanal tube decompression and metallic stents. However, colorectal perforation remains a life-threatening condition associated with high mortality. Cancer treatment strategies should be considered for bowel perforation related to colorectal cancer. The dispersion of cancer cells in the abdominal cavity via bowel perforation has a major influence on the prognosis of colorectal cancer patients. We analyzed the short- and long-term treatment outcomes of patients with bowel perforation caused by obstructive colorectal cancer Materials and Methods 18 Fifteen patients with bowel perforation caused by obstructive colorectal cancer underwent 19 emergency surgery at our institution between April 00 and March 01. Clinical outcomes were 0 retrospectively analyzed by age, sex, tumor location, tumor stage, preoperative APACHE II severity

8 score, time to surgery from diagnosis, operative method, and postoperative complications. The APACHE II scoring system is useful for assessing disease severity and prediction of prognosis., Disseminated intravascular coagulation (DIC) was evaluated using the diagnostic criteria of the 4 Japanese Association for Acute Medicine DIC scoring system. Tumor staging was based on the Union 5 for International Cancer Control tumor node metastasis staging system (seventh edition). After 6 excluding patients who died in hospital and those with Stage IV cancer, 10 cases were evaluated for 7 long-term prognosis, such as recurrence pattern and survival time. All patients provided written 8 informed consent for treatment and analysis Statistical analysis 11 All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical 1 University, Saitama, Japan), which is a graphical user interface for R (R Foundation for Statistical 1 Computing, Vienna, Austria). 4 Significance was evaluated by performing Student s t test, analysis of 14 variance, Mann Whitney U test, and χ test. Survival curves were plotted according to the Kaplan 15 Meier method and any differences were analyzed using the log-rank test. Differences were considered 16 to be significant if the P value was < Results 19 0 Clinicopathological data and surgical outcome 4

9 All patients underwent emergency surgery for large intestinal perforation. The median age of the patients at the time of surgery was 67.6 ± 11.6 years (range, 5 85 years) (Table 1). Tumor sites were the cecum ascending colon (n = ), transverse colon (n = ), descending colon (n = ), sigmoid colon (n = 5) and rectum (n = 4). Tumor staging was Stage II (n = 5), Stage III (n = 6) and Stage IV (n = 1). Surgical procedures were primary resection and anastomosis (n = ), Hartmann s operation (n = 7), simple ileostomy or colostomy and elective resection (n = ), and simple colostomy (n = ). Short-term prognosis Five cases were diagnosed with DIC (%) (Table ). The median preoperative APACHE II score was 15 (range, 10 9). The median time to operation was 8.5 hours. In nine cases (60%), we predicted the presence of colorectal cancer before surgery. Endotoxin adsorption therapy was performed in seven cases (47%). Postoperative complications were surgical site infection (n = 9), DIC (n = 4), acute renal failure (n = 1), and atrial fibrillation (n = 1). There were 4 cases of in-hospital mortality, which gave an overall mortality rate of 6.7%. We compared the clinicopathological factors, disease severity and treatment between the mortality group (n = 4) and survival group (n = 11) (Table ). The mortality group had higher base excess, DIC score and APACHE II score (Fig. 1) Long-term prognosis 5

10 We examined clinicopathological factors, operative method, adjuvant chemotherapy, recurrence pattern, and survival time for 10 cases, which excluded the patient with Stage IV cancer and the fatal cases (Table 4). Five cases showed recurrence. The main recurrence patterns were peritoneal dissemination (n = ), liver metastasis (n = 1), and lymph node metastasis (n = 1). The median overall survival was 9.5 months. We compared prognosis between these 10 cases and 170 cases without perforation that underwent elective surgery for Stage II and III colorectal cancer in As shown in Figure A, compared with the non-perforation cases, those with perforation had a significantly higher recurrence rate (50% vs 0.6%, P = 0.07). The main recurrence pattern was liver metastasis (51%) in the non-perforation cases, and peritoneal dissemination was seen in 6%. Compared with the non-perforation cases, those with perforation had significantly more peritoneal dissemination (P = ) (Fig. B). Patients with perforation had a poorer 5-year survival rate than those without perforation (79.6% vs 4.9%, P = 0.01) (Fig. ) Discussion Colon perforation causes sepsis, DIC, and multiple organ failure as a result of bacterial peritonitis. The mortality for colon perforation is reportedly 17.4%.6%, 5,6 and the most frequent cause of colon perforation is colorectal cancer. 7 Surgery is the absolute adaptation of treatment for colon perforation. Time 6

11 from onset of colon perforation to peritonitis and sepsis is short, therefore, early diagnosis and treatment are required. Several reports show that SOFA, 8,9 APACHE II and POSSUM 10 scores are useful for assessing preoperative and postoperative severity of colon perforation. Indeed, APACHE II score was useful as an acute prognostic marker of colon perforation in our study. It is necessary to consider the oncological factors for colon perforation caused by obstructive colorectal cancer, and the best treatment method for patients remains controversial. Prevention or treatment of severe sepsis is the most important factor for determining optimal treatment. However, treatment method, including bowel anastomosis, should be based on quality of life following acute phase surgery and lymph node resection, as well as long-term prognosis of the malignant disorder. Tumor resection and bowel anastomosis were safely performed for some prior cases of bowel perforation caused by obstructive colorectal cancer. 11,1 However, it is unclear which patients are acceptable candidates for tumor resection with bowel anastomosis and lymph node dissection. Shibahara et al. reported that intensive management of radical lymph node dissection and surgical resection are recommended to improve long-term prognosis. 1 Considering long-term prognosis, tumor resection with bowel anastomosis and lymph node dissection should be undertaken if the general condition of the patient is acceptable. Severity scores can be used to predict postoperative organ dysfunction and thus represent a useful index to determine the optimal surgical method. For 7

12 example, cases with low APACHE II score undergo tumor resection with bowel anastomosis and lymph node dissection, and cases with high APACHE II scores undergo Hartmann s procedure or ileostomy (colostomy) without tumor resection For long-term prognosis, several studies have reported high recurrence rate and poor prognosis of patients with bowel perforation caused by obstructive colorectal cancer. 14,15 In patients with colon perforation on the oral side of the tumor, both local recurrence and peritoneal dissemination are likely because of the high number of free cancer cells at the tumor site. 16,17 In our study, patients with colon perforation showed a high recurrence rate and peritoneal dissemination was the most frequent recurrence pattern. Several reports show that colon perforation is a risk factor for cancer recurrence, 18,19 and adjuvant chemotherapy is useful for high-risk Stage II colon cancer. 0 In Japan, a clinical trial on the efficacy of tegafur uracil and leucovorin in Stage II colorectal cancer with a risk of recurrence (JFMC46-101) is now enrolling patients Conclusions It is necessary to consider preoperative status of patients with bowel perforation caused by obstructive colorectal cancer, using severity scores such as APACHE II, to determine the surgical method. If patients are acceptable candidates, we 8

13 4 should perform tumor resection with bowel anastomosis and lymph node dissection. It is also necessary to consider that bowel perforation is a high risk factor for cancer recurrence and the most frequent pattern of recurrence is peritoneal dissemination. Therefore, we must plan therapeutic strategies according to these considerations

14 References 1. Carraro PG, Segala M, Orlotti C, Tiberio G. Outcome of large-bowel perforation in patients with colorectal cancer. Dis Colon Rectum 1998; 41(11): Horiuchi A, Watanabe Y, Doi T, Sato K, Yukumi S, Yoshida M et al. Evaluation of prognostic factors and scoring system in colonic perforation. World J Gastroenterol. 007; 1 (): Kulkarni SV, Naik AS, Subramanian N Jr. APACHE-II scoring system in perforative peritonitis. Am J Surg. 007; 194(4): Kanda Y. Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant. 01; 48(): Tan KK, Zhang J, Liu JZ, Shen SF, Earnest A, Sim R. Right colonic perforation in an Asian population:predictors of morbidity and mortality.j Gastrointest Surg 009;1(1): Anwar MA, D Souza F, Coulter R, Memon B, Khan IM, Memon MA. Outcome of acutely perforated colorectal cancers:experience of a single district general hospital.surg Oncol 006;15(): Watt AM, Faragher IG, Griffin TT, Rieger NA, Maddern GJ. Self-expanding metallic stents for relieving malignant colorectal obstruction: a systematic review. Ann Surg. 007; 46 (1): Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H et al. The 10

15 SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 1996; (7): Vincent JL, de Mendonkça A, Cantraine F, Moreno R, Takala J, Suter PM et al. Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on sepsis related problems of the European Society of Intensive Care Medicine. Crit Care Med 1998; 6(11): Jiménez Fuertes M, Costa Navarro D. Resection and primary anastomosis without diverting ileostomy for left colon emergencies: is it a safe procedure? World J Surg. 01; 6(5): Nespoli A, Ravizzini C, Trivella M, Segala M. The choice of surgical procedure for peritonitis due to colonic perforation. Arch Surg. 199; 18(7): Gooszen AW, Tollenaar RA, Geelkerken RH, Smeets HJ, Bemelman WA, Van Schaardenburgh P et al. Prospective study of primary anastomosis following sigmoid resection for suspected acute complicated diverticular disease. Br J Surg. 001; 88(5): Shibahara K, Orita H, Koga T, Kohno H, Sakata H, Kakeji Y et al. Curative surgery improves the survival of patients with perforating colorectal cancer. Surg Today. 11

16 ; 40(11): Runkel NS, Schlag P, Schwarz V, Herfarth C. Outcomes after emergency surgery for cancer of the large intestine. Br J Surg.1991; 78(): Slanetz CA Jr. The effect of inadvertent intraoperative perfo-ration on survival and recurrence in colorectal cancer. Dis Colon Rectum. 1984; 7(1): Umpleby HC, Fermor B, Symes MO, Williamson RC. Viability of exfoliated colorectal carcinoma cells. Br J Surg. 1984; 71(9): Porter GA, O'Keefe GE, Yakimets WW. Inadvertent perforation of the rectum during abdominoperineal resection. Am J Surg ; 17(4) : Carraro PG, Segala M, Orlotti C, Tiberio G. Outcome of large-bowel perforation in patients with Colorectal Cancer. Dis Colon Rectum 1998; 41(11); Mandava N, Kumar S, Pizzi WF, Aprile IJ. Perforated colorectal carcinomas. Am J Surg 1996; 17(): Kumar A, Kennecke HF, Renouf DJ, Lim HJ, Gill S, Woods R et al. Adjuvant chemotherapy use and outcomes of patients with high-risk versus low-risk stage II colon cancer. Cancer. 015; 11(4): Sadahiro S, Morita S, Sasaki K, Sakamoto K, Ohge H, Takahashi T et al. Treatment Rationale and Study Design for Clinical Trial on the Efficacy of UFT/LV for Stage II Colorectal Cancer With Risk Factors for Recurrence (JFMC46-101). Clin Colorectal Cancer. 015; 14(4):

17 Figure Legends Figure 1 Comparison of the preoperative APACHE II score between mortality group (n=4) and survival group (n=11). The mortality group were higher APACHE II score (p=0.0). Figure (a) The overall recurrence rate were 50% of perforation cases and 0.6% of non-perforation cases. Compared to the non-perforation case, perforation cases were significantly higher recurrence rate ( P = 0.07). (b) The main recurrence pattern was liver metastasis (51%) of the non-perforation cases. The peritoneal dissemination were 6%. Comparison of the main recurrence pattern between with and without perforation. The perforation cases were significantly more peritoneal dissemination ( P = ). Figure Comparison of the 5 years survival rate between with and without perforation. The perforation cases were poor survival rate (79.6% vs 4.9%, P = 0.01). 1 1

18 14

19 Table Click here to download Table Table revice.docx 1 Table1 Clinicopathological data and surgical outcome n=15 Age 67.6 Sex Male/Female 10/5 Tumor sites Cecum 0 Ascending dolon (1%) Transvers colon (1%) Descending colon (1%) Sigmoid colon 5(%) Rectum 4(7%) Stage II 5(%) III 6(40%) IV 1(7%) Unclear (0%) Surgical procedure Simple colostomy (0%) Hartmann s operation 7(47%) Primary resection and anastomosis (1%) Simple ileostomy or colostomy and (0%) elective resection Curability Cur A 10(67%) Cur B or Cur C 5(%) 1

20 Table. Short-term prognosis n=15 DIC score <4 10(67%) 4 5(%) APACHEII <0 8(5%) 0 7(47%) Time to surgery from diagnosis(hour) 8.5 Preoperative diagnosis Colon cancer 9(60%) Others 6(40%) ICU admission Yes 7(47%) No 8(5%) PMX administration With 7(47%) Without 8(5%) Postoperative complications SSI 9(60%) DIC 4(7%) Renal failure 1(7%) Atrial fibrillation 1(7%) 8-Day mortality 0%

21 Table. Characteristics of Patients, Mortality group vs Survival group. Mortality group (n=4) Survival group (n=11) p value Age 67.7± ±10.1 p=0.498 Sex Male 7 Female 1 4 p=0.17 HCO p=0.50 Base excess p=0.05 DIC score 4.7 p=0.0 Preoperative daignosis Time to surgery from diagnosis Possible 6 Impossible 1 5 p= p=0.06 APACHE II 15 p=0.00 PMX administration With 4 Without 0 8 p=0.04

22 Table4. Clinical outcomes of 10 cases, which excluded the patient with Stage IV cancer and the fatal cases Case Age Sex Tumor sites Stage Surgical procedure Adjuvant chemotherapy Recurrence pattern Outcome Survival time (months) 1 61 F Ra II Simple colostomy and elective resection None None Alive M A II Simple ileostomy and elective resection UFT/LV None Alive F S II Primary resection and anastomosis FOLFOX Peritoneal dissemination Dead F S II Primary resection and anastomosis None None Alivel M S II Hartmann s operation UFT/LV Peritoneal dissemination Alive M Ra III Hartmann s operation UFT/LV Liver Dead M S III Hartmann s operation None Peritoneal dissemination Dead M T III Hartmann s operation UFT/LV None Alive M S III Simple ileostomy and elective resection UFT/LV None Alive M A III Hartmann s operation UFT/LV Lymph node Dead

23 5

24 Figure1 Click here to download Figure renamed_0df.tif

25 Figure (a) Click here to download Figure renamed_85505.tif

26 Figure (b) Click here to download Figure renamed_a57ac.tif

27 Figure Click here to download Figure renamed_74e7.tif

28 Cover Letter Click here to access/download Cover Letter Cover letter.docx

29 Copyright Statement Click here to access/download Copyright Statement copy right.pdf

30 Revice to reviewer Click here to access/download Cover Letter Revice to reviewer.docx