Published on September 30, 2015
1. Minimizing locoregional recurrences in colorectal cancer surgery
2. Review Article Minimizing locoregional recurrences in colorectal cancer surgery Vachan S. Hukkeri a, *, Subhash Mishra b , Md. Qaleem b , Satyaprakash Jindal b , Ramesh Aggarwal c , Vivek Choudhary c , Deepak Govil b a Resident, Indraprastha Apollo Hospital, GI Surgery, Sarita Vihar, Mathura Road, Delhi 10076, India b GI Surgery, Indraprastha Apollo Hospital, India c General Surgery, Indraprastha Apollo Hospital, India 1. Introduction Colorectal cancer is the third most common cancer in men and the second most common cancer in women worldwide. Almost 55% of the cases occur in more developed regions of the world. There is a wide geographical variation in incidence across the world, and the geographical patterns are very similar in men and women. Mortality is higher in the underdeveloped than in the developed countries. The incidence in India is relatively lower than that in countries like China, Japan, and Indonesia. In the Indian scenario, colorectal cancer stands fourth in men and third in women with respect to age-standardized incidence and mortality rates.1 SEER database reports that the overall 5-year survival for all cases of colorectal cancer is about 65%.2 Colorectal cancers present as localized disease in 39%; 36% present with involvement of the regional lymph nodes and 20% with metastatic disease. The 5-year survival in patients of colorectal cancer ranges from 90% in those with localized disease to 13% in those with distant disease. Colorectal cancer is most frequently diagnosed among people aged 65–74 years (median age 68). Colorectal cancer a p o l l o m e d i c i n e x x x ( 2 0 1 5 ) x x x – x x x a r t i c l e i n f o Article history: Received 29 July 2015 Accepted 30 July 2015 Available online xxx Keywords: Colorectal cancer Circumferential resection margin Total mesorectal excision Microsatellite instability a b s t r a c t Colorectal cancer is a major cause of morbidity and mortality worldwide. The Indian scenario also shows a similar trend, and this has been attributed to the changing dietary patterns. Recurrence in colorectal cancer is associated with many factors, some related to the tumor itself and some to the surgical principles applied. Understanding these factors and application of sound surgical principles can go a long way in decreasing the incidence of colorectal cancer. Here, we highlight the main biological and technical factors implicated in the recurrence of colorectal cancer. # 2015 Indraprastha Medical Corporation Ltd. Published by Elsevier B.V. All rights reserved. * Corresponding author. Tel.: +91 9910369502; mobile: +91 9036360278. E-mail addresses: email@example.com, firstname.lastname@example.org (V.S. Hukkeri). APME-314; No. of Pages 4 Please cite this article in press as: Hukkeri VS, et al. Minimizing locoregional recurrences in colorectal cancer surgery, Apollo Med. (2015), http://dx.doi.org/10.1016/j.apme.2015.07.018 Available online at www.sciencedirect.com ScienceDirect journal homepage: www.elsevier.com/locate/apme http://dx.doi.org/10.1016/j.apme.2015.07.018 0976-0016/# 2015 Indraprastha Medical Corporation Ltd. Published by Elsevier B.V. All rights reserved.
3. deaths are the highest among people aged 75–84 years (median age 73). 2. Recurrent disease Recurrence of disease occurs in about 30–50% of cases. The incidence of recurrence after curative resection for colorectal cancer is about 9.9% at 1 year, 26.2% at 3 years, and 31.5% at 5 years. Five-year recurrence rates range from 9.3% for stage I tumors to 56.1% for stage III disease. Locoregional recurrence occurs in 12.8% of patients at 5 years, and distant metastases occur in 26% of patients at 5 years. Distant sites of disease include the liver in 45%, lung in 10%, brain in 2%, bone in 2%, and other sites in 4%.3 Historically, the highest rate of recurrences was seen within the ﬁrst 2 years, but the median time to recurrence is increasing, especially for rectal cancers, and surveillance beyond 5 years may be necessary. The incidence of local recurrence is also higher for rectal cancers as compared to colonic malignancy.4,5 The risk factors associated with recurrence of colorectal cancer may either be tumor related or technical. The various tumor-related factors include 1) Stage of the disease 2) Grade of the tumor 3) Location of the tumor 4) Obstruction or perforation 5) Venous invasion 6) Perineural invasion 7) Low microsatellite instability 8) Diminished stream immune reaction 9) Aneuploidy 10) Mutant p53 gene expression The single most important factor that affects the recur- rence and survival is the stage of the tumor. The risk is greatest when the tumor has invaded beyond the conﬁnes of the bowel wall (T3 to T4) or involves nodes (N+) and is highest in patients with both.6 The 5-year survival of patients with stage I disease is >90%, whereas for stage IV, it is <10%. The two-tier system advocated for colorectal cancer grading is accepted by most pathologists today. It takes gland formation into account and deﬁnes high-grade tumors as the ones with <50% gland formation. Signet cell cancer is a relatively rare form of colorectal cancer. It is associated with a higher stage of the tumor at the time of diagnosis, coupled with high incidence of peritoneal seeding and overall poorer prognosis.7 Tumors located lower down and anteriorly in the rectum are associated with a higher incidence of local recurrence. The close anterior relation of the rectum to bladder and seminal vesicles in males, and uterus and vagina in females has been attributed to this. Perforated colorectal cancer has been associated with higher rate of recurrence and lower overall survival, as shown by Cheynel et al.8 Lymphovenous invasion has been attributed with a higher incidence of local recurrence.9 Perineural invasion (PNI) has been studied of late as a prognostic factor in colorectal cancer. The 5-year disease-free survival rate was fourfold greater for patients with PNI- negative tumors versus those with PNI-positive tumors (65% vs 16%). The 5-year overall survival rate was also better in PNI- negative tumors versus PNI-positive tumors (72% vs 25%).10 Microsatellite instability (MSI) in colorectal cancers is associated with right colonic lesions, and is more often of the mucinous, signet ring cell or medullary histologic type, poorly differentiated, and have a brisk lymphocytic inﬁltrate. MSI-high tumors are associated with longer survival than either MSI-low or microsatellite-stable tumors, both in HNPCC and in sporadic cases, despite being often poorly differentiat- ed. The presence of low MSI is associated with a higher rate of recurrence. The presence of tumor-inﬁltrating lymphocytes has been reported as a favorable prognostic factor.11 P53 gene mutation has been proven to be an adverse prognostic factor on the overall survival. The p53 mutation increases the risk of death by 2.82 times in patients with stage II and by 2.39 times in patients with stage III colon carcinoma.12 Technical factors mainly involve the adequacy of resection margins (radial, distal, and mesorectal) irrespective of the surgical method used. Since technical factors play a signiﬁcant role in the recurrence rate, Nelson et al.13 proposed certain surgical guidelines for the treatment of colorectal cancer. 3. Surgical guidelines The present surgical guidelines state that for colonic malig- nancy lymphadenectomy should extend to the level of the origin of the primary feeding vessel, and suspected positive lymph nodes outside the standard resection should be removed when feasible. Bowel margins of more than 5 cm, both proximally and distally, should be obtained. For rectal malignancy, an ideal bowel margin of 2 cm distally and 5 cm proximally, measured fresh with the use of full thickness, has been advised. The minimally acceptable distal margin for sphincter preservation is taken as 1 cm. Lymphovascular resection of the rectum should include a wide anatomic resection of the mesorectum, including the mesor- ectal fascia propria and 4 cm of clearance distal to the tumor and proximal ligation of the primary feeding vessel. Extended lateral lymphatic dissection is not supported based on the current evidence. Certain principles common for both colon and rectal cancers are En bloc resection should be performed for tumors adherent to local structures; inadvertent bowel perforation should be avoided as it increases the risk of recurrence; thorough abdominal exploration for metastatic and locally advanced primary and lymph node disease should be performed. Height of the tumor from anal verge also has an impact on the rate of recurrence. The tumors below the peritoneal reﬂection tend to be more inﬁltrative locally and are subjected to poorer intraoperative exposure and manipulation. The incidence of recurrence decreases as the height increases from the anal verge, with lower 1/3 tumors having a recurrence of 10–15%, middle 1/3 having 5–10%, and upper 1/3 rectal tumors a p o l l o m e d i c i n e x x x ( 2 0 1 5 ) x x x – x x x2 APME-314; No. of Pages 4 Please cite this article in press as: Hukkeri VS, et al. Minimizing locoregional recurrences in colorectal cancer surgery, Apollo Med. (2015), http://dx.doi.org/10.1016/j.apme.2015.07.018
4. 2–5%. Anterior tumors also tend to have increased chances of recurrence. Circumferential resection margin (CRM) is also an impor- tant factor in predicting recurrence. Tumor-free margin of at least 1 mm can be predicted with a high degree of certainty when the measured distance on MRI is at least 5 mm. Frequency of recurrence with positive CRM has been reported to be 19–22%, and with negative CRM, it is about 3–5%.14 Total mesorectal excision (TME) is associated with im- proved local control and better survival rates. The improved local recurrence rates with TME may be attributed to improved lateral clearance with removal of potential tumor deposits in the mesentery, as well as a decreased risk of tumor spillage from a disrupted mesentery. This improved local control appears to result in better survival.15 Negative surgical margins are also important with respect to chances of recurrence. Even with an optimal surgical technique (e.g., TME) and adjuvant radiotherapy, a positive distal margin is associated with a local recurrence rate approaching 40%,16 and a decreased 5-year survival rate.17 The number of lymph nodes retrieved from the surgical specimen should be more than 12 as stated by the NCCN guidelines. Presently, the removal of the mesorectum, which contains the terminal branches of the IMA and the draining lymph nodes, to the level of the proximal vascular pedicle rather than the absolute number of lymph nodes removed, is the important principle for rectal cancer resection.18 The presence of lymphatic and venous vascular invasions is also associated with a higher risk of colorectal cancer recurrence.19 The gross resected specimen is also assessed for the adequacy of resection. Quirke grouped the pathologic speci- men into three groups. These can give a fair idea about the possibility of recurrence. Grade 1 signiﬁes poor quality mesorectum, with deep clefts into the mesorectal fat that exposes the bared muscularis of the rectal wall. It is associated with a local recurrence rate of 41%. Grade 2 means intermediate quality mesorectum, with merely superﬁcial clefts into the mesorectal fat that do not expose the muscularis. This is associated with a 5.7% local recurrence rate. Grade 3 signiﬁes good quality mesorectum specimen, evincing a mesorectal fascial envelope that is intact circum- ferentially; it is associated with a 1.6% local recurrence rate.20 An abdominoperineal resection (APR) is mandatory if there is no space between the tumor and sphincter mechanism on digital rectal examination, if the tumor is growing into the sphincter, or if the tumor is ﬁxed to the pelvic ﬂoor. Any tumor involvement of surrounding structures, such as the prostate and seminal vesicles in men or the vagina in women, weighs heavily against a restorative procedure, although it is not an absolute contraindication.21 Cylindrical APR is a concept, which can reduce the rates of local recurrence. It is performed in the prone position for low rectal cancer; it removes more tissue around the tumor that leads to a reduction in CRM involvement and intraoperative perforations, which should reduce local disease recurrence. The cylindrical technique has the potential to improve patient outcomes substantially if appropriate surgical education programs are developed.22 4. Surgical technique Laparoscopic approach for colorectal cancer has been validat- ed in a number of studies. In a randomized trial including 340 patients who had received preoperative chemoradiotherapy, the patients were assigned to either undergo laparoscopic or open surgery. The outcomes with laparoscopic-assisted LAR were signiﬁcantly better with respect to the time to return of bowel function (38 vs 60 hours), time to resume a normal diet (85 vs 93 hours), and time to defecation (96 vs 123 hours). There were no signiﬁcant differences between the two groups with respect to involvement of the CRM, macroscopic quality of the TME specimen, number of harvested lymph nodes, and perioperative morbidity.23 A retrospective review of 5420 patients with rectal cancer showed that patients undergoing a laparoscopic proctectomy ( n = 1040) had a signiﬁcantly lower rate of blood transfusion (12.3 vs 4.3%), shorter length of hospital stay (5 vs 7 days), fewer postoperative complications (28.8 vs 20.5%), and lower 30-day morbidity (odds ratio 1.41; 95% CI 1.19–1.68).24 COlorectal cancer Laparoscopic or Open Resection (COLOR II) trial included 1044 patients and found that patients undergoing a laparoscopic approach had a similar macroscop- ic completeness of resection compared with patients under- going an open resection (88 vs 92%). They also had an equivalent rate of positive CRMs (10% vs 10%), median tumor distance to the distal resection margin (3 cm [range 2.0–4.8] vs 3 cm [range 1.8–5.0]), and a similar 28-day morbidity rate (40% vs 37%) and mortality rate (1% vs 2%).25 Robot-assisted approaches have also been found to be feasible and safe, and there appears to be no difference in number of lymph nodes harvested or circumferential margins resected as observed with open and laparoscopic approaches. No signiﬁcant difference in disease-free survival has been found between the three approaches.26 Preoperative imaging is an important aspect of preventing postoperative recurrence. After imaging and staging, neoad- juvant chemotherapy could be offered to all patients with a lesion of stage IIA and above. The neoadjuvant treatment consists of infusional 5-FU/RT or capecitabine/RT.27 5. Diagnosis of local recurrence Majority (80%) of recurrences occur in the ﬁrst 3 years after surgical resection of the primary tumor. Proper surveillance postoperatively includes periodic (3–6 months) examination with CEA levels. Colonoscopy has been recommended to be done annually for up to 5 years in case of high-risk malignancy. Colonoscopy should be done at 1 year if it was done preoperatively, but should be done within 3–6 months if not done preoperatively. Proctoscopy should be considered every 6 monthsfor3–5yearstoevaluateforlocal recurrenceattherectal anastomosis for patients who have undergone an LAR or transanal excision. Chest, abdominal, and pelvic CT scans are recommended annually for up to 5 years in stage II and III patients (i.e., patients considered at high risk of recurrence, for example those with lymphatic or venous invasion by the tumor a p o l l o m e d i c i n e x x x ( 2 0 1 5 ) x x x – x x x 3 APME-314; No. of Pages 4 Please cite this article in press as: Hukkeri VS, et al. Minimizing locoregional recurrences in colorectal cancer surgery, Apollo Med. (2015), http://dx.doi.org/10.1016/j.apme.2015.07.018
5. or with poorly differentiated tumors). Routine use of PET/CT to monitor for disease recurrence is not recommended.27 6. Conclusion Colorectal cancer is a common problem in the world including India. Recurrence is frequent and is associated with a lot of factors both related to the tumor and the surgical technique. We should monitor the biological factors and improve our surgical technique and understanding if we have to decrease the chances of recurrence. Most, if not all the factors, can be modiﬁed to improve the outcome and decrease the chances of recurrence. r e f e r e n c e s 1. GLOBOCAN, http://globocan.iarc.fr/Pages/ fact_sheets_cancer.aspx; 2012. 2. SEER database, http://seer.cancer.gov/csr/1975_2012/. 3. Manfredi S, Bouvier AM, Lepage C, et al. Incidence and patterns of recurrence after resection for cure of colonic cancer in a well deﬁned population. Br J Surg. 2006;93:1115. 4. Platell CFE. Changing patterns of recurrence after treatment for colorectal cancer. Int J Colorectal Dis. 2007;22:1223. 5. Sadahiro S, Suzuki T, Ishikawa K, et al. Recurrence patterns after curative resection of colorectal cancer in patients followed for a minimum of ten years. Hepatogastroenterology. 2003;50:1362. 6. Porter GA, Soskolne CL, Yakimets WW, et al. Surgeon- related factors and outcome in rectal cancer. Ann Surg. 1998;227:157. 7. Compton CC, Fielding LP, Burgart LJ, et al. Prognostic factors in colorectal cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med. 2000;124:979. 8. Cheynel N, Cortet M, Lepage C, Ortega-Debalon P, Faivre J, Bouvier AM. Incidence, patterns of failure, and prognosis of perforated colorectal cancers in a well-deﬁned population. Dis Colon Rectum. 2009;52(March (3)):406–411. 9. Dresen RC, Peters EEM, Rutten HJT, et al. Local recurrence in rectal cancer can be predicted by histopathological factors. Eur J Surg Oncol. 2009;35:1071. 10. Liebig C, Ayala G, Wilks J, et al. Perineural invasion is an independent predictor of outcome in colorectal cancer. J Clin Oncol. 2009;27(November (31)):5131–5137. 11. Lanza G, Gafà R, Santini A, et al. Immunohistochemical test for MLH1 and MSH2 expression predicts clinical outcome in stage II and III colorectal cancer patients. J Clin Oncol. 2006;24:2359. 12. Pricolo VE, Finkelstein SD, Hansen K, Cole BF, Bland KI. Mutated p53 gene is an independent adverse predictor of survival in colon carcinoma. Arch Surg. 1997;132(April (4)):371–374. 13. Nelson H, Petrelli N, Carlin A, et al. Guidelines 2000 for colon and rectal cancer surgery. J Natl Cancer Inst. 2001;93:583. 14. Nagtegaal ID, Quirke P. What is the role for the circumferential margin in the modern treatment of rectal cancer? J Clin Oncol. 2008;26:303. 15. Guillem JG. Ultra-low anterior resection and coloanal pouch reconstruction for carcinoma of the distal rectum. World J Surg. 1997;21:721. 16. Kim YW, Kim NK, Min BS, et al. Factors associated with anastomotic recurrence after total mesorectal excision in rectal cancer patients. J Surg Oncol. 2009;99:58. 17. Leo E, Belli F, Miceli R, et al. Distal clearance margin of 1 cm or less: a safe distance in lower rectum cancer surgery. Int J Colorectal Dis. 2009;24:317. 18. Monson JR, Weiser MR, Buie WD, et al. Practice parameters for the management of rectal cancer (revised). Dis Colon Rectum. 2013;56:535. 19. Rossoni MD, Telles JEQ, Rossoni AMO, Matias JEF. Risk factors for recurrence of stage I/II (TNM) colorectal adenocarcinoma in patients undergoing surgery with curative intent. J Coloproctol. 2013;33(1):28–32. 20. Maslekar S, Sharma A, Macdonald A, Gunn J, Monson JR, Hartley JE. Mesorectal grades predict recurrences after curative resection for rectal cancer. Dis Colon Rectum. 2007;50 (February (2)):168–175. 21. Marr R, Birbeck K, Garvican J, et al. The modern abdominoperineal excision: the next challenge after total mesorectal excision. Ann Surg. 2005;242(July (1)):74–82. 22. West NP, Finan PJ, Anderin C, Lindholm J, Holm T, Quirke P. Evidence of the oncologic superiority of cylindrical abdominoperineal excision for low rectal cancer. J Clin Oncol. 2008;26(July (21)):3517–4352. 23. Kang SB, Park JW, Jeong SY, et al. Open versus laparoscopic surgery for mid or low rectal cancer after neoadjuvant chemoradiotherapy (COREAN trial): short-term outcomes of an open-label randomised controlled trial. Lancet Oncol. 2010;11:637. 24. Greenblatt DY, Rajamanickam V, Pugely AJ, et al. Short-term outcomes after laparoscopic-assisted proctectomy for rectal cancer: results from the ACS NSQIP. J Am Coll Surg. 2011;212:844. 25. van der Pas MH, Haglind E, Cuesta MA, et al. Laparoscopic versus open surgery for rectal cancer (COLOR II): short-term outcomes of a randomised, phase 3 trial. Lancet Oncol. 2013;14:210. 26. Kang J, Yoon KJ, Min BS, et al. The impact of robotic surgery for mid and low rectal cancer: a case-matched analysis of a 3-arm comparison – open, laparoscopic, and robotic surgery. Ann Surg. 2013;257:95. 27. NCCN guidelines; 2015. a p o l l o m e d i c i n e x x x ( 2 0 1 5 ) x x x – x x x4 APME-314; No. of Pages 4 Please cite this article in press as: Hukkeri VS, et al. Minimizing locoregional recurrences in colorectal cancer surgery, Apollo Med. (2015), http://dx.doi.org/10.1016/j.apme.2015.07.018
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