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.

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: vachan_sh@rediffmail.com, gourihukkeri@gmail.com (V.S. Hukkeri).
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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
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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
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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.
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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