NGHIÊN cứu điều TRỊ PHẪU THUẬT và một số yếu tố NGUY cơ tái PHÁT, DI căn SAU PHẪU THUẬT UNG THƯ đại TRỰC TRÀNG tt tiếng anh

MINISTRY OF EDUCATION AND TRAINING
MINISTRY OF HEALTH
HANOI MEDICAL UNIVERSITY

HOÀNG MINH ĐỨC

RESEARCH ON SURGICAL OUTCOMES AND
RISK FACTORS OF RECURRENCE,
METASTASIS AFTER CURATIVE SURGERY
FOR COLORECTAL CANCER

Major: Gastrointestinal surgery
Code: 62720125

SUMMARY OF DOCTOR MEDICINE THESIS

Hanoi - 2019


THE THESIS IS COMPLETED AT:
HANOI MEDICAL UNIVERSITY

Scientific advisors: Assoc. Prof., Nguyen Thanh Long

First opponent: ...........................................................

Second opponent: .......................................................

Third opponent: .........................................................

This thesis is defended at University Thesis Examination Council,

held at Hanoi Medical University
At … hour … minute on … … … 2019

The thesis may be read at following libraries:
- National Library of Vietnam;
- Library of Hanoi Medical University;


INTRODUCTION
Colorectal cancer is one of the most common malignancies;
according to the 2019 statistics World Health Organization each year
there are 1,8 million new cases and almost 861,000 deaths in 2018.
Despite recent significant medical advancement in diagnosis and
treatment of colorectal cancer in the recent years, recurrence and
metastasis after curative surgery for colorectal cancer have still been
serious challenges to clinical doctors. In the world, there have been a
number of researches on postoperative recurrence of colorectal cancer,
and these researches show that the rate of recurrence is about 20%-30%,
of which 60%-80% of recurrences occur within the first 2 years after
surgery. Colorectal cancer is classified as recurrent when new malignant
lesions are found, either local or metastatic, in patients previously had
curative surgery for colorectal cancer. Risks of recurrence depend on
various factors, of which the major factors are disease stages, surgical
features and postoperative adjuvant treatment. In order to detect
recurrent colorectal cancer, it is necessary to conduct regular
postoperative examinations with following clinical and subclinical tests:
Carcinoembryonic antigen (CEA) test, liver ultrasound, chest X-ray,
flexible colonoscopy - biopsy, CT scan, MRI scan, PET - CT scans, etc.
For treatment of recurrent colorectal cancer, surgery is still the main
treatment method, however whether a surgery is possible depends on

site of recurrence and degree of tumor growth. Prognosis after surgery
for recurrent colorectal cancer depends on various factors, for example
time of recurrence after surgery, disease stage, and having adjuvant
treatment or not. In the recent years, the number of patients diagnosed
with recurrent colorectal cancer and underwent surgery has been
increasing. Nevertheless, in our country researches on this issue are still
limited. Therefore, researching on surgical outcomes and risk factors of
recurrence and metastasis after curative surgery for colorectal cancer is
necessary and has scientific implication for the purpose of generalizing
features of recurrence, treatment and outcomes of recurrence treatment
as well as identifying risk factors of recurrence after surgery for
colorectal cancer. Objectives of research:
1. Describing features of recurrence, metastasis after curative surgery
for colorectal cancer.


2. Assessing outcomes of surgery for recurrent and metastatic
colorectal cancer.
3. Analyzing a number of risk factors of recurrence, metastasis of
colorectal cancer.
CONTRIBUTIONS OF THE THESIS
1. Implications of the thesis
Results of this research shall help doctors of Gastrointestinal
surgery have more understandings of recurrence of colorectal cancer:
Site of recurrence, time of recurrence, metastasis, indication of surgery
for recurrent colorectal cancer and early and late outcomes of treatment.
Also, results of this research identify risk factors of recurrence, such as:
Age, disease stage, differentiation, histopathological type, features of
tumor growth by Bormann classification, and Petersen index (including
various factors: Vascular invasion, serosal invasion, invasion in

resection margin, necrotic tumors with perforation), which help
surgeons give advises on adjuvant treatment for patients having high
risks of recurrence.
This research has highly practical implications by providing
complete information about features of recurrence, indications and
methods of surgery and outcomes of treatment of recurrence after
curative surgery for colorectal cancer. Furthermore, this thesis provides
information about risk factors of recurrence, which can make treatment
after curative surgery for colorectal cancer be more effective.
This research has scientific implication with coherent layout and
appropriate method of data processing. Research data are processed by
modern medical algorithm being capable of properly solving the 3
objectives of research.
This thesis has creative, new and up-to-date features, and is the first
research that compares the 2 groups of patients with and without
recurrence for the purpose of identifying risk factors of recurrence in
Viet Nam.
2. Structure of thesis
The thesis comprises of 148 pages, with 87 tables, 5 charts, 2
diagrams and 20 images. The thesis has 4 chapters: Introduction (2
pages); Chapter 1 - Overview of literature (40 pages); Chapter 2 Subjects and methods of research (15 pages); Chapter 3 - Results of


research (36 pages); Chapter 4 - Discussion (50 pages) and Conclusion
(2 pages); the thesis has 255 references (18 in Vietnamese, and 255 in
English).
Chapter 1: OVERVIEW
1. Features of recurrence
Definition: Colorectal cancer is classified as recurrent when
new malignant lesions are found, either local or metastatic, in patients

previously had curative surgery for colorectal cancer, and at the same
time the current outcomes of anatomical pathology are similar to that of
the previous surgery.
Features of recurrence: Recurrence may be local (at
anastomosis, remaining colorectal section, surgical scar, trocar hole,
mesentery, or in the pelvis, etc.) or metastatic (in lung, liver, ovary,
peritoneum, etc.) Site of recurrence can be in any intra-abdominal
location, isolated or combined with metastasis. A recurrent tumor may
be local or invades other adjacent organs (invading vessels, kidney,
ureter, bladder, uterus, etc.). Rectal cancer has rate of local recurrence
(pelvis) higher than that of colon cancer, due to the characteristic of
invading surrounding organs in pelvic region via lymphatic system and
intravenous system. However, application of total mesorectal excision
(TME) and new chemoradiotherapy protocol has recently reduce rate of
recurrence of rectal cancer to 6%. The rate of anastomotic recurrence is
5 - 15% of the total number of patients, including invasive masses
outside of rectum and in front of sacrum. In contrast, colon cancer has
rate of retroperitoneal recurrence higher than that of rectal cancer.
According to Galandiuk et al., for colon cancer, rate of retroperitoneal
recurrence, metastasis within 5 years after surgery of is 15%, and rate of
local recurrence is 15%; meanwhile that of rectal cancer is 35% and 5%
respectively.
For rectal cancer, the overall rate of recurrence is about 30%
within 5 years after curative surgery. The rate of recurrence, metastasis
depends on whether the rectal cancer tumor is high or low: The research
on 6859 patients treated with surgery for rectal cancer shows that:
Comparing to rectal cancer with low tumor, the rate of liver and lung
metastases of rectal cancer with high tumor is higher, p=0,03, and there
is no difference in the rate of local recurrence.

2. Risk factors of recurrence, metastasis
- Histopathological type: Adenocarcinoma is the most common
histopathological type, accounting for 95% and has prognosis of
recurrence better than other types.
- Disease stage: Is the factor having the most important prognosis
value. The later the disease stage is, the higher the risk of recurrence is.
The TNM staging system of the World Health Organization and
American Joint Committee on Cancer (AJCC) 8th edition staging
system 2018, apart from creating a consensus for oncologists to
exchange information, also have prognosis implications. The research
of Tomoki Yamano on 4992 cases of colorectal cancer shows that the
recurrence rates of stages I, II, and III were 1.2%, 13.1%, and 26.3%,
respectively (for 3039 colon cancer patients), and 8.4%, 20.0%, and
30.4%, respectively (for 1953 rectal cancer patients).
- Differentiation and grade of tumor: Is an independent prognosis
factor, in which poor and no differentiation predict high risk of
recurrence.
- Tumor growth based on Borrmann’s classification: B-I/II (gross
appearance shows polypoid/ulcerative lesions without infiltration) have
better prognosis than B-III/IV (gross appearance shows
invasive/infiltrative ulcerated and poorly demarcated lesions).
- Lymphatic invasion, vascular invasion: Have bad prognosis.
- Perineural invasion: Results in increased rate of recurrence and
decreased overall survival.
- Number of dissected lymph nodes and metastatic nodes: When distant
metastasis does not present, the extent of lymphatic metastatic spread is
the most important factor in prognosis of postoperative survival time
and recurrence, metastasis. Dissection of lymph nodes must be proper
(at least to D2) and radical (at least 10 nodes) in order to evaluate

disease stage and obtain better prognosis of recurrence.
- Conditions of resection margin and total mesorectal excision - TME:
Before the time of total mesorectal excision (TME), local recurrence
often occur at the remained mesorectum (left after previous surgery) or
at the location of anastomosis.
- Petersen Index: Petersen Index is a multivariable assessment of
recurrence risk. One score shall be added if each of the following sign
present: Venous invasion, serosal invasion, and margin involvement,


and 2 scores shall be added if there is perforation through tumor. Total
score: 5.
+ 0-1 score: Low risk of recurrence
+ 2-5 score: High risk of recurrence
- Pre-operative CEA before surgery and postoperative follow-up:
Means bad prognosis, however this must be combined with other
prognosis factors in order to decide on adjuvant treatment after curative
surgery. After curative surgery, if CEA level does not return to normal,
the patient has high risk of recurrence and distant metastasis. According
to Chau I., follow-up on cases of colorectal cancer after surgery shows
that: CEA level being 1 unit higher than the value of the previous
examination has prognosis of recurrence in 74% of cases with
recurrence.
- Combination therapy after surgery helps kill the remained cancerous
cells. Cases treated with combination therapy after surgery have less
risk of recurrence.
- New prognostic factors: Due to development of molecular technique,
more and more genes as well as changes in chromosomes are identified
as involved in the regulation of cell cycle. Some of these factors can
help determine progression of disease in order to find appropriate

methods of treatment. Factors recently being explored include:
Thymidylate synthase, microsatellite instability, 18q loss, Kras
mutation, DCC, etc.
Chapter 2: SUBJECTS AND METHODS OF RESEARCH
2.1. Study population
- The population for researching on objective 1 and 2 are 53 patients
with recurrence who underwent the first surgeries in the 2 years of 2013
and 2014, and the second surgery (for recurrence) at Viet Duc
University Hospital.
- The population for objective 3 include 2 groups: 53 patients with
recurrence and 545 patients without recurrence. All of these 598
patients underwent their first surgeries in 2013 and 2014.
2.1.1. Patient selection criteria
- Recurrent cancer treated with curative surgery for colorectal
resection:
+ Having surgical methods or outcomes of anatomical pathology


showing colorectal segment with tumor, negative resection margin and
dissected lymphatic nodes.
+ Having results of anatomical pathology of carcinoma and current
outcomes of anatomical pathology being similar to that of the previous
one.
- Patients with non-recurrent colorectal cancer undergoing surgery
for colorectal resection, with clinical and subclinical follow-up and
examination not showing recurrent lesions.
2.1.2. Patient exclusion criteria:
- Medical records being incomplete.
- Patient with colorectal cancer but in the previous surgery colon was
not radically dissected (artificial anus was created without dissecting

tumor, bypass, etc.) or cancer cells present microscopically at the
resection margin.
- Patient having other cancerous disease.

2.2. Methods of research: Descriptive retrospective research.
* To solve the objective 1 and 2: We collect data of 53 patients with
recurrence undergoing surgeries at Viet Duc University Hospital.
Of the 53 patients with recurrence, information of the first surgeries
and the second surgeries are collected. These patients with recurrence is
regularly followed up after surgery, with collected information
including adjuvant treatment (chemical/radiotherapy), date of
recurrence, recurrence location, clinical symptoms, subclinical features,


diagnostic, and surgical method.
* To solve the objective 3: Medical records showing surgery for
primary tumor: 598 cases meeting selection criteria are selected and
divided into 2 groups of with and without recurrence. The group with
recurrence has 53 patients and the group without recurrence has 545
patients.
The two groups are compared using Chi-squared test, Fisher’s or
Mann Whitney algorithms on SPSS version 22.0 (SPSS, Inc, Chicago,
IL). A difference between the two groups analyzed by log-rank test
having P <0,05 is considered as a statistically significant difference.
Two qualitative variables are compare by using Chi-squared test (X2) when expected frequency is higher than 5, and when the frequency is <5
Fisher's exact test is be applied. For quantitative variables, Mann Whitney test is applied.
When p < 0,05, we calculate relative risk - RR. RR is calculated
according to the following formula (applicable to 2x2 table):
Risk factor of recurrence
Yes

No
With
a
c
recurrence
Group
Without
b
d
recurrence
Total
a+b
c+d

p1 = and p2 =
RR = = e
Explanation of RR: Risk of recurrence of the group without recurrent
factor decreases e% as compared to the group with recurrent factor.
In our research, we do not use OR (odd ratio), although OR and RR
do not have significant difference. However, RR is more related to risks
than OR.
2.3. Research criteria:
2.3.1. Research criteria for objective 1 and 2: Features and
outcomes of surgical treatment for recurrent colorectal cancer.
- Features of primary tumor and features of the first surgery:
Location of primary tumor, method of the first surgery, anatomical


pathological features of primary tumor, disease stage, method of
combination therapy.

- Clinical features: Age, gender, chief complaint, clinical symptom,
physical examination
- Subclinical characteristics: CEA, colorectal endoscopy,
ultrasound, pulmonary X-ray, thoracic - abdominal CT, abdominal whole body MRI, PET-CT
- Time of recurrence (by months): Is calculated from the first
surgery to the time of detection of local recurrence or distant metastasis
(equivalent to the definition of Disease-free survival).
- Preoperative diagnosis and intraoperative injury.
- Surgical indication and surgical method: Curative surgery - R0;
Resection - R1; Palliative surgery - R2; exploratory surgery: Operation
for discovery purpose.
- Operation time: time from skin incision to closure, in minutes.
- Intraoperative complication: Bleeding, injury to other organs
while removing adhesion, or revealing tumor lesion (duodenum, small
intestine, ureter, common bile duct, large blood vessels, etc.): Injury,
number of injuries and treatment.
- Early results: Time for intestinal circulation recovery; drainage
from abdominal space: Quantity, quality, time of removing drainage
(days), abdominal conditions after surgery: Normal, distension,
abdominal pain, abdominal guarding; Conditions of incision: Dry, wet,
bleeding, having fluid.
- Postoperative complications: Bleeding; anastomotic leakage;
surgical site infection; retracted stoma; electrolyte disorder; disruption
of abdominal incision; residual abscess, early postoperative bowel
obstruction; postoperative pancreatitis.
- Death after surgery.
- Length of stay.
- Remote results: Evaluation of recurrence, survival or death;
overall survival; rate of survival at selected points of time (6 months, 12
months, 24 months, 36 months, 48 months); postoperative survival time

of each surgical method.
2.3.2. Research criteria for objective 3: Factors affecting
recurrence
Criteria of patients: Age, gender


Criterial of tumor: Disease stage; Differentiation and grade of
tumor; Petersen Index evaluating risk of recurrence (0-5 score scale);
Number of metastatic lymph nodes and ratio of positive lymph nodes
and number of dissected nodes; rate of positive lymph nodes; lymphatic
or vascular invasion; perineural invasion; Histopathological type:
Adenocarcinoma, mucinous adenocarcinoma, Signet ring cell
carcinoma; mucinous organ:  50% and < 50%; Tumor growth based on
Borrmann’s classification; location of primary tumor.
* Criteria related to surgery: Number of dissected lymph nodes
and metastatic nodes: ≥ 12 lymph nodes and < 12 lymph nodes;
conditions of resection margin and total mesorectal excision (TME)
- Pre-operative CEA before surgery and postoperative follow-up:
Adjuvant treatment: Yes/No
2.4. Data analysis , processing: Using Microsoft Excel and SPSS
22.0.
Quantitative variables are analyzed to calculate the average value
(Descriptives), Qualitative variables are analyzed for frequency
observation (Frequency).
Two qualitative variables are compare by using Chi-squared test (X 2)
- when expected frequency is higher than 5, and when the frequency is
<5 Fisher's exact test is be applied. For quantitative variables, Mann Whitney test is applied.
- A difference between rates is considered as statistically significant
difference when p < 0,05.
Postoperative survival is illustrated by survival curve - using

Kaplan–Meier estimator.
Chapter 3: RESULTS OF RESEARCH
In 2013 and 2014, there were 598 patients with colorectal
cancer undergoing curative surgeries at Viet Duc University Hospital, of
whom there were 53 cases of recurrence.
3.1. Features of recurrence
- Average age is 56,53. There are 28 male patients, or 52,8%.
Male/female ratio is 1,12.


- Disease detection: During routine examination 13,2%; during
examination after having symptoms 86,8%. Admission for emergency
surgery due to bowel obstruction 13,2%.
- Average time to recurrence is 23,1 months, 60,9% of recurrence in the
first 2 years, 90,6% of patients have recurrence in the first 3 years after
surgery. - Average time to recurrence of the group having adjuvant
chemical treatment is 24,6 months, and that of the group not having
adjuvant treatment is 21,8 months.
- Average time to recurrence of each stage: stage I: 26,9 months, Stage
II: 22,2 months, Stage III: 24,5 months, Stage IV: 18,4 months.
- The rate of recurrence after surgery for rectal cancer of the group
having repeated surgery is 58,5%, recurrence at ascending colon is
15,1%, sigmoid colon 16,9%, transverse colon 3,6%, and descending
colon 5,7%.
- 13,2% of the patients do not have any symptom, and disease is found
during routine examination, 86,8% patients have clinical symptoms:
abdominal pain (47,2%), weight loss (16,9%), blood in stool (11,3%),
mucus in stool (13,2%), anal pain (13,2%), of whom 24,5% have
complications caused by tumor, including 13,2% bowel obstruction,
5,7% hydronephrosis, 1,9% occlusion of the lower extremity, 3,7%

biliary obstruction.
- 25 patients have elevated CEA level of more than 5ng/ml, taking up
47,2%. Average value of CEA is 46,8 ng/mL.
- Ultrasound finds 11 cases of liver metastasis (20,8%), chest Xray find
2 cases of lung metastasis (3,7%), 20 cases of recurrence on colon are
detected by colonoscopy (37,7%), abdominal - whole body 64-Slice CT,
MRI: Detected colorectal tumor in 20 cases (37,7%), Splenic metastases
1 case (1,9%), adrenal metastases, 1 case (1,9%), ovarian metastasis 2
cases (3,7%), abdominal lymph node 13 cases (24,5%), and PET CT
detected 9 cases of recurrent lesion (16,9%).
- Features of recurrence: may be isolated, invasive or combined with
metastasis: 7,5% of isolated recurrence in colon, 15,1% in tumor bed,
26,4% of isolated recurrence in pelvis (including rectal anastomosis),
1,9% recurrence in colon with local invasion, 5,7% recurrence in pelvis
with local invasion, 20,6% local recurrence with metastasis. Locations
of metastasis: liver (20,8%), lung (3,8%), ovary (3,8%).


3.2. OUTCOMES OF TREATMENT FOR RECURRENT
COLORECTAL CANCER
- Rate of curative surgery for R0 is 71,7%, palliative surgery 26,4%,
and exploratory surgery 1,9%. Rate of emergency surgery is 13,2%, and
elective surgery 86,8%. There is no case of complication or death after
surgery.
- Surgical method depends on location and growth of tumor:
Reresection of colon (40%), liver resection (9,5%), abdominoperineal
resection (9,4%), ovary resection (3,7%), resection of adrenal gland
(1,9%), resection of abdominal wall tumor (1,9%), extensive resection
(including small intestine, spleen, diaphragm, bladder, ureter, uterus,
vagina, oviduct, pelvic vessels) (13,2%).

- The rate of postoperative complication is 15,1%, surgical site infection
(3,7%), postoperative pancreatitis (3,7%), urine leakage (3,7%), partial
intestinal obstruction (1,9%), electrolyte disorder (1,9%). Complication
mainly occurs in the group undergoing curative surgery (11,3%).
Mortality rate is 0%.
- Median length of stay is 11,1 days.
- Average postoperative survival is 17,1 months. Postoperative survival
of the group undergoing curative surgery (28,89 months) is longer than
that of the group undergoing non-curative surgery (10,13 months),
p<0,001.
Graph 1. Postoperative survival time.

3.3. FACTORS AFFECTING RECURRENCE:


Table 1. Analysis of risk factors of recurrence, metastasis between
the 2 groups with and without recurrence (n = 598)
Features
Age (years)

Group with
recurrence
60,3  12,80

Group without
recurrence
55,0  12,98

(23-89)

(19-79)

Value
p=0,008

TNM stage:
I
7
93
II
21
247
p=0,0001
III
18
193
IV
7
6
Number of dissected lymph
6,7 ± 4,45
8,3 ± 5,65
p=0,081
nodes
Histopathological type
Adenocarcinoma
37
495
p=0,008
Mucinous adenocarcinoma

8
36
Signet ring cell carcinoma
1
2
Tumor growth based on
Borrmann’s classification
p=0,0001
12
425
BI/II
RR=0,11
34
108
BIII/IV
Mucinous organ
p=0,009
< 50%
38
497
RR=0,39
 50%
8
36
Differentiation
p=0,009
Well and moderately
40
481
RR=0,44

Poorly and none
13
62
Satellite tumor
Yes
1
2
p=0,243
No
52
543
Petersen Index
p<0,0001
Low risk group
41
522
RR=0,21
High risk group
12
23
Table 2. Multivariate analysis at stage I, II between the 2 groups
with and without recurrence (n = 368)


Features
Tumor growth based on
Borrmann’s classification
BI/II
BIII/IV
Lymphatic invasion

Yes (n=14)
No (n=354)

Group with
recurrence
(n=28,
7,6%)

Group without
recurrence
(n=340, 92,4%)

9 (0,03)
19 (0,25)

284
56

Value

p=0,0001
RR=0,12

p=0,047
3 (0,21)
11
RR=0,33
25 (0,07)
329
6,03  4,367

8,2  5,63
Number of dissected nodes
0.03
(1-19)
(1-41)
- Multivariate analysis of cases in state I, II shows that: Factors of tumor
growth, lymphatic invasion, number of dissected lymph nodes are the
factors that significantly affects recurrence.
Table 3. Multivariate analysis at stage III between the 2 groups with
and without recurrence (n = 211)
Features
Age (years)
Tumor growth based
on Borrmann’s
classification
BI/II (n=144)
BIII/IV (n=67)
Injury damaging
visceral peritoneum T4
Yes
No
Number of dissected
nodes

Group with
recurrence
(n=18)
51,56  14,813
(17-71)

Group without
recurrence
(n=193)
60,13  12,322
(26-89)

3 (0,02)
15 (0,22)

141
52

10
8

63
130

0.048
(1 side)

7,9444,452

8,435,671

0.992

Value
0.018
p=0,0001

RR=0,09


Postoperative adjuvant
treatment:
13 (0,07)
185
p=0,002
Yes
5 (0,38)
8
RR=0,17
No
- Multivariate analysis of cases in state III shows that: Factors of age,
tumor growth, T4 tumor, adjuvant treatment are the variables that
significantly affects recurrence.
CHAPTER 4: DISCUSSIONS
4.1. Features of recurrence
* Age and genders: Mean age of patients with recurrence is 56,53.
Mean age of other researches: Mean age in the research of Nguyễn Tiến
Sơn is 54,1 years old, Pham Thái Anh 58,1 years old, Bethesa and
Sugerbaker 63 years old, and this does not differ from mean age of
patient with colorectal cancer in general. There are 28 male and 23
female patients. Male/female ratio is 1,12. The gender ratio in our
research is > 1, which is almost not different from other researches in
Viet Nam and in the world, for example: Phạm Thái Anh 1,71, COLOR
1,1, CLASSIC 1,2.
Time to recurrence Mean time to recurrence in our research is 23,11,
and most of recurrence occur in the first 3 years (90,6%). According to
John P. Welch: About 2/3 of recurrence occur in the first 2 years after

the first surgery. Therefore we recommend patients to have routine
examinations within the first 3 years to early detect recurrence and
lesion for curative surgery.
* Disease stage at the surgery for primary tumor: Group at state II
takes up the highest percentage (39,7%), in which IIA 17%, II B 18,9%,
IIC 3,8%, and III 35,8%; 7 cases of state IV cancer, taking up 13,2%.
Comparing with the research on outcomes of surgery for primary
colorectal cancer of Nguyen Xuan Hung, Nguyen Cuong Thinh,
Nguyen Tien Son, our research shows similar results. Our research also
shows that the time to recurrence of colorectal cancer is related to stage
of the primary tumor at the time of the first surgery: The mean time to
recurrence of the group at stage I is 26,96 months, that of stage II and
III is 22,26 months and 24,54 months respectively, meanwhile that of
stage IV is 18,4 months.
* Disease detection: 7 cases of admission are due to detection in
routine re-examination, accounting for 13,2%, and the remained cases
(86,8%) are admitting to hospital due to clinical symptoms, especially


13 cases due to tumor complications, 6 cases due to bowel obstruction,
3 cases due to biliary obstruction, 2 cases due to hydronephrosis caused
by recurrent tumor, 1 case due to bowel obstruction combined with
hydronephrosis, 1 case due to occlusion of the lower extremity.
* Symptoms of recurrence: Not clear, clinical symptoms usually
occur when the tumor progresses. Occurrence of clinical symptom
depends on location of tumor and extent of invasion of tumor. Common
symptoms are: abdominal pain (47,2%), weight loss (16,9%), blood in
stool (11,3%), mucus in stool (13,2%), anal pain (13,2%), of whom
24,5% have complications caused by tumor, including 13,2% bowel
obstruction, 5,7% hydronephrosis, 1,9% occlusion of the lower

extremity, 3,7% biliary obstruction. According to ASCRS and ASCO,
routine examinations are compulsory for early detection of recurrent
lesions. Occurrence of symptom means the tumor has progressed.
* CEA test there are 53 patients, of whom 25/53 patients have CEA
elevated to more than 5 ng/ml (47,2%), and 8 patients have CEA
elevated to more than 100 ng/ml (15,1%). Beart R.W. and O’connell
M.J. report that elevated CEA is the first indicative sign which is
valuable in detecting recurrence and metastasis in 69% of cases of
recurrence. The research of Chau I. on changes of CEA after surgery in
139 patients undergoing surgery for colorectal cancer shows that in 46
patients with recurrence, a rise in CEA > 1 had a predictive value of
74% for recurrence or metastases
* Diagnostic imaging: Ultrasound detects 41 cases (77,4%),
colonoscopy 32 cases (60,3%), abdominal CT scan 38 cases (71,7%),
whole body CT scan 1 case (1,9%), pelvic MRI 2 cases (3,8%), PET CT
scan 9 cases (16,9%), pulmonary X-ray (53/53 patients).
* Features of recurrence of colon cancer and rectal cancer:
Recurrence of rectal cancer is usually local recurrence, with rate of
recurrence being higher than colon cancer, meanwhile colon cancer
usually has metastatic recurrence. Total mesorectal excision (TME) and
new chemoradiotherapy protocol has recently reduce rate of recurrence
of rectal cancer to 6%. Rate of local recurrence after surgery for rectal
cancer is 77,3%, lung metastasis 4,5%, liver metastasis 18,2%, and
peritoneal metastasis 4,5%. Rate of local recurrence of colon cancer is
77,4%, lung metastasis are 3,2%, liver metastasis 22,6%, and peritoneal
metastasis 16,1%.
4.2. Outcomes of treatment for recurrent colorectal cancer
* Surgical indication and curative surgery: Rate of curative surgery

in our research is 70,4%. Being different from recurrent gastric cancer,
rate of curative surgery after surgery for colon cancer is higher.
According to Trinh Hong Son: Of the 24 patients have recurrent gastric
cancer, there are 3 cases of gastric re-resection, 3,2% in the research of
Nguyen Ham Hoi, meanwhile the rate of curative surgery for recurrent
colorectal cancer in the research of Yamada K. is 72%, Hahnloser D. is
77%, Rodel is 80%, or up to 95% in the research of Wieser. Lesions
may be local or invasive to other adjacent organs or metastasis in
various organs. Therefore, surgical indication for recurrent and
metastatic colorectal cancer is considered when: The tumor can be
dissected and the recurrent lesion causes complications such as bowel
obstruction, peritonitis due to perforation, compression of other
abdominal organs (kidney, ureter) or bleeding. For recurrent colorectal
cancer, the issue to be considered is early detection of lesion and fully
assessment of extent of lesion and possibility of surgery for tumor
dissection.
* Post-operative early result: Median length of postoperative stay is
11,1 days, with the group undergoing radical surgery is 11,8 days, and
the group undergoing non-curative surgery and exploratory surgery is
9,3 days. Within the first 30 days after surgery, there is no case of death,
and according to Gosens, the rate of mortality is 0-5% in the first month
after surgery, and 8% in the third month. There are 8 cases with
postoperative complication (15,1%): partial intestinal obstruction
(1,9%), urine leakage (3,7%), surgical site infection (3,7%),
postoperative pancreatitis (3,7%), electrolyte disorder (1,9%). After
intensive treatment, all of these cases are stabilized and discharged from
hospital. The rate of complication depends on method of treatment for
tumor. For surgery for local cancer with invasion or for local recurrence
with invasion, surgery for dissection of invaded organs is necessary for
reaching cancer-related standards. Complications are anastomotic

leakage, abscess after surgery or peritonitis due to anastomotic
disruption. Causes of death are mainly related to infection, bleeding,
multiple organ failure, and cardiovascular problems and pulmonary
infarction. The method of supportive surgery or symptomatic treatment,
with tumor still being left behind (not meeting oncological standards)
takes up a relatively high rate in surgery for recurrent colorectal cancer,
in our research, this rate is 28,3%, which is similar to that in researches


of other author, being about 15-68% of cases. The rate of complication
shall be low in the cases not undergoing tumor dissection surgery, but
shall increase in the cases undergoing surgery for total dissection of
tumor. Bleeding is the main cause and the most severe complication
during operation, occurring in 0,2 - 9% of the cases, with rate of death
being up to 4%, especially with surgery for removing tumor in pelvic
space. However, in this research, we do not see any case of catastrophe,
or bleeding complication during or after surgery.
* Post-operative remote result: Of the 53 patients, we use patients’
information in their medical records to contact with 52/53 patients, and
there is only 1 case (1,9%) that we cannot contact with the patient or
their family so we do not have any information about their status after
surgery. Mean postoperative survival time of the whole group is 17,1
months, of which the longest postoperative survival time is 50 months
(currently the patient is still healthy), and the shortest is 3 months. A
number of researches report the rate of 5 year survival time being 2258% after curative surgery for R0 resection. Comparing the two groups
undergoing curative surgery and non-curative surgery by Kaplan Meier
graph, we see that the rate of survival after surgery of the group
undergoing curative surgery is higher than that of the group undergoing
non-curative surgery (mean: 24,9 months and 10,1 months, respectively,
p<0,001). The research of Caricato and colleagues on prognostic factors

after surgery for recurrent colorectal cancer for a total of 2204 patients
(from 1960 to 2000) demonstrated a mean R0 rate of 41,2% (range 9,8 72%). A surgery completely removing recurrent tumor is a good
prognostic factor to evaluate postoperative survival time as well as
postoperative quality of life of a patient, and is the treatment goal for
recurrent colorectal cancer. In order to reach that goal, early detection of
recurrence by routine examination after surgery is necessary. The group
having preoperative radiotherapy, combined with chemotherapy before
or after surgery, has better rate of survival than that of the group
undergoing surgery alone; the group undergoing palliative surgery or
symptomatic treatment of R2 has outcomes of survival and quality of
life being as bad as the group not undergoing surgery. As such,
treatment of recurrent colorectal cancer requires a multimodal treatment
protocol and good coordination of experts.


4.3. Risk factors of recurrence, metastasis: In 2013 and 2014, we
followed up 598 cases of colorectal cancer patients undergoing curative
surgery, the number of cases with recurrence was 53, being sorted into
the group with recurrence, and 545 cases without recurrence into the
group without recurrence. By using univariate and multivariate
comparisons, we see that: Prognosis of recurrence comprises of various
factors: Patients’ factors, treatment-related factors, and factors related to
tumor pathology.
* Age: Age is an independent prognostic factor for recurrence. Mean
age of patients with recurrent cancer is 55,02 (17-79), which is lower
than that of the group without recurrence being 60,35 (23 - 89)
(p=0,008). The prognostic factors of age of patients are different
between the two groups. The rate of old age patients with local
recurrence or metastasis is lower. In contrast, the group of young
patients who has colorectal cancer with a factor of family genetics has a

very high risk of recurrence up to 80%, and the rate of 5 year survival of
this group is 41%, as compared to 70% of the group of patients older
than 60 years old.
* Gender: Gender is an dependent prognostic factor for recurrence. A
number of researches showed that male patents have worse prognosis
than female patients, especially those with recurrent rectal cancer.
However in our research, while comparing the 2 groups of with and
without recurrence undergoing surgery in 2013 and 2014: We do not see
any difference in male/female ratio between the two groups (p=0,757).
* Disease stage: Disease stage by Duckes and TNM classifications is an
independent and most important prognostic factor for postoperative
outcomes, recurrence and 5 year survival. The rate of disease stages by
TNM classification of the group with recurrence: stage I 13,2%, stage II
39,6%, stage III 34,0%, stage IV 13,2%. Meanwhile this rate of the
group without recurrence is 17,3%, 45,8%, 35,8%, 1,1% respectively.
Comparing using Chi-squared test, we see that disease stage between
the 2 groups of with and without recurrence has a difference with p =
0,0001, which means that disease stage has an independent impact on
recurrence. According to Micu B and colleagues, disease stage has huge
statistically significant difference between the 2 groups of with and
without recurrence. The risk of recurrence increases together with
disease stage. In the research of Dziki, stage IIB and IIC have higher


risks of local recurrence than stage IIIA, when tumor invades out of
organ’s peritoneum into abdominal peritoneum or into surrounding
organs (T4a – 4b), the possibility of cancerous cells spreading into
abdominal space shall be higher. Therefore, a number of researches
proves that cases of T4bN0 should be reclassified into IIIA stage (for
colon cancer) and into IIIB (for rectal cancer). In contrast, cases in stage

III are treated with adjuvant chemotherapy while there was no
indication in stage II. Therefore, identification of high risk of recurrence
together with TNM stage is necessary for determining whether a patent
need postoperative adjuvant chemical treatment or not. According to
Giovanni M. and Elias D., the risk of recurrence after surgery depends
on extent of invasion to colon wall and lymphatic system, and according
to Astler - Coller the risk of recurrent colorectal cancer by each stage of
Dukes classification is 2% for stage A, 10-20% for stage B1, 20-35%
for Stage B2, and up to 50% for stage C. TNM Staging System is the
most widely used classification and has the highest degree of accuracy.
According to American Joint Committee on Cancer (AJCC) and
International Union Against Cancer (UICC), colorectal cancer has 4
stages. Adjuvant chemoradiotherapy treatment is mandatory for stage II
or III rectal cancer. For cases of stage I rectal cancer there is no
recommendation for adjuvant treatment, but with cases having high
risks absence chemoradiotherapy shall reduce risk of recurrence and
increase postoperative survival time.
* Lymphatic metastasis and ratio of positive lymph nodes: Are the
factors related to postoperative survival time, and as discussed in the
disease stage by TNM classification, cases of lymphatic metastasis are
in stage C by Dukes and stage III or higher (table 3.77). In researches
on lymphatic metastasis, metastatic lymph nodes having diameters of
less than 5mm can be considered as an important factors in evaluating
disease stage. Cases with lymph nodes < 5 mm in diameter has a
positive ratio of 50-78%. In the world, in order to accurately identify
metastatic lymph nodes, pathologist often use cytokeratin to mark
metastatic lymph nodes. In Viet Nam, in the recent many years the rate
of missed lymph node metastasis has been almost 0 due to use of
chemical for marking. While comparing feature of having lymphatic
metastasis or not between the 2 groups of with and without recurrence,

we do not find any difference: Of the group with recurrence, the number


of patients without lymphatic metastasis is 28, accounting for 60,9%,
and with lymphatic metastasis 18 (39,1%); or the group without
recurrence, the number of patients without lymphatic metastasis is 340
(63,8%), and with lymphatic metastasis 193 (36,2%); there is no
difference of lymphatic metastasis between the 2 groups with p=0,693.
* Tumor growth based on Borrmann classification: Rectal tumors
with the infiltrating type of growth have a significantly worse prognosis
than those with the expanding type. Expanding tumors have a welldelineated and circumscribed border of growth, while infiltrating
tumors have cluster or single cells leaving the tumor mass and
spreading into the bowel wall. Infiltrating tumors present more often
blood and lymphatic vessel invasion and have much higher risk of
metastases. The rate of 5 year survival in patients with expanding
tumors (polypoid or fungating) is 63.6% compared with 25.1% in
infiltrating tumors. According to Dziki, this difference is due to the fact
that symptoms in patients with expanding tumors occur earlier, so the
patients are diagnosed with disease earlier. In a research in Korea on
stage I cancer, the author points out that tumors with the infiltrating type
of growth affect recurrence p= 0,017. In our research, tumors with the
infiltrating type of growth (Borrmann stage III/IV) are found in 34/36
cases (73,9%) of the group with recurrence and 108/533 cases (20,3%)
of the group without recurrence, and by using Chi-squared test we see a
difference between the 2 groups in terms of types of tumor growth,
p=0,0001. The factor of tumor growth by Borrmann classification is an
independent prognostic factor. Analysis of this factor of the group with
early stages (state I and II): Group with recurrence: tumors with the
infiltrating type of growth are found in 19/28 cases (67,9%), and that in
the group without recurrence is 56/340 cases (16,4%), comparison

between the two groups finds a difference, p=0,0001. Or in the group in
the stage of lymphatic metastasis (stage III), tumors with the infiltrating
type of growth shows a difference between the 2 groups (p=0,0001).
* Differentiation of tumor: Differentiation is the most easily
diagnosed histological level and is a prognostic factor of recurrence. A
number of researches proves that histological level is an independent
prognostic factor, combining well and moderately differentiated tumor
into one type. 5 year survival rate is strictly correlated with tumor
differentiation and it is 72% for well, 47.5% for moderately and 25.4%


for poorly differentiation tumors. In this research, differentiation of the
2 groups of with and without recurrence has a difference (p=0,009 <
0,01), so low differentiation (including well and moderate
differentiation) shall have risk of recurrence lower than high
differentiation (including poor and no differentiation), or in other
words: Differentiation is an independent prognostic factor for
recurrence.
* Vascular invasion and lymphatic invasion: Is an independent
prognostic factor for recurrence. Male patients with factor of lymphatic
invasion have rate of quick recurrence being nearly 100% of recurrence
within 24 months. In the research of Micu B and colleagues, venous
invasion is described in 7 (3.7%) patients without recurrence and in 67
(59,8%) patients with recurrence, and the difference was highly
statistically significant, p <0,001. The factor of vascular invasion and
lymphatic invasion is sorted by American Society for Clinical
Pathology into the group having poor prognosis, and by UICC into
TNM staging system. In this research, we do not find this difference,
with p=0,13, but we find a difference while comparing groups in stage
I, II, with p=0,047. This can be explained by the impact of disease stage

on the factor of lymphatic invasion, so after removing the factor of
disease stage, we find a difference between the 2 groups.
* Mucinous component of tumor: While comparing feature of mucin
production in the 2 groups of with and without recurrence, we find rate
of mucin production of more than 50% in 36/533 (6,7%) cases in the
group without recurrence and in 8/46 (17,4%) in the group with
recurrence, and by comparing using Chi-squared test, we reach the
following conclusion: mucin production > 505 results in difference
between the two groups (p=0,009), or more mucinous structures means
higher risk of recurrence. This is also proved by a number of other
authors in the world, with p<0,001.
* Petersen Index score: Is an independent prognostic factor for
recurrence. Petersen Index score is calculated for the purpose of
evaluating risk of recurrence based on extents serosal invasion, venous
invasion, margin involvement and perforation through tumor. The scale
is from 0 - 5. One score shall be added if each of the following sign
present: Venous invasion, serosal invasion, and margin involvement,
and 2 scores shall be added if there is perforation through tumor. There


shall be 2 groups: Low risk group (0-1 score) and high risk group (2-5
scores). In the research of Micu B and colleagues, a Petersen Index
score of 2-5 (high risk group) was determined in 58 (51,8%) patients in
the recurrence group and in 5 (2,6%) patients without cancer recurrence.
This difference was highly statistically significant (p < 0,001). In our
study, result is as follows: in the group with recurrence 12 (22,6%)
patients have Petersen Index score of 2-5, and in the group without
recurrence: 23 (4,2%) patients have Petersen Index score of 2-5, and by
means of Chi-squared test we find a difference between the 2 groups,
p<0,0001. This once again confirms that Petersen Index score has a role

in prognosis of recurrence.
Number of dissected nodes on postoperative specimen: This factor is
related to surgical treatment. Postoperative specimens shall be sliced
and stained using microscope, and the number of dissected nodes shall
be counted by observing or using color markers. The number of
dissected nodes depends on 2 factors: One is related to the surgery, and
the other to process of counting nodes on the specimen. Medical
literature in the world show that patients with the number of dissected
nodes >10 have superior postoperative survival time and lower rate of
local recurrence as compared to those with the number of dissected
nodes <10. When the number of dissected nodes is less than 10,
regardless of stage, postoperative adjuvant radiotherapy or
chemotherapy treatment should be considered and consulted, especially
for patients with T3 tumor or high risk factors of recurrence. In our
research, the number of dissected nodes between the group with
recurrence (a mean of 6,78 nodes) and the group without recurrence (a
mean of 8,28 nodes) does not have difference, p=0,081. However,
further analysis by only accounting for cases in early stage (stage I, II),
the mean number of dissected nodes (with that of the group with
recurrence being 6,03 and the the group with recurrence being 8,2) has a
difference, p=0,03 (<0,05). Although in the early stage I, II lymphatic
metastasis has not occurred, however that more nodes are dissected
contributes to reducing risk of recurrence.
Adjuvant treatment: Adjuvant chemoradiotherapy before or after
surgery is usually indicated for stage I and II. In stage I patients with
high risks, adjuvant treatment should be considered. In our research,
only patients in State III or higher received adjuvant


chemoradiotherapy. In this research: Of the group with recurrence,

13/18 stage III patients received full course of chemotherapy (12
cycles), and of the group without recurrence 185/193 patients received
chemotherapy, and there is difference between the two groups or
adjuvant treatment affect recurrence p=0,002. Current main treatment
protocols, such as FOLFOX 4, 5FU-FA, FOLFOX6, FOLFIRI, have
been considered by various author in the world and in Viet Nam as
capable of reducing risks of recurrence, increasing postoperative
survival time, and having low toxicity.
In short, factors affecting recurrence of colorectal cancer in this
research are: Age, disease stage, differentiation and grade of tumor,
tumor growth by Borrmann classification, vascular invasion and
lymphatic invasion, rate of mucin production, Petersen Index score
(venous invasion, serosal invasion, margin involvement, perforation
through necrotic tumor), Number of dissected nodes, and adjuvant
chemotherapy treatment. Of the factors, disease stage and Petersen
Index score are the significant prognostic factors for recurrence.

CONCLUSION
After studying 53 patients underwent surgery for recurrent
colorectal cancer at Viet Duc University Hospital, we reach the
following conclusions:
1. FEATURES OF RECURRENCE
 Mean age of patients is 56,53. Male/female ratio is 1,12.
 Mean time to recurrence is 23,1 months, 60,9% of
recurrence in the first 2 years, 90,6% of patients have recurrence in the
first 3 years after surgery. Mean time to recurrence of the group having
adjuvant chemical treatment is 24,6 months, and that of the group not
having adjuvant treatment is 21,8 months.
 Mean time to recurrence of each stage: stage I: 26,9 months,
Stage II: 22,2 months, Stage III: 24,5 months, Stage IV: 18,4 months.

 Rate of recurrence after surgery for rectal cancer of the
group having repeated surgery is 58,5%, recurrence at ascending colon
is 15,1%, sigmoid colon 16,9%, transverse colon 3,6%, and ascending
colon 5,7%.
 13,2% of the patients do not have any symptom, and disease