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 SURG
Trang 1MINISTRY 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
Trang 2THE 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;
Trang 3Colorectal cancer is one of the most common malignancies;according to the 2019 statistics World Health Organization each yearthere are 1,8 million new cases and almost 861,000 deaths in 2018.Despite recent significant medical advancement in diagnosis andtreatment of colorectal cancer in the recent years, recurrence andmetastasis after curative surgery for colorectal cancer have still beenserious challenges to clinical doctors In the world, there have been anumber 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 aftersurgery Colorectal cancer is classified as recurrent when new malignantlesions are found, either local or metastatic, in patients previously hadcurative surgery for colorectal cancer Risks of recurrence depend onvarious factors, of which the major factors are disease stages, surgicalfeatures and postoperative adjuvant treatment In order to detectrecurrent colorectal cancer, it is necessary to conduct regularpostoperative 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 maintreatment method, however whether a surgery is possible depends onsite of recurrence and degree of tumor growth Prognosis after surgeryfor recurrent colorectal cancer depends on various factors, for exampletime of recurrence after surgery, disease stage, and having adjuvanttreatment or not In the recent years, the number of patients diagnosedwith recurrent colorectal cancer and underwent surgery has beenincreasing Nevertheless, in our country researches on this issue are stilllimited Therefore, researching on surgical outcomes and risk factors ofrecurrence and metastasis after curative surgery for colorectal cancer isnecessary and has scientific implication for the purpose of generalizingfeatures of recurrence, treatment and outcomes of recurrence treatment
as well as identifying risk factors of recurrence after surgery forcolorectal cancer Objectives of research:
1 Describing features of recurrence, metastasis after curative surgery
for colorectal cancer.
Trang 42 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 Gastrointestinalsurgery have more understandings of recurrence of colorectal cancer:Site of recurrence, time of recurrence, metastasis, indication of surgeryfor 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 oftumor growth by Bormann classification, and Petersen index (includingvarious factors: Vascular invasion, serosal invasion, invasion inresection margin, necrotic tumors with perforation), which helpsurgeons give advises on adjuvant treatment for patients having highrisks of recurrence
This research has highly practical implications by providingcomplete information about features of recurrence, indications andmethods of surgery and outcomes of treatment of recurrence aftercurative surgery for colorectal cancer Furthermore, this thesis providesinformation about risk factors of recurrence, which can make treatmentafter curative surgery for colorectal cancer be more effective
This research has scientific implication with coherent layout andappropriate method of data processing Research data are processed bymodern medical algorithm being capable of properly solving the 3objectives of research
This thesis has creative, new and up-to-date features, and is the firstresearch that compares the 2 groups of patients with and withoutrecurrence for the purpose of identifying risk factors of recurrence inViet Nam
2 Structure of thesis
The thesis comprises of 148 pages, with 87 tables, 5 charts, 2diagrams and 20 images The thesis has 4 chapters: Introduction (2pages); Chapter 1 - Overview of literature (40 pages); Chapter 2 -Subjects and methods of research (15 pages); Chapter 3 - Results of
Trang 5research (36 pages); Chapter 4 - Discussion (50 pages) and Conclusion(2 pages); the thesis has 255 references (18 in Vietnamese, and 255 inEnglish).
Chapter 1: OVERVIEW
1 Features of recurrence
Definition: Colorectal cancer is classified as recurrent whennew malignant lesions are found, either local or metastatic, in patientspreviously had curative surgery for colorectal cancer, and at the sametime the current outcomes of anatomical pathology are similar to that ofthe previous surgery
Features of recurrence: Recurrence may be local (atanastomosis, 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-abdominallocation, 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 ofinvading surrounding organs in pelvic region via lymphatic system andintravenous system However, application of total mesorectal excision(TME) and new chemoradiotherapy protocol has recently reduce rate ofrecurrence of rectal cancer to 6% The rate of anastomotic recurrence is
5 - 15% of the total number of patients, including invasive massesoutside of rectum and in front of sacrum In contrast, colon cancer hasrate of retroperitoneal recurrence higher than that of rectal cancer.According to Galandiuk et al., for colon cancer, rate of retroperitonealrecurrence, metastasis within 5 years after surgery of is 15%, and rate oflocal 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, metastasisdepends 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 lungmetastases of rectal cancer with high tumor is higher, p=0,03, and there
is no difference in the rate of local recurrence
Trang 62 Risk factors of recurrence, metastasis
- Histopathological type: Adenocarcinoma is the most common
histopathological type, accounting for 95% and has prognosis ofrecurrence 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 andAmerican Joint Committee on Cancer (AJCC) 8th edition stagingsystem 2018, apart from creating a consensus for oncologists toexchange information, also have prognosis implications The research
of Tomoki Yamano on 4992 cases of colorectal cancer shows that therecurrence 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%, and30.4%, 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 ofrecurrence
- Tumor growth based on Borrmann’s classification: B-I/II (gross
appearance shows polypoid/ulcerative lesions without infiltration) havebetter prognosis than B-III/IV (gross appearance showsinvasive/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 isthe most important factor in prognosis of postoperative survival timeand recurrence, metastasis Dissection of lymph nodes must be proper(at least to D2) and radical (at least 10 nodes) in order to evaluatedisease 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 recurrenceoften 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 signpresent: Venous invasion, serosal invasion, and margin involvement,
Trang 7and 2 scores shall be added if there is perforation through tumor Totalscore: 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 otherprognosis factors in order to decide on adjuvant treatment after curativesurgery 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 showsthat: CEA level being 1 unit higher than the value of the previousexamination has prognosis of recurrence in 74% of cases withrecurrence
- Combination therapy after surgery helps kill the remained cancerous
cells Cases treated with combination therapy after surgery have lessrisk 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 canhelp determine progression of disease in order to find appropriatemethods of treatment Factors recently being explored include:Thymidylate synthase, microsatellite instability, 18q loss, Krasmutation, DCC, etc
Chapter 2: SUBJECTS AND METHODS OF RESEARCH 2.1 Study population
- The population for researching on objective 1 and 2 are 53 patientswith recurrence who underwent the first surgeries in the 2 years of 2013and 2014, and the second surgery (for recurrence) at Viet DucUniversity Hospital
- The population for objective 3 include 2 groups: 53 patients withrecurrence and 545 patients without recurrence All of these 598patients underwent their first surgeries in 2013 and 2014
2.1.1 Patient selection criteria
- Recurrent cancer treated with curative surgery for colorectalresection:
+ Having surgical methods or outcomes of anatomical pathology
Trang 8showing colorectal segment with tumor, negative resection margin anddissected lymphatic nodes.
+ Having results of anatomical pathology of carcinoma and currentoutcomes of anatomical pathology being similar to that of the previousone
- Patients with non-recurrent colorectal cancer undergoing surgeryfor colorectal resection, with clinical and subclinical follow-up andexamination not showing recurrent lesions
2.1.2 Patient exclusion criteria:
- Medical records being incomplete
- Patient with colorectal cancer but in the previous surgery colon wasnot radically dissected (artificial anus was created without dissectingtumor, bypass, etc.) or cancer cells present microscopically at theresection 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 withrecurrence undergoing surgeries at Viet Duc University Hospital
Of the 53 patients with recurrence, information of the first surgeriesand the second surgeries are collected These patients with recurrence isregularly followed up after surgery, with collected informationincluding adjuvant treatment (chemical/radiotherapy), date ofrecurrence, recurrence location, clinical symptoms, subclinical features,
Trang 9diagnostic, and surgical method.
* To solve the objective 3: Medical records showing surgery forprimary tumor: 598 cases meeting selection criteria are selected anddivided into 2 groups of with and without recurrence The group withrecurrence has 53 patients and the group without recurrence has 545patients
The two groups are compared using Chi-squared test, Fisher’s orMann Whitney algorithms on SPSS version 22.0 (SPSS, Inc, Chicago,IL) A difference between the two groups analyzed by log-rank testhaving 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 <5Fisher'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 calculatedaccording to the following formula (applicable to 2x2 table):
Risk factor of recurrence
Group
Withrecurrence
Withoutrecurrence
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 risksthan 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
Trang 10pathological features of primary tumor, disease stage, method ofcombination therapy.
- Clinical features: Age, gender, chief complaint, clinical symptom,
physical examination
- Subclinical characteristics: CEA, colorectal endoscopy,
ultrasound, pulmonary Xray, 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: Operationfor 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, smallintestine, 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 bowelobstruction; 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, 12months, 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
Trang 11Criterial 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 nodesand number of dissected nodes; rate of positive lymph nodes; lymphatic
or vascular invasion; perineural invasion; Histopathological type:Adenocarcinoma, mucinous adenocarcinoma, Signet ring cellcarcinoma; mucinous organ: 50% and < 50%; Tumor growth based onBorrmann’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 frequencyobservation (Frequency)
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
A difference between rates is considered as statistically significantdifference when p < 0,05
Postoperative survival is illustrated by survival curve - usingKaplan–Meier estimator
Chapter 3: RESULTS OF RESEARCH
In 2013 and 2014, there were 598 patients with colorectalcancer undergoing curative surgeries at Viet Duc University Hospital, ofwhom 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
Trang 12- Disease detection: During routine examination 13,2%; duringexamination after having symptoms 86,8% Admission for emergencysurgery due to bowel obstruction 13,2%.
- Average time to recurrence is 23,1 months, 60,9% of recurrence in thefirst 2 years, 90,6% of patients have recurrence in the first 3 years aftersurgery - Average time to recurrence of the group having adjuvantchemical treatment is 24,6 months, and that of the group not havingadjuvant treatment is 21,8 months
- Average time to recurrence of each stage: stage I: 26,9 months, StageII: 22,2 months, Stage III: 24,5 months, Stage IV: 18,4 months
- The rate of recurrence after surgery for rectal cancer of the grouphaving repeated surgery is 58,5%, recurrence at ascending colon is15,1%, sigmoid colon 16,9%, transverse colon 3,6%, and descendingcolon 5,7%
- 13,2% of the patients do not have any symptom, and disease is foundduring 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% havecomplications 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 up47,2% 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 aredetected 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 2cases (3,7%), abdominal lymph node 13 cases (24,5%), and PET CTdetected 9 cases of recurrent lesion (16,9%)
- Features of recurrence: may be isolated, invasive or combined withmetastasis: 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 pelviswith local invasion, 20,6% local recurrence with metastasis Locations
of metastasis: liver (20,8%), lung (3,8%), ovary (3,8%)
Trang 133.2 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%, andelective surgery 86,8% There is no case of complication or death aftersurgery
- Surgical method depends on location and growth of tumor:Reresection of colon (40%), liver resection (9,5%), abdominoperinealresection (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%), partialintestinal obstruction (1,9%), electrolyte disorder (1,9%) Complicationmainly 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 thanthat of the group undergoing non-curative surgery (10,13 months),p<0,001
Graph 1 Postoperative survival time.
3.3 FACTORS AFFECTING RECURRENCE:
Trang 14Table 1 Analysis of risk factors of recurrence, metastasis between
the 2 groups with and without recurrence (n = 598)
932471936
495362
425
108
p=0,0001 RR=0,11 Mucinous organ
< 50%
388
49736
p=0,009 RR=0,39 Differentiation
Well and moderately
Poorly and none
4013
48162
p=0,009 RR=0,44 Satellite tumor
Yes
No
152
2543
p=0,243
Petersen Index
Low risk group
High risk group
4112
52223
p<0,0001 RR=0,21
Table 2 Multivariate analysis at stage I, II between the 2 groups
with and without recurrence (n = 368)