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ABBREVIATIONS
AJCC American Joint Commitee on Cancer
BN Patient
BTV Biological target volume
CLVT Computed Tomography
GĐ Stage
GTV Gross tumor volume
HT Chemotherapy
HXT Chemoradiotherapy
HMMD Immunohistochemistry
HMNT Ostomy
IGRT Image guided radiation therapy
IMRT Intensity modulated radiation therapy
IQR Interquartile range
M Metastasis
MBH Pathology
MRI Magnetic resonance imaging
N Lymph nodes
NCCN National Comprehensive Cancer Network
PET/CT Positron emission tomography/computed tomography
PT Surgical
RHM Anal margin
SUV max Standardized Uptake Value maximum
T Tumor
cTNM clinical TNM
pTNM pathological TNM
TRG Tumor regression grade
TT Rectum
XT Radiation
UTBM Adenocarcinoma

increased the rate of anal sphincter-preserving surgery (Elwanis et al, 2009: down-
stage after radiochemotherapy was 74.4%)
In Vietnam until now there have been no studies about this issue, specifically
assessing the effectiveness of preoperative radiochemotherapy for locally advanced
rectal cancer patients (T3, T4). Therefore, we are undertaking this study:
"Evaluating the effects of preoperative radiochemotherapy with Capecitabine in
low locally advanced rectal cancer"
2. Objectives
2.1. Evaluating the effectiveness of preoperative radiochemotherapy with
Capecitabine in low locally advanced rectal cancer
2.2. Assessing the side effects of this regime
3. The contributions of the thesis
- Confirmed the role and effectiveness of Capecitabine combined with
preoperative radiotherapy in low locally advanced rectal cancer. The
functional response: 100%; response rate 90.8%; complete response: 9.2%; the
down-stage: 46.0%. The tumor volume expended to rectal circumference
was decreased after treatment. Before treatment: 52.9% of patients with
tumors expanded entire circumference and this dropped 16.1% after
treatment. 2.3% of patients tumors had a complete response after treatment.
40.0% of patients fell over 10,000 mm3 tumor volume on 1.5Tesla magnetic
3
resonance image. 40.2% of patients had before treatment CEA levels >
5ng/ml, of these patients 91.4% had reduced levels of CEA after treatment.
79.3% of patients were operated, in which 67.8% had radical surgery and
12.6% underwent anal sphincter-preserving surgery. 9.2% of patients had
recurrence or metastasis and 11.5% of patients died in the follow-up of 36
months.
- Assessed the haematological, hepatic and renal toxicities of this regimen:
preoperative radiation plus Capecitabine in low locally advanced rectal cancer: low
toxicities, mostly grade 1 and 2.

Radiochemotherapy: Recent researches shows that 5FU is an attractive
radiosensitizer. Radiochemotherapy is indicated for locally advanced rectal cancer
(stage T3, T4), N(-/+). So far, many studies about preoperative radiochemotherapy
4
for rectal cancer found the positive results included down-stage, reduced local
recurrence and increased survival.
Chemotherapy options and doses for concomitant chemotherapy during radiation:
1. 5FU 325-350mg/m
2
+ Leucovorin 20mg/m
2
IV, bolus, d1-5, week 1 and 5
2. 5FU 400mg/m
2
+ Leucovorin 100mg/m
2
IV, bolus, d1,2,11,12,21,22
3. 5FU 1000mg/m
2
IV, bolus, d1-5, week 1 and 5
4. 5FU 250mg/m
2
IV continuous infusion on days 1-14 and 22-35 and
Oxaliplatin 50mg/m
2
IV d1,8,22,29
5. 5FU 225mg/m
2
continuous infusion 5 days per week, together with
radiotherapy

67%) and in responders to neoadjuvant chemoradiation (94% vs 60%). The ability
to perform a sphincter-saving procedure was 57%, greater in middle rectal location.
1.5.2. Vietnamese studies:
In Vietnam, radiation for rectal cancer was applied from the 1980s, only
using preoperative Cobalt radiotherapy with doses of 36Gy. Since 2000, linear
accelerators have been installed in Vietnam and have been used to treat rectal
cancer.
Đoàn Hữu Nghị (1994): preoperative radiotherapy is effective in reducing
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pain (71.1%), decreased sensation tenesmus and reduce the number patients of
bloody diarrhea (63.5%) in majority of cases. Author Pham Quoc Dat (2002): the
average survival following preoperative radiation therapy was 70 months, after
radiotherapy before and after surgery was 46.5 months and using radiotherapy
postoperatively was 36 months. Vo Quoc Hung (2004) reviewed some of the
clinical features and histology and evaluated the response of preoperative
radiotherapy in rectal cancer at Hospital K with doses of 36Gy and 45Gy. This
showed that 100% patients had improved functional symptoms, 41.0% patients had
reduced tumor size ≥ 50%, 51.8% patients had tumor change from fixed to mobile
after radiotherapy. Complications of preoperative radiotherapy include: perineal
pain 83.9%, cystitis 33.9%, 16.9% digestive disorders, ulcers and cirrhosis on the
irradiated area 8.9% and 7.1% intestinal adhesion. The rate of radical surgery was
78.5%, in which 21.4% had conservation surgery. Radiation therapy with a dose of
45Gy was better than 36Gy. Author Vo Van Xuan (2012) studied 56 rectal cancer
patients treated by preoperative hyperfractionated radiation showed the complete
response rate was 8.9%, partial response rate was 73.2%; entire response rate was
82.1%. Miles surgery was 48.2%, 10.7% Hartmann surgery, sphincter-preserving
surgery: 23.2%; ostomies surgery: 17.9%.
The studies of foreign authors showed that preoperative radiochemotherapy
(Capecitabine + Radiation) for locally advanced rectal cancer patients had good results
and increased the rate of radical and sphincter-preserving surgery. The response rate of

The method was clinical intervention study without control
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The sample size was calculated by the formula:
2.2.2. Steps
Patients who had the criteria will be selected in the study. Patient’ medical records
were made in the standard form. Data collection selected by medical research form
2.2.2.1. Clinical and test characteristics before treatment:
* Clinical characteristics
* Subclinical characteristics
+ Colonoscopy
+ Pelvic MRI
+ Tests to evaluate the state of distant metastasis
+ CBC tests
+ Blood biochemical tests
+ Histology tests
2.2.2.2. Treatment plan:
- All low rectal cancer patients with criteria received preoperative concurrent
chemoradiotherapy:

• Progressive Disease: At least a 20% increase in the sum of the longest
diameter of target lesions, taking as reference the smallest sum longest
diameter recorded since the treatment started or the appearance of one or
more new lesions
* Criteria for evaluation of tumor response:
+ Evaluate Response based on rectal examination before and after treatment:
* Evaluate response based on compared tumor size and mobility
* Based on compared the tumor volume with rectal circumference before and after
treatment
* Based on the down- stage according to Y. Mason classification
+ Assessing Response based on pelvic 1.5 Tesla MRI before and after
treatment:
* Evaluate response based on compared pelvic MRI before and after treatment on
each patient: rate of down-stage
* Evaluate response based on compared tumor volume before and after treatment
on each patient with tumors were cubic form. Assessed by pelvic 1.5 Tesla MRI:
the formula of tumor volume used: Volume = length × width × height × 0.52
• The change of tumor volume on MRI: tumor volume before treatment -
tumor volume after treatment
• The percentage of tumor reduced volume after treatment: = (tumor volume
before treatment - tumor volume after treatment) x100/the tumor volume
before treatment
• Compared the value of tumor volume before and after treatment with Paired-
Samples T Test
* Assess tumor stage and lymph nodes before and after treatment by pelvic 1.5
Tesla MRI with TNM classification of AJCC 2010
+ Assess Response by comparing CEA levels before and after treatment:
* Assess based on compared CEA before and after treatment in each patient with
CEA pre-treatment levels > 5ng/ml:
• Assess by CEA before and after treatment: CEA level before treatment -

Response: include complete response and partial response
No response: include stable disease and progressive disease
* Review the relationship between response with some factors such as age, sex,
stage of disease, histological type, pretreatment CEA levels
* Review the relationship between the tumor regression with some factors such as
age, sex, stage of disease, histological type, pretreatment CEA levels
+ In case of progressive disease after radiochemotherapy, patients treated by
radiation and chemotherapy or ostomies surgery
2.2.2.4. Assess the side effects (toxicities): according to WHO Common Toxicity
Criteria for Anticancer Drugs and the Common Terminology Criteria for Adverse
Events Version 4.0 (CTCAE) of National Cancer Institute 2009
2.3. STASTICS
* The information is encoded and processed by SPSS 16.0 software
* The statistical algorithms: description, comparative tests
CHAPTER 3: RESULTS
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3.2. Evaluate Response:
3.2.1. Functional response:
Table 3.1. The rate of post-treatment functional response
Functional response n %
The percentage of response,
patients identified (all symptoms)
< 50% 12 13,8
≥ 50%
75 86,2
Total 87 100
3.2.2. Evaluate Response based on rectal examination and rectoscopy before
and after treatment:
Figu
re 3.1. The tumor volume with rectal circumference (RCC)

CEA > 5,0ng/ml before treatment
Changing CEA levels before and after treatment
(ng/ml)
n %
Increased 3 8,6
Decreased < 5 14 40,0
Decreased 5 -<10 5 14,3
Decreased 10 -<20 4 11,4
Decreased > 20 9 25,7
Total 35 100
The percent of average CEA levels reduced after treatment: 52,0 ± 27,67%
3.2.5. Assess Response based on the rate of surgery:
Table 3.5. The rate of surgical patients after operation
Type of surgery n %
No surgery 18 20,7
Surgery
Sphincter-preserving 11 12,6
Miles 40 46,0
Hartmann 8 9,2
Ostomies 10 11,5
Total 87 100
Table 3.6. General response after treatment
Response n %
Complete Response 8 9,2
Partial Response 71 81,6
Stable Disease 2 2,3
Progressive Disease 6 6,9
Total 87 100
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Table 3.7. Multivariate analysis of the correlation between response after

CEA pre-treatment -0,065 0,622
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pT -0,231 0,10
Response after
radiochemotherapy
0,146 0,562
Table 3.9. Follow-up 36 months of treatment
n %
Stability 69 79,3
Recurrence, metastasis 8 9,2
Deaths 10 11,5
Total 87 100
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3.3. Side effects (toxicities) during and after treatment
3.3.1. Hematological toxicities:
Figure 3.4. Changing Hemoglobin toxicity grade before and after treatment
Figure 3.5. Changing Platelets toxicity grade before and after treatment
Figure 3.6. Changing Leukocytes toxicity grade before and after treatment
Figure 3.7. Changing Neutrophils toxicity grade before and after treatment
3.3.2. Hepatic renal toxicities:
Table 3.10. Hepatic renal toxicities
Grade of
toxicity
Before treatment After treatment
n % n %
Creatinin
0 83 95,4 84 96,6
1 3 3,5 3 3,4
2 1 1,1 0 0
Total 87 100 87 100

No symptom 84 96,6
Grade 1 3 3,4
Grade 2, 3 0 0
Total 87 100
Bảng 3.13. Side effects of radiation therapy on the gastrointestinal tract
Side effects
Grade 1 Grade 2
Grade 3, 4,5
n % n %
Anorectal mucositis 11 12,6 0 0 0
Anorectal ulcer 7 8,0 4 4,6 0
Small intestinal mucositis 15 17,2 0 0 0
Rectal perforation 0 0 0 0 0
Rectal obstruction 0 0 0 0 0
Total 87 patients
Bảng 3.14. Side effects of radiation therapy on genital-urinary tract
Side effects
Grade 1 Grade 2
Grade 3,
4, 5
n % n %
Cystitis noninfective 20 23,0 8 9,2 0
Vaginal inflammation 7/38 female 18,4 0 0 0
Total 87 patients
Bảng 3.15. Side effects of radiation therapy on the skin
Side effects
Grade 1 Grade 2
Grade 3, 4,5
n % n %
Pelvic pain 11 12,6 10 11,5 0

treatment: The number of patients in stage 3 and 4 were down-stage for both stages
comparing with before treatment: 29% of patients in stage 4 has dropped to 11.5%
after treatment, 46.0% (40/87) patients were down-stage for both stages 3 and 4.
The rate of tumor stage 4 reduced into stage 3 was 61.5%, higher than Vo Quoc
Hung (2004): 51.8%. It may be the reason that we combined chemoradiation
therapy for advanced rectal cancer patients but Vo Quoc Hung have used radiation
therapy alone. Soumarova R et al (2010): They acquired data of 78 patients from 1
January 2005 to 31 December 2007 with a locally advanced rectal cancer. All
patients were indicated for the neoadjuvant concomitant chemoradiotherapy due to
locally advanced tumor (T3 or T4) or lymph nodes involvement suspicion (N+).
Both radiotherapy (to pelvic region) and chemotherapy (capecitabine) were
administered. Downstaging was achieved in 69% of patients.
4.2.2. Assessing Response based on pelvic MRI 1.5 Tesla:
Due to the patient’ economic conditions and some patients had previously
implanted metallic part in the body, only 54/87 (62.1%) patients received pelvic
MRI before and after treatment. The downstage was 44.4% after treatment.
Especially 13.0% patients reduced to stage 1 or undetected abnormalities on MRI.
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By comparing the tumors and lymph nodes on 1.5 Tesla MRI we can assess
objectively the response rate after treatment.
35/54 (64.8%) patients had block-tumor on MRI. 94.3% patients had
reducted tumor volume after treatment, in which 40.0% patients decreased tumor
volume over 10,000mm
3
. If we assessed only the largest lesion diameter of the
tumor before and after treatment, the changing was not too big. But while
compared the tumor volume we assessed more exact about the response rate.
However, we can not calculate the tumor volume on all patients, especially in the
case of the linear form tumors.
Nougaret S Fau – Fujii et al (2012) studied sixteen patients treated by

years of age, stage 4, CEA levels> 5ng/ml (with p <0,05). Other factors such as
gender, histological type and degree, response status, but there were not statistically
significant differences. However, when conducted multivariate analysis the result was
only two factors affected on response: age and stage before treatment.
4.2.4. Assess Response based on the rate of surgery:
79.3% patients were undergoing surgery, in which 67.8% patients radical
surgery, 12.6% of patients underwent anal sphincter preservating
surgery. Compared with studies in other countries the rate of surgery is lower. In
Vo Van Xuan’ study (2012) the Miles’ surgery rate was 48.2%, 10.7% Hartmann,
anal sphincter conservation: 23.2%; ostomies: 17.9%. According to the research by
Vo Quoc Hung (2004): the rate of radical surgery 78.5% in which 21.4%
conservation surgery. It was explained by the proportion of surgical patients in this
study were not high (20.7%), many patients had improved the functional symptoms
and the patients were afraid to bring artificial anus. We had to convince our patients
to surgery, but they refused operation, so some other patients had disease
progression, Examing rectal after treatment we recorgnised the tumors fixed and
invaded sacral and adjacent organs, inoperable. So patients were continued to treate
by radiation and chemotherapy.
Table 4.1. Complete response rate in histopathological after preoperative
radiachemotherapy treatment for rectal cancer patients
Research n Complete response rate (%)
Kim JC et al (2005) 95 12
Elwanis M et al (2009) 43 9,3
De Bruin AF et al 60 13
Soumarova R Fau et al (2010)
78 10
Pham Cam Phuong (2013) 87 9,2
90.8% of patients had response after treatment in which 9.2% of patients
achieved complete response (no cancer cells on postoperative histopathology). The
response rate was higher than Vo Van Xuan (2012): complete response rate was

recurrence and metastasis were more improved.
The resuls of this study showed that a preoperative radiotherapy was
effective for advanced rectal cancer patients because it helped to down-stage,
increased the rate of radical and anal sphincter-preserving surgery.
4.3. Assess the side effects (toxicities) befere and after treatment:
4.3.1. Hematological toxicities:
Before treatment, some patients had anemia and low hemoglobin so at that
time they were indicated blood transfusion. 8.0% of patients with hemoglobin <100
g/l but this proportion increased to 12.6% after treatment. This suggested the
treatment process also affected to bone marrow, the anemia was improved after
treatment. Thereford, during and after treatment (preparation for surgery) some
patients were indicated blood transfusion and medication stimulating bone marrow
to make red blood cells.
On the hematopoietic system, thrombocytopenic toxicity was the most
difficult to recovery and clinicians often worry about this toxicity because if
platelet is lower the patients easely have bleeding symptoms including most
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dangerous cerebral and gastrointestinal hemorrhages. In this study, no patient had
2,3,4 grade of low platelet, only 10.3% patients had a 1 grade of thrombocytopenia,
none of patients had a symptomatic hemorrhage and no patient had a platelet
transfusion.
In addition to hematological toxicity was anemia and thrombocytopenia,
during radiochemotherapy, the clinicians needed to evaluate the number of
leukocytes. If patients had leukopenia they may have a risk of infection and death.
84.0% patients had normal leukocytes and 16.0% patients had a 1,2,3 grade of
lower white blood cell but patients had any infection syndrome. 85.2% of patients
had normal neutrophils, 12.6% patients had a 1 grade of low neutrophil, 1.1% of
patients had a grade 2 low neutrophil, only 1.1% had a grade 3 of neutropenia after
treatment. The patients were closely monitored and indicated drugs which can
stimulate bone marrow to make leukocytes and used prophylactic antibiotic

grade 1.2 and can be recovered.
There was a little effect on hepatic and renal functions. The difference of
mean creatinine values before and after treatment was not statistically significant
with p = 0.16. Comparing the average value of AST before and after treatment
there was any statistically significant difference with p = 0.145.
4.3.3. Other side effects:
The combination of chemotherapy and radiotherapy before surgery in order
to improve a effectiveness of treatment for low locally advanced rectal cancer
patients had less adverse effects, high safety and the patient could tolerate.
In this study, the dose of capecitabine was lower than those using in other
regimens (825mg/m
2
dose vs 1250mg/m
2
) so the side effects was acceptable and
not high. The majority of patients had a grade 1 and 2 adverse effects from
chemotherapy, it didn’t affect to patient's life. 23% of patients had nausea, mainly
grade 1,2 in which the grade 1 was 20.7%. 20.7% of patients vomiting grade 1 and
2, in which mainly level 1 (18.4%). 1.1% of patients with grade 1 of alopecia. 4.6%
of patients with level 1 diarrhea and 1.1% of patients with a grade 2 diarrhea.
There were 3 patients with mild hand foot syndrome but the patients do not must to
be stopped the treatment. After treatment this syndrome also gradually decreased
Author Corvo R et al (2003): the study using capecitabine during
radiotherapy (825 mg/m2/day through a bid administration). Severe hand-foot
syndrome occurred in 7-15% of patients, representing the most commonly observed
toxicity. It is noteworthy that severe diarrhea with capecitabine during radiotherapy
was not common. Leukopenia frequently occurred but was mild and reversible.
Research shows that a high probability of pathological complete response (up to
31%) with capecitabine and radiation, with an increased probability of sphincter-
sparing surgical procedures. Soumarova R Fau et al (2010) acquired data of 78

protected.
During chemoradiotherapy, it should be noted both the side effects of
chemotherapy and radiation therapy. The digestive system is often early affected of
the these effects. With a dose radiotherapy of 46Gy in pelvic area, the organs
around such as small intestine, bladder and vagina are affected. 18.4% of female
patients had mild vaginitis, acceptable. 32.2% of patients had cystitis grade 1 and 2,
but only 8 patients (9.2%) with symptoms of urgency, dysuria and should be used
antibiotics.
The most dangerous side effects in abdominal when radiation are bowel
necrosis, intestinal perforation. In this study there are no patient with intestinal
perforation and obstruction during radiotherapy. However, 17.2% of patients with
symptoms of mild intestinal inflammation, no need for drugs, 12.6% of patients
with anorectal mucositis grade 1. 4.6% of patients with anorectal ulcer grade 2 and
8.0% of patients with anal-rectal ulcers level 1. These patients are often
accompanied by skin ulceration of the anal margin after radiation. In some cases we
have to use additional treatment for ulceration caused by radiation to reduce these
undesirable effects.
Despite 39.1% of patients with symptoms erythema inflammation skin on
treated area, but only 12.6% of patients with perineal skin ulceration, causing
perineal pain. For each patient, there are different pain threshold, some patients
have perineal skin ulceration but without analgesic, some cases needed to use
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analgesics. 13.8% of patients had ulcers and perineal pain, leukopenia, they were
pause capecitabine and radiation therapy until symptoms have reduced (usually 5-7
days).
The side effects of radiation therapy was higher than some authors in the
world. It could be due to the patient's state, the diet and the radiotherapy system of
Vietnam and foreign countries are different. Author Kim JS et al (2002): Grade 3
toxicities were as follows: hand-foot syndrome (7%), fatigue (4%), diarrhea (4%),
and radiation dermatitis (2%).

- There was a correlation between age, the before treatment stage with the
after treatment response
- 9.2% patients with recurrence and metastasis, 11.5% patients died during
the follow-up of 36 months
2. Side effects:
Radiotherapy combined preoperative capecitabine regimen for low locally
advanced rectal cancer was safe, acceptable, low toxicity:
- The undesirable effects on hematological, hepatic, renal system were
mostly level 1, 2.
- Nausea, vomiting, stomatitis, diarrhea with low rates: 23.0%, 20.7%, 1.1%,
5.7%, respectively. 3.4% of patients with hand foot syndrome grade 1.
- 17.2% of patients with small intestinal inflammation, 12.6% of patients
with anorectal mucositis and 12.6% of patients with anorectal ulceration, mainly
grade 1.
- 39.1% of patients red inflamed skin on treated area, 12.6% skin ulcers;
24.1% of patients with anal pain level 1 and 2. 32.2% of patients with cystitis and
18.4% female patients had vaginitis, mainly grade 1.
- 13.8% of patients interrupted treatment because of the side effects.
RECOMMENDATIONS
1. Preoperative radiochemotherapy (46 Gy + Capecitabine) should be applied
for locally advanced rectal cancer patients because this regime is highly effective,
low toxicity, increase the rate of radical and anal sphincter-preserving surgery
2. It is necessary after treatment to follow up long-term on free progress
survival, relapse, metastasis, over all survival in the group of locally advanced
rectal cancer patients treated by preoperative radiochemotherapy and adjuvant
treatment to make further conclusions about effectiveness