nghiên cứu ứng dụng xạ trị áp sát suất liều cao kết hợp xạ ngoài và cisplatin điều trị ung thư tóm tắt tiếng anh

ABBREVIATIONS
AJCC American Joint Committee on Cancer
ASCO American Society of Clinical Oncology
CTV Clinical Target Volume
CR Completed Respon
EBRT External Beam Radiation Therapy
FIGO Fédération Internationale de Gynécologie et d'Obstétrique
GTV Gross Tumor Volume
HDR High Dose Rate
HPV Human Papilloma Virus
IHC Immunohistochemistry
IV Irradiated Volume
LDR Low Dose Rate
PR Partial Respon
PTV Planning Target Volume
TV Treatment Volume
UICC Union for International Cancer ControL
WHO World Health Organization
1
INTRODUCTION
1. Scientific aims
Cervical cancer is one of the most common cancers in women. It is the
first leading cause of death in women in the world. In 2008, there are 529 800
new cases of cervical cancer worldwide (accounting for 9% of total newly
cancer patients) and an estimated 275.100 women die of this disease (8% of
total cancer deaths). According to a cancer registry in Hanoi from 1998 to 2007
in Vietnam, there are 2.093 new cases of cervical cancer, accounted for 7.3% of
total cancers in women, with age-standardized incidence rate of 6.8 / 100.000.
Although the screening program of cervical cancer has been deployed but
the rate of inoperable stage (IIB, III) cervical cancer is still account for over
50% of new cases. For early stages, cervical cancer has high cure rate with

surgery or radiation therapy alone, or a combination of the two methods.
However, patients in the later stages as IIB, III have low response rate and high
relapse rate, this has promoted new studies to find the effective treatments, and
one of the regimens mentioned that chemotherapy in concurrent with radiation.
The roles of chemotherapy in combined with radiation therapy aims to increase
the sensitivity of tumors to radiotherapy and kill the metastatic lesions. A series
of prospective trials have shown that cisplatin in combined with radiation have
high response rate and survivals than radiation alone have. Patients with stage
IIB-IIIB cervical cancer, radiation therapy is external beam pelvic radiation in
combined with brachytherapy. Both low-dose rate (with Radium 226, cesium
137) and high-dose rate (with Ir-192) brachytherapy are currently being used.
Recently, high-dose rate brachytherapy is preferred for higher efficiency, higher
safety and shorter duration of treatment. High-dose rate brachythepary has been
applied in K hospital since 8/2008 but no reports of results, which is why we
conduct research “Evaluating the results of high-dose rate brachytherapy in
combined with external beam radiation therapy and cisplatin in the treatment of
stage IIB-IIIB cervical cancer”.
2. Objectives
2.1. To evaluate the results of high-dose rate brachytherapy in combined with
external beam radiation therapy and cisplatin in the treatments of stage IIB-IIIB
cervical cancer.
2.2. To assess the toxicity of high-dose rate brachytherapy in combined with
external beam radiation therapy and cisplatin in the treatments of stage IIB-IIIB
cervical cancer.
3. The contributions of the thesis
Confirmed the role and effectiveness of HDR brachytherapy in combined
with EBRT and cisplatin in the treament of stage IIb-IIIb cervical cancer.
2
Overall response rate was 90.5%, complete response rate was 73.2%. The 1
year, 2 years, 3 years and 4 years overall survival rates were respectively

97.8%, 90.7%, 80% and 40.4%. Average survival time of the patients was 42.1
± 1.2 (months). The 4-year overall survival rate of the response patients were
higher than the not response patients were (42.0% compared with 14.9%), p
<0.01. The 4-year overall survival rate of anemia patients were lower than those
who were not anemia (14.5% compared with 47.5%), p <0.01. The local
recurrence rate was 8.2%. The metastasis rate was 16.6% which is the most
common location of lung metastases (5%).
To assess the hematological toxicities, the hepatic and renal toxicities of
the regimen. Leukopenia, neutropenia, anemia are the most common toxicity,
higher rates in the last cycles of chemotherapy.
Evaluating the late toxicities of the gastrointestinal tract and the urinary
tract showed that gastrointestinal complications were 74.4%, bleeding proctitis
accounted for the highest percentage (40.8%), followed by diarrhea (31.2%),
rectovaginal fistula (0.6%), intestinal necrosis (0.6%). Urinary complications
were 10.1%, including dysuria (5.7%), irritation during urination (3.8%),
hematuria (0.6%). The rate of late complications in the first year was 69.3%, the
second year was 14.0%, the third year was 1.2%, no patients had the late
toxicities in the fourth year. Average time of post-treatment late toxicities was
7.9 ± 5.5 months.
4. The structure of the thesis
The thesis consists of 108 pages, with 4 main chapters: Introduction 2
pages , Chapter 1 (Overview) 35 pages 35, Chapter 2 (Patients and Methods) 17
pages, Chapter 3 (results) 24 pages, Chapter 4 (discussion) 27 pages,
Conclusion and recommendation 3 pages.
The thesis has 28 tables, 6 pictures and photos and 15 diagrams, 128
references (102 Vietnamese and 26 English).
CHAPTER 1: OVERVIEW
1.1. The burden of cervical cancer
1.2. Anatomy and histology of the cervix
1.3. Risk factors

1.4. Pathogenesis of cervical cancer
1.5. Screening
1.6. Diagnostic workup
1.6.1. Carcinoma in situ
1.6.2. Invasive cervical cancer
1.6.2.1. Signs and symptoms
3
1.6.2.2. Tests
1.6.3. Staging
AJCC Tumor- Node- Metastases (TNM) and International Federation of
Gynecology and Obstetrics (FIGO) Surgical Staging Systems for Carcinoma of
the Uterine Cervix
TNM FIGO
T(Tumor
)
T
2B
II
B
Tumor with parametrial invasion
T
3
III
Tumor extends to pelvic wall and/or involves lower
third of the vagina and/or causes of hydronephrosis or
nonfunctioning kidney
T
3A
III
A

Tumor involves lower third of the vagina, no
extension to pelvic wall
T
3B
III
B
Tumor extends to pelvic wall and/or causes of
hydronephrosis or nonfunctioning kidney
N (Regional lymph node):
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
M (Distant Metastasis)
M0 No distant metastasis
M1 Distant metastasis
Stage T N M
IIB T2b N0 M0
III T3 N0 M0
IIIA T3a N0 M0
IIIB
T3b Any N M0
T1-3 N1 M0
AJCC (2010). Cancer staging manual, seventh edition.
1.7. Treatment of cervical cancer
1.7.1. The treatment of carcinoma in situ
1.7.2. The treatment of stage IA
1.7.3. The treatment of stage IB-IIA
4
1.7.4. The treatment of stage IIB-III
Chemoradiation

- Single- agent weekly Cisplatin with the dosage of 40 mg/m
2
in 5 weeks.
- A typical regimen of EBRT is 50 Gy, followed by 50 Gy to point A with
brachytherapy for a total dose of 65 Gy to point A.
1.7.5. The treatment of stage IV
1.7.6. Improvements in the treatment of cervical cancer
1.7.6.1. Accelerated radiation therapy
1.7.6.2. Brachytherapy in the treatment of cervical cancer
- Low-dose rate brachytherapy
- High-dose rate brachytherapy
1.7.6.3. Chemoradiation
1.7.6.4. Best supportive care
1.8. Cisplatin drug informations
1.9. Common toxicities of the regimen
1.10. Previous studies
Foreign studies:
Lorvidhaya et al [74] studied of 1992 cervical cancer patients were treated
with high dose rate brachytherapy, the 5 years relapse-free suvival of stage IB,
IIA, IIB, IIIA, IIIB, IVA, IVB were respectively 79.5%, 70%, 59.4%, 46.1%,
32.3%, 27.8% and 23.1%. Research by JC Kim et al [64] on 135 stage IIIA-IIIB
cervical cancer patients were treated with chemoradiation, the 5 years overall
survival rate was 37.5%. In results announced by Toita T et al [115] in 40 stage
IIB-IIIB cervical cancer patients, the 3 years overall survival was 79%.
Teshima et al [112] published results of treatment of 430 patients (171 patients
LDR, HDR 259 patients) in combined with external beam radiation therapy, the
grade 2 and 3 pelvic toxicity rates of HDR were higher than those of LDR (10%
vs. 4%, p = 0.002). In the study by Arai et al [29] on 147 stage I patients, 256
stage II patients, 515 stage III patients, 104 stage IV patients showed grade 3
and 4 toxicity rate in the rectum was 4.1%, in the bladder was 1.2%, in the

small intestine was 1.1%. Author Nakato T et al [83] did the study in 210 stage
IIIB cervical cancer patients, the results showed the rate of late toxicities in
HDR and LDR groups were respectively 6% and 10%.
Vietnamese studies:
Bui Dieu studied on 226 stage IB-IIA cervical cancer patients at Hospital
K from 1992 to 2003, the 5-year overall survival rates of the Caesium 137
brachytherapy group and Radium 226 brachytherapy group were respectively
65.5% and 50.8%. The study by Nguyen Van Tuyen on 331 patients with stage
IB-II cervical cancer treated with surgery in combined with radiotherapy in
5
from 1999 to 2002, the recurrence rate after 5 years was 11.7%, metastasis rate
was 15.0%, the 5-year overall survival rate was 76.4% , the 5-years disease-free
survival rate was 74.3%. The results from study of Thi Tuyet Anh Cung et al on
45 patients with stage IIB-IIIB cervical cancer treated with chemoradiation
showed the response rate was 88.9%.
Chapter 2: PATIENTS AND METHODS
2.1. Patients
157 patients with stage IIB-IIIB cervical cancer were treated with cisplatin
in combined with high-dose rate brachytherapy and external beam radiation
therapy from 8/2008 to 8/2011 at K hospital.
2.1.1. Patient criteria
- The patients with stage IIB - IIIB cervical cancer according to TNM and
FIGO classification are eligible for this study.
- Histopathology was carcinoma of the cervix
- No prior chemotherapy or radiotherapy
- The patients must have a performance status of 0, 1 and 2 ECOG score
(Eastern Cooperative Oncology Group).
- Blood counts are in the normal range (granulocytes> 2000/ml, platelets>
100.000/ml, Hb> 9g/dl).
- Total serum bilirubin < 1.5 mg/dL and SGOT, SGPT <2.5 x normal.

- Serum creatinine <1.5 x normal and serum ure < 10,9 mmol/l.
- Patients who do not suffer from other acute and chronic severe diseases.
- Patients have reliable follow-up information.
2.1.2. Exclusion criteria of patients.
- The patients have PS of 3-4 according to ECOG score.
- The patients are not in stage IIB-IIIB.
- Patients who dropped out during treatment.
- Patients have abnormal bone marrow functions or hepatic failure or renal
failure.
- Patients who are pregnant, breast-feeding.
- Patients have other sever diseases (cardiovascular, psychiatric disorders, other
cancers ).
2.2. Methods
2.2.1. Research design: Randomized un-controlled clinical trial. All eligible
patients were enrolled the trial.
2.2.2. Sample size
6
The sample size was calculated by the formula:
n =
2
2/1
α
−
Ζ
2
)1(
d
PP
−
2.2.3. Steps

2.2.3.1. Clinical and test characteristics before treatment
• The clinical features:
+ Age, sex, time from first symptoms on admission (in months), the
symptoms: abnormal vaginal bleeding, back pain
+ Clinical examination: To evaluate tumor location, size, shape (warts,
sores, infection ), and bleeding, extensive surrounding tissue
• Laboratory tests
+ Complete blood count
+ Blood chemistries
+ SCC-Ag serum for monitoring during and after treatment.
• Radiologic tests
+ All patients underwent MRI to evaluate the spread of the tumor.
+ CT sim plan radiation therapy.
+ Abdominal ultrasound: assessment of other organs, abdominal lymph
nodes.
+ Chest X-ray: detecting metastatic lung lesions. Chest- CT if required for
better disease evaluation.
+ Bone- scan: detecting metastatic bone lesions.
• Histopathology: Histopathological classification according to WHO.
• Confirmed diagnosis is based on clinical and histopathology.
• Staging of the disease is based on clinical and MRI.
2.2.3.2. Treatment plan
• Intravenous cisplatin
- Cisplatin 40 mg/m
2
IV weekly x 5 weeks in concurrent with EBRT
- Cisplatin does not use in the day of brachytherapy.
- External radiation is started 2-2.5 hours after cisplatin injection.
Administration:
- Before the drug infusion: 1.5-2 liters Glucose 5% or 0.9% Natriclorid IV

- Cisplatin is diluted with 500 mL 0.09 percent sodium chloride for
injection. Patients were given Manitol 10-20% (100 ml for 20 mg
cisplatin/m2). Fluid administration should be adequate to establish a urine
flow of at least 100 mL/hour for two hours prior to and two hours after
cisplatin administration.
7
- Other drugs: Odansetron x 8 mg, Depersolon x 30 mg IV before cisplatin
injection and 200ml 0.9% Natriclorid, Odansetron x 8 mg IV after
cisplatin injection to prevent side effects.
Patients were assessed for their general condition, symptoms, complete
blood count, live function and kidney function tests prior to each treatment
cycle. If neutrophils <2.0 x 10
9
/l or platelets <100 x 10
9
/l or the other grade
2-3 toxicities (except anemia), chemotherapy should be delayed until
recovering.
• External beam radiation therapy
- Posture patients:
+ Lie on your back.
+ Two hand on her chest.
- CT simulation confirmed adequate coverage of the iliac lymph nodes. The
caudad extent of disease can be determined by inserting radiopaque
markers in the cervix or at the lowest extent of vaginal disease. Potential
internal organ motion must be taken into account, particularly in the
design of lateral treatment fields.
- Anterior- posterior pelvic radiation fields
+ Body in the 0 position.
+ The upper limit: S1-S2 or L4-L5.

+ The lower limit: including vaginal and orifice of ureter with stage II,
III.
+ The lateral limits: Head of the femur.
The body turns 180 degrees.
- Lateral pelvic radiation fields.
+ Body turns 90 degrees to the left or 270 degrees to the right.
+ The goal is increasing the pelvic lymph nodes dosage and decreasing
surface dosage.
+ The front limit: pubic bone.
+ The behind limit: sacrum bone.
+ The lower and upper limits are the same as interior- posterior fields.
Dose and fractionation:
+ Fractionation of 1,8-2 Gy/ day, 5 days/ week.
+ Total dose: 50 Gy
+ Increase dose 10 Gy for patients with large lesions in pelvic lymph
nodes parameter.
• High- dose rate brachytherapy
- Prepare the patient:
+ Patients enema before treatment.
+ Used prophylactic antibiotics.
8
+ Injection premedication before 10-15 minutes.
+ Foley bladder sonde during treatment.
- Brachytherapy is usually delivered using afterloading applicators that are
placed in the uterine cavity and vagina. Vaginal packing is used to hold
the tandem and colpostats in place and to maximize the distance between
the sources and the bladder and rectum. Radiographs should be obtained
at the time of insertion to verify accurate placement, and the system
should be repositioned if positioning can be improved.
- Radioactive sources: Iridum use 192 (HDR)

- Paracentral doses are most frequently expressed at a single point, usually
designated Point A. This reference point has been calculated in a number
of different ways. The most accepted definition of Point A is a point 2 cm
lateral to the cervical collar and 2 cm above the top of the colpostats,
measured at their intersection with the tandem midpoint on the lateral
radiograph.
- The time and dose of radiation therapy: a treatment period is 8-30
minutes, 4-6 times, once a week, every 5-7 Gy in fractionation. Total dose
of 60-65 at point A. Depending on the size of the primary tumor, stage of
disease, response to radiotherapy of the tumor that total radiation dose can
be changed to achieve optimal efficiency.
2.3 Monitoring and evaluation criteria
A. Outcomes
∗ Response criteria: Imaging modalities for response evaluation should be
MRI. According to RECITS: Complete response; Partial response, Stable
disease, Progressive disease.
∗ Definition of outcomes
- Getting information of the patients by routine examination, mails or phone
numbers.
- On study criteria: The day start the treatment
- Off study criteria:
+ Death.
+ Lost to follow-up.
+ Withdrawal of consent for any further data submission.
- Reviewing the 1-year, 2-year, 3-year and 4-year overall survivals.
- Recurrent events: New lesions appear at ≥ 6 months after treatment.
Confirmed recurrence by clinical examination, imaging, cytology and
histopathology (if possible).
- Metastasis events: metastasis diagnosis based on clinical examination,
diagnostic imaging, cytology and histopathology (if possible).

- Status of patients: Alive, death, healthy, recurrence or metastasis.
9
- The overall disease-free survival was defined as the time from
randomization until loco regional recurrence, metastasis, or death by any
cause.
B. Common toxicities
∗ Hematological toxicities, hepatic toxicities and renal toxicities
Common Toxicity Criteria for Anticancer Drugs (WHO)
Adverse Event Grade 0 Grade I GradeII GradeIII Grade
IV
Leukocytes
(x 10
3
)
≥ 4 3 - 3,9 2 - 2,9 1-1,9 < 1
Neutrophils
(x 10
3
)
≥ 2 1,5 - 1,9 1 - 1,4 0,5-0,9 < 0,5
Hemoglobin
(g/L)
≥ 125 100-24,9 80- 99,9 65-79,9 < 65
Platelets (x 10
3
) 150-450 75 - 149 50- 74,9 25-49,9 < 25
SGOT and/or
SGPT
≤ 40 40,1-100 100,1-200 200,1-800 ≥ 800,1
Creatinin

(mmol/L)
≤ 120 120,1-180 180,1-360 360,1-720 ≥ 720,1
∗ Late complications: the urinary and gastrointestinal systems
2.4. Data collection and statistics
2.4.1. Collecting data based on the available medical records
2.4.2. Data processing
∗ The information is encoded and processed by SPSS 16.0 software.
∗ The statistical algorithms: description, comparative tests
∗ Analysis of survival: Using Kaplan-Meier estimator to estimate
survival.
CHAPTER 3: RESULTS
3.1. Patient characteristics
Staging characteristic
Stage Patients %
10
IIB T2b N0 M0 101 64,3
IIIA T3a N0 M0 10 6,4
IIIB
T3b N0 M0 28 17,9
T3b N1 M0 11 7
T1 N1 M0 0 0
T2 N1 M0 3 1,9
T3a N1 M0 4 2,5
Total 157 100
Table 3.1: Staging characteristic
3.2. Outcomes
3.2.1. Near outcomes
Response rates according to stage
Stage IIB IIIA IIIB Total
P

n % n % n % n %
Complete response 76 75,2 9 90,0 30 65,2 115 73,2
>0,05
Partial response 16 15,8 0 0,0 11 23,9 27 17,3
Stable disease 6 6,0 1 10,0 1 2,2 8 5,0
Progressive disease 3 3,0 0 0,0 4 8,7 7 4,5
Total 101 100,0 10 100,0 46 100,0 157 100,0
Table 3.2.1.1 Response rates according to stage
Response rates according to ages
Results Response Not response
P
n % n %
< 50 38 26,8 8 53,3
< 0,05
≥ 50 104 73,2 7 46,7
Total 142 100,0 15 100,0
Table 3.2.1.2 Response rates according to ages
Response rates according to anemia status
Result Response Not response
P
n % n %
Anemia 45 91,8 4 8,2
> 0,05
11
Not anemia
97 89,8 11 10,2
Table 3.2.1.3 Response rates according to anemia status
Response rates according to histopathology
Result Response Not response
P

n % n %
Squamous cell carcinomas 127 91,4 12 8,6
> 0,05
Adenocarcinomas 10 76,9 3 23,1
Adenosquamous carcinomas 5 100,0 0 0,0
Table 3.2.1.4 Response rates according to histopathology
3.2.2. Far outcomes (monitoring after treatments)
Mortality
Figure 3.2.2. Mortality
Overall survival
Kaplan- Meier Survival 1 year 2 years 3 years 4 years
Cumulative mortality 2 9 15 31
Cumulative survival ratio (%) 97,8 90,7 80,0 40,4
Median survival time ± standard
deviation (months)
42,1 ± 1,2
Table 3.2.2.1. Overall survival according to time after treatment
Overall survival according to staging characteristics
Stage IIB IIIA-IIIB
Number of patients 101 56
Death patients 18 13
Survival ratio (%) 44,2 40,0
12
Median survival time ±
standard deviation (months)
42,8 ± 1,4 40,6 ± 1,9
LogRank Test: χ
2
= 0,107; degrees of freedom 1; P > 0,05
Table 3.2.2.2. Overall survival according to staging characteristics

Overall survival according to response characteristics
Response Not response
Number of patients 142 15
Death patients 23 8
Survival ratio (%) 42,0 14,9
Median survival time ± standard
deviation (years)
3,6 ± 0,1 2,4 ± 0,3
LogRank Test: χ
2
= 17,18; degrees of freedom 1; P < 0,01
Table 3.2.2.3. Overall survival according to response characteristics
Overall survival according to anemia status
Anemia Not anemia
Number of patients 108 49
Death patients 20 11
Survival ratio (%) 14,5 47,5
Median survival time ±
standard deviation (months)
36,3 ± 1,7 43,2 ± 1,3
LogRank Test: χ
2
= 6,9; degrees of freedom 1; P < 0,01
Table 3.2.2.4. Overall survival according to anemia status
13
Local- recurrences and metastases
Organs n Tỷ lệ (%)
Metastasis Liver metastases
2 1,3
Supraclavicular metastases 6 3,8

Mediastinal lymph nodes 4 2,6
Peritoneal metastases 4 2,6
Lung metastases 8 5
Bone metastases 2 1,3
Local-recurrence
Local recurrance and
pelvic
13 8,2
Total
39 24,8
Table 3.2.2.5. Local- recurrences and metastases
3.3. Toxicities and complications
3.3.1. Hematological toxicities, hepatic toxicities and renal toxicities
General toxicities
Table 3.3.1.1 General toxicities
Leukocytes Neutrophils Hgb Platelets GOT/GPT Creatinin
n % n % n % n % n % n %
Grade 0 108 68,8 105 66,9 49 29,7 134 85,2 146 92,9 150 95,1
Grade 1 45 28,4 47 29,9 83 52,8 20 12,7 9 5,7 4 2,8
Grade 2 3 2,1 2 1,4 22 15,4 3 2,1 2 1,4 2 1,4
Grade 3 1 0,7 2 1,4 2 1,4 0 0,0 0 0,0 1 0,7
Grade 4 0 0,0 1 0,7 1 0,7 0 0,0 0 0,0 0 0,0
Total 157 100,0 157 100,0 157 100.0 157 100,0 157 100,0 157 100,0
Neutropenia
14
Figue 3.3.1.1 Neutropenia
Comment: Neutropenia is mainly grade 1 and 2. Neutropenia increases in the
last cycles.
Anemia
Figue 3.3.1.2. Anemia

Comment: Anemia is mainly grade 1 and 2. Anemia increases in the last cycles
Platelet toxicities
Figue 3.3.1.3. Platelet toxicities
Comment: Platelet toxicities are mainly grade 1. Platelet toxicities increases in
the last cycles
Liver toxicities
15
Figue 3.3.1.4. Liver toxicities
Comment: Liver toxicities are mainly grade 1. Liver toxicities increase in the
last cycles.
Renal toxicities
Table 3.3.1.2. The change in serum creatinine after treatment
Before
treament
After
1 week
After
2 weeks
After
3 weeks
After
4 weeks
After
5 weeks
n % n % n % n % n % n %
Gr 0 157 100,0 157 100,0 156 99,3 157 100,0 153 97,2 152 96,5
Gr 1 0 0,0 0 0,0 1 0,7 0 0,0 2 1,4 4 2,8
Gr 2 0 0,0 0 0,0 0 0,0 0 0,0 2 1,4 0 0,0
Gr 3 0 0,0 0 0,0 0 0,0 0 0,0 0 0,0 1 0,7
Gr 4 0 0,0 0 0,0 0 0,0 0 0,0 0 0,0 0 0,0

Total 157 100,0 157 100,0 157 100,0 157 100,0 157 100,0 157 100,0
Comment: There are 4 patients who have higher level creatinin serum than
normal.
16
3.3.2. Late complications
Gastrointestinal and urinary tracts complications
COMPLICATIONS N %
Bleeding proctitis 64 40,8
Diarrhea 49 31,2
Rectovaginal fistula 1 0,6
Intestinal necrosis 1 0,6
Rectal vaginal stenosis 2 1,2
Total 117 74,4
Urinary tract
Dysuria 9 5,7
Irritation during urination 6 3,8
Hematuria 1 0,6
Total 16 10,1
Table 3.3.1.2 Gastrointestinal and urinary tracts complications
Late complications after time of treatment
n %
The first year 109 69,3
The second year 22 14
The third year 2 1,2
The fourth year 0 0
Total 133 84,5%
Table 3.3.1.3. Late complications
CHAPTER 4: DISCUSSION
4.1. Patients characteristics
Staging characteristics

In total of 157 patients, stage IIB patients have highest rate (64.3%),
followed by patients with stage IIIB (29.3%), only 6.4% of patients in stage
IIIA. According to Cung Thi Tuyet Anh, 45 patients were treated with
concurrent chemotherapy and HDR brachytherapy, the stage IIB rate was
55.6% and the stage IIIB rate was 44.4%.
17
Table 4.1.1 Staging characteristics of patients
Researcher n Stage
IIB
StageIII
A
Stage
IIIB
Le Phuc Thinh (2005) 999 66,96% - 32,03%
Ngo Thi Tinh (2005) 243 52,8% 2,6% 45,3%
Nguyen Ba Duc et al (2005) 30 20% - 80%
Cung Thi Tuyet Anh (2007) 45 55,6% - 44,4%
Rose et al (1999) 526 52,28% 2,8% 41,82%
Nguyen Tien Quang (2012) 157 64,3% 6,4% 29,3%
The results of our study similar to Le Phuc Thinh’s study about staging
rates, however, differ from the results of Ngo Thi Tinh, Cung Thi Tuyet Anh.
4.2. Results
Response rates

Numbe
r of
patients
Stage
Overall
respons

e (%)
Complet
e
response
(%)
Partial
response
(%)
Duenas-Gonzalez 2005 80 IB
2
-IIB 100 55 45
Zarbá 2003 36 IIB-
IVA
97,1 88,8 8,3
Watanabe 2006 25 IIB-
IVA
96 88 8
Nguyen Ba Duc 2004 30 IIB-
IIIB
96,7 83 13,7
Tran Tu Quy 2005 46 IB-IIIB 93,4 76 17,4
Cung Thi Tuyet Anh 2007 45 IIB-
IIIB
88,9 84,4 4,4
Nguyen Tien Quang 2012 157 IIB-
IIIB
90,5 73,2 17,3
Table 4.2.1. Response rates
Zarba (2003) dis the study on 36 patients with stage IIB-IVA cervical
cancer, the overall response rate was 97.1% (88.8% CR, 8.3% PR). Cung Thi

Tuyet Anh (2007) did the study on 45 cases of stage IIB-IIIB cervical cancer,
the response rate was 88.9%. The research of Watanabe (2006) showed overall
response rates of stage IIB-IVA patients were 96%.
18
According to those results, the response rates of cervical cancer patients
were treated with concurrent chemoradition are very high. The results of our
study are the same as other studies.
Response rate according to ages
When comparing the response rates in 2 groups of patients over 50 years
of age and under 50 years of age, response rates of patients ≥ 50 years of age
was 73.2%, higher than patients <50 years of age (26, 8%). This difference is
statistically significant with P <0.05. Of the patients <50 years old, the not
response group was 53.3%, nearly 2 times higher than the response group. This
difference is statistically significant with P <0.05.
Response rate according to anemia status
When studying the relationship between response and anemia, we found a
complete response rate of patients without anemia group was 91.8%, higher
than the anemia group (89.8%). However, this difference was not statistically
significant (P> .05). According to Gillian Thomas (2002), the 5-year overall
survival in the over hemoglobin 120g / L group was 74%, in the hemoglobin
110-119 g / L group was 52% and the hemoglobin upper 110 g / L group was
only 45%. The relationship between anemia and hypoxia are still controversial,
but scientists have demonstrated hypoxia causes irradiation and chemotherapy
resistance of the cancer cells.
Response rate according to histopathology
Our results showed the response rates of squamous cells carcinoma group
was 91.4%, higher than the adenocarcinoma group (76.9%). However, this
difference was not statistically significant (P> 0.05).
Hong JH did the research histopathology of cervical cancer; he found that
adenocarcinoma type and adenosquamous carcinoma type have a worse

prognosis than squamous cells carcinoma type. JS Lea compared
adenocarcinoma type and adenosquamous carcinoma type, the result showed
adenocarcinoma have a better prognosis than adenosquamous carcinoma, in the
same period, the recurrence and metastatic rates of adenosquamous carcinoma
cases were higher.
4.2.2. Far results
Mortality
In our research, 31/157 patients died (19.7%). Number of death patients
in the second, the third and the fourth year were respectively 2 patients, 7
patients, 6 patients and 16 patient. Thus, the number of patients who died in the
4th year was more than 50% of all deaths.
Overall survival
The results showed the 1 year, 2 years, 3 years and 4 years overall
survival rates were 97.8%; 90.7%, 80.0%; 40.4%, respectively. The 4th year
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overall survival rate increased in stage IIB-IIB cervical cancer patients, who
were treated with chemoradiation, the mortality rate in 4th year was hight. In
our study, median survival time was 42.1 ± 1.2 months.
n Stage Overall survival
Shingo Kato at al 120 IIB-IIIB 2 years survival 79,6%
Kim JC, at al 135 IIIA-IIIB 5 years survival 37,5%
Takashi Nakano at al 100 IIB-IIIB 5 years survival 51,1%
Toita T at al 40 IIB-IIIB 3 years survival 79%
E Song at al 88 IB2-IVA 3 years survival 69,5%
Nguyen Tien Quang 157 IIB-IIIB
3 years survival 80,0%
4 years survival 40,4%
Table 4.2.2. Overall survival
In general the first 3-year overall survival rates were high in all studies. In
our study, the 4th year survival rate was dropped to 40.4%, this trend is the

same as the results of Kim JC (5-year survival was 37.5%).
Overall survival according to staging characteristics
Staging is a important prognostic factor for survival. According to Hee-
Chul Park et al, 233 patients stage IIIA-IIIB cervical cancer stage IIIA-IIIB had
5-year overall survival rate of 60.6%. Demanes DJ et al did the study in 62
cervical cancer patients from stage I-IVA, the 5-year overall survival rates of
patients with stage IIB and IIIB were respectively 47% and 39%. In our study,
the analysis of survival rates according disease stage results showed overall
survival of patients was 44.2% stage II, stage III is higher than 40.0%. This
difference was not statistically significant with P> 0.05.
Overall survival according to response rate
The results showed the overall survival rates of patients with response
group is 42.0%, higher than that of non-response (14,9%). This difference is
statistically significant with P <0.01. Classe JM studied on 175 patients with
stage IB2-IVA cervical cancer; the results showed that patients with complete
20
response had a better disease-free survival and overall survival compared to
partial response patients.
4-year overall survival according to anemia status
Many studies have shown that there is a close association between
anemia, hypoxia response with response rate and survival rate in the treatment
of cervical cancer. According to Gillian Thomas (2002), the 5-year overall
survival in the over hemoglobin 120g / L group was 74%, in the hemoglobin
110-119 g / L group was 52% and the hemoglobin upper 110 g / L group was
only 45%. The relationship between anemia and hypoxia are still controversial,
but scientists have demonstrated hypoxia causes irradiation and chemotherapy
resistance of the cancer cells. This difference is statistically significant with P
<0.01. Thus, the result of our study was similar to results of Gillian Thomas.
Local-recurrence and metastases
In our study, there were 26 metastatic patients accounted for 16.6%. The

more common metastatic organs were lung metastases 5%, supraclavicular
lymph nodes metastases (3.8% ), mediastinal lymph nodes metastases (2.6%),
peritonial metastases (2.6%), liver metastases (1.3%), bone metastases (1.3%).
There were 13 patients with local and pelvis recurrence (8.2%). According to
Pearcey R et al, in 253 patients with squamous cell carcinomas cervical cancer,
the results showed the local-recurrence rates was 27%, followed by peritoneum
(14%), liver (4%), lung (17%), bone (3%). Bui Dieu did the study in the
patients were treated with Radium 266 and Caesium 137 brachytherapy, the
recurrence rates were 6.2% and 4.4%, the metastatic rates were 23% and 15.9%,
the most common organ was pelvic lymph nodes in, followed by lung and
supraclavicular lymph nodes.
4.3. Toxicities and complications
4.3.1. Hematologycal, hepatic and renal toxicities
Neutropenia
The neutropenia rate was 33,2%. Neutropenia is mainly grade 1 and 2.
Neutropenia increases in the last cycles.
Anemia
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In our study, the rate of patients with anemia was 70.3%, grade 1 was
52.8%, grade 2 was 15.4%, grade 3 was 1.4% and the grade 4 was 0.7%.
According to research by Ngo Thi Tinh, the rates of anemia were 88.7% , the
rates of grade 1,2 and 3, anemia were respectively, 11.3%, 46.6 % and 31%.
Anemia rate increased in the last cycles. This result may be due to cumulative
doses or nutrition of patients.
Platelets toxicities
The rate of patients who had platelets toxicities was 14.8%. Platelet
toxicities are mainly grade 1. Platelet toxicities increase in the last cycles. The
treatment should be delayed until the platelets count recover.
Liver and kidney toxicities
In our study, the rate of increased GOT and / or GPT was 7.1%, which is

lower mainly grade 1 and 2. Thus, hepatotoxicity in our study is acceptable.
Nephrotoxicity occurs during treatment (assessed through serum creatinine) in
our study was very low with only 7 cases (4.9%).
4.3.2. Late complications
133/157 patients had side effects from radiation therapy (84.5%),
gastrointestinal tract complications was 117 patients (74.4 %) and urinary tract
complications was 16 patients (10.1%). In patients with gastrointestinal
complications the bleeding proctitis accounted for the highest rate 40.8%,
followed by diarrhea (31.2%), rectovaginal fistula (0.6%), intestinal necrosis
(0.6%). Urinary tract complications were 16 patients (10.1%), of which dysuria
was 5.7%, irritation during urination was 3.8% and hematuria was 1 patient. In
total 133 patients had complications (Table 3:25), the patients with
complications occurring in the first year accounted for the highest percentage
(69.3%), followed by the 2nd year (14%), only 2 patients had complications in
the first 3 years, no patient had any complications in the 4
th
. In the study of
Toita T et al, bleeding proctitis rate was 9% and interitis was 15%. According
to research by Ngo Thi Tinh, urinary tract complications was 10.5%, diarrhea
was 60.5%, bleeding proctitis was 54.4%, rectal stenosis was 3.4% Thus, the
late complications in the digestive system and the urinary tract of our results are
higher than the results of studies abroad.
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CONCLUSION
1. Treatment results
1.1. Near results
- The overall response rate was high (90.5%), complete response rate was
73.2%, partial response rate was 17.3%, stable disease was 5% and progress
disease was 4.5%.
- Response rates in patients ≥ 50 years of age group are higher than patients <50

years of age group (73.2% compared with 26.8%), p <0.05.
- The response rates of patients without anemia group were higher than patients
in anemia group (91.8% compared with 89.8%), p> 0.05.
- The response rates of the squamuos cell carcinomas group were higher than
the adenocarcinomas group (91.4% compared with 76.9%), p> 0.05.
1.2. The far results
- The 1 year, 2 years, 3 years and 4 years overall survival rates were
respectively 97.8%, 90.7%, 80% and 40.4%.
- The average survival time of patients was 42.1 ± 1.2 (months).
- 4-year survival rates of all patients with stage IIB group were higher than
patients on stage IIIA-IIIB group (44.2% compared with 40.0%), p> 0.05.
- 4-year overall survival rate of patients ≥ 50 years of age was higher than
patients <50 years of age (41.6% compared with 39.1%), p> 0.05.
- 4-year overall survival rate of response patients was higher than no response
patients (42.0% compared with 14.9%), p <0.01.
- 4-year overall survival rate of patients without anemia was higher than
patients with anemia (47.5% compared with 14.5%), p <0.01.
- Percentage of patients with local and pelvic recurrence was 8.2%. Metastasis
rate was 16.6% which is the most common organs of lung metastases (5%),
supraclavicular lymph nodes metastasis (3.8%), mediastinal lymph nodes
metastases (2.6%); peritonial metastases (2.6%), liver metastases (1.3%), bone
metastases (1.3%).
2. Toxicities and complications
2.1. Hematological, liver and kidney toxicities
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- Leukocyte toxicities rate was 31.2%, neutropenia was 33.1%, mostly grade 1
and 2. Grade 3 and 4 neutropenia was 2.1%. Neutropenia increased in the last
cycles.
- The rate anemia patients were 70.3%, mostly grade 1 and 2. Neutropenia
increased in the last cycles.

- The rate of platelets toxicities was 14.8%, mainly grade 1, no cases of grade 3
and 4. Platelets toxicities increased in the last cycles.
- The rate of high GOT and/or GPT patients was only 7.1% , no cases of grade
3 and 4. Hepatic toxicities increased in the last cycles
- Percentage of high creatinine serum patients was 4.9%.
2.2. Late complications
- Complications in the gastrointestinal tract were 74.4%, the bleeding proctitis
accounted for the highest rate 40.8%, followed by diarrhea (31.2%),
rectovaginal fistula (0.6%), intestinal necrosis (0.6%).
- Urinary tract complications were 16 patients (10.1%), of which dysuria was
5.7%, irritation during urination was 3.8% and hematuria was 1 patient.
- The patients with complications occurring in the first year accounted for the
highest percentage (69.3%), followed by the 2nd year (14%), only 2 patients
had complications in the first 3 years, no patient had any complications in the
4
th
year. The average time post-treatment of late complications was 7.9 ± 5.5
months.
RECOMMENDATIONS
The high-dose rate brachytherapy in combined with external beam
radiation therapy and cisplatin regimen in the treatment of stage IIB-IIIB
cervical cancer should be widely used to improve the response rates and
survivals for patients.
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