Nghiên cứu kết quả hóa trị bổ trợ trước phác đồ TC và tỷ lệ bộc lộ một số dấu ấn liên quan đến ung thư lưỡi giai đoạn III IV (m0) tt tieng anh

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INTRODUCTION
Tongue cancer is the most common cancer of oral cancers. According to GLOBOCAN
2018, there are about 354,860 new cases and 177,354 deaths caused by oral cancers with
male/female ratio of 2.27 every year. In Vietnam, there were about 1,877 new tongue cancer
cases in male, while 922 new cases in female in 2018. Definitive diagnosis for tongue cancer
is achieved by histopathological result.
In Vietnam, rate of tongue cancer patients diagnosed at stages III and IV remains high.
At these stages, neo-adjuvant chemotherapy (also known as chemotherapy prior to surgical
intervention and radiotherapy) helps downstage the disease, facilitate surgery and
radiotherapy, reduce complications and restrict metastasis. Around the world, the taxane and
cisplatin combination regimen is more effective due to low-cost, popularity, simple
implementation, and has fewer side effects than others. Recent studies have shown that apart
from classic prognostic factors, the prognosis of tongue cancer also depends on several
molecular biomarkers of the tumor such as expressions of p53, Her2 and EGFR. In Vietnam,
there have never been any studies evaluating result of neo-adjuvant TC chemotherapy
regimen combined to surgery or radiotherapy for treatment of tongue cancer, as well as the
correlation between some molecular biomarkers and the prognosis.
Therefore, we did a study with topic: “Research of neo-adjuvant TC chemotherapy
regimen result and expression rates of some markers related to tongue cancer at stages III and
IV (M0)” for 2 goals:
1.

Evaluation of response rate and side effects of pre-operative and/or pre-radiotherapy
neo-adjuvant TC chemotherapy regimen for treatment of tongue cancer at stages III
and IV (M0).

2.

Determination of expression rates of p53, EGFR and Her2 markers and some factors

related to overall survival of patient with stages III and IV tongue cancer.

1. Necessity of the Study
Tongue cancer is a common disease; but its symptoms are atypical at early stages
leading many patients have to be hospitalized at stages III and IV. At these stages, an initial
surgery is a large operation requiring experienced surgeons, patients usually feel tired after
surgery and their post-operative chewing, swallowing and saying functions are affected.
Meanwhile, treatment of stages III and IV (M0) using neo-adjuvant chemotherapy helps
reduce sizes of tumors and lymph nodes, facilitate surgery and radiotherapy, reduce


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complications and restrict metastasis. Many studies around the world have demonstrated that
neo-adjuvant combination regimen containing taxane and cisplatin is more effective and less
side effects than some others. In addition, treatment efficacy doesn’t only depend on the
choice of regimen but also on prognostic factors such as disease’s stage, histopathological
type, and age of patient. Recent studies have shown that prognosis of the disease also
depends on several molecular biomarkers of the tumor such as expressions of p53, Her2, and
EGFR. However, there are very few studies on regimens and the correlation between
molecular biomarkers and prognosis in Vietnam. These are reasons promoting us to do this
study.
2. New contributions of the thesis
Through a study on 125 patients with stages III and IV (M0) tongue cancer who received
neo-adjuvant TC chemotherapy regimens, we found that average age of getting the disease
was 52.5, the most common age group was from 41 to 60 years old, accounting for 76%, and
the male/female ratio was 3.6/1. After 3 chemotherapy cycles, complete response rate
accounted for 14.4%; partial response rate was 44%; non-remission rate was 36.8%; and
4.8% of participants became progressed. Most participants had grades 1 and 2
thrombocytopenia. There was no grade 3 or 4 thrombocytopenia case recorded. Rates of

participants having grade 3 leukopenia on courses I, II and III were 28%, 24.8%, and 23.2%
respectively. Rates of participants having grade 3 leukopenia on course I, II and III were
22.4%; 26.4% and 25.6% respectively. Vomiting and nausea mainly occured at grades 1 and
2. Myalgia and peripheral neuropathy complications also occurred at grades 1 and 2.
Averaged overall survival (OS) was 36.48 ± 2.23 months. 5-year survival rate reached
24.1%. OS of surgical group after neo-adjuvant chemotherapy was higher than that of postradiotherapy combined with chemotherapy group after neo-adjuvant chemotherapy (42.32
versus 30.03 months). The EGFR-positive expression rate was 36.8%. There were a
correlation between EGFR expression and stage T and disease’s stage. Her2-positive
expression rate was 4.8%. There was a correlation between Her2 expression and nodal
metastasis (N). The p53-positive expression was 33.6%. There was no correlation between
p53 expression and gender, stage T, nodal metastasis, disease stage, histological grade and
response status. Stage T, nodal metastasis status, disease’s stage, response status and EGFR
expression status were factors affecting to overall survival.
3. Thesis’s layout
The thesis consists of 123 pages: 2 pages of “Introduction”, 2 pages of the
“Conclusion” and 1 page of the “Proposal”. It has 4 chapters: “Literature Review” chapter


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accounting for 34 pages, 18 pages of “Material and Method” chapter, “Result” chapter
accounting for 31 pages, and 30-page “Discussion” chapter. The thesis also has 38 tables, 15
charts, 1 picture and 110 references (11 references in Vietnamese and 99 others in English).


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CHAPTER 1: LITERATURE OVERVIEW
Worldwide research context
Lisa did a study on neo-adjuvant CF regimen on 195 patients with oral squamous cell

carcinoma and concluded that pre-operative chemotherapy can reduce rate of mandibulotomy.
Moreover, Zhong et al. did a phase-III study on 256 patients with oral squamous cell
carcinoma in situ using a neo-adjuvant TPF regimen, followed by surgery, post-operative
adjuvant radiotherapy, and result showed that clinical response rate was 80.6%. In addition,
Stefano studied the neo-adjuvant TC regimen, followed by simultaneous radiotherapy and
chemotherapy. After 3 TC cycles, complete response rate was 20.9%; partial response rate
was 53.5%. Salama et al. did a Phase-II study on 222 patients with recurrent and metastatic
head and neck cancer at stages III and IV (M 0) treated by TC regimen followed by
simultaneous chemotherapy and radiotherapy for radical treatment, complete response rate
was 75%. Similarly, Vokes showed a complete response rate of 75.3%.
Xia did a research on 111 patients with oral squamous cell carcinoma, EGFR expression
result showed that 12% of EGFR expressions were (+++), 25% of expressions were (++),
63% of expressions were (+) or (-). There was a correlation between immunohistochemistry
expression of EGFR and nodal metastasis and distant metastasis. Chen’s study showed that
57.6% of patients had EGFR expression, 40.7% of patients had Her-2 overexpression. The
EGFR-positive group had a shorter OS than negative group. However, Her-2 expression did
not affect overall survival. Temam et al. only analyzed p53-gene sequencing in early-stage
head and neck squamous cell carcinoma, his result showed that among 105 patients, there
were up to 40 patients with p53 gene mutations, accounting for 37%.
Vietnam context
According to Le Van Quang’s study implemented on 117 patients with stages III and IV
(M0) mobile tongue cancers who underwent chemotherapy before CF regimen at K hospital,
After 3 cycles, complete response rate was 12%; 50.4% for partial response rate; nonremission rate was 30.8%; progressive disease accounted for 6.8 %. According to stage, stage
III response rate was 75% while stage IV accounted for 57.6%. Fully degenerated cells rate
after treatment was 12.7%.
About overall survival: 1-year, 2-year, 3-year, 4-year and 5-year overall survival rates
were 75.2%; 57.5%; 45.2%; 39.2% and 22.4 % respectively. The overall survival by stage:
stage III rate was 42.5% and stage IV accounted for 11.3%. Difference was statistically
significant.

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CHAPTER 2: MATERIAL AND METHODS
2.1. MATERIAL
2.1.1. Criteria for patient selection
- Patients with mobile tongue cancer at stages III, IV (M0) according to AJCC 2010
- Histopathological diagnosis of tumor is squamous cell carcinoma
- Age from 18 to 70 years old
- Scale of performance status (ECOG) from 0 to 2
- Bone marrow, liver, and kidney functions are good
- Do not have other diseases at risk of death and have no other cancer.
- Have a full information record
2.1.2. Exclusion criteria
- Patients do not meet above criteria
- Patient has no information about disease status after treatment.
2.2. METHODS
2.2.1. Research design
Research methods: Descriptive study.
2.2.2. Sample size
a. Calculation of sample size by rate of response to TC regime

N = Z (21−α / 2 )

p.(1 − p )
d2

Sample size:

N: Sample size Z 1-α/2 = 1.96 d = 0.1
p: Rate of response to TC regimen is 56%, which means, p = 0.56
Minimum sample size is 95 patients. A 125-patient sample was chosen.
2.2.3. Method: Patients meeting all above criteria were recruited for the study. Patients
received full clinical and subclinical evaluations before, during and after treatment, including
immunohistochemistry test for specimens to determine expression rates and extents of p53,
EGFR, and Her-2. Patients were treated by neo-adjuvant regimens with Docetaxel 75mg/m2
or Paclitaxel 175mg/m2 in day 1; Cisplatin 100 mg/m2 in day 2. Response and side effect
statuses were evaluated after each cycle. After 3 cycles, a medical consultancy was did to
decide whether patients should continue to receive surgery or radiotherapy or a combination
of 2 methods. Patients continued to be monitored for overall survival after treatment. All
information was fully recorded according to consistent medical record form.
2.2.4. Data analysis: Information was encoded and processed by SPSS 20.0 software.
- Average rate, standard deviation, maximum and minimum values were calculated.


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- A comparison of statistical significance test with p < 0.05. OS was analyzed by the
Kaplan - Meier method. The Log-rank test method was used to compare overall survival
between two groups.
Chapter 3: RESULTS
After doing a study on 125 patients from 2012 to 2018, we had some following conclusions:
3.1. SOME CLINICAL AND HISTOPHATHOLOGICAL CHARACTERISTICS OF
STUDIED PATIENT GROUP
3.1.1. Age and gender
Table 3.1. Distribution of age and gender
Male

Female
Summary
Age
Pts
%
Pts
%
Pts
%
≤ 40
5
4
3
2,4
8
6,4
41 - 50
36
28,8
11
8,8
47
37,6
51 - 60
39
31,2
9
7,2
48
38,4

≥ 61
18
14,4
4
3,2
22
17,6
Sum
98
78,4
27
21,6
125
100
Observation: Average age was 52.5 ± 8.6, age group from 41 to 60 is the most common,
accounting for 76%. Male / female ratio was 98/27 = 3.6/1.
3.1.2 Disease’s stage
Table 3.7. Distribution of T-N stage clinically
N0
N1
N2
N3
Sum
Pts %
Pts %
Pts %
Pts %
Pts
%
N

T
T2
0
0
1
0,8
10 8
1
0.8 12
9,6
T3
26 20,8
13 10,4 2
1,6
0
0
41
32,8
T4
33 26,4
36 28,8 3
2,4
0
0
72
57,6
Sum 59 47,2
50 40,0 15 12,0 1
0,8 125 100
Observation: Among 125 patients, there were 72 stage-4 patients, which reached the

highest rate (57.6%). Patients at stages N0 and N1 were 47.2% and 40% respectively,
accounting for the highest rates.
3.1.3. Treatment methods
Table 3.10. Treatment methods
Methods
Pts
%
Resect half tongue + resect lymph nodes or half tongue + resect 63
50,4
lymph nodes + resect jaw bone
Post-neoadjuvant chemo radiotherapy
62
49,6
Sum
125
100
Observation: 63 patients received surgical inventions to resect half tongue + resect lymph
nodes or half tongue + resect lymph nodes + resect jaw accounted to 50.4% (therein, 2


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patients were resected half tongue + resected lymph nodes + resected jaw). 62/125 patients
received post-chemo radiotherapy, accounting for 49.6%.
3.2. RESPONSE AND SIDE EFFECTS STATUSES
3.2.1. Response status according to chemotherapy course
Table 3.11. Response status after chemotherapy cycles
Respone
CR
PR

SD
PD
∑
Pts
Pts
Pts
Pts
%
%
%
%
status
Cylce I
0
0
31
24,8 93
74,4 1
0,8
125
Cycle II
0
0
66
52,8 58
46,4 1
0,8
125
Cycle III
18

14,4 55
44
46
36,8 6
4,8
125
After 3 cycles 18
14,4 55
44
46
36,8 6
4,8
125
Observation: After 3 cycles, complete response rate was 14.4%, parital response rate
accounted for 36.8%, non-remission rate was 36.8%; progressive disease accounted for 4.8%.
Response rate increased gradually through chemotherapy cycles.
3.2.2. Response status after 3 cycles
Table 3.12. Response status by age and gender after 3 cycles
Response status
CR+PR
SD +PD
p
Factors
Pts
%
Pts
%
Age (n=125)
≤ 50
34

61,8
21
38,2
P = 0,492; OR = 1,28
CI 95% 0,62-2,64
> 50
39
55,7
31
44,3
Gender (n=125)
Male
54
55,1
44
45,9
P=0,154; OR = 0,51
CI 95% 0,21-1,29
Female
19
70,4
8
39,6
Observation: Response status by age and gender didn’t have a statistically difference.
Table 3.13. Response status by T, N
CR+PR
SD +PD
Tổng
Stage
p

Pts
%
Pts
%
Pts
* T(n=125)
T2
3
25
9
75
12
0,041
T3
24
58,5
17
41,5
41
T4
46
63,9
26
36,1
72
* N (n=125)
N0
43
72,9
16

27,1
59
P=0,002
N1,2,3
30
45,5
36
55,5
66
* Stage (n=125)
III
24
64,9
13
36,1
37
P=0,342
IV
49
55,7
39
44,3
88
Observation: Response rates of patients with stage T4 and T3 disease were 63.9% and
58.5% respectively, while 72.9% and 45.5% were response rates of nodal metastasis and non-


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nodal metastasis groups respectively. Stage-III patient’s response rate was higher than that

of stage-IV patient.
Table 3.14. Response status by histological grade
Histologica CR+PR
SD +PD
∑
p
l grade
Pts
%
Pts
%
Pts
I
10
52,6
9
47,4
19
P=0,853
II
46
59,7
31
40,3
77
III
17
58,6
12
41,4

29
Observation: Response rates of patients with histological grades 1, 2 and 3 were 52.6%,
58.6% and 59.7% respectively.
3.2.3. Patient rates were designated to receive surgery or radiotherapy after 3
chemotherapy cycles
Table 3.15. Designation of surgery or radiotherapy after neo-adjuvant chemotherapy.
Surgery
Radiation
Methods
Pts
%
Pts
%
T
T2
5
4
7
5,6
T3
26
20,8
15
12
T4
35
28
37
29,6
Sum

66
52,8
59
47,2
N
N0
34
27,2
25
20
N1,2,3
32
25,6
34
27,2
Sum
66
52,8
59
47,2
Observation: After 3 cycles, patient rate designated to receive radiotherapy was 47.2%.
3.2.4. Cell degeneration after chemotherapy
Table 3.16. Cell degeneration rate
Cell degeneration rate
Pts
%
<5%
6
9,5
5 - 49%

28
44,4
50 - 99%
20
31,8
100%
9
14,3
Tổng
63
100
Observation: Among 66 patients designated to receive surgery, there were 63 people
receiving surgery. Post-operative histopathological result showed that 14.3% of patients
had no cancer cell.
Table 3.17. Cell degeneration rate by stage
Rate
≤ 50 %
> 50 %
∑
p
Pts
%
Pts
%
Pts
%
T


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T2
7
11,1
2
3,2
9
14,3
P=0,118
T3
10
15,9
15
23,8
25
39,7
T4
17
27,0
12
19,0
29
46,0
N
N0
16
25,4
19
30,1
35

55,5
P=0,142
N1,2,3
18
28,6
10
15,9
28
44,5
Observation: When all participants were divided into 2 groups: cell degeneration rate ≤ 50%
and cell degeneration rate > 50% groups for comparation of degeneration level after treatment
with factors such as T, N and disease’s stage. We didn’t found any statistically difference.
3.2.5. Side effects
Table 3.19. Side effects on hematology, liver and kidneys after 3 chemotherapy cycles.
Times / ∑ Cycles
%
Low hemoglobin
186/375
49,6
Leukopenia
256/375
68,3
Low granulocytes
102/375
74,7
Thrombocytopenia
53/375
14,1
Elevated SGOT
50/375

13,3
Elevated Creatinine
17/375
4,5
Observation: low hemoglobin rate acconted for 49.6%; leukopenia rate was 68.3%, low
granulocytes rate was 74.7%; thrombocytopenia rate was 14.1%. Elevated SGOT and
creatinin rates were 13.3% and 4.5% respectively.
3.2.5.2. Side effects on hematology by treatment cycle
Table 3.20. Side effects on hematology
Level 0 Level I Level II Level III Level IV
∑
Pts % Pts % Pts % Pts % Pts %
Hemoglobin
Cycle I
74 59,2 43 34,4 5
4,0 3
2,4 0
0
125
Cycle II
61 48,8 42 33,6 19 15,2 3
2,4 0
0
125
Cycle III
54 43,2 44 35,2 24 19,2 3
2,4 0
0
125
Leukopenia

Cycle I
57 45,6 14 11,2 18 14,4 37 29,6 12 9,6 125
Cycle II
50 40,0 17 13,6 19 15,2 26 20,8 13 10,4 125
Cycle III
57 45,6 13 10,4 17 13,6 28 22,4 10 8
125
Granulocytes
Cycle I
30 24,0 15 12,0 17 13,6 35 28,0 28 22,4 125
Cycle II
33 26,4 16 12,8 12 9,6 31 24,8 33 26,4 125
Cycle III
32 25,6 13 10,4 19 15,2 29 23,2 32 25,6 125
Thrombocytopenia
Cycle I
108 86,4 16 12,8 1
0,8 0
0
0
0
125
Cycle II
106 84,8 19 15,2 0
0
0
0
0
0
125

Cycle III
108 86,4 17 13,6 0
0
0
0
0
0
125


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Observation: Low hemoglobin maily occurred at grades 1 and 2. Grade-4 leukopenia
accounted for 6.7%. There was no patient with thrombocytopenia at grades 3 and 4.
3.2.5.3. Side effects on liver and kidneys by treatment cycle
Table 3.21. Side effects on liver and kidneys by treatment cycle
Level 0
Level I
Level II Level III Level IV ∑
Pts % Pts % Pts % Pts % Pts %
SGOT
Cycle I
98 78,4 26 20,8 1
0,8 0
0
0
0
125
Cycle II
109 87,2 16 12,8 0

0
0
0
0
0
125
Cycle III 118 94,4 7
5,6 0
0
0
0
0
0
125
Creatinin
Cycle I
122 97,6 3
2,4 0
0
0
0
0
0
125
Cycle II
120 96,0 5
4,0 0
0
0
0

0
0
125
Cycle III 116 92,8 9
7,2 0
0
0
0
0
0
125
Observation: Grade-II elevated SGOT level only occurred in the first course, accounting for
0.8%. There was no patient with elevated creatinin level at grade 2, 3 or 4.
3.2.5.5. Other side effects
Table 3.22. Distribution of other side effects by patient
Level 0 Level I
Level II Level III Level IV Sum
Side effects
Pts % Pts % Pts Pts % Pts % Pts
Nausea
34 27,2 39 31,2 25 20 27 21,6 0
0
125
Vomitting
61 48,8 24 19,2 18 14,4 22 17,6 0
0
125
Mucositis
110 88,0 8
6,4 2

1,6 0
0
0
0
125
Nerve pain 78 62,4 41 32,8 6
4,8 0
0
0
0
125
Fatigue
20 16,0 89 71,2 16 12,8 0
0
0
0
125
Observation: Other side effects maily occurred at grades I, II; and didn’t occur at grade IV.
3.3. OVERALL SURVIVAL
Overall survival


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Chart 3.1. Graph of overall survival
Table 3.23. Table of 1-year, 2-year, 3-year, 4-year and 5-year overall survivals
OS
1 year
2 year
3 year

4 year
5 year
%
78,4
60,2
46,5
37,2
24,1
Observation: 5-year overall survival rate was 24.1%. Average overall survival was 36.48 ±
2.23 months.
3.4. RATES OF EXPRESSION OF P53, EGFR AND HER2 MARKERS AND SOME
FACTORS RELATED TO OVERALL SURVIVAL
3.4.1. Rates of expression of p53, EGFR and Her2 markers
Rate of expression of EGFR marker
Chart 3.1. Rate of expression of EGFR marker
Observation: Rate of EGFR-positive expression was 36.8%

Correlation between EGFR expression status with pathological characteristics
Table 3.24. Correlation between EGFR status with pathological characteristics
Factors
Positive
Negative
Sum
p
(Pts)
(Pts)
(Pts)
Age
≤ 50
21

34
55
P = 0,776; OR = 1,11
CI 95% 0,53-2,31
> 50
25
45
70
Gender


13

Male
38
60
98
P = 0,383; OR = 1,50
CI 95% 0,60-3,77
Female
8
19
27
T
T2,3
14
39
53
P = 0,039; OR = 0,44
CI 95% 0,21-0,97

T4
32
40
72
N
Positive
23
36
59
P = 0,632; OR = 1,19
CI 95% 0,58-2,47
Negative
23
43
66
Stage
III
9
28
37
P = 0,049
IV (M0)
37
51
88
Histological grade
I
9
10
19

II
30
47
77
P = 0,216
III
7
22
29
Response status
CR + PR
25
48
73
P = 0,483
SD + PD
21
31
52
Observation: There was a correlation between EGFR expression status with stage T and
disease’s stage. There was no correlation between expression of EGFR status with age,
gender, nodal metastasis, histological grade, response status.
Rate of expression of Her2 marker
Chart 3.3. Rate of expression of Her2 marker
Observation: Rate of expression of Her2-positive was 4.8%
Correlation between expression of Her2 status with pathological characteristics
Table 3.25. Correlation between expression of Her2 status with pathological characteristics
Factors
Positive
Negative

Sum (Pts) p
(Pts)
(Pts)
Age
≤ 50
4
51
55
P = 0,252; OR = 2,67
CI 95% 0,47-15,13
> 50
2
68
70
Gender
Male
6
92
98
P = 0,188; OR = 0,94
CI 95% 0,89-0,99
Females
0
27
27
T
T2,3
2
51
53

P = 0,645; OR = 0,67
CI 95% 0,12-3,78
T4
4
68
72
N
Positive
6
60
66
P = 0,018; OR = 1,1
CI 95% 1,02-1,19
Negative
0
59
59


14

Stage
III
0
37
37
P = 0,104
IV (M0)
6
82

88
Histological grade
I
0
19
19
II
5
72
77
P = 0,459
III
1
28
29
Response status
CR + PR
4
69
73
P = 0,674
SD + PD
2
50
52
Observation: There was a correlation between expression of EGFR status with nodal
metastasis status (N). There was no correlation between expression of EGFR status with age,
gender, stage T, disease’s stage, histological grade, response status.
Rate of expression of p53 marker
Chart 3.4. Rate of expression of p53 marker

Observation: Rate of expression of p53-positive was 33.6%
Correlation between expression of p53 status with pathological characteristics
Table 3.26. Correlation between expression of p53 status with pathological characteristics
Factors
Positive
Negative
Sum (Pts) p
(Pts)
(Pts)
Age
≤ 50
24
31
55
P = 0,035; OR = 2,24
CI 95% 1,05-4,76
> 50
18
52
70
Gender
Male
30
68
98
P = 0,178; OR = 0,55
CI 95% 0,23-1,32
Female
12
15

27
T
T2,3
18
35
53
P = 0,941; OR = 1,03
CI 95% 0,49-2,18
T4
24
48
72
N
Positive
19
40
59
P = 0,755; OR = 0,89
CI 95% 0,42-1,87
Negative
23
43
66
Stage
III
10
27
37
P = 0,313
IV (M0)

32
56
88
Histological grade
I
8
11
19
II
28
49
77
P = 0,218
III
6
23
29


15

Response status
CR + PR
27
SD + PD
15

46
37

73
52

P = 0,342

Observation: There was no correlation between expression of p53 status with gender, stage T,
nodal metastasis status, disease’s stage, histological grade, response status.

3.4.2. Some factors related to overall survival
3.4.2.1. 5-year overall survival by T

Chart 3.5. Graph of 5-year overall survival by T
Observation: overall survival rates of grades T2 and T3 groups, which were 39.4% and
6.5% respectively, were higher than that of grade T4 group. Difference was statistically
significant with p=0.025.
3.4.2.2. 5-year overall survival by N


16

Chart 3.6. Graph of 5-year overall survival by N
Observation: overall survival rate of N0 group was higher than that of nodal metastasis
group, overall survival rates of two groups were 35.1% and 10.0% respectively with p =
0.000.
3.4.2.3. 5-year overall survival by stage

Chart 3.7. Graph of 5-year overall survival by stage
Observation: Stage-III patient’s 5-year overall survival was 48.1%, which was much
higher than that in stage-IV patient as 7.9%. Difference was statistically significant with
p= 0.002.

3.4.2.4. 5-year overall survival by treatment method


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Observation: overall survival rate of post-neoadjuvant-chemotherapy surgery group was
44.4%, which was much higher than that in post-neoadjuvant-chemotherapy combined
chemotherapy and radiotherapy group as 29.0% with p= 0.005.
3.4.2.6. 5-year overall survival by response to neoadjuvant-chemotherapy

Chart 3.10. Graph of 5-year overall survival by response to neoadjuvant-chemotherapy
Observation: overall survival rate of response group was 36.7%, which was higher than that
in non-response group (11.6%). Difference was statistically significant with p=0.002.
3.4.2.7. Correlation between EGFR expression status with overall survival


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Chart 3.11. 5-year overall survival by EGFR expression status
Observation: overall survival of EGFR-postive group was shorter than that in EGFRnegative group. Difference was statistically significant with p= 0.016.
3.4.2.8. Correlation between Her2 expression status with overall survival

Chart 3.12. 5-year overall survival by Her2 expression status
Observation: Correlation between Her2 expression status and overall survival wasn’t seen
3.4.2.9. Correlation between p53 expression status with overall survival


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Chart 3.13. 5-year overall survival by p53 expression status

Observation: Correlation between p53 expression status and overall survival wasn’t seen
CHAPTER 4. DISCUSSION
4.1. SOME CLINICAL AND PATHOLOGICAL CHARACTERISTICS
4.1.1. Age and gender
In our study, 95.6% of patients were above 40 years old, while the most common agegroup was from 41 to 60 years old (accounting for 76%). This result was also similar to those
of domestic and foreign authors. A study of Fabio et al showed that the most common agegroup was from 41 to 60 years old, accounting for 46%. Nguyen Van Tai’s study in 2018
showed that age-group above 50 accounted for the majority, while age-group from 51 to 60
years old was the most common.
All TC studies showed that male patient rate was higher that of female, a possible reason
was that men receive many negative effects from many risks causing tongue cancer such as
smoking, drinking alcohol... Male / female ratio in our study was 3.6/1, which was suitable
with Pham Cam Phuong’s study, reported that male / female ratio was 4.5/1. Stefan’s study
(2013) on 6241 tongue-cancer patients showed that male / female ratio was 2.88/1.
4.1.2. Disease’s stage
Our result showed that among 125 patients, there was 12 patients with stage T2 disease
(9.6%), all of them had cervical nodes and positive cytology results; 41 patients with stage T3
disease (32.8%), 72 stage T4 patients (57.6%) with invasive lesions of anterior tonsil pillar,
mouth floor, and/or tongue muscles.


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Stage N: Our result was similar to those of other authors. A study of Zhong et al.
(2012) on 256 tongue-cancer in situ patients showed that patient rates with stages N 0, N1 and
N2 disease were 43%, 36.7% and 20.3% respectively.
Recruited patients had stages III and IV (M0) disease, after stage arrangement, rates of
patients with stages III and IV disease were 32% and 68% respectively. With people group
similar with that of above, Le Van Quang’s study also showed a similar result with 27.4% of
patients at stage III, and 72.6% of patients at stage IV. A comparison of correlation between
stage T and clinical nodal metastasis showed a difference: stage T4 had a higher nodal

metastasis rate (31.2%).
4.2. RESPONSE AND SIDE EFFECTS STATUSES
4.2.1. Response to neo-adjuvant chemotherapy
Chemotherapy regimen
Pre-operative chemotherapy was usually applied for advanced cancers of head, face and
neck. Initial studies used CF regimen. Then, some authors added taxane (docetaxel and
palitaxel) to CF regimen to make TCT regimen. This new regimen showed a higher response
rate, but also more side effects. In Vietnam, most patients had average BMIs, poor intakes
and were difficult to tolerate a 3-drug regimen. So, cisplatin combined with taxane
(docetaxel and palitaxel) could help patients achieve high response rates and good tolerances.

General response rate by chemotherapy cycles
In our study, all patients received full treatments for 3 cycles. Response status was
increased gradually by chemotherapy cycles. After 3 cycles, complete response rate was
14.4%, parital response rate accounted for 36.8%, non-remission rate was 36.8%; progressive
disease accounted for 4.8%. Till now, no author in Vietnam has reported neo-adjuvant
chemotherapy result by this regimen, however, some studies for other regimens for patientgroup like ours were did. According to Le Van Quang’s result of CF regimen study, complete
response rate was 12%, parital response rate accounted for 50.4%, non-remission rate was
30.8%; progressive disease accounted for 6.8%. Salama et al. did a Phase-II study on 222
patients with recurrent and metastatic head and neck cancer at stages III and IV (M 0) treated
by TC regimen followed by simultaneous chemotherapy and radiotherapy for radical
treatment, his result showed that complete response rate was 75%. Similarly, Vokes (2003)
showed a complete response rate after using neo-adjuvant TC chemotherapy for 69 patients
with recurrent and metastatic head and neck cancer in situ as 75.3%.


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CF and TC are the most common 2-drug regimens. Both of them had high complete
response rates, helping reduce sizes of tumor and lymph nodes, facilitate future surgery for

radical treatment.
Response rate by disease’s stage
In our study, response rates after using 3 chemotherapy cycles for patients with stages III
and IV disease were 64.8% and 55.7% respectively. There was a difference of response
levels between stages T and N with p < 0.05. After doing a study on neo-adjuvant Paclitxel
and Cisplatin regimen on patients with head and neck squamous cell carcinoma at stage IV,
Stefano (2011) reported a response rate after 3 chemotherapy cycles of 74.4% for this stage.
The author thought that his response rate was higher than that in some other studies due to
more chemotherapy cycles used and higher dose for Paclitaxel on his study.
Designation of surgery after 3 chemotherapy cycles by disease’s stage
After 3 neo-adjuvant TC cycles, 66 patients were designated to receive surgery,
accounting for 52.8%.
So, pre-operative neo-adjuvant chemotherapy significantly
contributed to reduce sizes of tongue tumor and cervical nodes to make surgery more easy. In
2003, Licitra reported his study on 195 with oral squamous cell carcinoma, study’ result
showed that neo-adjuvant chemotherapy helped reduce mandibulotomy rate [83].
Post-treatment cell degeneration
According to Zhong, patient-group with a good response on histopathology, that is only
below 10% of cancer cells remained on their specimens, had overall and progression-free
survivals higher significantly than those in poor-response group. Among 63 operated
patients, 9 people had no cancer cell on their post-operative specimens, accounting for 14.3%.
However, this result didn’t absolutely reflect histopathological response rate of the regimen
because we didn’t do any re-biopsies for patient-group treated by post-chemotherapy
radiation. Our study result was different from results of other authors, this was due to our
study only implemented on tongue squamous cell carcinoma, but not on other sites in the oral
cavity.
4.2.2. Side effects
4.2.2.1. Side effects on hematology, liver and kidneys
Chemotherapy drugs didn’t only affect to cancer cells, but also normal cells of the body,
especially cells having fast division speeds such as cells lining the digestive tract, hair cells,

red blood cells, and white blood cells. This factor affected to patient’s treatment course and
life quality, patients may be even died due to chemotherapy drugs.
Side effects on hematology
Low hemoglobin
Among 375 patients treated by chemotherapy, 129 people got grade-1 low hemoglobin
(34.4%), 48 patients had grade-2 low hemoglobin (12.8%). When doing a comparision with
other studies, which also used TC regimen or other 2-drug regimens or even 3-drug TCF


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regimens, results were similar.
Rajesh et al (2018) also studied 70 patients with stage T4 oral cancer, 56 people were
treated by TC regimen, his result showed that only 2 patients had low hemoglobin at grade 3
or 4 (3.6%).
Stefano et al (2011) studied 43 patients with recurrent and metastatic head and neck
cancer at stage IV (M0) from January, 1999 to December, 2002 by neo-adjuvant TC
chemotherapy regime. After 3 cycles, 10 patients had low hemoglobin at grades 1 and 2
(23.3%), and no patient had low hemoglobin at grade 3 or 4. Therefore, TC regime helped
reduce side effect of low hemoglobin.
Leukopenia
Before treament, all patients had normal leukocyte and granulocyte counts, but during
taxane and cisplatin combination regimen, grade-3 leukopenia occured on 91/375 cycles,
accounting for 24.3%. Grade-4 leukopenia rate was 9.3%. Grade-3 leukopenia rates on
courses I, II and III were 29.6%; 20.8% and 22.4 respectively. Grade-4 leukopenia rates on
courses I, II and III were 9.6%; 10.4% and 8.0% respectively. Leukopenia rates at grades 3
and 4 were 25.3% and 24.8% respectively (caculated by 375 cycles).
Gibson (2005) stated that TC regimen had a lower side effect of leukopenia compared to
that of CF regimem. So, leukopenia rate at our patient-group treated by TC regimen was
similar to results of other author around the world, and was lower than CF patient-group.

Thrombocytopenia
In our study, thrombocytopenia rate after 3 cycles was 14.1% (rates of patient with
stages 1 and 2 thrombocytopenia were 13.9% and 0.2% respectively, no thrombocytopenia
patient was at stage 3 or 4). Thrombocytopenia rate by each cycle: cycle 1 (12.8%), cycle
2 (15.2%), cycle 3 (13.6%).
Another study by Basaran (2013), a study on using TC regimen on 50 patients with
recurrent and metastatic recurrent and metastatic head and neck cancer, showed that
thrombocytopenia condition was uncommon, it mainly occured at grades 1 and 2 (3.9% and
1% respectively), both thrombocytopenia rates at grades 3 and 4 were 1%. Gibson reported
that rates of thrombocytopenia patient at grades 3 and 4 treated by TC regimen were 3% and
1% respectively. When comparing with CF, TC regimen had fewer thrombocytopenia. Thus,
TC regimen also showed little side effect on thrombocytopenia, if any, it mainly occured at
mild level, grades 1 and 2.
Toxicities on liver and kidneys
TC regimen rarely caused elevated liver enzymes. In our study, grade-II elevated
SGOT was only seen in coruse I with a rate of 0.8%. Most pts had grade-I elevated SGOT.
Cisplatin caused a severe accumulation of side effects on the kidneys. However, our
result showed that there was no patient with elevated creatinine level at grades 2, 3 and 4.
Grade 1 elevate creatinine level were 2.4%, 4.0% and 7.2% at courses 1, 2 and 3 respectively.


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Foreign authors also reported similar results. According to Stefano et al. (2011), TC regimen
rarely caused side effects on liver and kidneys, there were no patient with elevated creatinine
or liver enzyme level at grades 3 and 4. In general, side effects on hematology, liver and
kidneys were few, no patient had life-threatening side effects.
4.2.2.1. Other side effects
Vomiting and nausea
In the treatment regimen, antiemetic was designated during chemotherapy and for postchemotherapy prophylaxis. Our result showed that rates of patients having grades I, II and III

nausea were 31.2%; 20%; 21.6% respectively; no patient had a grade-4 nausea. Rate of
patients having grades I, II and III vomiting were 19.2%; 14.4%; 17.6% respectively; no
patient had a grade-4 vomiting.
Myalgia
Myalgia was often associated with a treatment using paclitaxel. However, this condition
was usually mild. As in Adamo’s study (2003), only 5.8% of patients appeared this condition
and all of them had grade-2 myalgia. Gibson’s study result (2005) showed that there was no
patient with grades 3 and 4 myalgia in total of 108 patients treated by TC regimen. Our result
was similar: myalgia condition mainly occured at grades I and II, accounting for 6.4% and
1.6%, respectively.
Side effects on the peripheral nervous system
Side effects on the peripheral nervous system mainly occured at grades I and II,
accounting for 32.8% and 4.8% respectively. There was patient with grade III or IV side
effects. Stefano’s study result also showed that rate of patients having side effects on
peripheral nervous system was 11.6%, of which there were only 2 patients with grade 3 side
effects and no patient had grade 4 side effects. In Gibson’s study, there was no patients having
side effects on the peripheral nervous system at grade 4, while grade 3 rate was 5%.
These side effects were often associated with a treatment using paclitaxel. Patients were
advised something about lifestyle to minimize these effects, such as keeping warm the body,
avoiding exposure to cold temperatures, including refrigerators and air conditioners, drinking
warm water, and using protective equipment.
4.3. Overall survival
Overall survival
In our study including 123 patients, 1-year, 2-year, 3-year, 4-year and 5-year overall
survivals were 78.4%; 60.2%; 46.5%; 37.2% and 24.1% respectively. According to Stefano’s
study on neo-adjuvant TC chemotherapy regimen, average OS was 24 months, patient rates
having 3-year and 5-year overall survivals were 37% and 26%, respectively. Vokes’s study
result showed that 2-year and 3-year overall survival rates were 77% and 70%, respectively
after neo-adjuvant treatment by palitaxel combined to carboplatin by week for 69 patients
with recurrent and metastatic head and neck cancer in situ.

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When doing a comparision with other 2-drug regimens, such as CF regimen, overall
survival also showed similar results. Le Van Quang (2013) studied neo-adjuvant CF regimen,
and reported that 1-year, 2-year, 3-year, 4-year and 5-year overall survivals were 75.2%,
57.5%, 45.2%, 39, 2% and 22.4% respectively.
4.4. EXPRESSION RATES OF MARKERS P53, EGFR AND HER2 AND SOME
FACTORS RELATED TO PROGNOSIS OF TONGUE CANCER
4.4.1. Expression rates of markers p53, EGFR and Her2
Expression rate of marker EGFR and correlation between it and pathological
characteristics
Our result showed that among 125 patients, 46 people had EGFR-positive expressions,
accounting for 36.8%. There was a correlation between EGFR expression status and stage T,
disease stage with p = 0.039 and p = 0.049. There was no correlation between EGFR
expression and age, gender, nodal metastasis, histological grade, and response in our study.
When comparing to other authors, EGFR-positive expression rate ranged from 35% to 60%,
depending on studies. Xia’s study showed no correlation between immunohistochemistry
expression of EGFR with stage T (p > 0.21), there were however a correlation between it with
nodal metastasis and distant metastasis.
Expression rate of marker Her2
Expression rate of marker Her2 varied widely between different studies. Hanken et al.,
when studying 196 oral-cancer patients, found that 2% of patients had Her2-positive.
However, Xia et al. (1999) showed that 36% of patients had Her2-positive in his study.
Similarly, the study of Chen et al. (2003) showed that 40.7% of patients had Her2-positive .
In our study, this rate was 4.8%. The reason for such differences may be due to sample sizes
of the authors were not large enough and materials of the studies were different.
We found that there was no correlation between Her2 expression status and age, gender,
stage T, disease’s stage, histological grade. Our response status was similar to Chen’s result.

Expression rate of marker p53
In our study, rate of patients having p53-positive immunohistochemistry was 33.6%.
Temam found that 37% of the patients in his study were positive for p53
immunohistochemistry. Author Perrone also gave a similar result, but slightly higher (45%).
We found that there was no correlation between p53 expression and gender, stage T,
nodal metastasis, disease’s stage, histological grade, response status. Perrone also asserted
that there was no correlation between above factors with stage T, nodal metastasis.
4.4.2. Some factors related to prognosis of tongue cancer at stages III and IV
Overall survival by some factors
We analyzed overall survival by stage T. Our result showed that survival rates of patient
with stages T2 and T3 disease were 39.4% and 6.5% respectively, and both of them were
higher than that in stage-4 group. If nodal metastasis wasn’t appeared, prognosis was good,


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but when patients had nodal metastasis, their prognosis was much worse and 5-year survival
rate was halved. In our study, 5-year survival rate in groups with and without clinical nodal
metastasis were 35.1% and 10.0%, respectively.
In the study, 5-year survival rate of stage-III patients was 48.1%, much higher than that
in stage IV group (7.9%). When comparing 5-year survival rate by gender, no difference was
found. OS difference between groups below and over 50 years was not statistically significant
with p > 0.05. Group having responses after neo-adjuvant chemotherapy had a 5-year survival
rate of 36.7%, higher than that in non-response group (11.6%).
Overall survival by treatment method: average OS of surgical and radiotherapy groups
after neo-adjuvant chemotherapy were 42.32 and 30.03 months respectively, and 5-year
survival rates were 44.4% and 29.0% respectively. The difference was statistically significant
with p = 0.005. Thus, neo-adjuvant chemotherapy helped increase rate of patient who
received surgical intervention, the group had a longer overall survival.
Overall survival by immunohistochemistry

Overall survival of EGFR-positive group was shorter than that negative group, the
difference was statistically significant with p = 0.016. In EGFR-positive group, average overall
survival was 29.1 months, lower than that in negative group (40.2 months). However, we found
that Her2 and p53 did not affect to overall survival with p = 0.739 and p = 0.277 respectively.
A study of Xia et al. showed that both EGFR and Her2 affectd to overall survival. Chen et
al. suggest that EGFR expression status affected to overall survival, particularly, EGFR-positive
group had a shorter overall survival than that in negative group with p = 0.001. However, Her-2
expression status did not affect to overall survival, with p = 0.928.
CONCLUSION
Through a study on 125 patients with stages III and IV (M0) disease treated by neo-adjuvant
TC regimen at K hospital from 1/2012 to 10/2016, we made some following conclusions:
1. Response and side effects statuses
- After 3 cycles, complete and partial response rates accounted for 14.4% and 44%
-

-

respectively; non-remission rate was 30.8%; progressive patients accounted for 6.8 %.
Low hemoglobin was mainly occurred grades 1 and 2. There was no patient with low
hemoglobin at grade 3 or 4.
Rates of patient with grade-3 leukopenia at courses I, II and III were 28%; 24.8% and
23.2% respectively. While, rates of patient with grade-4 leukopenia courses I, II and III
were 22.4%; 26.4% and 25.6% respectively.
Vomiting and nausea mainly occured at grades 1 and 2.
Myalgia and peripheral neuropathy complications mainly occured at grades 1 and 2.