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

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 M 0.. There

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 withmale/female ratio of 2.27 every year In Vietnam, there were about 1,877 new tongue cancercases 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 surgicalintervention and radiotherapy) helps downstage the disease, facilitate surgery andradiotherapy, reduce complications and restrict metastasis Around the world, the taxane andcisplatin combination regimen is more effective due to low-cost, popularity, simpleimplementation, and has fewer side effects than others Recent studies have shown that apartfrom classic prognostic factors, the prognosis of tongue cancer also depends on severalmolecular 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 chemotherapyregimen combined to surgery or radiotherapy for treatment of tongue cancer, as well as thecorrelation between some molecular biomarkers and the prognosis

Therefore, we did a study with topic: “Research of neo-adjuvant TC chemotherapyregimen 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 (M 0 ).

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 stagesleading many patients have to be hospitalized at stages III and IV At these stages, an initialsurgery is a large operation requiring experienced surgeons, patients usually feel tired aftersurgery and their post-operative chewing, swallowing and saying functions are affected.Meanwhile, treatment of stages III and IV (M0) using neo-adjuvant chemotherapy helpsreduce sizes of tumors and lymph nodes, facilitate surgery and radiotherapy, reduce

2complications and restrict metastasis Many studies around the world have demonstrated thatneo-adjuvant combination regimen containing taxane and cisplatin is more effective and lessside effects than some others In addition, treatment efficacy doesn’t only depend on thechoice of regimen but also on prognostic factors such as disease’s stage, histopathologicaltype, and age of patient Recent studies have shown that prognosis of the disease alsodepends on several molecular biomarkers of the tumor such as expressions of p53, Her2, andEGFR However, there are very few studies on regimens and the correlation betweenmolecular biomarkers and prognosis in Vietnam These are reasons promoting us to do thisstudy.

2 New contributions of the thesis

Through a study on 125 patients with stages III and IV (M0) tongue cancer who receivedneo-adjuvant TC chemotherapy regimens, we found that average age of getting the diseasewas 52.5, the most common age group was from 41 to 60 years old, accounting for 76%, andthe male/female ratio was 3.6/1 After 3 chemotherapy cycles, complete response rateaccounted for 14.4%; partial response rate was 44%; non-remission rate was 36.8%; and4.8% of participants became progressed Most participants had grades 1 and 2thrombocytopenia There was no grade 3 or 4 thrombocytopenia case recorded Rates ofparticipants 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 were22.4%; 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 reached24.1% OS of surgical group after neo-adjuvant chemotherapy was higher than that of post-radiotherapy combined with chemotherapy group after neo-adjuvant chemotherapy (42.32versus 30.03 months) The EGFR-positive expression rate was 36.8% There were acorrelation between EGFR expression and stage T and disease’s stage Her2-positiveexpression rate was 4.8% There was a correlation between Her2 expression and nodalmetastasis (N) The p53-positive expression was 33.6% There was no correlation betweenp53 expression and gender, stage T, nodal metastasis, disease stage, histological grade andresponse status Stage T, nodal metastasis status, disease’s stage, response status and EGFRexpression 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

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

Xia did a research on 111 patients with oral squamous cell carcinoma, EGFR expressionresult showed that 12% of EGFR expressions were (+++), 25% of expressions were (++),63% of expressions were (+) or (-) There was a correlation between immunohistochemistryexpression of EGFR and nodal metastasis and distant metastasis Chen’s study showed that57.6% of patients had EGFR expression, 40.7% of patients had Her-2 overexpression TheEGFR-positive group had a shorter OS than negative group However, Her-2 expression didnot affect overall survival Temam et al only analyzed p53-gene sequencing in early-stagehead and neck squamous cell carcinoma, his result showed that among 105 patients, therewere 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; non-remission rate was 30.8%; progressive disease accounted for 6.8 % According to stage, stageIII response rate was 75% while stage IV accounted for 57.6% Fully degenerated cells rateafter treatment was 12.7%

About overall survival: 1-year, 2-year, 3-year, 4-year and 5-year overall survival rateswere 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 statisticallysignificant

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

) 1 (

d

p p

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, includingimmunohistochemistry 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 effectstatuses were evaluated after each cycle After 3 cycles, a medical consultancy was did todecide 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 Allinformation 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

- A comparison of statistical significance test with p < 0.05 OS was analyzed by theKaplan - Meier method The Log-rank test method was used to compare overall survivalbetween 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

Age Male Pts % Female Pts % Summary Pts %

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

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

Resect half tongue + resect lymph nodes or half tongue + resect

lymph nodes + resect jaw bone

63 50,4

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

8patients were resected half tongue + resected lymph nodes + resected jaw) 62/125 patientsreceived 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

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

Observation: Response status by age and gender didn’t have a statistically difference.

Table 3.13 Response status by T, N

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

Table 3.15 Designation of surgery or radiotherapy after neo-adjuvant chemotherapy.

Methods SurgeryPts % Radiation Pts %

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 %

Observation: Among 66 patients designated to receive surgery, there were 63 people

receiving surgery Post-operative histopathological result showed that 14.3% of patientshad no cancer cell

Table 3.17 Cell degeneration rate by stage

Rate ≤ 50 % > 50 % ∑ p

Pts % Pts % Pts % T

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 treatmentwith factors such as T, N and disease’s stage We didn’t found any statistically difference

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 andcreatinin 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

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

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

3.4.1 Rates of expression of p53, EGFR and Her2 markers

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

(Pts)

Negative (Pts)

Sum (Pts) p Age

CI 95% 0,53-2,31

Gender

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

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

(Pts)

Negative (Pts) Sum (Pts) p Age

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

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

(Pts)

Negative (Pts) Sum (Pts) p Age

Response status

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 statisticallysignificant with p=0.025

3.4.2.2 5-year overall survival by N