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

1 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 goals: 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) 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 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 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 this study 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 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 and thrombocytopenia There was no grade or thrombocytopenia case recorded Rates of participants having grade leukopenia on courses I, II and III were 28%, 24.8%, and 23.2% respectively Rates of participants having grade leukopenia on course I, II and III were 22.4%; 26.4% and 25.6% respectively Vomiting and nausea mainly occured at grades and Myalgia and peripheral neuropathy complications also occurred at grades and 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 Thesis’s layout The thesis consists of 123 pages: pages of “Introduction”, pages of the “Conclusion” and page of the “Proposal” It has chapters: “Literature Review” chapter 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, picture and 110 references (11 references in Vietnamese and 99 others in English) 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 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 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 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 to - 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 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 / ) 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 Response and side effect statuses were evaluated after each cycle After cycles, a medical consultancy was did to decide whether patients should continue to receive surgery or radiotherapy or a combination of 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 - 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 2,4 6,4 41 - 50 36 28,8 11 8,8 47 37,6 51 - 60 39 31,2 7,2 48 38,4 ≥ 61 18 14,4 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 0,8 10 0.8 12 9,6 T3 26 20,8 13 10,4 1,6 0 41 32,8 T4 33 26,4 36 28,8 2,4 0 72 57,6 Sum 59 47,2 50 40,0 15 12,0 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, 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 31 24,8 93 74,4 0,8 125 Cycle II 0 66 52,8 58 46,4 0,8 125 Cycle III 18 14,4 55 44 46 36,8 4,8 125 After cycles 18 14,4 55 44 46 36,8 4,8 125 Observation: After 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 cycles Table 3.12 Response status by age and gender after 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 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 25 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- 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 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, and were 52.6%, 58.6% and 59.7% respectively 3.2.3 Patient rates were designated to receive surgery or radiotherapy after chemotherapy cycles Table 3.15 Designation of surgery or radiotherapy after neo-adjuvant chemotherapy Surgery Radiation Methods Pts % Pts % T T2 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 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 % 50 % ∑ p Pts % Pts % Pts % T 10 T2 11,1 3,2 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 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 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 Level I Level II Level III Level IV ∑ Pts % Pts % Pts % Pts % Pts % Hemoglobin Cycle I 74 59,2 43 34,4 4,0 2,4 0 125 Cycle II 61 48,8 42 33,6 19 15,2 2,4 0 125 Cycle III 54 43,2 44 35,2 24 19,2 2,4 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 10 125 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 0,8 0 0 125 Cycle II 106 84,8 19 15,2 0 0 0 125 Cycle III 108 86,4 17 13,6 0 0 0 125 12 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 year year year year 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 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 28 37 P = 0,049 IV (M0) 37 51 88 Histological grade I 10 19 II 30 47 77 P = 0,216 III 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 51 55 P = 0,252; OR = 2,67 CI 95% 0,47-15,13 > 50 68 70 Gender Male 92 98 P = 0,188; OR = 0,94 CI 95% 0,89-0,99 Females 27 27 T T2,3 51 53 P = 0,645; OR = 0,67 CI 95% 0,12-3,78 T4 68 72 N Positive 60 66 P = 0,018; OR = 1,1 CI 95% 1,02-1,19 Negative 59 59 14 Stage III 37 37 P = 0,104 IV (M0) 82 88 Histological grade I 19 19 II 72 77 P = 0,459 III 28 29 Response status CR + PR 69 73 P = 0,674 SD + PD 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 11 19 II 28 49 77 P = 0,218 III 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 17 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 18 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 19 Chart 3.13 5-year overall survival by p53 expression status Observation: Correlation between p53 expression status and overall survival wasn’t seen CHAPTER 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 20 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 cycles Response status was increased gradually by chemotherapy cycles After 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% 21 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 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 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 chemotherapy cycles by disease’s stage After 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, 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 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 22 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 patients had low hemoglobin at grade or (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 cycles, 10 patients had low hemoglobin at grades and (23.3%), and no patient had low hemoglobin at grade or 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 and 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 cycles was 14.1% (rates of patient with stages and thrombocytopenia were 13.9% and 0.2% respectively, no thrombocytopenia patient was at stage or 4) Thrombocytopenia rate by each cycle: cycle (12.8%), cycle (15.2%), cycle (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 and (3.9% and 1% respectively), both thrombocytopenia rates at grades and were 1% Gibson reported that rates of thrombocytopenia patient at grades and 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 and 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, and Grade elevate creatinine level were 2.4%, 4.0% and 7.2% at courses 1, and respectively 23 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 and 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 and 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 patients with grade side effects and no patient had grade side effects In Gibson’s study, there was no patients having side effects on the peripheral nervous system at grade 4, while grade 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 24 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, 25 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: Response and side effects statuses - After 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 and There was no patient with low hemoglobin at grade or 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 and Myalgia and peripheral neuropathy complications mainly occured at grades and 26 Expression rates of markers p53, EGFR and Her2 and some factors related to overall - - survival (OS) Average OS was 36.48 ± 2.23 months 5-year overall survival rate was 24.1% After neo-adjuvant chemotherapy, average OS of surgical patient group was higher than that of radiotherapy group (42.32 vernus 30.03 months) EGFR-positive expression rate was 36,8% There was a correlation between EGFR expression status and stage T and disease stage Her2-positive expression rate was 4.8% There was a correlation between Her2 expression status and nodal metastasis status N P53-positive expression rate was 33.6% There was no correlation between p53 expression status and gender, stage T, nodal metastasis status, disease’s stage, histological grade, response status Stage T, nodal metastasis status, disease’s stage, response and expression statuses were factors affacting to overall survival SUGGESTIONS - TC chemotherapy regimen should be used before surgical treatment or radiotherapy to improve treatment efficacy for patients with stages III and IV (M0) tongue-cancer - Test of immunohistochemistry expression of EGFR should be designated during treatment of tongue cancer at stages III and IV (M0) ... 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... 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 28 37 P = 0,049 IV (M0) 37 51 88 Histological grade I 10 19 II 30 47 77 P = 0,216 III 22 29 Response... 0,12-3,78 T4 68 72 N Positive 60 66 P = 0,018; OR = 1,1 CI 95% 1,02-1,19 Negative 59 59 14 Stage III 37 37 P = 0,104 IV (M0) 82 88 Histological grade I 19 19 II 72 77 P = 0,459 III 28 29 Response status