1 ĐẶT VẤN ĐỀ Ung thư hạ họng thanh quản có tỷ lệ bệnh mắc cao, ước tính năm 2012 có khoảng 115.130 bệnh nhân mới mắc trên toàn cầu. Tại Việt Nam, bệnh đứng thứ hai trong các ung thư vùng đầu cổ, sau ung thư vòm. Phần lớn bệnh nhân ung thư hạ họng thanh quản đến viện khi bệnh đã ở giai đoạn muộn (III-IV) u lớn lan rộng, đã di căn hạch, hoặc di căn xa nên điều trị ít hiệu quả, tiên lượng xấu. Trước đây, điều trị chủ yếu là phẫu thuật cắt bỏ toàn bộ thanh quản, mất đi khả năng phát âm, ảnh hưởng lớn đến chất lượng sống, tỉ lệ tái phát và di căn cao. Trong 30 năm gần đây, hóa trị kết hợp xạ trị là những phác đồ cơ bản trong ung thư hạ họng thanh quản. Luciano de Souza Viana (2015) cho thấy Taxane và Platin là phác đồ có tính đáp ứng cao, ít độc tính ở bệnh nhân ung thư đầu cổ. Andreas Dietz (2009) thấy phác đồ cisplatin và paclitaxel cũng cho thấy tính an toàn và ít độc tính trên bệnh nhân ung thư hạ họng thanh quản. Mặc dù vậy, các nghiên cứu trên chưa đánh giá đầy đủ về đáp ứng, độc tính, các yếu tố tiên lượng. Ở Việt Nam, hiện chưa có nghiên cứu nào sử dụng phác đồ paclitaxel – cisplatin ở bệnh nhân ung thư hạ họng thanh quản. Tìm kiếm phác đồ điều trị đáp ứng tốt, ít độc tính và an toàn là rất cần thiết. Do đó, đề tài nghiên cứu: “Nghiên cứu ứng dụng hóa trị trước phối hợp hóa xạ trị đồng thời ung thư hạ họng thanh quản giai đoạn III, IV(M0)’’ với hai mục tiêu: 1. Đánh giá kết quả điều trị ung thư hạ họng thanh quản giai đoạn III, IV (M0) bằng hóa trị trước phác đồ paclitaxel và cisplatine kết hợp hóa xạ trị đồng thời. 2. Nhận xét một số yếu tố liên quan đến kết quả điều trị. 2 Những đóng góp mới của đề tài Lần đầu tiên tại Việt Nam, nghiên cứu hóa trị trước phác đồ paclitaxel và cisplatin kết hợp với hóa xạ đồng thời trên bệnh nhân UT HHTQ giai đoạn muộn. Kết quả cho thấy hiệu quả tốt của phác đồ, chất lượng cuộc sống bệnh nhân được cải thiện. Đáp ứng chủ quan sau hóa trị trước (HTTr) 100%. Đáp ứng khách quan theo RECIST 1.1, sau điều trị 61%. Sống thêm sau 3 năm theo dõi là 31,7%. Nghiên cứu cũng đã chỉ ra một số yếu tố ảnh hưởng đến đáp ứng khách quan, chủ quan sau HTTr và sau hóa xạ đồng thời (HXTĐT). Kết quả này cho thấy phác đồ có tính hiệu quả cao. Nghiên cứu cho thấy tỷ lệ độc tính thấp lên huyết học, chức năng gan, thận và độc tính ngoài hệ tạo huyết khác. Nghiên cứu cũng cho thấy tỷ lệ di căn và các yếu tố ảnh hưởng đến tử vong ở bệnh nhân. Từ đó cho thấy mức độ an toàn của phác đồ. Bố cục của luận án Luận án gồm 123 trang, 38 bảng, 17 biểu đồ; 120 tài liệu tham khảo trong đó có 114 tài liệu nước ngoài. Phần đặt vấn đề 2 trang, tổng quan tài liệu 30 trang, đối tượng và phương pháp nghiên cứu 19 trang, kết quả nghiên cứu 34 trang, bàn luận 36 trang, kết luận 2 trang. CHƯƠNG 1. TỔNG QUAN TÀI LIỆU 1.1. ĐẶC ĐIỂM UNG THƯ HẠ HỌNG THANH QUẢN 1.1.1. Tỷ lệ mắc ung thư hạ họng thanh quản Ung thư biểu mô thanh quản trên thế giới ước tính khoảng 1,7% tổng số mới mắc. 1.1.2. Tỷ lệ mắc theo tuổi và giới: Tuổi hay gặp là 40- 60 tuổi, hiếm gặp ở người trẻ dưới 40 tuổi. Nam và nữ tỷ lệ khoảng từ 4:1 và 20:1.
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1.1. ĐẶC ĐIỂM UNG THƯ HẠ HỌNG THANH QUẢN · thấy tính an toàn và ít độc tính trên bệnh nhân ung thư hạ họng thanh quản. Mặc dù vậy, các nghiên
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1
ĐẶT VẤN ĐỀ
Ung thư hạ họng thanh quản có tỷ lệ bệnh mắc cao, ước tính năm
2012 có khoảng 115.130 bệnh nhân mới mắc trên toàn cầu. Tại Việt Nam,
bệnh đứng thứ hai trong các ung thư vùng đầu cổ, sau ung thư vòm. Phần
lớn bệnh nhân ung thư hạ họng thanh quản đến viện khi bệnh đã ở
giai đoạn muộn (III-IV) u lớn lan rộng, đã di căn hạch, hoặc di căn xa
nên điều trị ít hiệu quả, tiên lượng xấu.
Trước đây, điều trị chủ yếu là phẫu thuật cắt bỏ toàn bộ thanh quản,
mất đi khả năng phát âm, ảnh hưởng lớn đến chất lượng sống, tỉ lệ tái
phát và di căn cao. Trong 30 năm gần đây, hóa trị kết hợp xạ trị là
những phác đồ cơ bản trong ung thư hạ họng thanh quản.
Luciano de Souza Viana (2015) cho thấy Taxane và Platin là
phác đồ có tính đáp ứng cao, ít độc tính ở bệnh nhân ung thư đầu cổ.
Andreas Dietz (2009) thấy phác đồ cisplatin và paclitaxel cũng cho
thấy tính an toàn và ít độc tính trên bệnh nhân ung thư hạ họng thanh
quản. Mặc dù vậy, các nghiên cứu trên chưa đánh giá đầy đủ về đáp
ứng, độc tính, các yếu tố tiên lượng.
Ở Việt Nam, hiện chưa có nghiên cứu nào sử dụng phác đồ
paclitaxel – cisplatin ở bệnh nhân ung thư hạ họng thanh quản. Tìm
kiếm phác đồ điều trị đáp ứng tốt, ít độc tính và an toàn là rất cần thiết.
Do đó, đề tài nghiên cứu: “Nghiên cứu ứng dụng hóa trị trước phối
hợp hóa xạ trị đồng thời ung thư hạ họng thanh quản giai đoạn III,
IV(M0)’’ với hai mục tiêu:
1. Đánh giá kết quả điều trị ung thư hạ họng thanh quản giai đoạn
III, IV (M0) bằng hóa trị trước phác đồ paclitaxel và cisplatine
kết hợp hóa xạ trị đồng thời.
2. Nhận xét một số yếu tố liên quan đến kết quả điều trị.
2
Những đóng góp mới của đề tài
Lần đầu tiên tại Việt Nam, nghiên cứu hóa trị trước phác đồ
paclitaxel và cisplatin kết hợp với hóa xạ đồng thời trên bệnh nhân
UT HHTQ giai đoạn muộn. Kết quả cho thấy hiệu quả tốt của phác
đồ, chất lượng cuộc sống bệnh nhân được cải thiện. Đáp ứng chủ
quan sau hóa trị trước (HTTr) 100%. Đáp ứng khách quan theo
RECIST 1.1, sau điều trị 61%. Sống thêm sau 3 năm theo dõi là
31,7%. Nghiên cứu cũng đã chỉ ra một số yếu tố ảnh hưởng đến đáp
ứng khách quan, chủ quan sau HTTr và sau hóa xạ đồng thời
(HXTĐT). Kết quả này cho thấy phác đồ có tính hiệu quả cao.
Nghiên cứu cho thấy tỷ lệ độc tính thấp lên huyết học, chức
năng gan, thận và độc tính ngoài hệ tạo huyết khác. Nghiên cứu cũng
cho thấy tỷ lệ di căn và các yếu tố ảnh hưởng đến tử vong ở bệnh
nhân. Từ đó cho thấy mức độ an toàn của phác đồ.
Bố cục của luận án
Luận án gồm 123 trang, 38 bảng, 17 biểu đồ; 120 tài liệu
tham khảo trong đó có 114 tài liệu nước ngoài. Phần đặt vấn đề 2
trang, tổng quan tài liệu 30 trang, đối tượng và phương pháp
After treatment, 11 patients (26,83%) have been metastatic. It
took about 33.99 months for metastatic
3.1.4.2. Survial monitoring
Fig 3.16. Survival duration after
treatment
Table 3.11. Main cause of death
of patients
Causes No (n) (%)
Metastatic 10 35,7
Recur 5 17,9
Exhausted 13 46,4
Total 28 100
No metastatic,
73,2%
Metastatic,
26,8%
survival without disease,
9.8%Survival with
disease, 21.9%
Dead, 68.3%
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Fig 3.17. Survive more after
treatment
Table 3.19. Survival monitoring
after treatment
Time No.
(n)
(%)
After 12 months
to be treated
20/41 48,8
After 24 months
to be treated
14/41 34,2
After 36 months
to betreated
13/41 31,7
The average of over survival of patients was about 20.2 months.
3.2. FACTORS IMPACTING THE RESULTS OF TREATMENT
* Factors affecting subjective response after treatment
Table 3.13. Factors affecting subjective response after treatment
Response
Symptom
No Yes p OR
N % N %
PS hospitalize PS=1 5 45.5 6 54.5
0.0419 5.42
(1.11-26.47) PS=0 4 13.3 26 86.7
Total 14 9 22 32 78.0
Table 3.14. Factors affecting the objective response after
chemoirradiotherapy Response
Iterms No Yes
p OR
(95%CI) N % N % Subjective response after chemotherapy
No 7 77,8 2 22,2 0,017
8,94 (1,28-100,0) Yes 9 28,1 23 71,9
Subjective response after chemoirradiotherapy
Yes 11 78,6 3 21,4
<0,001 16,13
(3,24-80,22) No 5 18,5 22 81,5
Total 16 39,0 25 61,0
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3.2.2. Factors affecting the over survival and death rate
* Relationship between accepted treatment with over survival and
motarity risk
Fig. 3.18. Relationship between
accepted treatment and over
survival
Fig. 3.19. Relationship between
accepted treatment and motarity risk
* Relationship between subjective response, PS, with motarity risk
and over survival
Fig 3.20. Relationship between
subjective response, PS, with
over survival after induction
chemotherapy
Fig 3.21. Relationship between
subjective response, PS, with over
survival after chemotherapy
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Fig 3.22. Relationship between PS
of hopitalization with over survival
Fig 3.23. Relationship between
PS with over survival after
chomoradiotherapy
* Relationship between objective response with over survival and
motarity risk
Fig 3.24. Relationship between objective response with over
survival
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Fig 3.25. Relationship between over survival with T phase
* Relationship between characteristics of patient with over
survival and motarity risk
Fig 3.26. Over survival from having symtomps to hopitalization
CHAPTER 4. DISCUSSION
4.1. TREATMENT RESULTS OF HYPOPHAZYNGEAL CANCER IN
PHASE III, IV (Mo)
4.1.1. Characteristics of patients
4.1.2. Efficiency of induction chemotherapy with regime of TC in
combination with chemoradiotherapy
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*Accepted the executive therapy
Patients rejected the surgery to open the trachea and to open the
stomach could been died early, respiratory failure and exhausted
because of inability in eating. Therefore, it would affect the rate of
survival and survival duration in this research.
* Assessment of the subjective response and changing the personal
status during treatment
- Changing the personal status during treatment
The results are similar with Tran Bao Ngoc (2011), In contrast,
in the research of Ngo Thanh Tung (2011), 100% of of patients was
in PS=0 and PS=0 was 13.3% after treating by chemoradiotherapy.
* Assessment of the subjective response during treatment
Subjective response after treating by induction chemotherapy
TC: the results of this research was agreed with previous research by
Tran Bao Ngoc (2011), response to induction chemotherapy was
63.71%, reduced by 34% and no change about 3.5%.
Subjective response after treating by chemoradiotherapy:
Compared with Ngo Thanh Tung (2011), it had the completed
response about 56.7%. Those results are higher than this research
because authors only studied on patients who had response after
induction chemotherapy. In the meanwhile, the present study was
implemented on the patients who were response and non-response to
chemotheraphy with TC regimen.
- Quality of life through treatment
Our research is similar to that of Tran Bao Ngoc (2011). QoL score
after treatment for tasting, tasting from 23.4 to 31.2, talk point after
treatment was 27.7, cough score is 19.5, dry mouth 60.2, saliva spray
51.1.
In conclusion, subjective response in our study was higher than
that of chemoradiotherapy using TCF regimen of Tran Bao Ngoc and
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chemoradiotherapy of Ngo Thanh Tung. The TC regimen in our study
was less tiring and felt better. In particular, using non-surgical TC
chemotherapy, patients can still communicate during and after
treatment. This has positive implications for patients as they
communicate with the society.
* Assessment of objective response of induction chemotherapy with
TC regimen in combination with chemoradiotherapy
- Level of objective response after induction chemotherapy
The results of this study were higher than that of the study of
Luciano de Souza Viana (2016), with complete response of 5%,
partial response of 50%, and general response of 55%. However, the
results of this study were lower than that in the research of Prakash B
(2008), with complete response of 65% and partial response of 26%.
In conclusion, response rates of induction chemotherapy were
comparable to TCF regimen and were higher than CF regimen, if
they were compared with TAX 323.
- Level of objective response of chemoradiotherapy
Although this study and previous study of Prakash B (2008)
used the same regimen, the results of this study were lower, with
91% of response of chemoradiotherapy. In the study of Luciano de
Souza Viana (2016), the complete response was 40%. Studies in
TAX 323 showed that responses of chemoradiotherapy of TCF group
was 72% and 59% for CF treatment group
In conclusion, response rate of chemoradiotherapy in this study
was similar to the TCF regimen of TAX 323. This study also showed
that the response rate was higher than that in the previous studies
using CF regimen.
4.1.3. Side effects of induction chemotherapy with TC regimen in
combination with chemoradiotherapy
* Side effect on hematopoietic system
The results of this study were lower than those of Tran Bao
Ngoc, leukemia reduced aproximately 51.7% (59 patients) for
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induction chemotherapy and 59.1% (68 patients) for
chemoradiotherapy treatment. These results were also lower than
Ngo Thanh Tung (2011), the rate of reducing white blood cell was
43.4% (3 and 4 level about 5%). The reducing rate of granulocytes
was about 28.3% (3.3% at level 3).
The reducing rate of neutrophil in this study (5/12 patients) were
similar to that of Prakash B et al. (2008) study who used
chemoradiotherapy with paclitaxel and carboplatin regimen. This
result was also lower than Lauren C et al. (2014). This study was
much lower than the TAX 323 study, in which CF toxicity was
52.5% and 76.9% for TCF group.
* Side effect on liver, kidney and some biochemical indicators of
blood
Toxicity to liver function: This research was higher than Tran
Bao Ngoc (2011). However, it was lower than that in Ngo Thanh
Tung (2011).
Toxicity to kidney function: The results in this study were lower
than that of Tran Bao Ngoc (2011). However, it was higher than that
of Ngo Thanh Tung (2011).
*Toxicity to non-hematopoietic system
Vomiting / nausea: Compared with Luciano de Souza Viana
(2015), the rate of vomit was 25% during treatment of chemotherapy
with TC, in which 21.7% of level 1, 3.3% of level 2.
Non-haematopoietic toxicities were controlled at the time of
initiation of treatment. In the trial of Hitt (2005), the rate of oral
mucositis was significantly higher in the CF group due to higher
doses of 5-FU compared with the TCF dose; thus patient was
postponed to treat due to toxicity.
Suggestions from overseas studies have suggested a new
direction for research in Vietnam because of the fact that research on
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treatment and care to improve the quality of life of patients has not
been properly considered.
4.1.4. Over survival and metastatic after treatment
* Metastatic monitoring
The results of this study was higher than that of Prakash B.
Chougule et al (paclitaxel and carboplatin regimen) with a metastatic
rate of 21% (9/43 patients). The results also were higher than that in
Ngo Thanh Tung (2011) with the metastatic rate of 13.3%.
According to Ngô Thanh Tùng (2011), lung metastatic accounts for
half of patients in hypophazyngeal cancer who were treated by
chemoradiotherapy with cisplatin regimen.
* Over survival after treatment
* Mortality rate: Compared with chemoradiotherapy using TC
regimen of Andreas Dietz et al. (2009), the survival rate after 36
months was 43%, corresponding to the 36-month mortality rate of
57%. This study had a higher mortality rate as the patients were at the
later stages III, IV, in which most of patients were in stage IV.
Compared to Luciano de Souza Viana (2015), 15% of alive and
85% of dead after 3 years of follow-up and all 15% of patients live
on progressive disease.
Compared with the research of Prakash B et al. (2008) using
regimen of paclitaxel and carboplatin, it showed that after 3 years of
monitoring (49 months), the survival rate was 19/44 (43.18%).
The present results showed that the survival rate after 36 months
was higher compared with chemoradiotherapy using in study of Ngo
Thanh Tung (2011) for hypophazyngeal cancer patients in stage III,
IV 14%, in which survival duration of 36 months after treatment was
14% and disease-free survival was 5%.
Major reasons of mortality:
Compared with the previous study of Ngo Thanh Tung (2011),
the main cause of death from progressive disease accounted for
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38.5%; recurrence of 15.4%; metastatic 15.4%; and exhausted
20.5%.
Thus, patients with hypophazyngeal cancer should receive
special nutritional care while treating patients with TC regimen. In
addition, carefulness should be taken to ensure breathing for
respiratory tract. It would reduce the risk of mortality for patients if
the patient's health has been taken carefully.
Survival duration after treatment:
Complete survival duration after treatment in this study was
slightly lower than that in the study of Luciano de Souza Viana
(2015), average survival duration was 13 months.
4.2. FACTORS AFFECTING THE TREATMENT OUTCOMES
4.2.1. Factors affecting the treatment outcomes using TC regimen
in combination with chemoradiotherapy
* Factors affecting subjective response after treatment There was a relationship between detection time of disease to
admission in hopital and subjective response of induction chemotherapy. Patients who are diagnosed early have been more likely to treat because, it was not only better functional response but also for ensuring the better health. Therefore early detection and timely treatment have been necessary to ensure effective treatment.
The results of this study showed that factors affected the subjective response of chemoradiotherapy were detection time of disease until hopitalization, PS when hopitalized and subjective response of induction chemotherapy (p<0.05).
Thus, the health of patients has been an important factor contributing to ensuring good treatment outcomes. The early detection and treatment have played an important role in ensuring better treatment outcomes. * Factors affecting objective response after induction chemotherapy
Results in our study showed that stage T, stage of disease, age, history of drinking and smoking, time from to detect disease to
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hopitalization did not affect objective response of RECIST (p> 0.05); in constrast, PS when hospitalized had an effect on objective response (p <0.05). Compared with Luciano de Souza Viana (2016), factors affecting treatment response included age (p = 0.038), T-stage (p = 0.037) and calcium level (p = 0.038). It is unlikely with this study, all patients were in the late phase of disease, the tumor was widespread and induction chemotherapy was assigned priority and no surgery was designated for those patients.
It can be seen that this study demonstrated that the patient conditions would play an important role in treating cancer after chemical treatment. * Factors affecting objective response after chemoradiotherapy
Results showed that after treatment with chemoradiotherapy, factors such as N stage, T stage, disease stage, alcohol and smoking history, duration from onset to hospitalization, PS when hospitalization and PS after induction chemothrapy did not affect the level of response according to RECIST 1.1 (p > 0.05). In the meanwhile, objective response of induction chemotherapy and subjective response of chemoradiotherapy were affected objective response of chemoradiotherapy (p<0.05).
Similar with study of Luciano de Souza Viana et al. (2016), this study showed that induction chemotherapy treatment afftected to response of chemoradiotherapy (p<0.001).
Factors affecting objective response of chemoradiotherapy in this study were similar with previous study of Tran Bao Ngoc (2011). Factors include age, gender, time to detect disease and hospitalization, smoking and drinking, T stage, N stage and histophathology did not have any significant effect on the objective response of chemoradiotherapy. Ngo Thanh Tung (2011) also showed that factors such as cancer stages, phase TNM, putting nasogastric, PS, number of treatment days and cycle number of cicplatin would affect to regimen of radiotherapy with cisplatin (p<0.05).
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4.2.2. Factors affecting on over survival and risk of death
* Relationship between treatment adherence with o risk of death and over survival
Results shows the important role of adherence to the treatment regimen. This result is similar to Tran Bao Ngoc in head and neck cancer patients, where adherence to treatment regimens increases the over survival for patients.
* Relationship between subjective response, personel status and over survival
Research results show that tumor treatment should pay attention to clinical manifestations. In fact, squeezing tumors causes shortness of breath, making the patient unable or unable to eat normal food. These long-term symptoms cause malnutrition, poor physiology, and patients are more likely to die prematurely.
* Relationship between objective response with risk of death and
over survival
Similar with study of Prakash B (2008) that using regimen of
carboplatin and palitaxel, the results indicated that objective response
affected to survival of patients. The percentage of patients who could
be over survival within 5 years for response group was about 59%
and 34% for non-response group (p=0.015).
Thus, the results of this study showed the effectiveness of
response to medicine and mortality in patients. This may help
clinicians to select other treatments if the early stage of induction
chemotherapy is not effective.
* Relationship between disease stage and risk of death and over
survival
Comparison with Andreas Dietz (2009) in patients with
hypophazyngeal cancer patients was treated with sequential
chemotherapy with TC regimen, the results suggested that over
survival did not have any relationship with disease stage.
Stage T affected the risk of death indicating that early diagnosis
reduces the risk of death in hypophazyngeal cancer patients.
49
* Relationship between patient characteristics and risk of death and
over survival
This research is similar to that of Tran Bao Ngoc (2011). Thus,
patients who were diagnosed early ≤ 6 months had significantly
longer over survival compared to those who were diagnosed after 6
months.
CONCLUSION
1. Assessment of treatment outcomes using TC regimen in
combination with chemoradiotherapy
- Efficiency of chemotherapy in combination with
chemoradiotherapy:
+ PS and subjective response: after induction chemotherapy,
decrease or disappear of functional symptoms. The personal status was
73.2% PS = 0, after the chemoradiotherapy was 12.2% PS = 0. The
quality of life tended to improve after induction chemotherapy and after
chemoradiotherapy indices of in pain, dysphagia, sensory, speech,
communication, cough and fatigue decreased.
+ Objectively response: overall response was 78% after induction