头颈部癌症治疗趋势幻灯片.ppt

1、頭頸部癌症治療趨勢,馬偕醫院癌症中心頭頸部癌症小組 耳鼻喉科頭頸外科 呂宜興醫師,George Washington Crile,1864-1943 Surgeon focus on thyroid gland and neck Dutch, Scottish-Irish descent Excision of cancer of the head and neck JAMA 1906; 47: 1780-1788.,Treatment of N0 neck,Prevalence of occult metastasis: 10% (47% in T1/T2 tongue ca, 40% T2

2、 FOM ca) Supraglottic ca T3N0M0: BND vs no ND, recurrence 7.8% vs 20%, but the same survival rate. SND for N0 of tongue ca: level I, IIa, III,Treatment of N0 neck,The sensitivity of CT scan (or MRI) in diameter of neck mass: 1.1cm (Radiology 1998;207:123-130) Thickness and local recurrence in N0 of

3、tongue ca: 8mm 49%, 3-7mm 26%, 2mm 0% Local large nerves (lingual and hypoglossal nerves) invaded in tongue ca, then R/T indicated,T2N1M0,Treatment: SND level I,II,III +/- XRT or SND I,II,III,(IV,V) Oropharyngeal ca level V 應該做, oral tongue ca 可以不作level V pN1 without ECS 應該可以不用 post OP CCRT Resectab

4、le or Curable,How to prevent shoulder drop after treatment in pt of head and neck cancer,Preserve SAN (SAN,C2,C3 neuron may be related to the function of shoulder) Avoid dissecting level V L/N Nerve graft after sacrifice SAN Rehabilitation exercise,How to reduce the severity of xerostomia,IMRT Amifo

5、stine drug Submandibular gland transposition (Transposition of the contralateral submaxillary gland to the submental region is proposed as a method for preventing asialia following salivary gland irradiation during radiotherapy for oropharyngeal cancer. The method should be reserved for patients wit

6、h oropharyngeal cancer without lymph node metastases on the contralateral side.),Submandibular gland transposition,All the glands survived transfer and functioned well postoperatively as demonstrated on the salivary flow and the radioisotope studies. The surgical transfer was relatively simple and a

7、dded 45 minutes to the surgical procedure. There were no complications attributed to the submandibular gland transfer. Laryngoscope. 2001 Feb;111(2):347-52. Long-term outcomes of submandibular gland transfer for prevention of postradiation xerostomia : prevented xerostomia in 83% of the study patien

8、ts. The approach appears to be oncologically sound and safe. Arch Otolaryngol Head Neck Surg. 2004 Aug;130(8):956-61,The swallowing function after treatment of head and neck cancer,Better in female Worse in hypopharyngeal/laryngeal cancer Worse in re-R/T group,Specimen of neck dissection,如果在病理標本分Lev

9、el I, II, III, IV,V : 用鐵絲及鐵牌綁住標本,如果切成一塊一塊,可能會遺漏部分ECS現象 發展molecular staging in HNSCC,來解釋1.regional failure in N0 neck! 2.skip metastasis 3.better prognostication,Light microscopy: cell differentiated, depth of invasion,. Molecular biology: 1.percentage of aneuploidy 越少,預後越差 建議手術 2.Proliferation 3.EGF

10、R 4.VEGF(vascular endothelial growth factor) .,Definition of 染色體異常（aneuploidy）,The occurrence of one or more extra or missing chromosomes leading to an unbalanced chromosome complement, or, any chromosome number that is not an exact multiple of the haploid number 以人類為例,如果染色體數目不是23倍數,就是aneuploidy,Pro

11、liferation,Accumulation of p53 was found in 78.2% of the cases, and it was related to a high Ki-67 labeling index and higher histologic grade. The results demonstrate association of HPV with more than one third of laryngeal carcinomas studied, mainly glottic tumors. Tumors with increased cell prolif

12、eration were more frequently high grade, with p53 accumulation and lymph node metastasis. Am J Clin Pathol. 2006 Aug;126(2):284-93,DNA-flow cytometry of head and neck carcinoma: the importance of uniform tissue sampling and tumor sites,Flow cytometric DNA ploidy measurements using deparaffinized tum

13、or specimens were performed on 46 squamous cell carcinomas of the head and neck, including 22 carcinomas of the oropharynx, 18 carcinomas of the larynx and six carcinomas of the oral cavity. Aneuploidy was found in 14 of these tumors with carcinomas of the larynx and oral cavity showing almost equal

14、 percentages of DNA aneuploidy (10/18 and 3/6, respectively). In contrast, only 1 of the oropharyngeal carcinomas was aneuploid. Accurate microscopy-controlled sampling of tumor tissue from the histological tissue blocks was found to be mandatory in order to obtain reliable ploidy measurements Europ

15、ean Archives of Oto-Rhino-Laryngology Volume 249, Number 3 / May, 1992,There was a trend for those p53-positive tumours with the strongest expression to have more DNA aneuploidy and deregulation of proliferation organization than weaker expressors; but there were no differences in proliferation rate

16、 or outcome of radiotherapy. These studies suggest that p53 protein stabilization as assessed by immunohistochemistry does not have any major relationship with the biological characteristics and outcome of squamous cell cancer treated by accelerated radiotherapy. Br J Cancer. 1995 Jun;71(6):1248-52.

17、,1cm3 tissue = 109 cells 1mm3 tissue = 106 cells 0.1mm3 tissue = 103 cells 0.01mm3 tissue = 1 cells can do metastasis N+ vs N-, biology of neck metastasis is different from biology of primary tumor. Metastasis with endothelial cell (vascularity) vs Tumor invasion with tumor cell,R.S. Kerbel et al Na

18、ture Reviews Cancer 2004; 4; 423,NEJM 2004; 351;3;215-6,Neoplastic Angiogenesis Not All Blood Vessels Are Created Equal,Isaiah J. Fidler, D.V.M., Ph.D.,N Engl J Med 2005;353:999-1007.,N Engl J Med 2005;353:999-1007.,CEC in vascular disorders,Vox Sanguinis (2005)88, 19,Light microscopy: cell differen

19、tiated, depth of invasion,. Molecular biology: 1.percentage of aneuploidy 越少,預後越差 建議手術 2.Proliferation 3.EGFR 4.VEGF(vascular endothelial growth factor) .,Tumor cell IL-6 Macrophage TNF- (endothelial cell) TGF- (Tumor cell) PDGF-BB endothelial cell Induction of apoptosis in endothelial cell will tri

20、gger a second wave on endothelial and tumor cell. Tumor cell activated by TGF -(a kind of EGF epidermal growth factor), endothelial cell activated by EGFR.,Tumor cell growth Angiogenesis Detachment and invasion of basement membrane Attachment and direct invasion massive growth,Tumor necrosis factor,

21、The most abundant cellular sources of TNFa are macrophage and monocyte. In response to inflammatory stimulation, macrophage or monocyte secretes TNFa that can induce apoptotic or necrotic cell death of certain tumor cell lines.,Transforming growth factor - ,TGF-b regulates growth and proliferation o

22、f cells, blocking the growth of many different cell types. Binding of transforming growth factor b (TGF-b) to its cell surface receptor Type II leads to the phosphorylation of the Type I receptor by Type II. 移轉型生長因子-beta(TGF-b) 的分子可以停止細胞增長，但是又可以在其他階段促進細胞生長。 Vanderbilt-Ingram癌症中心的主任Hal Moses博士和他的實驗室研

23、究人員，於1985 年辨識出TGF-b，這種物質具有生長刺激物和生長抑制的作用。從那段時間之後，TGF-b在直腸、乳房和其他癌症中所扮演的角色便獲得研究人員的廣泛研究。 TGF-b 通常會抑制細胞生長，但是，很多實質性腫瘤會過度表現 TGF-b ，而使細胞不完全被抑制事實上，有時候它們因為TGF-b的訊息使腫瘤細胞的生長比正常細胞更快。,Transforming growth factor - ,TGF-alpha is a member of the EGF family of cytokines. Membrane-bound pro-TGF-alpha is biologically a

24、ctive and seems to play a role in mediation of cell-cell adhesion and in juxtacrine stimulation of adjacent cells. Expression of TGF-alpha is widespread in tumors and transformed cells.,Platelet-derived growth factor,PDGF是一種多生類(polypeptide)生長因子，它會和目標細胞表面的專一受器作用，而引發一連串生化反應；它由兩條多太鏈組成，A鏈和A鏈組成PDGF-AA；B鏈

25、和B鏈組成PDGF-BB。其主要來源於血小板，也曾有學者從骨質中粹取出來，其他像是傷口處的巨噬細胞，附近的血管壁平滑細胞及內皮細胞等也會分泌PDGF。,Tumor cell IL-6 Macrophage TNF- (endothelial cell) TGF- (Tumor cell) PDGF-BB endothelial cell Induction of apoptosis in endothelial cell will trigger a second wave on endothelial and tumor cell. Tumor cell activated by TGF -

26、(a kind of EGF epidermal growth factor), endothelial cell activated by EGFR.,Epidermal growth factor receptor EGFR,Receptor for EGF, but also for other members of the EGF family, as TGF-alpha,amphiregulin, betacellulin, heparin-binding EGF-like growth factor, GP30 and vaccinia virus growth factor. I

27、t is involved in the control of cell growth and differentiation,Marker for lymph nodes metastases,E48 antigen Pemphigus vulgaris antigen expression,A quantitative reverse transcription-PCR (Q-RT-PCR) assay based on TaqMan technology using the squamous cell-specific antigen E48 (Ly-6D) as molecular m

28、arker. The detection limit of E48 Q-RT-PCR was a single tumor cell in a background of 106 peripheral blood mononuclear cells. E48 Q-RT-PCR showed an increase in sensitivity from 56 to 67% and an increase in frequency of reached diagnosis from 97 to 100% compared with cytology. The specificity decrea

29、sed from 100 to 92%. Quantitative Molecular Detection of Minimal Residual Head and Neck Cancer in Lymph Node Aspirates Clinical Cancer Research Vol. 9, 755-761, February 2003,The squamous cell-specific antigen E48 (Ly-6D) as molecular marker,Pemphigus vulgaris antigen (PVA),pemphigus vulgaris antige

30、n (PVA), a rapid QRT-PCR assay for PVA was then developed and incorporated into a prototype instrument capable of performing fully automated RNA isolation and QRT-PCR. The automated analysis with PVA provided perfect discrimination between histologically positive and benign lymph nodes and correctly

31、 identified two lymph nodes with micrometastatic tumor deposits. These assays were completed (from tissue to result) in 30 minutes, thus demonstrating the feasibility of intra-operative staging of SCCHN SLNs by QRT-PCR Ferris RL et al ,Cancer Research 65, 2147-2156, March 15, 2005,HPV (+) 不易復發,The a

32、ssociation between HPV16 infection and HNSCC in specific sites suggests the strongest and most consistent association is with tonsil cancer, and the magnitude of this association is consistent with an infectious etiology. Clin Otolaryngol. 2006 Aug;31(4):259-66,Head Neck. 2006 Jul 5;,Head and neck c

33、ancer is the worlds sixth most common cancer, but despite advances in treatment, there has been no significant decline in the mortality rate. In recent years, there has been mounting epidemiologic and experimental evidence of a role for human papillomavirus (HPV) as the etiologic agent of a subset o

34、f head and neck cancers. The association is strongest for oropharyngeal cancers, especially those of the tonsil. HPV 16 is invariably the predominant type. HPV-positive cancers have been shown to be biologically distinct, clustering among nonsmokers and light drinkers, and have been associated with

35、a favorable prognosis. This review examines the current findings of HPV in head and neck cancers and discusses implications for developing new treatments.,Future management of HNSCC-1,Combined therapy: + operation + chemotherapy + radiotherapy + targeted therapy + immune therapy (HPV or EBV positive) + gene therapy,Future management of HNSCC-2,Gene therapy: p53 protein EGFR: Erbitux , Irresa , Tarceva Vascular endothelial growth factor (VEGF) reception: Avastin. Targeted cytotoxic cell therapy: cisplatin-derived drug, Xeloda(5FU),Tumor-dendritic cell fusion as a bas