头颈部肿瘤ppt课件.ppt

1、头颈部肿瘤概述头颈部肿瘤概述口腔肿瘤口腔肿瘤新辅助化疗新辅助化疗2019 ASCO流行病学占全身恶性肿瘤的占全身恶性肿瘤的5 5第第6 6大常见的恶性肿瘤大常见的恶性肿瘤肿瘤相关死亡原因的第肿瘤相关死亡原因的第8 8位位头颈部肿瘤的患者有可能罹患第头颈部肿瘤的患者有可能罹患第2 2个原发性的头颈部、肺个原发性的头颈部、肺部或食管的肿瘤部或食管的肿瘤病因吸烟和嗜酒吸烟和嗜酒口咽癌：人乳头瘤病毒口咽癌：人乳头瘤病毒(HPV)60-70%(HPV)60-70%鼻咽癌：鼻咽癌：EBVEBVHPV+口咽部肿瘤的疗效和生存情况口咽部肿瘤的疗效和生存情况均比均比HPV-的肿瘤要好的肿瘤要好治疗前血浆治疗前血

2、浆EBV-DNA水平越高，则治疗后出现水平越高，则治疗后出现远处转移的概率越高；监测随访远处转移的概率越高；监测随访Humanpapillomavirusandsurvivalofpatientswithoropharyngeal cancer.N Engl J Med.2019 Jul 1;363(1):24-35.头颈部肿瘤特点90%90%以上以上EGFREGFR过表达过表达以鳞癌为主以鳞癌为主视、听、嗅觉、呼吸、发声、进食、容貌视、听、嗅觉、呼吸、发声、进食、容貌局部结构复杂、险隘，安全边缘有限局部结构复杂、险隘，安全边缘有限“不可切除的病变不可切除的病变”没有定义没有定义不同部位特点不

3、同喉癌：喉癌：声门上区声门上区肿瘤在确诊时通常已经为局部晚期；肿瘤在确诊时通常已经为局部晚期；但是但是声门区声门区肿瘤发现时多为早期，治愈率非常高：约肿瘤发现时多为早期，治愈率非常高：约80%90%80%90%咽癌：大约咽癌：大约60%的下咽部肿瘤患者已属局部晚期伴区的下咽部肿瘤患者已属局部晚期伴区域淋巴结转移，预后通常都很差域淋巴结转移，预后通常都很差分期唇部、口腔及口咽部肿瘤根据唇部、口腔及口咽部肿瘤根据瘤体大小瘤体大小界定界定T分期分期声门区、声门上区、喉咽及鼻咽部肿瘤根据各自声门区、声门上区、喉咽及鼻咽部肿瘤根据各自亚区亚区侵犯侵犯情况界定情况界定T分期分期除了鼻咽癌的区域淋巴结（除了

4、鼻咽癌的区域淋巴结（N）分期之外，对于不同）分期之外，对于不同部位肿瘤的部位肿瘤的N及远处转移（及远处转移（M）的界定标准是一致的）的界定标准是一致的喉、口咽、下咽：喉、口咽、下咽：VII区（上纵膈）转移也被认为是区（上纵膈）转移也被认为是区域淋巴结转移区域淋巴结转移治疗特点T1-2N0M0T1-2N0M0期期:单纯手术或单纯放疗单纯手术或单纯放疗局部晚期局部晚期:手术手术+放疗放疗+化疗化疗复发和转移，姑息性化疗放疗复发和转移，姑息性化疗放疗+化疗化疗+手术手术鼻咽癌主要以放化疗为主鼻咽癌主要以放化疗为主新辅助治疗例如：对可手术切除的局部晚期喉癌、咽癌，术前诱例如：对可手术切除的局部晚期喉癌

5、、咽癌，术前诱导化疗导化疗/同步放化疗不仅可以提高保喉率，而且可提同步放化疗不仅可以提高保喉率，而且可提高患者生存率高患者生存率放疗原发病灶和受侵淋巴结需要每天2.0 Gy，总量为70 Gy或以上的剂量对于颈部风险较低的淋巴结群的放疗剂量为每天2.0 Gy，总量50 Gy或以上化疗新辅助化疗同步放化疗（根治性、辅助性）辅助化疗姑息化疗靶向治疗西妥昔单抗西妥昔单抗 早中期：同步放疗 晚 期：单药或联合化疗尼妥珠单抗（尼妥珠单抗（nimotuzumab）吉非替尼、厄洛替尼：未观察到临床受益吉非替尼、厄洛替尼：未观察到临床受益不良预后因素淋巴结包膜外受侵和淋巴结包膜外受侵和/或手术切缘阳性：或手术切

6、缘阳性：术后进行辅助术后进行辅助性化放疗性化放疗其他不良预后因素：其他不良预后因素：多个阳性淋巴结（无包膜外受多个阳性淋巴结（无包膜外受侵）、血管侵）、血管/淋巴管淋巴管/神经周围侵犯、原发肿瘤神经周围侵犯、原发肿瘤T4aT4a及具及具有有IVIV区淋巴结阳性区淋巴结阳性术后放疗，但是否进行放化疗术后放疗，但是否进行放化疗可根据临床判断可根据临床判断复发和(或)转移复发病变可治愈：复发病变可治愈：应积极寻求根治性手术应积极寻求根治性手术 或同步放化或同步放化（靶）疗（靶）疗无局部治愈可能：无局部治愈可能：姑息性化疗和姑息性化疗和(或或)靶向治疗靶向治疗 支持治疗支持治疗姑息化疗的中位生存时间大

7、约为6个月，1年生存率大约为20%Induction ChemotherapyInduction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer.The Department of Veterans Affairs Laryngeal Cancer Study GroupN Engl J Med.1991;324(24):1685332 ptsmedian follow-up of 33 monthssurgery+radiot

8、herapyinduction chemotherapy+radiotherapySalvage surgerycisplatin+fluorouraci（PF）Focus on larynx preservation 2-year survival:68%:68%P=0.1195Larynx preservation in pyriform sinus cancer:preliminary results of a European Organization for Research and Treatment of Cancer phase III trial.EORTCHead and

9、Neck Cancer Cooperative Group J Natl Cancer Inst.2019202 ptssurgery+radiotherapyinduction chemotherapy+radiotherapySalvage surgerycisplatin+fluorouraci（PF）Focus on larynx preservation Induction-chemotherapy arm vs.Surgery armOS:44:25 months3-year survival:57%:43%PFS:25:20 monthsTPF vs.PFInduction ch

10、emotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck:long-term results of the TAX 324 randomised phase 3 trial.Lancet Oncol.2019;12(2):153-9 Median follow-up of 6.0 years(72.2 months)55 centers 501 patientsncb

11、i.nlm.nih.gov/pmc/articles/PMC4356902/pdf/nihms667891.pdfOS:70.6 vs.34.8 moPFS:38.1 vs.13.2 mohypopharyngeal and laryngealPFS:20.9 vs.10.1 moOS:51.9 vs.23.5 moLong-term results of GORTEC 2000-01:A multicentric randomized phase III trial of induction chemotherapy with cisplatin plus 5-fluorouracil,wi

12、th or without docetaxel,for larynx preservation.France213 ptsMedian follow-up 105 months TPF vs.PFThe 5-and 10-year larynx preservation rates 74.0%vs.58.1%70.3%vs.46.5%The 5-and 10-year LDFFS rates 67.2%vs.46.5%63.7%vs.37.2%OS,PFS no difference (LDFFS:larynx dysfunction-free survival)ASCO2019Taxane-

13、cisplatin-fluorouracil as induction chemotherapy for advanced head and neck cancer:a meta-analysis of the 5-year efficacy and safety.Springerplus.2019;4:208.7 randomized clinical (mata analysis)TPF vs.PF 3-year OS rate(HR:1.14;95%CI:1.03 to 1.25;P=0.008)3-year PFS rate(HR:1.24;95%CI:1.08 to 1.43;P=0

14、.002)5-year OS rate(HR:1.30;95%CI,1.09 to 1.55;P=0.003)5-year PFS rate(HR:1.39;95%CI,1.14 to 1.70;P=0.001)The TPF induction chemotherapy improved PFS and OS compared with PFInduction Chemotherapy vs.Concurrent ChemoRTLong-Term Results of RTOG 91-11:A Comparison of ThreeNonsurgical Treatment Strategi

15、es to Preserve the Larynx inPatients With Locally Advanced Larynx Cancer J Clin Oncol 2019;31:845-852Patients with stage III or IV glottic or supraglottic squamous cell cancerlaryngectomy-free survival(LFS)(PF)For selected patients with hypopharyngeal and laryngeal cancers less than T4a in extent,in

16、ductionchemotherapyused as part of a larynx preservation strategyis category 2AThus,induction chemotherapy has a category 3recommendation for the management of both locally and regionally advanced oropharyngeal cancerInduction Chemotherapy in Oral Squamous Cell CarcinomaRandomized Phase III Trial of

17、 Induction Chemotherapy With Docetaxel,Cisplatin,and Fluorouracil Followed by Surgery Versus Up-Front Surgery in Locally Advanced Resectable Oral Squamous Cell Carcinoma J Clin Oncol.2019;31(6):744-51256 patientsLocallyadvancedResectable Oral Squamous Cell Carcinoma,TPFMedian follow-up of 30 monthsc

18、N2Induction chemotherapy+Concurrent chemoradiotherapyInduction chemotherapy followed by concurrentchemoradiotherapy(sequential chemoradiotherapy)versusconcurrent chemoradiotherapy alone in locally advanced headand neck cancer(PARADIGM):a randomised phase 3 trialLancet Oncol 2019;14:25764145 patients

19、 across 16 sitesMedian follow-up of 49 months Induction chemotherapy+Concurrent chemoradiotherapy Concurrent chemoradiotherapy3-year overall survival was 73%vs.78%OSPFSPhase III randomized trial ofinduction chemotherapyin patients with N2 or N3 locally advancedhead and neck cancer.J Clin Oncol.2019;

20、32(25):2735285 patients,with N2 or N3 diseaseFollow-up of 30 monthsInduction chemotherapy+Concurrent chemoradiotherapy Concurrent chemoradiotherapyNO difference:OS,Relapse-FreeSurvival,Distant Failure-Free SurvivalIs there a role for induction chemotherapy in the setting of concomitant chemoradiatio

21、n in locally advanced head and neck cancer:A systematic review and meta-analysis of randomized controlled trialsMeta-analysis,5 RCTs(4 TPF,1 PF)1229 patientsIndu-chemotherapy+concomitant chemoradiation concomitant chemoradiationOS,PFS no difference have a trendDisease control,CR Imply that selected

22、patients may benefit from the addition of induction chemotherapyASCO2019New aspects regarding the induction chemotherapy with TPF and radio chemotherapy in head and neck cancer GermanyMeta-analysis,5 RCTs(TPF)1060 patients,locally advanced53.4%oropharyngeal,17.3%hyopharyngeal,6.4%laryngeal,18.5%oral

23、 cavity,4.4%other SCCHNTPF+concomitant chemoradiation concomitant chemoradiationNot result in a significant improvement of OS(Hazard Ratio:0.950,0.791-1.140,p=0.579)ASCO2019Radiotherapy plus cetuximabRadiotherapy plus cetuximab for locoregionally advanced head and neck cancer:5-year survival data fr

24、om a phase 3 randomised trial,and relation between cetuximab-induced rash and survival Lancet Oncol.2019;11(1):21-8424 pts:locoregionally advanced squamous-cell carcinoma(oropharynx,hypopharynx,or larynx)73 centresmedian follow-up 60 monthsradiotherapy aloneradiotherapy plus cetuximabOS:49.0 months

25、versus 29.3 months5-year overall survival was 45.6%versus 36.4%Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma:RTOG 0522.J Clin Oncol.2019 Sep 20;32(27):2940-50.891 analyzed patientsMedian follow-up 3

26、.8 yearsCetuximab plus cisplatin-radiationcisplatin-radiation alone3-year PFS(61.2%v.58.9%,P=.76),3-year OS(72.9%v.75.8,P=.32)p16-positive compared with p16-negative PFS(72.8%v.49.2%,P .001)OS(85.6%v.60.1%,P .001),EGFR expression did not distinguish outcomeShould not be prescribed routinelyOral Cavi

27、tyVery advanced2019 ASCOHead and Neck CancerlPhase III randomized trial of standard fractionation radiotherapy with concurrent cisplatin versus accelerated fractionation radiotherapy with panitumumab in patients with locoregionally advanced squamous cell carcinoma of the head and neck:NCIC Clinical

28、Trials Group HN.6 trialCanadal320 pts lWith a median follow-up of 46.4 monthslPFS of PMab+AFX was not superior to CIS+SFXWeekly paclitaxel,carboplatin,cetuximab(PCC),and cetuximab,docetaxel,cisplatin,and fluorouracil(C-TPF),followed by risk-based local therapy in previously untreated,locally advance

29、d head and neck squamous cell carcinoma(LAHNSCC)MD Anderson Cancer Centerphase IIMedian follow-up of 18.4 months 136 patients Mutational patterns of HPV+and HPV-squamous cell carcinomas of the head and neck(SCCHN)and their interference with outcome after adjuvant chemoradiation:A multicenter biomark

30、er study of the German Cancer Consortium Radiation Oncology Group Germany208 patients211 exons from 45 genes HPV+：enriched for activating mutations in driver genes(PIK3CA 27%,KRAS 8%,NRAS 4%,HRAS 2%)HPV-：loss-of-function alterations in tumor suppressor genes(TP5367%,CDKN2A 30%,PTEN 4%,SMAD4 3%)media

31、n follow-up of 55 months,loss-of-function tumor suppressor gene mutations negatively interfere with efficacy of adjuvant cisplatin-based chemoradiation,whereas activating driver gene mutations define poor risk specifically in HPV-driven SCCHNAntitumor activity and safety of pembrolizumab (MK-3475)in

32、 patients with advanced squamous cell carcinoma of the head and neck:Preliminary results from KEYNOTE-012 expansion cohort ChicagoORR(Objective Response Rate)was 18.2%31.3%with stable diseaseBiomarker analysis is ongoingFinal overall survival analysis of EXAM,an international,double-blind,randomized

33、,placebo-controlled phase III trial of cabozantinib(Cabo)in medullary thyroid carcinoma(MTC)patients with documented RECIST progression at baseline.France是RET，VEGFR2和MET酪氨酸激酶的强效抑制剂，于2019年11月被美国FDA批准用于MTC的治疗median follow up time 52.4 moN=330median OS 26.6 mo vs 21.1 mo (p=0.241).median OS 44.3 mo vs

34、18.9 mo (p=0.026),For 126 pts with RET M918T mutations Efficacy and safety of lenvatinib for the treatment of patients with 131I-refractory differentiated thyroid cancer with and without prior VEGFtargeted therapy.London PFS 18.3 vs.3.6 mo2019.4 FDAUtilization and outcomes of low dose versus high do

35、se cisplatin in head and neck cancer patients receiving concurrent radiation.Milwaukee1,091 ptsLD(40 mg/m2)，HD(75 mg/m2)The total cumulative dose 322.5 mg vs.475.8 mgOS favoring the HD group(log rank test,p 0.001)75%censored in both cohortsDifferential impact of cisplatin dose intensity on human pap

36、illomavirus(HPV)-related(+)and HPV-unrelated(-)locoregionally advanced head and neck squamous cell carcinoma(LAHNSCC).Canada （retrospective）Median follow-up was 4.3 yrs5 year OS was inferior for HPV（-）CDDP 200 vs.200 mg/m2 (44%vs 62%,p 0.01)But not to HPV（+）A meta-analysis of weekly cisplatin versus

37、 three weekly cisplatin chemotherapy plus current radiotherapy for advanced head and neck cancer.Yue Zhang Southern Medical University,Guangzhou,China779 patients of 10 studies Three weekly cisplatin CRT didnt differ with weekly in OS and LRFS(locoregional recurrence-free survival)A meta-analysis co

38、mparing cisplatin-based to carboplatin-based chemotherapy in moderate to advanced squamous cell carcinoma of head andneck(SCCHN).Qinyang Li,Nanfang Hospital,Southern Medical University,Guangzhou,ChinaPatients with CDDP-based CT can achieve a higher OS,but there is no significant difference in LRCBio

39、radiotherapy for head and neck cutaneous squamous cell carcinoma,Philadelphia68 patients Median follow-up 30 monthsPhase II study with conventional radiotherapy+cetuximab in patients with advanced larynx cancer who responded to induction chemotherapy:An organ preservation TTCC study.Spain93 patients

40、,one armMedian follow-up:48 monthsLEDFS(the laryngo-esophageal dysfunctionfree survival)rate was clearly higher than the critical value and with an acceptable toxicity with this protocol,so it is warranted to move to a phase III trialThe role of cetuximab in induction chemotherapy:Comparison of APF-

41、C(nab-paclitaxel,cisplatin,5-FU+cetuximab)with APF,both followed by chemoradiation therapy(CRT),in patients with locally advanced head andneck squamous cell carcinoma(HNSCC).St.LouisBackground:Cetuximab improved OS in patients with HNSCC when added to definitive RT or to palliative chemotherapy60 pt

42、s Two year OS and DSS(disease-specific survival)were similar between APF+C and APF,even when stratified for p16 status.Concurrent chemoradiation using weekly versus tri-weekly cisplatin in locally advanced squamous cell carcinoma of the head and neck(SCCHN):A comparative analysis.AtlantaOut of 120 s

43、tudies,23 with a total of 2,303 patients Weekly cisplatin combined with radiation in locally advanced SCCHN is comparable in efficacy and safety to tri-weekly based regimens.总结个体化治疗，综合和治疗对部分选择的患者，诱导化疗是可行的，在局部疾病控制、器官保留方面可以带来益处，能降低远处转移发生率，并有可能转化为生存获益诱导化疗仍缺乏有效的筛选标记靶向治疗，特别是免疫治疗未来会带来突破THANKS同步放化疗随机临床试验支持

44、几种顺铂的使用方案（例如每周，每天，但大多数医疗中心采用高剂量顺铂治疗（每3周100 mg/m2）口腔癌口腔癌口腔癌鼻咽癌在头颈部肿瘤中，它具有最高的远处转移倾向。局部晚期鼻咽癌在根治性放疗（未行化疗）后很容易出现孤性局部复发。区域复发不常见，仅占患者的10%19%治疗前血清/血浆中EBV-DNA水平与早期鼻咽癌(I期和II期)的预后有关，治疗前血浆EBV-DNA水平越高，则治疗后出现远地转移的概率越高联合使用放疗和铂类药物化疗已被证实肿瘤的局部控制率可以从54%增加到78%鼻咽部肿瘤患者治疗后，推荐的随访内容包括定期体检和甲状腺功能的评估（每612个月检测TSH水平）在20%25%的接受颈部

45、放疗的患者当中可检测出TSH水平增高鼻咽癌初始治疗决策手术放疗同步放化疗新辅助化疗唇、口腔、咽、喉、鼻窦、涎腺等唇、口腔、咽、喉、鼻窦、涎腺等pembrolizumab是西妥昔单抗疗效(1013%)的约两倍EGFR-抑制剂在HPV-阳性肿瘤中疗效不佳pembrolizumab在HPV-阳性和HPV-阴性肿瘤中均有相似活性水平缓解率可能低估患者的获益比例病情稳定或即使最初经历疾病进展的患者一旦接受免疫治疗最终可能变为长期生存期的获益Nonetheless,interest in the role of induction chemotherapy was renewed several year

46、s ago for a few reasonsAdvances in surgery,RT,and concurrent systemic therapy/RT have yielded improvements in local/regional control thus,the role of distant metastases as a source of treatment failure has increased and induction chemotherapy allows greater drug delivery for this purposeMost randomi

47、zed trials of inductionchemotherapy followed by RT and/or surgery compared to locoregional treatment alone,which were published in the 1980s and 1990s,did not show an improvement in overall survival with the incorporationof chemotherapy.273in selected patients,induction chemotherapy couldfacilitate

48、organ preservation,avoid morbid surgery,and improve overall quality of life of the patient even though overall survival was not improved.Because total laryngectomy is among the procedures mostfeared by patients,281 larynx preservation was the focus of initial studies诱导化疗治疗头颈鳞癌的争议 上海交通大学医学院附属第九人民医院 郑

49、家伟发布时间：2019-5-2 11:24:40头颈部由于特殊的解剖部位和复杂的功能，给恶性肿瘤的治疗提出了挑战。早期头颈癌，无论采用手术或放疗，均能获得良好的效果，无需多手段治疗；但遗憾的是，60%的头颈癌就诊时已属晚期（III、IV期），5年生存率徘徊在10%20%之间。对大多数局部晚期、肿瘤无法切除及需器官保存的肿瘤患者，目前公认的标准治疗是同期化放疗。对肿瘤复发或远处转移的患者，如果肿瘤对铂类或紫杉醇类药物治疗不敏感，则只能给予患者支持治疗。诱导化疗（induction chemotherapy）是指手术或放疗前进行的化疗，又称为新辅助化疗（neoadjuvant chemothera

50、py），作为肿瘤化学治疗的一种方式，用于头颈鳞癌已有近30年的历史，但其在肿瘤治疗中的确切作用一直颇受争议。争论的焦点是在提高局部控制率和生存率方面的确切作用，争议产生的主要原因，是其理论上明显的优势与以往临床试验显示诱导化疗对患者生存率没有明显改善之间的矛盾。文献报道的各种诱导化疗方案的随机对照试验（RCT）结果不一，有些称显著有效，有些则认为无效，但多数研究认为，PF诱导化疗虽然暂时有效甚至显效，但不能显著提高这类患者的远期生存率。屠规益教授认为：从临床医师的角度而言，我们要求的是确实（有“根治性”）有效的实用方案，可以在临床上重复应用。迄今为止，化疗在恶性肿瘤尤其是造血系统肿瘤的治疗中已