頭頸部腫瘤研究動態(tài)

頭頸部腫瘤研究動態(tài)1精選ppt口腔、

咽、

喉、

鼻腔、

副鼻竇、

甲狀腺2精選ppt

頭頸部腫瘤概況

發(fā)生率占所有新發(fā)腫瘤的3%飲酒、吸煙是共同病因>90%為頭頸部鱗癌(SCCHN)HPV感染可能為不良預(yù)后因素早期患者(I,II)治愈率較高(>80%)局部晚期及轉(zhuǎn)移者預(yù)后較差–5年生存率<40%3精選ppt治療方法疾病分期T1N0-1或T2N0T2N1或T3-4或N2-3復(fù)發(fā)或M1治療手術(shù)或放療多學(xué)科治療手術(shù)和/或放療多學(xué)科治療化療4精選ppt頭頸部鱗狀細胞癌全身治療的里程碑

Methotrexate

(palliation,

ICT,

CCRT)

1960s

Cisplatin,

5-Fluorouracil,

Bleomycin1970s1980s1990s2000sCombination

chemotherapy

regimensCarboplatinICT

with

PF

voor

larynx

preservationPaclitaxel,

docetaxelChemotherapy→survival↑(Pignon,

2000)Targeted

therapiesICT

重新評估

(TPF

regimen)Sequential

therapy

(ICT

CCRT)?5精選pptESMOClinicalPracticeGuidelines2021 Locoregionallyadvanceddisease

Level

ofevidence

Grade

ofrecommendation

I

IIIIIIIAABAASurgeryRTorCCRTConcomitantCTandRT*CetuximabplusRTICTRTfororganpreservationCCRTfororganpreservation*incaseofmutilatingsurgeryandinnonresectablediseaseGregoireVetal,AnnOncol2021:21(suppl5):VI84-VI866精選ppt頭頸部鱗癌的預(yù)后I期、II期–––占所有患者約1/360%-80%可根治性切除/放療常伴第二原發(fā)癌，幾率甚至高于局部復(fù)發(fā)III期、IV期––––占所有患者約2/3常需多學(xué)科綜合治療40%-80%會出現(xiàn)局部復(fù)發(fā)10%-30%出現(xiàn)遠處轉(zhuǎn)移Clinicaloptions/oncology7精選ppt誘導(dǎo)化療用于局部晚期頭頸癌的爭議

既往文獻報道的各種誘導(dǎo)化療方案的隨機對照試驗結(jié)果不一但多數(shù)研究認為，PF誘導(dǎo)化療雖然暫時有效但不能顯著提高這類患者的遠期生存率。TPF較于PF誘導(dǎo)化療：

提高保喉率

提高生存率與否結(jié)果不一

毒性增加與否結(jié)果不一8精選ppt?

同期放化療

(CCRT)仍是LRA-SCCHN的標(biāo)準(zhǔn)治療.

放療與靶向治療聯(lián)合能否取代CCRT仍不確定?HPV(p16)是LRA-SCCHN,(OPC)重要的預(yù)后因素?HPV(p16)也是R/M-SCCHN的預(yù)后因素?PF+cetuximab是R/M-SCCHN的標(biāo)準(zhǔn)治療?器官功能保存取得一定進展9精選ppt主要進展甲狀腺癌：臨床研究索拉菲尼可顯著改善放射性碘〔RAI)難治的分化型甲狀腺癌〔DTC〕患者的無進展生存期Cabozantinib被FDA批準(zhǔn)用于治療甲狀腺髓樣癌頭頸部鱗癌HPV與頭頸部腫瘤關(guān)系基因組分析確定了頭頸部鱗癌一些潛在的新的治療靶點10精選ppt甲狀腺癌的臨床研究頭頸部鱗癌治療進展〔一〕精選ppt浙江腫瘤發(fā)病情況浙江省惡性腫瘤發(fā)病率〔287.39/10萬〕與死亡率〔178.33/10萬〕與全國水平接近發(fā)病率增長速度最快的是甲狀腺癌、宮頸癌、卵巢癌、乳腺癌、和結(jié)直腸癌〔29.95%、11.62%、5.44%和4.85%〕前5位癌：肺癌、肝癌、胃癌、結(jié)直腸癌和食管癌2000年來惡性腫瘤是我省第一死因。2021年導(dǎo)致居民期望壽命損失3.54歲〔2021年，77.41歲〕2021年業(yè)務(wù)技術(shù)報告〔藍皮書〕精選ppt精選ppt甲狀腺癌未分化型甲狀腺癌〔anaplasticthyroidcarcinoma，ATC)，包括髓樣癌和未分化甲狀腺癌，約占甲狀腺癌的10%，平均生存時間為3~10個月。分化型甲狀腺癌(differentiatedthyroidcarcinoma，DTC)，包括乳頭狀和濾泡狀甲狀腺癌，約占甲狀腺癌的85%。絕大多數(shù)可通過手術(shù)聯(lián)合放療取得較好的治療效果約5-15%進展期DTC患者對治療不敏感既往對治療不敏感的進展期DTC患者無有效治療手段精選ppt精選pptWilhelmSM,etal.CancerRes2004;64:7099–109AngiogenesisRaf內(nèi)皮細胞或周細胞細胞核VEGFR-2PDGFR-βMEK細胞凋亡腫瘤細胞增殖PDGFVEGFEGF存活Ras細胞核RasERKRafMEK細胞凋亡ERKPDGF-βVEGF旁分泌刺激索拉非尼KIT/Flt-3/

RET索拉非尼：同時靶向作用于細胞增殖和血管生成頭頸部腫瘤進展

一項比較索拉非尼vs.撫慰劑

一線治療RAI-RDTC的研究主要終點：PFS(獨立中心評估)次要終點：OS、RR、平安性、TTP、DCR、DOR、索拉非尼暴露(AUC0-12)分層因素：獨立區(qū)域(北美或歐洲或亞洲)、年齡(<60歲或60歲)進展時允許：撫慰劑組患者交叉接受索拉非尼治療(根據(jù)研究者判斷)索拉非尼組患者可繼續(xù)接受索拉非尼治療(開放階段)(根據(jù)研究者判斷)BroseMS,etal.2021ASCOAbstract4.

RAI-RDTC=放射性碘難治性分化良好甲狀腺癌局部晚期或轉(zhuǎn)移性RAI-RDTC(N=417)既往14個月內(nèi)PD既往未接受化療、靶向治療或地塞米松;ECOGPS0-2足夠TSH抑制(<0.5mU/l)安慰劑PObid索拉非尼400mgPObid每日R1:1DECISION：研究設(shè)計DECISION：PFS(主要終點，獨立中心評估)

索拉非尼較撫慰劑顯著延長PFS，提高ORRNmPFS(天)索拉非尼207329(10.8)安慰劑210175(5.8)HR:0.587;95%CI:0.454-0.758;P<0.00011008060402000100200300400500600700800900時間(天)PFS(%)BroseMS,etal.2021ASCOAbstract4.索拉非尼安慰劑ORR(%)12.20.5DCR(%)54.133.8精選ppt精選ppt精選ppt精選ppt精選ppt精選ppt精選ppt精選ppt精選ppt卡博替尼〔cabozantinib〕與撫慰劑比照可明顯提高轉(zhuǎn)移性甲狀腺髓樣2021年11月FDA批準(zhǔn)cabozantinib用于治療轉(zhuǎn)移性甲狀腺髓樣癌總?cè)虢M330人癌患者的PFS精選ppt頭頸部鱗癌治療進展〔二〕HPV與頭頸部腫瘤關(guān)系基因組分析確定了頭頸部鱗癌一些潛在的新的治療靶點31精選ppt●一些HPV〔如HPV16，HPV18〕導(dǎo)致惡性轉(zhuǎn)化●HPV16isthepredominantvariantofHPVinSCCHN●HPV16canbeidentifiedbyitssurrogatemarker,p162●p16

is

classically

downregulated

in

SCCHN

but

is

upregulated

in

HPV+

cancers2,3HPV:

A

family

of

viruses

infecting

skin

and

mucous

membranes87%

HPV16126%

HPV+1All

SCCHNOropharyngeal

SCCHN36%

HPV+1●AlternativemethodsforHPVdetectionincludeHPVE6oncogeneexpression andHPVDNA2 1.KreimerAR,etal.CancerEpidemiolBiomarkersPrev2005;14:467–475 2.PannoneG,etal.InfectAgentCancer2021;7:4 3.KumarB,etal.JClinOncol2021;26:3128–313732精選pptHPV+

and

HPV–

SCCHN

can

display

different

characteristics1

Prognosis3比HPV–更低的死亡率和疾病進展的風(fēng)險

Incidence4,5越來越多的發(fā)病與HPV–腫瘤在歐洲和美國 Riskfactors1,2高風(fēng)險的性行為，使用大麻〔相比吸煙和飲酒，口腔衛(wèi)生不良,HPV-〕

Patientprofile2 Youngerage (by~5years)vsHPV–HPV+然而，在選擇適當(dāng)治療時，HPV狀態(tài)不應(yīng)該是一個因素 1.GillisonML,etal.JNatlCancerInst2021;100:407–420 2.ButtWT,etal.AnnKEMU2007;13:169?178 3.RaginCC,TaioliE.IntJCancer2007;121:1813–1820 4.ChaturvediAK,etal.JClinOncol2021;29:4294–4301 5.LicitraL,etal.HematolOncolClinNAm2021;22:1143–1153 6.NCCNClinicalPracticeGuidelinesinOncology:HeadandNeckCancersV2;202133精選pptHPV+

versus

HPV-

SCCHN:

生存率研究Gillison,

2000Licitra,

2006N

pts

252

90Subsite

H&N

oroph%

HPV

25

19

TXSurg

and/or

RTSurg

(100%)

+RT

(66%)

HR0.400.26Fakhry,2021Lassen,2021Rischin,2021Ang,2021Posner,2021

96156185316111

Lar/orophLar/pharynx*

H&N+

oroph

oroph4022576850ICT→CCRTRT$CCRT

±

TPZCCRTICT→CCRT0.360.360.360.330.20*74

of

the

156

had

OPC,

with

p16-positivity

of

32%;

+Rate

of

DM

similar

for

p16+

or

p16-

cases,

trend

for

improvedoutcome

with

TPZ

in

the

p16-

cohort

;

$Dahanca

5

trial:

In

subsequent

predictive

analysis

of

RT+/-nimorazole,

nimorazolehad

better

LCR

than

the

placebo

arm

only

in

the

p16-

cohort

(HR

0.69,

p=0.02)34精選pptOverall

survivalOverall

survivalEXTREME:

Overall

Survival

by

p16

Statusp16+

patientsMonthsp16?

patientsMonthsNumber

of

patients

at

riskNumber

of

patients

at

risk0.10.00.80.70.60.50.40.30.21.00.903691215182124270.10.00.80.70.60.50.40.30.21.00.90369121518212427CT

+

cetuximab

(n=18)CT

(n=23)CT

+

cetuximab

(n=178)CT

(n=162)182315181217111210

78663421100178162150128126

92935661474033191510

61000HR

(95%

CI)p-value0.63

(0.30–1.34)0.22HR

(95%

CI)p-value0.82

(0.65–1.04)0.11HRs

are

CT

+

cetuximab

vs

CT.CI,

confidence

interval;

HR,

hazard

ratio.35精選pptProportion

AliveProportion

AliveSPECTRUM:

Overall

Survival

by

p16

Status

Median

OS(95%

CI)

monthsPmab

+

CT

(n

=

165)CT

alone

(n

=

153)11.8

(9.8

-

14.0)

8.6

(6.9

-

11.3)P16-

patientsP16+

patients

Median

OS(95%

CI)

months

Pmab

+

CT

(n

=

56)CT

alone

(n

=

37)10.9

(7.1

-

12.6)12.1

(7.6

-

17.4)Quantitative

interaction

test

p-value

=

0.332100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

0%02468

10

12

14

16

18

20

22

24

26

28

30

32Months100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

0%0246810

12

14

16

18

20

22

24

26

28

30MonthsHR

=

0.96

(95%CI:

0.59

-

1.57)p-value

=

0.88HR

=

0.73

(95%CI:

0.57

-

0.94)p-value

=

0.0236精選pptHPV012HR(95%Cl)243648p6072OS2.66(1.16-6.09)0.02PFSTimeinmonths1.63(0.80-3.32)0.18p16HR(95%Cl)p012OS2436482.27(1.04-4.98)60720.04PFS1.45Timein(0.73-2.88)months0.290.8ProbabilityProbability0.8ProbabilityProbability0.40.80.40.80.00.40.00.40.00.00.80.8ProbabilityProbabilityProbabilityProbability0.40.80.40.80.00.40.00.40.00.0P16p-value=0.027Timeinmonths60Overall

Survival0122436486072negativenegativeProgression-freeSurvivalbyHPVst

atu

sTimeinmonths012243648p-value=0.014

6072Mehra

et

al.

E1395

&

E3301:

HPV

/

p16

status

in

R/M

HNSCC

OverallSurvivalbyHPVstatusHPVpositiveHPV

p-value=0.014Timeinmonths0122436486072Progression

Free

Survival

Timeinmonths

Progression-freeSurvivalbyHPVstatusHPVpositiveHPVnegativeHPVpositiveHPV

p-value=0.053

p-value=0.053By

HPV

status

(-ISH)(Pos

Survival

Neg:

status

54)

HPVpositive

HPVnegativeOverall

11;

byHPVBy

p16

status

(>80%

staining)0122436486072

positiveP16negative(Pos

SurvivalNeg

status

54)Overall

12;

byP16p-value=0.091Timeinmonths012243648p-value=0.027

6072P16positiveP16negativeTimeinmonths01224364872Progression-freeSurvivalbyP16statusProgression-freeSurvivalbyP16status

P16positive

P16negative

P16positive

e=0.091

P16negativep-valu37精