scch&n cancer report
TRANSCRIPT
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Study of target therapy “Cetuximab”on the squamous cell carcinomas of
the head and neck (SCCHN)
Student ID : Student : HDate :2009
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Outline
Introduction Squamous cell carcinomas of the head and neck
(SCCHN) EGFR’s role on SCCHN RT/CT’s influence on SCCHN Cetuximab was used on the locally advanced SCCHN Cetuximab was used on the first line recur/meta
SCCHN Cetuximab was used on the 2nd line recur/meta
SCCHN Conclusions
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Cancers arising in the upper aerodigestive tract, including the oral cavity, pharynx and larynx
Tumors are further classified byHistological type (Adenocarcinomas,
Squamous cell carcinomas )
Brain tumors are excluded as they behave, and are treated,very differently
3
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Squamous cell carcinomas are derived from: The epithelium lining the aerodigestive tract Account for approx. 90% of primary head and neck
cancers
SCCHN occur in a range of different sites resulting in: Distinct clinical presentations and outcomes. Are treated differently than other head and neck
cancers4
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Stage of tumor is determined at diagnosis Staging helps assess prognosis and different treatment
TNM system is often used in all solid tumors: T – size of primary tumor N – involvement of lymph nodes M – presence of metastases
T definitions are specific to the site of each primary tumor
N and M definitions in SCCHN are as same as for other tumors
5American joint committee on cancer staging (AJCC),
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Squamous cell carcinomas head& neck
Prof J-L Lefebvre, personal communication
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Factors contributing to the etiology of H&N cancersresearches Dep. collected the following data:
Agent/factor Cancer site Agent/factor Cancer site
Tobacco Oral, larynx Occupational Exposure:
Textile industryPrinting tradeAsbestosWoodNickelMustard gasSulfuric acid
Oral, pharyngealOral, pharyngealLarynxNasal (Larynx)NasalLarynxLarynx
Alcohol Oral, larynx
Areca nuts Oral
Oral snuff Oral
Infectious agents:
HPVHSVEBV
OralOralNasopharynx
Radiation Salivary gland7Cancer of the larynx, www.FIRSTConsult.com, Elsevier, (07.11.09).
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PatientENT / Oral (Surgeon)
Radiation oncologist
Oncologist
Data source: 2007 Oct 20 1st wave survey by APR
70% patients are diagnosed by ENT and oral surgeonsSome successful experience in penetrating radiation oncologist andENT surgeon segmentsTreatment strategy generally follow protocol in multidisciplinary team
Diagnosis & surgery CT
RT & CT
ENT and Oral surgeons represent majorpatients source and treat trend
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99http://www.fda.gov/Cetuximab combined RT used in locally advanced H & N Ca,Cetuximab monotherapy used in the Recur / meta H & N after platinum failure
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“Evidence for a role for the EGFrin the inhibition and
pathogenesis of various cancers has led to the rational design and development of agents that selectively target this receptor.”*EGFr message transmission result in cancer cells----
Bernier J. and Schneider D.(2006)
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EGFr is expressed in a variety of solid tumors
Lung(NSCLC)
Colorectal
Head & Neck(SCC)
Head & neck cancer 90 – 100%
Lung cancer (NSCLC) 40 – 91%
Colorectal cancer 72 – 84%
Breast cancer 14 – 91%
Ovarian cancer 35 – 70%
Renal cell cancer 50 – 90%
Cunningham et al. 2004; Grandis et al.1996; Salomon et al. 1995; Walker & Dearing.1999; Folprecht et al.2004
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Cetuximab is an IgG1 MAbtargeting the EGFr
Binding blocks EGFrsignaling, the message transmission and inhibits proliferation, angiogenesis ,metastasis, stimulates apoptosis and differentiation
combined chemotherapy or radiation , can enhance the anti-tumor effect
Fc region may induce antibody-dependent cell-mediated cytotoxicity(ADCC) (immune response)
Bernier J. and Schneider D.(2006)
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IgG1 IgG1 ((cetuximabcetuximab))
Lysis of antibody-coated cell
MAXIMIZE ANTI-TUMOUR ACTIVITY
EGFR MEDIATED Anti-tumour Activity
IgG1 MEDIATED ADCC
Fan Z, et al. Fan Z, et al. Cancer ResCancer Res.1993;53:4322.1993;53:4322--8 8
Cetuximab: IgG1-Induced Antibody-Dependent Cell Cytotoxicity (ADCC)
Attachment
IgG1 attachment surface antigen ,trigger NK identify ca.cell by antibody
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1414Ang K. K, et al. 2002
High EGFr expression in SCCHN is linked to lower survival and increased risk of locoregional relapse
0
25
50
75
100
0 1 2 3 4 5
Years from randomization
p=0.0006Overall survival
n=155EGFr>median
EGFrmedian
Locoregional relapse
Aliv
e (%
)
Years from randomization
0
25
50
75
100
0 1 2 3 4 5
EGFr>median
EGFrmedian
p=0.003
n=155Fa
iled
(%)
inhibit EGFr pathway extened tumor progression
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Treatment modalities in SCCHN
CTSurgery RT Alone PalliationRT + CT
locally advrec/met SCCHN
refractory
• Early disease is treated with surgery or radiotherapy alone• Locally advanced SCCHN
• Radiotherapy for patients at intermediate risk• Chemoradiotherapy for high-riska disease
• Recurrent and/or metastatic disease• Chemotherapy is main treatment
• Combination therapies are associated with increased toxicities– eg mucositis and swallowing dysfunction
aStage III–IV disease, excluding T1–2 N1 and T3 N0
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16Cooper ,J.S., et al. 2004
Acute adverse effects: grade 3 or higher 34% with RT alone vs 77% with CRT (p<0.001)
Subj
ects
(%)
Hematologic
Mucous membrane
Pharynx and esophagus
Nausea and vomiting
Upper GI tr
actSkin
Infection
Salivary gland (xerostomia)
Neurologic
Genitourin
ary tract
Anemia0
20
40
60
RT alone (n=231)Combined RT + cisplatin (n=228)
80
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Early deaths due to treatment-related complications
Late deaths due to treatment-related complications
45%
21%9%
10% 9%
6%
Cause of death Time of occurrence, years median (range)
Disease progression 1.5 years (0.3–8.6)
Comorbidities 1.9 years (0.07–8.8)
Treatment-related 0.3 years (0.03–3.4)
Second primary tumors 3.5 years (1.5–10.1)
Unknown 5.1 years (1.1–9.5)
Argiris ,A., et al. 2004
15% of patient died for the SE of CT/RT not for cancer.
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BONNER Study 2006
Bonner,J .A., et al. 2006
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2020
354:567-78, 2006
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Stratified by
KPS (Karnofsky performance status)
Nodal involvement Tumor stage RT fractionationa
Stage III and IV non metastatic
SCCHN(n=424)
RT (n=213)
Cetuximab + RT (n=211)Cetuximab initial dose (400 mg/m2)1 week before RTCetuximab (250 mg/m2) + RT (weeks 2–8)b
Cetuximab + RT in locally advanced SCCHN: phase III study design
Bonner,J .A., et al. 2006
R
• Primary endpoint: duration of locoregional control
• Secondary endpoints: OS, PFS, RR, and safety
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Months
Cetuximab + RT (n=211)
Loco
regi
onal
cont
rol (
%)
100
80
60
40
20
00 10 20 30 40 50 60 70
RT (n=213)14.9 24.4
Hazard ratio = 0.68 (95% CI: 0.52–0.89)Log-rank p=0.005
Phase III study: locoregional control
Cetuximab + RT RT p-value
Locoregionalcontrol rate 3-year 47% 34% <0.01
Bonner,J .A., et al. 2006
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Months
Cetuximab + RT (n=211)
Ove
rall
surv
ival
(%)
100
80
60
40
20
00 10 20 30 40 50 60 70
RT (n=213)29.3 49.0
Hazard ratio = 0.74 (95% CI: 0.57–0.97)Log-rank p=0.03
Cetuximab + RT RT p-value
Survival rate 3-year 55% 45% 0.05
Phase III study: overall survival
Bonner,J .A., et al. 2006
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Side effectRT
(n=212)Cetuximab
+ RT p-valuea
Mucositis/stomatitis 52% 56% 0.44
Dysphagia 30% 26% 0.45
Radiation dermatitis 18% 23% 0.27
Xerostomia 3% 5% 0.32
Fatigue/malaise 5% 4% 0.64
Acne-like rash 1% 17% <0.001
Infusion-related reactionsb 0% 3% 0.01
Bonner,J .A., et al. 2006will not increase the incidence of RT side effects
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EXTREME StudyPlatinum-Based Chemotherapy
± Cetuximab in Head and Neck Cancer
Vermorken,J .B., et al. N Engl J Med 2008
First line R /M SCCHN
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Randomized phase III multicenter study
Treatment: platinum (cisplatin or carboplatin) plus 5-FU, with or without cetuximab
80 sites in 17 European countries
No prior EGFr testing was required for study entry
Patients were stratified according to: Prior chemotherapy KPS (< 80 vs ≥ 80)
Vermorken,J .B., et al. 2006
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RANDOMIZED
Group ACetuximab 400 mg/m2 initial dose
then 250 mg/m2 weekly +EITHER carboplatin (AUC 5, d1) OR cisplatin (100 mg/m2 IV, d1)
+ 5-FU (1000 mg/m2/day IV, d1-4): 3-week cycles
(6 cycles maximum)
Group B
EITHER carboplatin (AUC 5, d1) OR cisplatin (100 mg/m2 IV, d1)
+ 5-FU (1000 mg/m2/day IV, d1–4):3-week cycles
(6 cycles maximum)
No treatment
Cetuximab
Progressive disease or
unacceptable toxicity
Patients stratified according to:• KPS (<80 vs ≥80)• Prior chemotherapy (yes vs no)
Vermorken,J .B., et al. 2006
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Primary endpoint Overall survival time
Secondary endpoints Duration of response Time to progression Response rate Assessment of quality of life (QoL) Safety
Vermorken,J .B., et al. 2006
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Cetuximab +platinum / 5-FU
(n=222)Platinum / 5-FU
(n=220)Median age (range) 56 years (37–80) 57 years (33–78)
Men / women 89% / 11% 92% / 8%
Recurrence/metastasisLocoregional recurrenceMetastasisa
54%46%
54%46%
Primary metastatic disease 8% 7%aIncluding also distant metastasis and locoregional recurrence
Vermorken,J .B., et al. 2006
distribution of diseases are average
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10.1 months
7.4 months
Patients at risk Survival time (months)
220 173 127 83 65 47 19 8 1222 184 153 118 82 57 30 15 3
HR (95% CI): 0.797 (0.644; 0.986)Strat. log-rank test: 0.0362
CTX onlyCetuximab + CTX
Surv
ival
pro
babi
lity
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 3 6 9 12 15 18 21 24
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EXTREME: overall survival
Vermorken,J .B., et al. 2006
First time R/M SCCHN over 10M in survival.
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EXTREME: Progression-free survival (PFS)
Patients at risk PFS time (months)
220 103 29 8 3 1222 138 72 29 12 7
HR (95%CI): 0.538 (0.431, 0.672)Strat. log-rank test: <0.0001
CTX onlyCetuximab + CTX
Prog
ress
ion
free
(%)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 3 6 9 12 15
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5.6 months3.3 months
Vermorken,J .B., et al. 2006
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Cetuximab + platinum/5-FU
(n=222)Platinum/5-FU
(n=220) p-valuea
ORR [CR + PR], % [95% CI]
35.6[29.3–42.3]
19.5[14.5–25.4]
0.0001
DCR [CR + PR + SD], %[95% CI]
81.1[75.3–86.0]
60.0[53.2–66.5]
<0.0001
Vermorken,J .B., et al. 2006
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0
5
10
15
20
25
Anemia
Neutro
penia
Thrombo
cytop
enia
Nause
a
Vomitin
g
Diarrhe
aStom
atitis
Dyspn
eaPne
umon
iaAcn
e-like
rash
Infus
ion re
actio
nMos
t rel
evan
t gra
de 3
/4 a
dver
se e
vent
s (%
)
Platinum / 5-FU (n=215) Cetuximab + platinum / 5-FU (n=214)
Vermorken,J .B., et al. 2006
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Type of study Disease Treatment ReferencePhase I Mixed CDDP + cetuximab Shin 2001
Phase I/II/III Pt-sensitive Pt-based CT ±cetuximab
Paclitaxel + cetuximab
Burtness 2005Bourhis 2006
Vermorken 2007Hitt 2007
Phase II Pt-refractory Cetuximab alonePlatinum + cetuximab
Vermorken 2007Baselga 2005Herbst 2005
Cetuximab: summary of clinical studiesin recurrent/metastatic SCCHN
three clinical trials confirm the efficacy, refractory of patientsthe side effects and efficacy hard to balance.
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Grades (General Definitions)
· 0 = No adverse event or within normal limits · 1 = Mild adverse event · 2 = Moderate adverse event · 3 = Severe and undesirable adverse event · 4 = Life-threatening or disabling adverse event · 5 = Death related to adverse event
severity of side effects were divided into Grade0-5
Cetuximab side effects of most below the Grade 3,side effects and survival appear positively related .
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3737Herbst ,R.S., et al. 2005
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Time (months)0 3 6 9 12 15 18 21 24 27
Prop
ortio
n
28 12 6 3 1 1Grade 024 16 11 5 3 1 1Grade 127 22 15 9 7 4 1 1 1Grade 2/3
Grade 0 Grade 1
Grade 2/3
No. of eventsMedian survival
[95% CI]2.2 months
[1.9–4.3]
27 (96%)Grade 0
24 (100%)5.4 months
[2.7–6.7]
Grade 125 (93%)
7.1 months[4.1–11.1]
Grade 2/3
Overall survival by severity of skin rash
balance the side effects and efficacy, SE can tolerance, handle, encouraged treat
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Phase III study: change of QoL* as a function of time Cetuximab + RT significantly improves locoregional control and overall
survival without adversely affecting QoL, maintain quality of life.
Curran ,D., et al. 2007*Postbaseline scores for the QLQ-C30
Glo
bal h
ealth
sta
tus
/ QoL
scor
e 100
80
60
40
20
0
-20
Visit
RadiotherapyRadiotherapy / ERBITUX
Baseline Week 4 Month 4 Month 8 Month 12
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TreatmentNo. of
patients RR DCR MSTTP
(median)
Cetuximab1 103 13% 46% 5.9 months 2.3 months
Cetuximab + platinum2 96 10% 53% 6.2 months 2.8 months
Cetuximab + CDDP3 79 10% 56% 5.2 months 2.2 months
Retrospective study4
All patients 151 3% 15% 3.4 months N/A
CT only 43 0% 9% 3.6 months N/A
1. Vermorken JB, et al. 2007; 2. Baselga J, et al. 2005;23:5568–5573. Herbst RS, et al. 2005; 4. Vermorken JB, et al. 2005;
Cetuximab ±CDDP or a variety of second-linetreatments:clinical outcomes
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Cetuximab is also active in second-line setting in patients with platinum-refractory SCCHN
In second-line setting Cetuximab + platinum showed similar results to Cetuximab monotherapy
Vermorken JB, et al. 2007; Baselga J, et al. 2005;Herbst RS, et al. 2005; Vermorken JB, et al. 2005;
Conclusions: platinum-refractory second-line
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only proposal of the target treatment on 2008 NCCN guideline
National Comprehensive Cancer Network
Cetuximab as the most effective treatment for different stages of SCCHN,either LA,RT,R/M +cisplain+5Fu and monotherapy.
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ThanksThanksfor your attentionfor your attention