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SCCH&N cancer report
1. Study of target therapy “Cetuximab”
on the squamous cell carcinomas of
the head and neck (SCCHN)
Student ID :
Student : H
Date :2009
1
2. 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
2
3. Cancers arising in the upper aerodigestive tract,
including the oral cavity, pharynx and larynx
Tumors are further classified by
Histological type (Adenocarcinomas,
Squamous cell carcinomas )
Brain tumors are excluded as
they behave, and are treated,
very differently
3
4. 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
cancers
4
5. 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
5
American joint committee on cancer staging (AJCC),
7. Factors contributing to the etiology of H&N cancers
researches Dep. collected the following data:
Agent/factor Cancer site Agent/factor Cancer site
Tobacco Oral, larynx Occupational Exposure:
Alcohol Oral, larynx
Textile industry Oral, pharyngeal
Areca nuts Oral Printing trade Oral, pharyngeal
Asbestos Larynx
Wood Nasal (Larynx)
Oral snuff Oral Nickel Nasal
Infectious agents: Mustard gas Larynx
Sulfuric acid Larynx
HPV Oral
HSV Oral
EBV Nasopharynx
Radiation Salivary gland
7
Cancer of the larynx, www.FIRSTConsult.com, Elsevier, (07.11.09).
8. ENT and Oral surgeons represent major
patients source and treat trend
70% patients are diagnosed by ENT and oral surgeons
Some successful experience in penetrating radiation oncologist and
ENT surgeon segments
Treatment strategy generally follow protocol in multidisciplinary team
Radiation
RT & CT
oncologist
ENT / Oral
Patient (Surgeon)
Diagnosis & surgery CT
Oncologist
8
Data source: 2007 Oct 20 1st wave survey by APR
9. Cetuximab combined RT used in locally advanced H & N Ca, 9
http://www.fda.gov/
Cetuximab monotherapy used in the Recur / meta H & N after platinum failure
10. “Evidence for a
role for the EGFr
in 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----
10
Bernier J. and Schneider D.(2006)
11. EGFr is expressed in a variety
of solid tumors
Colorectal
Head & neck
90 – 100%
cancer
Lung
Lung cancer
40 – 91%
(NSCLC) (NSCLC)
Colorectal cancer 72 – 84%
Breast cancer 14 – 91%
Head & Neck
(SCC) 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 11
12. Cetuximab is an IgG1 MAb
targeting the EGFr
Binding blocks EGFr
signaling, 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)
12
Bernier J. and Schneider D.(2006)
13. Cetuximab: IgG1-Induced Antibody-Dependent
Cell Cytotoxicity (ADCC)
IgG1
(cetuximab)
cetuximab)
Attachment Lysis of
antibody-coated cell
EGFR MEDIATED IgG1 MEDIATED
Anti-tumour Activity ADCC
IgG1 attachment surface antigen ,trigger NK identify ca.cell by antibody
MAXIMIZE ANTI-TUMOUR ACTIVITY
Fan Z, et al. Cancer Res.1993;53:4322-8
Res.1993;53:4322- 13
14. High EGFr expression in SCCHN is linked to lower
survival and increased risk of locoregional relapse
Overall survival Locoregional relapse
100 100
p=0.0006 p=0.003
75 75 EGFr>median
Failed (%)
Alive (%)
EGFrmedian
50 50
EGFrmedian
25 25
EGFr>median
n=155 n=155
0 0
0 1 2 3 4 5 0 1 2 3 4 5
Years from randomization Years from randomization
inhibit EGFr pathway extened tumor progression Ang K. K, et al. 2002
14
15. Treatment modalities in SCCHN
locally adv
rec/met SCCHN
refractory
Surgery RT Alone RT + CT CT Palliation
• 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
15
III–IV disease, excluding T1–2 N1 and T3 N0
16. Acute adverse effects: grade 3 or higher
34% with RT alone vs 77% with CRT (p<0.001)
80
RT alone (n=231)
60 Combined RT + cisplatin (n=228)
Subjects (%)
40
20
0
us ting ract kin io
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i a a g i I t S c t om l og tra nem
log r ph vom r G e
Inf eros
t
eu
ro
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ry A
to mb eso e ri
a e nd p (x N
ou
m m
He us x an sea
d a Up nd
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o
uc ary
n au yg Ge
M N ar
Ph liv
Sa
16
Cooper ,J.S., et al. 2004
17. 9%
21% 10% 9% Early deaths due to treatment-related
complications
6% Late deaths due to treatment-related
complications
45%
15% of patient died for the SE of CT/RT not for cancer.
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)
17
Argiris ,A., et al. 2004
24. RT Cetuximab
Side effect (n=212) + 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
will not increase the incidence of RT side effects 24
Bonner,J .A., et al. 2006
25. First line R /M SCCHN
EXTREME Study
Platinum-Based Chemotherapy
± Cetuximab in Head and Neck Cancer
Vermorken,J .B., et al. N Engl J Med 2008 25
26. 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)
26
Vermorken,J .B., et al. 2006
27. Patients stratified according to:
Group A
Cetuximab 400 mg/m2 initial dose • KPS (<80 vs ≥80)
then 250 mg/m2 weekly + • Prior chemotherapy (yes vs no)
R
EITHER carboplatin (AUC 5, d1)
A Cetuximab
OR cisplatin (100 mg/m2 IV, d1)
N + 5-FU (1000 mg/m2/day IV, d1-4):
D 3-week cycles
O (6 cycles maximum) Progressive
M disease or
unacceptable
I toxicity
Z Group B
E
EITHER carboplatin (AUC 5, d1)
D OR cisplatin (100 mg/m2 IV, d1) No treatment
+ 5-FU (1000 mg/m2/day IV, d1–4):
3-week cycles
(6 cycles maximum)
Vermorken,J .B., et al. 2006 27
28. 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. 200628
29. distribution of diseases are average
Cetuximab +
platinum / 5-FU Platinum / 5-FU
(n=222) (n=220)
Median age (range) 56 years (37–80) 57 years (33–78)
Men / women 89% / 11% 92% / 8%
Recurrence/metastasis
Locoregional recurrence 54% 54%
Metastasisa 46% 46%
Primary metastatic disease 8% 7%
aIncluding also distant metastasis and locoregional recurrence
29
Vermorken,J .B., et al. 2006
33. Most relevant grade 3/4 adverse events (%)
10
15
20
25
0
5
An
em
ia
N
eu
t ro
Th pe
ro ni
a
m
bo
cy
to
pe
n ia
N
au
se
a
Vo
m
itin
g
Platinum / 5-FU (n=215)
D
ia
rr h
ea
St
om
at
itis
D
ys
pn
ea
Pn
eu
m
on
Ac ia
ne
- li
ke
In ra
fu sh
Cetuximab + platinum / 5-FU (n=214)
si
on
re
ac
tio
n
Vermorken,J .B., et al. 2006
33
35. Cetuximab: summary of clinical studies
in recurrent/metastatic SCCHN
Type of study Disease Treatment Reference
Phase I Mixed CDDP + cetuximab Shin 2001
Phase I/II/III Pt-sensitive Pt-based CT ± Burtness 2005
cetuximab Bourhis 2006
Vermorken 2007
Paclitaxel + cetuximab Hitt 2007
Phase II Pt-refractory Cetuximab alone Vermorken 2007
Platinum + cetuximab Baselga 2005
Herbst 2005
three clinical trials confirm the efficacy, refractory of patients 35
the side effects and efficacy hard to balance.
36. Grades (General Definitions)
severity of side effects were divided into Grade0-5
· 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
Cetuximab side effects of most below the Grade 3,
side effects and survival appear positively related . 36
38. 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.
100
Global health status / QoL score
Radiotherapy
80 Radiotherapy / ERBITUX
60
40
20
0
-20
Baseline Week 4 Month 4 Month 8 Month 12
Visit 38
*Postbaseline scores for the QLQ-C30 Curran ,D., et al. 2007
39. Cetuximab ±CDDP or a variety of second-line
treatments:clinical outcomes
No. of TTP
Treatment patients RR DCR MS (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;23:5568–557
3. Herbst RS, et al. 2005; 4. Vermorken JB, et al. 2005; 39
40. Conclusions:
platinum-refractory second-line
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; 40
41. National Comprehensive Cancer Network
only proposal of the target treatment on 2008 NCCN guideline
Cetuximab as the most effective treatment for different stages of SCCHN, 41
either LA,RT,R/M +cisplain+5Fu and monotherapy.