Transcript Recent Advance in Head & Neck Cancer

Recent Advance in Head &
Neck Cancer
Presented by CR 謝燿宇
N Engl J Med 2008;359:1143-54.
Recent Advance in Head & Neck
Cancer
Molecular progression
 Signal transduction of EGFR
 HPV and antitumor vaccine
 Concurrent chemoradiotherapy
 Post-op chemoradiotherapy
 Induction chemotherapy
 Target agents

Head & Neck cancer
Major prognostic factors:
 Presence of locoregional metastasis
 Vascular or lymphatic invasion
 Positive surgical margins
 Extracapsular spread of tumor cells from
involved lymph nodes into soft tissue of
the neck
Head & Neck cancer
Alterations in the p53 tumor-suppressor
gene represent an early event in
progression, 50% of early progression has
p53 mutation
 Mutations in the p16 gene: an inhibitor of
cyclindependent kinase, associated with
later stages of tumor progression

Head & Neck cancer
Amplification, up regulation, down regulation or deletion
CXCR4, and its ligand,
SDF-1, appear to bind
together to direct
tumor cells at primary
sites to metastatic
organ sites,
suggesting that such
an interaction may
play a key role in the
homing of metastatic
cells
Head & Neck cancer

EGFR and two of its ligands, EGF and
TGF-α, are overexpressed in many solid
tumors, including squamous-cell
carcinoma of the head and neck, and are
linked to a poor prognosis after treatment
Head & Neck cancer
In Panel A, epidermal growth factor receptor
(EGFR) is a transmembrane protein with intrinsic
tyrosine kinase activity that regulates cell growth
in response to binding of its ligands, such as
epidermal growth factor (EGF), transforming
growth factor α (TGF-α), and
others. Ligand binding induces EGFR
dimerization and activates several EGFRmediated signaling pathways, including
Ras/mitogen–activated protein kinases
(MAPKs, such as extracellular signal-regulated
kinase [ERK] and c-Jun N-terminal kinase [ JNK]),
Janus kinase–signal transducers and activators
of transcription ( JAK–STAT),
phosphatidylinositol 3-kinase–protein kinase B
(PI3K–AKT), phospholipase C-γ–protein kinase
C (PLC-γ–PKC), and others. These signaling
pathways are responsible for the activation of
several transcription factors, such as Sp1, c-Jun,
c-Fos, and c-Myc, which consequently regulate
gene expression, supporting cell-cycle
progression, cell proliferation, invasion,
angiogenesis, and metastasis. DG denotes
diglyceride, Egr1 early growth response protein,
ELK-1 ets-like gene 1, Grb2 growth factor
receptor-bound protein 2, JNKK JNK kinase,
MEK MAPK kinase, MEKK MEK kinase,
mTOR mammalian target of rapamycin, PIP2
phosphatidylinositol 4,5-bisphosphate, p70S6K
p70 S6 kinase, Raf-1 c-raf-1 protein, SH2 Src
homology 2, Sos-1 son of sevenless homolog 1,
and S6 subunit protein 6.
Head & Neck cancer
In Panel B, four receptor proteins
have been identified as members
of the EGFR family. These
include EGFR (or erbB1),
HER2/neu (or erbB2), erbB3, and
erbB4. Multiple EGF-like ligands
bind to EGFR or other receptors
of the family, leading to
homodimerization or
heterodimerization of the
receptors. The dimerization of the
receptors, except the erbB3
homodimer, results in
autophosphorylation of tyrosine
residues in the cytoplasmic
domain of the receptors and
thereby activates signal
transducers at corresponding
docking sites, followed by
activation of downstream
signaling cascades. Since erbB2
has no known natural ligands, it
can form heterodimers only with
other members of the family. HBEGF denotes heparin-binding
EGF-like growth factor, and NRG
neuregulin.
Head & Neck cancer
Smoking and alcohol abuse are major risk
factors
 Importance of HPV in oropharyngeal
cancer, especially in p53 mutation (-) or
risk factor (-) patients

Head & Neck cancer



HPV: virtually all female cervical caner
N Engl J Med 2007;356:1944-56. HPV DNA
was detected in 72% of 100 oropharyngeal
tumor specimens, and 64% of the patients
were seropositive for HPV-16 E6, HPV-16 E7,
or both
Exposure to HPV increased the association
with oropharyngeal cancer, regardless of the
use of tobacco and alcohol
Head & Neck cancer


HPV-positive tumors: bearing a unique gene
expression profile with minimal molecular
alterations appeared to have more favorable
outcomes after therapy
HPV-negative tumors, which show frequent
molecular and cytogenetic changes — such as
p53 mutations, loss of p16INK4a, p15INK4b
cyclin D1 overexpression, or an increased copy
number of EGFR and chromosome 7 —
appeared to have less favorable outcomes
Head & Neck cancer
Goal: obtaining a high cure rate while
preserving vital structures and function
 Organ preservation should be taken into
account early on and should be attempted
with all treatment approaches
 Recent advance in treatment: 3D
conformal R/T, integrate of C/T in
treatment, introduction of target agents

Concurrent
chemoradiotherapy
Aldelstein DJ et al
RT alone
100 pts, HNSCC
stage III/IV
RT: 66-72Gy, conventional, 1.8-2Gy/fx
Cisplatin: 20mg/m2/d
5FU: 1000mg/m2/d
CCRT
Oral cavity
4%
Oropharynx
44%
Hypopharyn
x
16%
Larynx
36%
Infusion,
D1-D4
D22-D25
Residual dz
or recurrence
Primary site resection +/- neck dissection
5yr
OS
RFS
Dist. Metsfree
survival
OS with
primary site
preserve
Local control
without
resection
RT
48%
51%
75%
34%
45%
CCRT
50%
62%
84%
42%
77%
p value
0.55
0.04
0.09
0.004
<0.001
Survival benefit from better local control
Cancer 2000; 88: 876-883
Forsatiere et al: N Engl J Med 2003;349:2091-8.
Radiotherapy
Head & Neck cancer

3D Conformal radiotherapy: as effective as
conventional radiotherapy with regard to
local control, it can reduce late toxicity,
xerostomia, improved saliva flow (Lee et al: Int J
Radiat Oncol Biol Phys 2006;66:966-74; Garden et al: Int J Radiat
Oncol Biol Phys 2007;67:438-44)

Radiotherapy typically a single fraction on
a schedule of 5 days per week for 7 weeks:
hyperfraction v.s. accelerated fraction
(Bourhis: Lancet 2006;368:843-54.)
Future Trials
RTOG H-0129:
Phase III trial evaluating
1. No significant difference
intensified RT
given
with
In acute
or concurrently
late toxicity
The benefit of
CCRT or Eligible
cisplatin for2. definitive
therapy.
fractionation radiotherapy
patientsaltered
T2N2-3
or
T3/T4
Sq
cell
of
oral
decreases with increasing age
cavity, oropharynx,
larynx,
and
3. The benefit is
uncertain
for
patients who are older than
hypopharynx
70 years
 Standard RT (70 Gy/7 w) vs. concom.
boost (72 Gy/ 6 w) both + cisplatin

Post-op chemoradiotherapy
Head & Neck cancer
RTOG 9501
Cisplatin 100mg/m2, D1, D22, D43
XRT 60Gy/30fx, Boost 6Gy/3fx
Surgery
416 pts, HNSCC,
high risk of
recurrence
Positive
margin
Surgery
17%
LN>2 or
extracapsular 83%
extension
Oral cavity
Cisplatin + XRT
XRT
27%
Oropharynx 42%
Hypopharyn
10%
x
Larynx
21%
N Eng J Med 2004; 350: 1937-1944
High-risk features:
1. presence of a
positive margin
2. extracapsular
spread outside the
lymph nodes
3. lymphovascular
Invasion
4. Perineural
invasion
5. multiple positive
lymph nodes
RTOG 9501
45.9 months follow-up time
DFS
OS
LRR
Dist Mets
as 1st
event
CCRT
40%
52.5%
19%
23%
RT
30%
45%
30%
20%
p value
0.01
0.19
0.01
0.46
Acute adverse
effect
Late adverse effect
CCRT
77%
21%
RT
34%
17%
p
value
0.001
0.29
hematological,
mucosa,
GI tract
N Eng J Med 2004; 350: 1937-1944
Cisplatin 100mg/m2, D1, D22, D43
XRT 54Gy/27fx, Boost 12Gy/6fx
EORTC 22931
Surgery
167 pts, HNSCC
stage III/IV
Cisplatin + XRT
Surgery
XRT
pT3/T4 + any N
pT1/T2 + N2/N3
pT1/T2 + N0/N1 + unfavorable patho
Oral cavity
Margi
n
Perineur
al
invasion
Extracapsul
ar spread
Vascular
embolis
m
Positive
28%
13%
57%
20%
Negativ
e
71%
85%
43%
80%
Unknow
n
1%
2%
26%
Oropharynx 30%
Hypopharyn
20%
x
Larynx
22%
Unknown
1%
N Eng J Med 2004; 350: 1945-1952
EORTC 22931
C/T on time
without
delay
1st
88%
2nd
66%
3rd
49%
5yr
PFS
5yr OS
LRR
Dist
Mets
CCRT
47%
53%
18%
21%
RT
36%
40%
31%
25%
p value
0.04
0.02
0.007
0.61
Acute
Mucosa
mucosa
fibrosis
reaction
Xerostomi
a
Severe
leukopeni
a
CCRT
41%
10%
14%
16%
RT
21%
5%
20%
-
p value
0.001
N Eng J Med 2004; 350: 1945-1952
Head & Neck cancer
EORTC 22931 and RTOG 9501:
 Two risk factors were associated with a
significant benefit from concurrent
chemoradiotherapy:
 Extracapsular extension
 Positive surgical margins

Sequential chemoradiotherapy
(induction chemoradiotherapy)
Head & Neck cancer



TPF: more leukopenia and neutropenia, but did
not lead to more frequent infectious
complications when patients received
prophylactic antibiotics.
TPF led to fewer treatment delays and was
associated with fewer deaths from toxic effects
(2.3% in the TPF group and 5.5% in the PF
group).
PF was associated with more grade 3 or4 events
of thrombocytopenia, nausea, vomiting,
stomatitis, and hearing loss than was TPF
Targeted therapy
Bonner et al. N Engl J Med 2006;354:567-78.
No decrease in distant metastasis rate
↓32% locoregional progression
↓26% risk of death
Similar toxicity between two groups
Take home message
HPV (+): favorable outcome
 Enhance local control provide survival
benefit: CCRT
 Induction chemotherapy: add taxane
 Cetuximab: benefit with R/T, CRT data
unavailable yet

Head & Neck cancer