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Recent Advance in Head & Recent Advance in Head & Neck CancerNeck Cancer
Presented by CR Presented by CR 謝燿宇謝燿宇N Engl J Med 2008;359:1143-54.
Recent Advance in Head & Neck CRecent Advance in Head & Neck Cancerancer
Molecular progressionMolecular progressionSignal transduction of EGFRSignal transduction of EGFRHPV and antitumor vaccineHPV and antitumor vaccineConcurrent chemoradiotherapyConcurrent chemoradiotherapyPost-op chemoradiotherapyPost-op chemoradiotherapy Induction chemotherapyInduction chemotherapyTarget agentsTarget agents
Head & Neck cancerHead & Neck cancer
Major prognostic factors: Presence of locoregional metastasisVascular or lymphatic invasionPositive surgical marginsExtracapsular spread of tumor cells from i
nvolved lymph nodes into soft tissue of the neck
Head & Neck cancerHead & Neck cancerAlterations in the p53 tumor-suppressor ge
ne 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 cancerHead & 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 cancerHead & Neck cancerEGFR and two of its ligands, EGF and TG
F-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 cancerHead & Neck cancerIn 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), andothers. Ligand binding induces EGFR dimerization and activates several EGFR-mediated 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 cancerHead & Neck cancerIn 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 receptorsof 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. HB-EGF denotes heparin-binding EGF-like growth factor, and NRG neuregulin.
Head & Neck cancerHead & Neck cancerSmoking and alcohol abuse are major risk
factors Importance of HPV in oropharyngeal canc
er, especially in p53 mutation (-) or risk factor (-) patients
Head & Neck cancerHead & Neck cancer HPV: virtually all female cervical canerHPV: 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 cancerHead & Neck cancer HPV-positive tumors: bearing a unique gene exp
ression 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 cancerHead & Neck cancerGoal: obtaining a high cure rate while
preserving vital structures and functionOrgan 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 chemoradiotherConcurrent chemoradiotherapyapy
100 pts, HNSCCstage III/IV
RT alone
CCRT
RT: 66-72Gy, conventional, 1.8-2Gy/fx
5yr5yr OSOS RFSRFSDist. Mets-Dist. Mets-
free free survivalsurvival
OS with OS with primary site primary site
preservepreserve
Local control Local control without without
resectionresection
RTRT 48%48% 51%51% 75%75% 34%34% 45%45%
CCRTCCRT 50%50% 62%62% 84%84% 42%42% 77%77%
p valuep value 0.550.55 0.040.04 0.090.09 0.0040.004 <0.001<0.001
Oral cavityOral cavity 4%4%
Oropharynx Oropharynx 44%44%
HypopharynHypopharynx x 16%16%
Larynx Larynx 36%36%
Aldelstein DJ et al
Cancer 2000; 88: 876-883
Cisplatin: 20mg/m2/d5FU: 1000mg/m2/d
Infusion, D1-D4D22-D25
Primary site resection +/- neck dissection
Residual dz or recurrence
Survival benefit from better local control
Forsatiere et al: N Engl J Med 2003;349:2091-8.
RadiotherapyRadiotherapy
Head & Neck cancerHead & Neck cancer3D 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 TrialsFuture TrialsRTOG H-0129RTOG H-0129: Phase III trial evaluating : Phase III trial evaluating
intensified RT given concurrently with intensified RT given concurrently with cisplatin for definitive therapy. Eligible cisplatin for definitive therapy. Eligible patients T2N2-3 or T3/T4 Sq cell of oral patients T2N2-3 or T3/T4 Sq cell of oral cavity, cavity, oropharynx,oropharynx, larynx, and larynx, and hypopharynxhypopharynx
Standard RT (70 Gy/7 w) vs. concom. Standard RT (70 Gy/7 w) vs. concom. boost (72 Gy/ 6 w) both + cisplatinboost (72 Gy/ 6 w) both + cisplatin
1. No significant difference In acute or late toxicity
2. The benefit of CCRT or altered fractionation radiotherapy
decreases with increasing age3. The benefit is uncertain forpatients who are older than
70 years
Post-op chemoradiotherapyPost-op chemoradiotherapy
Head & Neck cancerHead & Neck cancer
RTOG 9501
416 pts, HNSCC, high risk of recurrence
XRT
Cisplatin + XRT
Cisplatin 100mg/m2, D1, D22, D43XRT 60Gy/30fx, Boost 6Gy/3fx
Surgery
Surgery
Positive Positive margin margin 17%17%
LN>2 or LN>2 or extracapsular extracapsular
extension extension 83%83%
Oral cavityOral cavity 27%27%
Oropharynx Oropharynx 42%42%
HypopharynHypopharynx x 10%10%
Larynx Larynx 21%21%
N Eng J Med 2004; 350: 1937-1944
High-risk features:1. presence of a po
sitive margin2. extracapsularspread outside the ly
mph nodes3. lymphovascularInvasion4. Perineural invasio
n5. multiple positive ly
mph nodes
DFSDFS OSOS LRRLRRDist Mets Dist Mets
as 1st as 1st eventevent
CCRTCCRT 40%40% 52.5%52.5% 19%19% 23%23%
RTRT 30%30% 45%45% 30%30% 20%20%
p valuep value 0.010.01 0.190.19 0.010.01 0.460.46
N Eng J Med 2004; 350: 1937-1944
45.9 months follow-up time
Acute adverse Acute adverse effecteffect Late adverse effectLate adverse effect
CCRTCCRT 77%77% 21%21%RTRT 34%34% 17%17%p p
valuevalue 0.0010.001 0.290.29hematological,
mucosa, GI tract
RTOG 9501
N Eng J Med 2004; 350: 1945-1952
EORTC 22931
167 pts, HNSCCstage III/IV
XRT
Cisplatin + XRT
Cisplatin 100mg/m2, D1, D22, D43XRT 54Gy/27fx, Boost 12Gy/6fx
Surgery
Surgery
MargiMarginn
PerineurPerineural al
invasioninvasion
ExtracapsulExtracapsular spreadar spread
Vascular Vascular embolisembolis
mm
Positive Positive 28%28% 13%13% 57%57% 20%20%
Negative Negative 71%71% 85%85% 43%43% 80%80%
UnknowUnknown n 1%1% 2%2%
Oral cavityOral cavity 26%26%
Oropharynx Oropharynx 30%30%
HypopharynHypopharynx x 20%20%
Larynx Larynx 22%22%
Unknown Unknown 1%1%
pT3/T4 + any NpT1/T2 + N2/N3pT1/T2 + N0/N1 + unfavorable patho
5yr 5yr PFSPFS 5yr OS5yr OS LRRLRR Dist Dist
MetsMets
CCRTCCRT 47%47% 53%53% 18%18% 21%21%
RTRT 36%36% 40%40% 31%31% 25%25%
p valuep value 0.040.04 0.020.02 0.0070.007 0.610.61
Acute Acute mucosa mucosa reactionreaction
Mucosa Mucosa fibrosisfibrosis
XerostomiXerostomia a
Severe Severe leukopenileukopeni
aa
CCRTCCRT 41%41% 10%10% 14%14% 16%16%RTRT 21%21% 5%5% 20%20% --
p valuep value 0.0010.001
C/T on time C/T on time without without delaydelay
1st1st 88%88%
2nd2nd 66%66%
3rd 3rd 49%49%
N Eng J Med 2004; 350: 1945-1952
EORTC 22931
Head & Neck cancerHead & Neck cancerEORTC 22931 and RTOG 9501: Two risk factors were associated with a sig
nificant benefit from concurrent chemoradiotherapy:
Extracapsular extensionPositive surgical margins
Sequential chemoradiotherapy Sequential chemoradiotherapy (induction chemoradiotherapy)(induction chemoradiotherapy)
Head & Neck cancerHead & 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 therapyTargeted therapy
Bonner et al. N Engl J Med 2006;354:567-78.
↓32% locoregional progression ↓26% risk of death
No decrease in distant metastasis rate
Similar toxicity between two groups
Take home messageTake home messageHPV (+): favorable outcomeHPV (+): favorable outcomeEnhance local control provide survival benEnhance local control provide survival ben
efit: CCRTefit: CCRT Induction chemotherapy: add taxaneInduction chemotherapy: add taxaneCetuximab: benefit with R/T, CRT data unCetuximab: benefit with R/T, CRT data un
available yetavailable yet
Head & Neck cancerHead & Neck cancer