Recent Advance in Head Neck Cancer Presented by CR 謝燿宇 N Engl J Med 2008;359:1143-54.

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


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

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%





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%





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

Recent Advance in Head Neck Cancer Presented by CR 謝燿宇 N Engl J Med 2008;359:1143-54.

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