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THERAPIES FOR HEAD AND NECK
CANCERS
KAREN A. VILLANUEVA M.D. FPCP, FPSMO
CONSULTANT
MANILA DOCTORS HOSPITAL
ASIAN HOSPITAL AND MEDICAL CENTER
Identify Candidate Compounds
Screening
Preclinical Evaluation
Production and Formulation
Phase I, II, III, IV Clinical Trials
General Medical Practice
Toxicology Pharmacology Biochemistry
ONCOLOGYDrug Development
Steps in cancer drug development
CytotoxicsMolecular targeted treatment
CYTOTOXICS
Phase nonspecific
1. Cycle-nonspecific- kill non dividing cells
2. Cycle specific, phase nonspecific- are effective only if the cells proceed through the generation cycle, but they can inflict injury at any point in the cycle
Phase specific
- are effective only if present during a particular phase of the cycle
ONCOLOGYPrinciples of Chemotherapy
Antibiotics
AntimetabolitesS
(2-6h) G2
(2-32h)
M(0.5-2h)
Alkylating agents
G1
(2-h)
G0
Vinca alkaloids
Mitotic inhibitors
Taxoids
Cell cycle level
Action sites of cytotoxic agents
ONCOLOGYPrinciples of Chemotherapy
Busulfan CytosineEtoposide Bleomycin L-asparaginase
Carmustine Arabinoside Teniposide DactinomycinHydroxyurea
Chlorambucil Floxuridine Vinblastine DaunorubicinProcarbazine
Cisplatin Fluorouracil Vincristine Doxorubicin
Cyclophosphamide Mercaptopurine Vindesine Mitomycin-c
Ifosfamide Methotrexate Taxoids Mitoxantrone
Melphalan Plicamycin
Alkylating
Agents
Anti-
Metabolites
Mitotic
InhibitorsAntibiotics Others
Classification of cytotoxic agents
ONCOLOGYPrinciples of
ChemotherapyINCREASED EFFICACY
Different mechanisms of action Compatible side effects
Different mechanisms of resistance
ACTIVITY SAFETY
Aim of combination therapy
1960 1980
Medical therapies in head and neck cancers
2000
MTX 5FU Cisplatin TaxanesBiotherapies
targeted therap.AnthracyclineBleomycin
Mitomycin
Vinblastin Oncovin
Alkylating Agents
Target DNA Causes cross-linking of DNA strands Cytotoxicity is probably a result of
damage to DNA templates Cell cycle specific but not phase
specific
CISPLATIN Platinum agent MOA:Binds and crosslinks DNA strands Toxicity:
- cumulative renal insufficiency
- peripheral sensory neuropathy
- ototoxicity
Cont.
- severe nausea and vomiting
- hypokalemia, hypomagnesemia Administered through IV infusion Antiemetics and hydration are very
important Metabolites are excreted in the urine
CARBOPLATIN Platinum agent MOA: covalent binding to DNA Toxicity:
- myelosuppression
- nausea and vomiting
- less nephrotoxic than cisplatin IV infusion Metabolized in the urine
Antimetabolites
Fluorouracil
MOA: Interferes with DNA synthesis by blocking thymidylate synthethase.
Interferes with RNA function and protein synthesis.
Cell cycle S phase specific
Toxicity:
myelosuppression
mucositis
diarrhoea
vein pigmentation
hand foot syndrome
Administered as IV push or IV infusion Usually given in combination with
leucovorin in other regimens Drug degradation occurs in the liver
GEMCITABINE Gemzar MOA: cytidine analog that inhibits
ribonucleotide reductase IV infusion Myelosuppression, nausea, vomiting Nearly entirely excreted in the urine
Mitotic Spindle Agents These drugs bind to microtubular proteins,
thus inhibiting microtubule assembly and resulting in dissolution of the mitotic spindle structure.
Promote microtubular resistance to depolymerization, resulting in the production of non functional microtubules.
Cell cycle M phase specific
PACLITAXEL Taxoids Taxol MOA: Anti-microtubules resulting to mitotic arrest Toxicity:
neutropenia
anaphylactic shock
myelosuppression
nausea and vomiting
neuropathy
alopecia
arthralgias and myalgias Administered as IV infusion over 3-24
hours Premedicate with steroids, H2 receptor
antagonist, anti histamine Special filtered tubing is required
DOCETAXEL Taxoids Taxotere MOA: Anti-microtubules resulting to mitotic
arrest Toxicity:
Anaphylaxis
fluid retention
myelosuppression
nausea and vomiting
stomatitis Administered as IV infusion over 1 hour Premedicate with dexamethasone one day
before until one day after Majority are excreted in the feces
A phase III trial of docetaxel, cisplatin and 5-fluorouracil (TPF) vs.
cisplatin and 5-fluorouracil (PF) induction chemotherapy followed by chemoradiotherapy in patients with
locally advanced squamous cell carcinoma of the
head and neck (SCCHN) – TAX 324Posner MR et al.
Special Session (Oral)
TAX 324: study design
Carboplatinum AUC 1.5 weekly
Daily radiotherapy
Locally advanced SCCHN:
organ preservation, resectable withlow curability, unresectable
R
TaxotereCisplatin5-FU
D1D1D1–5
75 mg/m2
100 mg/m2
1000 mg/m2
TPF
3 x TPF q3w
Cisplatin5-FU
D1D1–5
100 mg/m2
1000 mg/m2
PF
3 x PF q3w
Survival time (months)Number of patients at risk
TPF: PF:
255 234 196 176 163 136 105 72 52 45 37 20 11246 223 169 146 130 107 85 57 36 32 28 10 7
Su
rviv
al p
rob
ab
ilit
y (%
)
0 6 12 18 24 30 36 42 48 54 60 66 72
0
10
20
30
40
50
60
70
80
90
100
TPF (n=255)PF (n=246)
Log-rank p=0.0058Hazard ratio=0.70
TAX 324: overall survival
TAX 324: authors’ conclusions
TPF is the most effective combination regimen for induction chemotherapy TPF regimens improve survival and engender less
toxicity in locally advanced SCCHN, compared with PF
TPF is now the standard of care for induction chemotherapy
TPF is the appropriate platform for curative therapy,to which new molecularly targeted therapies should be added
Targeted treatment for head and neck
cancers
EGFR expression inselected human tumors Tumor type % of tumors expressing EGFR (range)
Head and neck 90 – 100%
Colon 75 – 89%
Prostate up to 100%
Pancreatic up to 95%
Breast up to 91%
Renal up to 90%
Cervix up to 82%
Non-small cell lung cancer up to 80%
Ovarian up to 77%
Bladder up to72%
Primary glioblastoma up to 63%
EGFR expressionis associated with poor
prognosis• The EGFR is expressed in 90-100% of head
and neck cancers
• EGFR expression is associated with:– Reduced disease-free survival
– Reduced overall survival
– An increased risk of metastasis/invasion
in a number of different solid tumor types, including
head and neck cancer
EGFR inhibition via Monoclonal
Antibodies
ERBITUX IN SCCHN
EGFR signaling
Baselga. Eur J Cancer 2001;37 Suppl 4:S16-S22.
Cetuximab (ERBITUX®) Mode of action
ERBITUX
ERBITUXCharacteristics
• ERBITUX is an IgG1 monoclonal antibody (MAb)
• ERBITUX comprises four polypeptide chains: two
identical heavy and two identical light chains
• ERBITUX targets the human EGFR with a higher
affinity than its natural ligands (TGF-α, EGF), thus
competitively inhibiting their binding
• ERBITUX promotes the internalization and
degradation of EGFR, leading to down regulation of
cell surface receptors and reduced receptor signaling
Toxicity:
myelosuppression
nausea and vomiting
acne like rash Administered as IV infusion over 2 hours
ERBITUXSummary of clinical
studies in head and neck cancerPhase Treatment - ERBITUX Studies
Locally advanced SCCHN
I / III + radiotherapy
Robert 2001; Bonner 2006
Recurrent and/or metastatic SCCHN (first-line)
III + chemotherapy Burtness 2005
Recurrent and/or metastatic SCCHN progressing on platinum
II + chemotherapy Trigo 2004; Baselga 2005; Herbst 2005
Recurrent and/or metastatic nasopharyngeal carcinoma
II + chemotherapy Chan 2005
Current treatment standards
in locally advanced SCCHN
Radiotherapy
only
Radiotherapy
Erbitux+
Radiotherapy
Chemotherapy+
ü
ü
RT + Erbitux in locally advanced
SCCHN
RT + Erbitux (n=211)
Erbitux initial dose (400 mg/m2)Erbitux (250 mg/m2) + RT (wks 2–8)
Stage III and IV non-metastatic SCCHN
RT (n=213)
Bonner et al. NEJM 2006
R
Primary endpoint: duration of locoregional control
Secondary endpoints: OS, PFS, RR, QoL, and safety
Erbitux in locally advanced SCCHN:
Bonner Phase III study
N=424
Erbitux in locally advanced SCCHN: Significant benefit in
locoregional control
Months
Locore
gio
nal
con
trol
(%)
100
80
60
40
20
00 10 20 30 40 50 60
14.9months
24.4 months
HR=0.68 [95% CI: 0.52–0.89] p=0.005 3-year control rate
47%
34%
Bonner et al. NEJM 2006
RT + ErbituxRT
Erbitux in locally advanced SCCHN:
5-year survival update
HR=0.73 [95% CI: 0.56–0.95]p=0.018
Bonner et al. Lancet Oncol 2010
100
90
80
70
60
50
40
30
20
10
00 10 20 30 40 50 60 70
Ove
rall
su
rviv
al
(%)
29.3months
49.0 months
46%
5-year survival rate
36%
Months
RT + ErbituxRT
Erbitux in locally advanced SCCHN:
Skin rash correlates with survival
Months
Pro
bab
ilit
y of
surv
ival
(%)
100
80
60
40
20
00 10 20 30 40 50 60 70
10
30
50
70
90
Grade 2–4 rash group (n=127)
Grade 0/1 rash group (n=81)
> 68.8 months
HR=0.49 (95% CI: 0.34–0.72)p=0.002
25.6 months
Bonner et al. Lancet Oncol 2010
Erbitux in locally advanced SCCHN
Adding Erbitux to RT has proven to significantly Prolong survival Control disease longer Increase response rate
Erbitux in metastatic or
recurrent SCCHN
CT plus Erbitux in 1st-line SCCHN:
Consistent efficacy regardless of CT type
Author Phase N RegimenORR (%)
Median PFS (months)
Median OS (months)
Vermorken 2008 III 442 PF
PF + Erbitux20 36*
3.35.6*
7.410.1*
Burtness 2005 III 117 Cis + Placebo
Cis + Erbitux1026*
2.74.2
8.09.2
Bourhis2006 I/II 53 PF + Erbitux 36 5.1a 9.8
Hitt 2007 II 42 Pacli + Erbitux 60 5.0 NRb
Buentzel2007 II 23 Pacli/Carbo + Erbitux 56 5.0a 8.0
Vermorken et al. NEJM 2008; Burtness et al. JCO 2005; Bourhis et al. JCO 2006; Hitt et al. ASCO 2007; Buentzel et al. ASCO 2007
*Statistically significantaTTP: bMedian OS not reached after a median follow-up of 5.6 months
1st-line SCCHN: EXTREME trial
Erbitux in 1st-line SCCHN EXTREME: Phase III study design
Erbituxuntil PDr/m SCCHN
• Prior CT
• KPS (<80 vs ≥80)
CT + Erbitux
Primary endpoint: OS Secondary endpoints include: PFS, RR, safety
CT Cisplatin (100 mg/m2 IV, day 1) orCarboplatin (AUC 5, day 1) + 5-FU (1000 mg/m2 IV, days 1–4)Every 3 weeks, up to 6 cycles
ErbituxInitial dose 400 mg/m2
then 250 mg/m2 weeklyuntil progressive disease (PD)
N=442
CT
Vermorken et al. NEJM 2008
Erbitux in 1st-line SCCHNEXTREME: Significant RR
benefit
CT (n=220)
Resp
on
se r
ate
(%
)
CT + Erbitux(n=222)
40
20
0
30
10
OR=2.33 (95% CI: 1.50–3.60)p<0.001
20
36
CR=0.9 CR=6.8
Adding Erbitux almost doubles RR
Updated from Vermorken et al. NEJM 2008CR: complete response
Erbitux in 1st-line SCCHN EXTREME: significant PFS benefit
Pro
gre
ssio
n-f
ree s
urv
ival
(%)
0 3 6 9 12 15
5.6 months3.3 months
HR=0.54 (95% CI: 0.43–0.67)p<0.001
CT (n=220)CT + Erbitux (n=222)
Months
0
10
20
30
40
50
60
70
80
90
100
+ 2.3 months
Vermorken et al. NEJM 2008
CT + Erbitux in 1st-line SCCHN
• Adding Erbitux to platinum-based CT– Significantly improves OS
– Significantly increases PFS
– Almost doubles RR
• CT + Erbitux is feasible in SCCHN patients
• Benefit of Erbitux regardless of known biomarkers
• CT + Erbitux is the standard in 1st-line SCCHN
Cetuximab Plus Platinum-Based Chemotherapy
Progress under platinum
15 October 1998
One cycle cetuximab + platinum
9 November 1998
Summary of Treatments
Squamous Cell Carcinoma ( Maxillary, Ethmoid, Lip, Oral, Oropharynx, Hypopharynx, Glottic, Larynx, Supraglottic, Occult Primary )
1. Primary Systemic with concurrent RT
- Cisplatin alone - Cis-infusional 5FU
- 5FU - Carbo-infusional 5FU
- Cis-Pacli - Cetuximab
-Nimotuzumab
2. Post op chemo-RT
- Cisplatin alone
3.Induction followed by chemo-RT
- Docetaxel -Cisplatin -5FU
Nasopharyngeal CA
- Cisplatin with RT followed by Cisplatin and 5FU
THANK YOU
